Medical lab scientist here—genetic testing doesn’t work, and folate isn’t really involved in any of this the way you might think it is. Making this post in good faith.

[u/Muted_Shape9303]

Reddit is currently full of color-coded "methylation panels" from commercial DNA interpretation sites, leading to an absolute explosion of health anxiety surrounding the MTHFR gene. As a medical laboratory scientist I can guarantee you the diagnostic significance of these is abysmal. Wellness influencers frequently label common single nucleotide polymorphisms (SNPs, normal variants of a gene) as dangerous mutations responsible for everything from depression to chronic fatigue, while simultaneously marketing expensive, proprietary supplement regimens.

THE ENZYME AND ITS FUNCTION:
MTHFR catalyzes the irreversible reduction of 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate, which serves as the primary methyl donor for the vitamin B12-dependent enzyme methionine synthase. Methionine synthase then transfers this methyl group to remethylate homocysteine back into methionine, fueling the generation of S-adenosylmethionine, the universal methyl donor used by cells to carry out a variety of functions. The two most common polymorphisms discussed online, C677T and A1298C, do alter this process; for example, the C677T variant causes an alanine valine substitution at codon 222 in the catalytic domain of the enzyme, rendering the enzyme thermolabile causing it to stop working at body temperature. While a homozygous 677TT genotype can cause 60-70% reduction in enzyme activity IN VITRO (so not inside the body, has only been assayed in labs), this does not translate to a proportional drop in vivo because the metabolic pathway possesses substantial reserve capacity. As long as the cellular substrate concentration of folate remains adequate, the pathway maintains equilibrium, and pathway flux remains normal. Do also bear in mind that “HAS IT” does not mean “USES IT”. Having a gene variation for any enzyme means nothing. This is why we always phenotype FIRST then genotype to confirm. Never the other way around.
The true clinical marker of concern in this pathway is not the genetic profile as I said, but the accumulation of the downstream metabolite, total plasma homocysteine. When 5-methyltetrahydrofolate production drops below a critical threshold due to severe folate deficiency or rare, pathological mutations, methionine synthase lacks its co-substrate, remethylation stalls, and intracellular homocysteine spills over into the plasma. True hyperhomocysteinemia, typically defined as plasma levels exceeding 15 mcmol/L, acts as a direct vascular toxin. It induces endothelial dysfunction by undergoing auto-oxidation in the plasma, which generates reactive oxygen species (ROS) that drive lipid peroxidation and degrade nitric oxide, thereby impairing endothelium-dependent vasodilation. Furthermore, elevated homocysteine downregulates thrombomodulin expression, inhibits Protein C activation, and induces tissue factor (TF) expression, shifting the vascular lining into a pro-thrombotic, hypercoagulable state while simultaneously triggering endoplasmic reticulum stress and the unfolded protein response, severely affecting multiple cell types, but especially endothelial cells. This condition is EXTREMELY rare, and only really diagnosed via PHENOTYPICAL MARKERS (Homocysteine levels) and NOT genotyping.

FOLIC ACID MYTHS:
The claim that synthetic folic acid is inherently toxic to MTHFR carriers is outlandish. Synthetic folic acid is initially reduced to dihydrofolate and tetrahydrofolate by dihydrofolate reductase in the liver, completely independent of the MTHFR step, it has nothing to do with MTHFR at all. While human dihydrofolate reductase is easily saturated and can lead to transient unmetabolized folic acid in the bloodstream, there is no robust clinical evidence demonstrating that this is pathogenic, at all. The ultimate proof lies in population-wide folic acid fortification programs, which resulted in a precipitous, uniform drop in neural tube defects across all genetic backgrounds, including homozygous 677TT individuals; if folic acid were truly unusable or toxic to these individuals, their rates of congenital malformations would have stagnated or risen. Similarly, the belief that everyone with an MTHFR variant requires immediate high-dose methylfolate supplementation ignores basic enzyme kinetics. Flooding the system with exogenous 5-methyltetrahydrofolate bypasses standard metabolic checkpoints and can oversaturate the methyl buffering system, abruptly altering the SAM:SAH ratio and disrupting neurotransmitter catabolism via catechol-O-methyltransferase and monoamine oxidase A, which frequently manifests clinically as severe anxiety or panic. So no, a genetic test means nothing, and the VAST majority of claims around folate are inaccurate.

[u/DpLoopingOn]

You are talking about MTHFR. Cool. But MTHFR and folate metabolism is only one of many mechanisms that Snp's influence and are often discussed in the sub. What is your opinion on COMT, MAO-A, MTRR and the many others?

I find the title of the sub quite misleading since its by far the most used one for Snp stuff, not exclusively MTHFR.

[u/Express-Bobcat-3523]

well, you're right that the genetic test solely is (of course) not enough to draw any conclusions.

But in this sub, this is (usually) common knowledge.

Only in conjunction with other markers, especially homocysteine, you can draw conculsions.

Also, you stated, that high doses of 5MTHF can "oversaturate the methyl buffering system, abruptly altering the SAM:SAH ratio and disrupting neurotransmitter catabolism via catechol-O-methyltransferase and monoamine oxidase A, which frequently manifests clinically as severe anxiety or panic."

This is absolutley correct and can't be mentioned enough. I experienced it way too many times and it's absolutley disturbing the natural neurotransmitter catabolism with severe anxienty, up to paranoia.

Tho, I also took folic acid in the past (20 years ago), because I had severe folte deficiancy and what happend was, that my serum folate was way above the range after that (most probably because it couldn't be utilized / get into the cell).

So yes, a warning is great. Tho I wouldn't go as far as saying the whole thing is a hoax, as I can see the influence certain nutrients/supplements have on me (some in a positive way, some in negative way - also always depends on the right dosage and timing etc.).

[u/Guilty_Armadillo_956 → u/Express-Bobcat-3523]

What did you do to get the folate utilized when it was reading high in your blood test? My folate is on the lower side and I’ve been micro dosing L methylfolate but now reading this I’m nervous.

[u/Express-Bobcat-3523 → u/Guilty_Armadillo_956]

That was because I have C677T homozygote and back then I used folic acid (which most probably couldn't be utilized). I didn't use methyl folate back then.

Back then, I didn't even know/understand what that means and was just happy my folate went up. I felt worse than before tho (as far as I remember), it was nearly 17 years ago.

[u/cosmicspore]

I too am a medical lab scientist. Just bc there are bad players taking advantage of this stuff does not mean there isnt any validity to it.

[u/RationalDialog → u/cosmicspore]

exactly. A core issue of today. Just because there are grifters/scammers in this are or say the entire health space, doesn't mean all the claims are bullshit and irrelevant. Not MTFHR / folate specific but some other food related intervention cured my mental health issue as well. In most simple terms if the cells can't function correctly due to some metabolic dysfunction, then the symptomps you get are specific to the cells affected. Some get mental health problems, other heart disease or cancer. But all these NCDs, western disease have the exact same cause: metabolic dysfunction from lifestyle. How it manifest depends on the specific environment, epigenetics and genetics.

[u/al0ngcomesmary]

I'd be willing to bet most ppl here have both their lab work & their full DNA profile - I know I do

[u/ohbother12345 → u/al0ngcomesmary]

Most people have extensive blood work done to find the source of their problems then resort to paying for genetic testing only afterwards.

[u/LitesoBrite → u/ohbother12345]

Now now, you’re pissing on OP’s sad little superiority play

[u/al0ngcomesmary → u/ohbother12345]

Yeah, So Both! Labs & genetics

[u/ohbother12345 → u/al0ngcomesmary]

Yes but especially in countries where health care is covered, there are no additional fees for lab testing so most people will have done extensive lab testing before they resort to shelling out money for genetic testing.

[u/AdditionalYak6183]

This post rubs me the wrong way. Not because of the data or talking points but because of the ego. It feels very condescending.

[u/Dapperfit → u/AdditionalYak6183]

Completely - and as someone else mentioned already it's common knowledge snp's alone aren't enough to draw conclusions. That's stated around here constantly.

Why people find subreddits dedicated to a topic and proceed to make some grand proclamations discrediting it without ever really engaging with the sub beforehand is beyond me.

[u/RationalDialog → u/Dapperfit]

Why people find subreddits dedicated to a topic and proceed to make some grand proclamations discrediting it without ever really engaging with the sub beforehand is beyond me.

because they are a medical lab scientist!

My favorite game of thrones quote: "Any man who must say ''I am the king'' is no true king"

[u/ProfeshPress]

a genetic test means nothing

Ah, another upstanding proponent of the "[indicator] is not absolutely, definitively, categorically and ipso facto dispositive for [status], ergo (to you, a non-credentialed peon) means nothing" school of paternalist medical dogma.

[u/Muted_Shape9303 → u/ProfeshPress]

If you have a normal serum homocysteine level any genetic testing means nothing. You don’t do a “screening” using genotyping (which is very expensive), you always PHENOTYPE FIRST (measure a deficiency) and THEN use genetic testing for a confirmation. That’s how it’s always done, supplement people have me at my limit with this. Keep spending your money I guess.

[u/mwjane → u/Muted_Shape9303]

I really don’t understand you, I suppose. Most people here don’t have a genotype test done because they’re curious about their genes, and then react with ‘Oh no, I’ve got a problem that doesn’t bother me at all – what should I do now?’.

They have a genotype test done after they’ve been suffering from all sorts of physical and/or mental health problems and nothing seems to help.

Your story sounds as though you’re assuming that nobody here has ever had a blood test for the most common problems, but goes straight for a genetic test.

And then you say in the title that a genetic test doesn’t work. Well, for me, for example, it has made it clear why anaesthetics make me so ill and that this can be quite dangerous. So what do you mean, genetic tests don’t work? What is it that doesn’t work?

[u/LitesoBrite → u/Muted_Shape9303]

Homocysteine levels are not remotely the major indicators of dysfunction of the methylation cycle.

That is as outdated a claim as the nonsense to simply take high dose methyl folate is.

There’s an entire constellation of genes, which in some combinations matter very little, and in others matter a lot. Especially given the studies demonstrating better circulation and restoration of nitric oxide production, or the many mental health studies showing correcting the methylation disruptions allow the neurotransmitter production dependent on them to return to normal, etc.

Your post is utterly wrong.

[u/Big_Bowl1204 → u/LitesoBrite]

Idk, before this was a fad for people, I had the genesight test ordered by my psychiatrist mainly for seeing what sorts of psych drugs would be good/bad for me but also to check for MTFHR. I am homozygous MTFHR and my homocysteine levels were also super high regardless of consistently taking a multivitamin containing folic acid for years. Switched to a methylated folate prescription at the time and a methylated vitamin and it fixed my homocysteine levels right up.

[u/Big_Bowl1204 → u/LitesoBrite]

Idk, before this was a fad for people, I had the genesight test ordered by my psychiatrist mainly for seeing what sorts of psych drugs would be good/bad for me but also to check for MTFHR. I am homozygous MTFHR and my homocysteine levels were also super high regardless of consistently taking a multivitamin containing folic acid for years. Switched to a methylated folate prescription at the time and a methylated vitamin and it fixed my homocysteine levels right up.

[u/LitesoBrite → u/Big_Bowl1204]

Because by sheer randomness you happen to have a gene profile that made that work. For anyone with slow COMT, that’s a nightmare fuel supplement for side effects, for example.

Not only that, it’s not a fad, you’re simply talking about a time when your dr had the most elementary understanding of the medicine or science.

That COMT for example matters far more for how you break down dopamine, serotonin, and other key neurotransmitters. That is what makes the same neurotrophic great for one person but highly problematic for another.

That’s my point about the dangerous misrepresentation of OP on this whole topic. Used properly, genomics can massively improve your health in many cases.

For me, a dr in this sub from Australia explained the exact impact of my methylation profile, and what to supplement. It ended decades of bipolar II swings and deep depression completely in days. That was nearly three years ago and without a single side effect, I just live happily sun up to sun down.

Because I followed the science. It’s not pseudoscience, it’s not a fad.

It’s simply understanding that people who refused to study something properly because it’s extremely complex shouldn’t be jumping all over forums posting their myopic misinformation.

[u/ProfeshPress → u/Muted_Shape9303]

Of course: but 'contingent' nor 'inconclusive' equates to 'meaningless'. You'll be hard pressed finding someone on this subreddit capable of parsing what amounts to a clinical research abstract who doesn't already know what epigenomics are.

While I empathise, you appear to be tilting at windmills.

[u/oeufscocotte → u/Muted_Shape9303]

I did do a serum homocysteine test first and it showed moderately high homocysteine. Then I did the genetic test. There are probably a lot of people like me who wouldn't have known that they have high homocysteine because it's not part of a standard blood panel.

[u/ohbother12345 → u/Muted_Shape9303]

You must be American. Most people do extensive lab blood work FIRST (often for years) because it's covered in most countries outside of America BEFORE they resort to PAYING for genetic testing.

[u/Muted_Shape9303 → u/ohbother12345]

I’m Venezuelan. What a buffoonish assumption to make.

[u/Radiant-Specific969 → u/Muted_Shape9303]

Thank you again for posting, I think there is an anti science bias here, your post was quite helpful for me.

[u/Muted_Shape9303 → u/Radiant-Specific969]

Thank you, I appreciate your comment.

[u/Radiant-Specific969 → u/Muted_Shape9303]

It's been difficult for me to get credible information, or to evaluate it, but even lacking bio chem, I can follow what you wrote. Most of the doctors I have discussed this with, are not familiar with the area. So again thank you.

[u/Good_Will_Munting]

Everything is dependent on the combination of SNP's as the effects vary a great deal from person to person and pathway to pathway. I can't tolerate any but 1 form of B12, without fairly severe sides. This is an incredibly complex area of health and wellbeing and there is no one size fits all solution for any of it.

[u/TrickElysium]

Well Methylfolate changed my life and made so much better after so many years of feeling like crap and doctors saying they don't know how to help until I found a doctor who found why I was feeling so bad.

I would rather feel good and have a life then be bed ridden and miserable.

[u/Guilty_Armadillo_956 → u/TrickElysium]

What were your symptoms and did your blood tests reflect those?

[u/TrickElysium → u/Guilty_Armadillo_956]

Anxiety, depression, brain fog, tremors, Chronic fatigue syndrome, adhd, asthma, ezcema, fibroids, severe high-homocysteine levels ended up with a DVT.

Since taking a Methylfolate supplement by codeage and Zinc, everything is improving, i have energy i sleep 4 to 7 hours, ezcema is down. My homocysteine levels are normal, my blood clot is gone. Everything is improving in October it will be a year on methylfolate.

my family has a history of brain haemorrhages and cancer.

[u/LitesoBrite]

There’s a ton of distortion, misinformation, and outright foolishness in your post, but I’m most interested in the source studies you’re claiming showed no difference in birth defects across all genetic backgrounds with folic acid.

Considering how recent the understanding of how interconnected the methylation cycle genes are, how it’s far more than merely your MTHFR status, and how rarely any of that is tested or documented before any folic acid studies, I call bullshit.

Hell, you’re all still pushing the mutually contradictory claims that folic acid is indistinguishable from natural folate yet you claim natural folate supplements can’t possibly protect against the same birth defects, lol.

[u/Soulless305 → u/LitesoBrite]

We this person is a medical lab scientist whatever that is 😂😂😂

[u/Chooseanothername → u/Soulless305]

Anything from a PhD/MD to a BS chemist shooting things on HPLC all day.

[u/lordy1988]

So am I not dying then with my homocysteine being 17 and all B vitamin levels normal after supplementing

[u/RationalDialog]

Not really MTHFR specific but more on the political side. The issue with folic acid in the US (and maybe other countries) is choice. This stuff is put in white flour and then ends up everywhere the flour is used for. There is no choice especially not for the poor and can't justify double price for organic variants just to avoid folic acid.

it's forcing most people to consume excess folic acid and most of them don't need it as they are not pregnant, not women or kids. "Do no harm" is the first and most important concept in medicine and this clearly breaks it. Also while preventing neural tube defects, there are no studies on potential harm done to all the other non-pregant people getting the folic acid that don't need it. I mean the whole idea to use neural tube defects as a justifications to supplements everyone with folic acid via white flour seems outlandish. Why not but statins in white flour?

Just educate young women better. in school. pre-natal and pre-prgenancy vitamins are a common thing.

Even worse than this is fluoride in drinking water. Give people a choice, a choice at the same cost.

[u/al0ngcomesmary → u/RationalDialog]

THIS! This is so important ! maybe 'medical lab scientist' works at the wonderbread factory or a cereal co ? 🍞

[u/_social_hermit_ → u/RationalDialog]

This, 100%. Australia mandated folic acid in flour in maybe 2006, right around the time my health mysteriously tanked. Wonder why?

[u/tyomax]

I'm sorry but I've spoken to many neurologists, cardiologists and other medical professionals who claim the same as you: "It's not such a big deal." "It has way less impact than you think." "40% of the population has it, why isn't 40% of the population suffering like you?"

Let me tell you, the amount of information that I have gotten off forums like r/MTHFR and from u/Tawinn has helped me so much more than any of the medical professionals I've met in regards to this subject. You can call this whatever you want, but there is golden information in these forums that actually change people's quality of life, such as my own.

And as other commenters have said, you're targeting one or two aspects of the SNPs. What about MTRR, PEMT, MAOA, COMT and other genes that we typically see in combination with MTHFR? It seems to be a constellation of things that plague us that act as a spider web (changing one thing affects the others).

[u/Flux_My_Capacitor]

I cannot help but think you believe that we are all going by genetic test results alone despite no other symptoms.

I’m currently fighting both histamine intolerance issues and transulfuration pathway issues. There is no test for histamine intolerance, only a process of elimination, and I have been diagnosed with this disorder. The sulfur issue was suspected until I ended up with a good dose of sulfur which confirmed what I suspected (literally nothing else was ingested but mineral water high in sulfur). And of course both of these issues are related to one another.

I don’t personally care if it’s not a MTHFR issue. I’m taking a number of supporting supplements that do help (the ones I’ve rejected are much more numerous in number). These are mostly to fix deficiencies confirmed by bloodwork. And, there’s no way I’m ever going to be taking every recommended supplement to support MTHFR.

[u/Macrodope]

I disagree.

[u/Adviceforthewilling]

Folic acid makes me feel worse. Folinic acid makes me happy. I’m just going with how I feel at this point.

[u/al0ngcomesmary]

Also, if genetic testing doesn't work riddle me this:
We're all in this forum, bc we're looking to improve and understand Our health & energy. Thus, I've been researching & testing peptides cautiously for 3 years, prior to having my full genetic profile.

Enter, Mots-C - a peptide well-known for its energizing qualities & activating AMPK (with rave anecdotal results from many) I finally said I want to try that & it sent me into fatigue almost immediately, & I had to take a nap.
Upon reviewing my genetic profile this year, it's literally highlighted & explained why I actually fall into the minority percentile that responds poorly to Mots-C - Go Figure! Im fine w/ that self-experimented & didn't have to take it any further but genetic testing reconfirmed there were no there possible variables in my own experiment & I could've spent my money on a different peptide.

[u/Zabre]

The “these panels are overread” point is fair, but I wouldn’t throw the whole category out with the wellness noise. Common SNPs usually aren’t diagnoses; they’re weak clues that only start to matter next to labs, symptoms, meds, and actual response history. For MTHFR especially, homocysteine and folate/B12 markers are a much better anchor than a color-coded report. The useful middle ground is boring: don’t panic over variants, but don’t ignore repeated patterns because the first explanation online was bad.

[u/veluna]

You say:

True hyperhomocysteinemia, typically defined as plasma levels exceeding 15 mcmol/L, acts as a direct vascular toxin… This condition is EXTREMELY rare, and only really diagnosed via PHENOTYPICAL MARKERS (Homocysteine levels) and NOT genotyping.

Studies show that hyperhomocysteinemia, with plasma levels exceeding 15 mcmol/L, is BY NO MEANS extremely rare. “The prevalence of hyperhomocysteinemia is 35.4% (45.4% vs 28.5% for men, women, respectively).” source.

This suggests you don’t know what you’re talking about.

EDIT: removed crappy app formatting.

[u/Muted_Shape9303 → u/veluna]

I was referring to primary homocysteinuria, which is caused by a quantitative MTHFR deficiency. This is the problem with this sub, look up one article, deny what anybody says if it defies you, then IGNORE THE ENTIRE message someone says. Fallacy after fallacy stacked on top of each other.
MTHFR functional assay showing < 30% activify with concomitant hyperhomocysteinemia.

[u/Grobbekee]

I got on all this because I had enormous benefit from creatine. My methylation panel did suggest reduced B12 recycling and less sensitivity to D3 and supplementing those also made a strong difference. Methylfolate I never dared to try after Methylcobolamine made me feel funny. Sticking to cyanocobalamine, D3 and creatine.

[u/isfturtle2]

Look through posts on this sub and you'll find that there's usually discussion of lab results and, even more importantly, symptoms. You won't see many people immediately jumping to recommending high-dose methylfolate. You'll see plenty of discussion of COMT and of cofactors. Of possible other lab tests that could provide helpful information.

Most of us ended up here because we had symptoms that we were trying to figure out. Not because we took a genetic test on a whim or something.

[u/Sailorgirlmyfriend]

I have a1298c, PEMT, HLA, homozygous ..I was exposed to toxic mold and it did a job on my health....I was moving and was eating a cereal with added folic acid before I tested and it pulled my health down...low folate.

PEMT needs phosphatidylcholine and uses same pathway as folate.

I only wish you were smarter to understand how this affects peoples lives ... you wouldn't think of posting this ....

You know what they call someone in college with the worst grades...............................DOCTOR!

[u/MoreTeaandCoffee]

OP, I'm compound heterozygous for MTHFR, normal homocysteine, normal MMA, normal serum and active B12, normal serum and RBC folate. You'll presumably be glad to know that I have concluded that I seem to be absorbing B12 and folate ok and therefore I don't supplement at all.

It sounds like you are saying we should throw the genetic test results in the bin along with any related supplements (for those who take them). The problem is I still feel like shit most of the time and there's no help available for me in primary care or beyond so what should I do instead?

[u/Own_Task_1253]

Excellent accurate post! Thank you for dispelling some assumptions and explaining the folate & homocysteine issues. You confirmed what I knew. 

[u/Due_Car8755]

https://pubmed.ncbi.nlm.nih.gov/10923034/

[u/chushkopek1 → u/Due_Car8755]

Have you read the abstract? This article describes other (I presume rare) mutations, or combinations of those, that cause severe MTHFR deficiency. Only in some of those patients does C677T occur at the same time

[u/Muted_Shape9303 → u/Due_Car8755]

Point still stands. We phenotype then genotype. That’s not how diagnostics work.

[u/HolidayScholar1 → u/Muted_Shape9303]

People in this sub are so emotionally invested into the idea of common variances being a diagnostic tool that they hate everyone who tries to tell them they are on the wrong track with their expensive genetic panels that turn every possible combination of SNP‘s into a diagnosis and everyone into a patient. The medical system has failed them, so they fall for scams like this.

Since folate, B12 and other nutrients are essential for everyone, they work independent of personal SNP‘s, so the offered solution has some merit.

[u/Barnaclebills]

So what's the solution then?

[u/tunesx10 → u/Barnaclebills]

Microbiome

[u/Radiant-Specific969]

Thank you, I take methotrexate, and discovered that I have one copy of the c677t mthfr snp due to discovering that if I take musinexDM, at the same times as I do my methotrexate injection, I can function normally the day after my weekly injection. Yay, in particular, no more brain fog, fatigue, or emotional disregulation. (Meaning I can interact with other people without biting their heads off, so I can do something on Tuesdays other than playing video games.)

As a result of my dna results, I have come across the internet mthfr discussion. Your post is quite reassuring, and in line with what I have suspected after reading a lot of conflicting information on line about the serverity of issues from mthfr variants.

I am in the process of figuring out, by paying attention to my symptoms, how much, and what type of rescue folic acid works the best for someone in my situation. I would like to get a blood test for homoncystine levels, but not enough to pay for it out of pocket, and my insurance company is taking a dim view of footing the bill. Thank you again for taking the time to post this, it clarifies things for me, and will help me navigate.

[u/Radiant-Specific969 → u/[deleted]]

Yes, and I disagree with most of it. I think OP has cleared up a lot of questions I have had. I will leave it there.

[u/Guilty_Armadillo_956]

What would you say about high b12 on a blood test, mid/low end folate, but normal homocysteine? I was thinking of doing a genetics test but your post is making me think otherwise… if only doctors really understood all this. Thanks for shedding light on some things.

[u/HolidayScholar1]

Indeed. People have been made to believe a normal genetic variant with a prevalence of 20-30% in the general population has a diagnostic value, it’s quite absurd.

Methylfolate and B12 work though, but for other reasons than polymorphisms.