What is MTHFR, and What Does Your Result Mean?

You have been tested for MTHFR, the result came back positive, and now you are trying to work out how worried you should be. The short answer is that the result on its own tells you very little. MTHFR is a common gene variant, most people reading this will carry at least one copy, and a large proportion of people who carry even the slower version have completely normal bloodwork. What determines whether it matters is not the gene. It is what that gene has to work with and how it is expressed, and that is measurable.

What MTHFR actually is

MTHFR stands for methylenetetrahydrofolate reductase. It is an enzyme, and the MTHFR gene is the instruction manual for building it.

The enzyme has one job. Folate from food cannot be used by the body in the form it arrives in. It has to be converted through several steps into an active form called 5-MTHF, and MTHFR carries out the final step. Slow that step down and the whole methylation cycle downstream of it slows with it.

Standard testing looks at two positions on the gene:

• C677T, the more studied of the two
• A1298C

You inherit one copy of each gene from each parent, so for either position you can have no variants, one, or two. One copy is called heterozygous. Two copies is homozygous.

A note on the word “mutation”. These are properly called variants or polymorphisms, because they are far too common to be mutations in the usual sense. The word has stuck, and it makes the result sound more alarming than it is.

How common is it?

Common enough that finding it says very little about you specifically.

The frequency of the C677T variant runs at roughly 30 to 40% of gene copies in populations of European and Asian descent, and is considerably lower in sub-Saharan Africa.¹ At those frequencies, carrying at least one copy is unremarkable.

That matters for how you read your result. A finding shared by a third or more of the population is not an explanation for why you feel unwell. It is one piece of information among many.

Enzymes are like highways

Think about driving on a highway with almost no traffic. All lanes open, no obstructions, everyone at full speed. That is an enzyme with no variants. Substrates flow through and products get made.

Now make it busier. Holiday traffic, slower going, lanes filling up. That is roughly one copy of the variant.

Now put yourself in peak hour. The highway has become a car park. That is two copies. The enzyme has limited capacity to move things through, so precursors bank up behind it and you end up short of the end product.

There is a measured version of this. In one of the original studies of C677T, enzyme activity in people with two copies was around 30% of normal, and in people with one copy around 65%.² The variant changes a single amino acid in the enzyme, and that change affects how well the enzyme holds onto its cofactor, which is where the loss of activity comes from.²

But traffic has alternate routes. If one pathway is congested, others can sometimes pick up the slack. It is not always ideal, but it happens. Problems occur when the alternate routes are also slow, and that is why two people with identical gene results can look completely different.

MTHFR is one worker in a large factory

Methylation is a production line. The factory makes SAM (S-adenosylmethionine), glutathione, biopterin (BH4) and the building blocks of DNA, which in turn give you energy, neurotransmitters, hormones and cell repair.

For the line to run, every part has to arrive in the right order at the right time. Folate from your food goes on the conveyor belt at the start. MTHFR is the worker at the end of that first stage.

If that worker is slow, the whole line slows, no matter how capable everyone downstream is. But the reverse is also true. Any worker anywhere on the line can slow things down. MTHFR is simply the one that got famous.

And if you are not eating foods containing natural folate, or you are living largely on processed foods fortified with synthetic folic acid, the workers do not have much to work with regardless of how fast they are.

What are the symptoms of an MTHFR mutation?

This is the question most people want to know the answer to.

The symptoms commonly attributed to MTHFR are the ones associated with impaired methylation or raised homocysteine. They include:

• Fatigue that does not improve with rest
• Brain fog and difficulty concentrating
• Low mood, anxiety, irritability
• Headaches and migraines
• Poor tolerance of alcohol or of chemical smells
• Reacting badly to supplements, particularly folate and B12
• Recurrent miscarriage or fertility difficulties
• Raised homocysteine on a blood test

Keep in mind that every symptom on that list has many possible causes, and none of them is specific to MTHFR. Thyroid problems, iron deficiency, poor sleep, gut dysbiosis and a dozen other things produce the same picture. A symptom list cannot confirm a gene is causing anything.

The last item is different from the rest. Homocysteine is measurable, and it is the marker that tells you whether the pathway is actually struggling in you. Which makes it far more useful than the gene result.

Why two people with the same result look completely different

Here is the finding that should change how you read your test.

A large proportion of people carrying the slower version of MTHFR have entirely normal homocysteine levels.³ The gene is the same. The outcome is not.

What separates them is mostly nutrient status.

Folate. Homocysteine tends to be raised in people with two copies of C677T mainly when folate status is low. With good folate status, the difference between genotypes largely disappears.³

Riboflavin. The variant works by weakening how the enzyme binds its cofactor, and that cofactor is made from riboflavin, vitamin B2. In a trial in people with two copies of C677T, riboflavin lowered homocysteine.⁴ The genetic weakness is specifically in cofactor binding, so cofactor availability matters more in these people than in everyone else.

Everything else on the line. B12, B6, zinc, magnesium and the enzymes downstream all affect what happens to the folate once MTHFR has finished with it.

So the gene sets a constraint. Your nutrient status, your gut, your stress load and your other genes determine whether that constraint ever becomes a problem. This is the same pattern that shows up throughout genetics, and it is why I keep saying a variant is a question rather than an answer.

What the genetics bodies say about testing

The American College of Medical Genetics and Genomics advises that MTHFR testing has minimal clinical utility and should not be part of a routine workup for clotting disorders. Meta-analyses failed to support a link between MTHFR variants and venous blood clots, or between raised homocysteine and coronary heart disease.⁵ Obstetric and haematology bodies in the United States and United Kingdom take the same position.⁵

I think that position is right as far as it goes. Ordering an MTHFR test to explain clots or heart disease is not supported by the evidence, and a great deal of alarming advice has been built on associations that did not hold up.

Where I differ is what follows from it. The genetics bodies are answering a narrow question: does this gene result predict a specific disease well enough to guide medical management? It does not. That is a different question from whether folate metabolism is worth understanding in someone with fatigue, raised homocysteine and a poor response to supplements. For that, I would still rather look at the pathway, and I would look at it using markers rather than the gene.

It is also worth separating two different things. A single MTHFR test, ordered to explain a clot or a miscarriage, is what the genetics bodies are advising against, and they are right. A broader gene panel, read by someone who uses it as a map alongside your symptoms and your bloodwork, is a different use of the same technology. The problem has never been the information. It is treating one result as an answer.

What to do with a positive result

Not “which supplement”. I am not going to tell you that, and anyone who does so without knowing anything else about you is guessing.

The most common problem I see in practice is someone who was put on active folate or a stack of methyl donors on the strength of a gene result, and who felt considerably worse. That happens often enough that it should be the default expectation rather than a surprise.

What is worth doing instead is finding out whether the pathway is actually struggling:

• Homocysteine. The single most useful marker. It tells you whether the cycle is backing up. Worth knowing that it can also be too low, which means something quite different.
• Folate and B12. Serum B12 is a poor marker on its own. MMA, and MCV on a full blood count, give a better picture of whether B12 is functionally sufficient.
• Riboflavin status, given that the variant impairs cofactor binding specifically.
• The rest of the picture. Thyroid, iron, gut function and inflammation all affect this pathway and all produce the same symptoms.

A marker sitting inside the reference range is not the same as a marker at a level that works well for you, which is a theme that runs through most blood testing and one I have written about in the context of thyroid results.

Two kinds of food removal

One more thing, because it comes up constantly.

Removing whole foods on the strength of a gene result is usually a mistake. I have written about what happens when people restrict sulfur foods for years because of a CBS variant, in the article on sulfur intolerance. Years of narrowing your diet to manage a symptom tends to cost more than it gains.

Synthetic folic acid is a different case, and here I would remove it.

Folic acid is not found in real food. It is a synthetic, oxidised form that has to be reduced by an enzyme called DHFR before your body can use it, and human capacity to do that is surprisingly poor. In one study, human liver reduced folic acid at less than 2% of the rate seen in rat liver, with roughly a fivefold variation between individuals.⁶ In another, researchers sampled blood directly from the portal vein after a dose and found that 80% of the absorbed folic acid was still unconverted, while natural dietary folate had been almost completely converted by the same gut.⁷

So the human body handles food folate well and synthetic folic acid poorly. Note that this is a limitation of DHFR rather than of MTHFR, which means it applies whatever your genotype. You do not need a gene result to justify it.

In practice that means favouring folate from food, such as leafy greens, legumes, eggs and liver, and reducing fortified processed foods. In Australia, folic acid is added to wheat flour for bread-making by law, so bread is the main everyday source for most people.

This matters most in pregnancy, and it is where I would be most specific.

I recommend a prenatal supplement that uses methylfolate rather than folic acid. In a randomised trial in women of childbearing age, the active form of methylfolate raised red blood cell folate, the marker used to assess neural tube defect risk, more effectively than the same amount of folic acid.⁸ It also avoids a known problem with folic acid, which is that high intakes can mask a B12 deficiency.

Two things to get right if you make that switch. First, check the label says L-methylfolate, [6S]-5-MTHF, or a named form such as Metafolin or Quatrefolic. Some cheaper products use a mixed form that is only half as active.⁹ Second, and more important, do not leave a gap. The neural tube closes by about day 28 after conception, often before a pregnancy is confirmed.

Where this leaves you

Getting tested was not a waste. It gave you a clue about where your biochemistry might be less robust than average, and that is useful context.

What it did not give you is a diagnosis, an explanation for your symptoms, or a supplement protocol. MTHFR is one gene, surrounded by many others that matter just as much and that determine whether this one ever causes trouble.

An experienced practitioner can usually work out which parts of the pathway need support from your symptoms and your functional test results, without any gene testing at all. The genes tell you about capacity. The markers tell you what is actually happening.

Frequently asked questions

What is MTHFR?
MTHFR is an enzyme that carries out the final step in converting dietary folate into its active form, 5-MTHF. The MTHFR gene codes for that enzyme. Two common variants are routinely tested, C677T and A1298C, and either can slow the enzyme down.

What are the symptoms of an MTHFR mutation?
The symptoms usually attributed to it are fatigue, brain fog, low mood, headaches, poor tolerance of supplements and recurrent miscarriage. All of these have many other causes and none is specific to MTHFR. The one meaningful marker is homocysteine, which is measurable and tells you whether the pathway is actually struggling.

How serious is an MTHFR mutation?
Usually not very. The C677T variant is present in roughly 30 to 40% of gene copies in European and Asian populations,¹ and a large proportion of people who carry even two copies have normal homocysteine.³ Whether it matters depends on nutrient status rather than on the gene result itself.

What is the difference between heterozygous and homozygous MTHFR?
Heterozygous means one copy of the variant, homozygous means two. In the original work on C677T, enzyme activity was around 65% of normal with one copy and around 30% with two.² That is a measure of laboratory enzyme activity rather than a prediction of how you will feel.

Should I take methylfolate if I have MTHFR?
Not automatically, and not on the strength of a gene result alone. Reacting badly to active folate and methyl donors is a common experience, and the usual reason is that something else in the pathway needed attention first. Homocysteine, B12 and riboflavin status tell you far more about what is needed than the genotype does.

Do doctors recommend MTHFR testing?
Generally no. The American College of Medical Genetics and Genomics advises that MTHFR testing has minimal clinical utility and should not form part of a routine workup for clotting disorders, and obstetric and haematology bodies take the same position.⁵ Meta-analyses did not support the links to blood clots or heart disease that the testing was originally based on.

Does MTHFR cause high homocysteine?
It can, but mainly when folate status is low. With adequate folate, the difference between genotypes largely disappears.³ Riboflavin also matters, because the variant impairs the enzyme’s ability to hold its riboflavin-derived cofactor, and riboflavin lowered homocysteine in people carrying two copies.⁴

References

1. Riboflavin and methylenetetrahydrofolate reductase. In: Madame Curie Bioscience Database. NCBI Bookshelf, NBK6145.
2. Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genetics. 1995;10(1):111-113.
3. Jacques PF, Bostom AG, Williams RR, et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation. 1996;93(1):7-9.
4. McNulty H, Dowey le RC, Strain JJ, et al. Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C→T polymorphism. Circulation. 2006;113(1):74-80.
5. Hickey SE, Curry CJ, Toriello HV. ACMG practice guideline: lack of evidence for MTHFR polymorphism testing. Genetics in Medicine. 2013;15(2):153-156. (Reaffirmed by the ACMG Board in 2020.)
6. Bailey SW, Ayling JE. The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake. PNAS. 2009;106(36):15424-15429.
7. Patanwala I, King MJ, Barrett DA, et al. Folic acid handling by the human gut: implications for food fortification and supplementation. American Journal of Clinical Nutrition. 2014;100(2):593-599.