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Nutrition Science Hub · Folate

MTHFR gene mutation
and methylfolate:
the folate your body uses.

MTHFR is the enzyme that makes the final, active form of folate (Vitamin B9) your cells use. Common gene variants make it work a little slower in some people. Methylfolate (5-MTHF) is that active form, ready to use, so it works whatever your genes. Here’s what MTHFR really is, how common the variants are in India, the difference between folic acid and methylfolate, unmetabolised folic acid, B12, testing, pregnancy, folate foods and how to read a label.

This guide is general education. If you are pregnant, trying to conceive or have been prescribed folic acid, keep taking it and talk to your doctor before changing anything.

By Evo Hominus™Updated 13 min read
See the short answerTry the Nutrient Gap Finder
~70%less MTHFR enzyme activity with two copies of the C677T variant
~11%of MTHFR genes in North India carry the C677T variant
400 mcgof folic acid a day before pregnancy, advised by the WHO
220 mcgdaily folate need for adult women in India (300 mcg for men)

What is the MTHFR gene mutation? The short answer

The Short Answer

What is the MTHFR gene mutation?

MTHFR is a gene that makes an enzyme called methylenetetrahydrofolate reductase. The enzyme makes 5-MTHF, the active form of folate your cells use. Common variants, mainly C677T and A1298C, make the enzyme work more slowly. They are very common, usually cause no symptoms, and methylfolate supplies the active form directly.

Think of folate as raw material moving down a factory line. Food folate and folic acid enter at different points, and the last machine on the line, the MTHFR enzyme, turns folate into its working form, 5-methyltetrahydrofolate (5-MTHF). That is the form in your blood, and it helps recycle homocysteine and make the building blocks for DNA.

A gene “mutation” here is really a common variant, a small spelling difference in the gene that many healthy people carry. With one copy of the C677T variant the enzyme works at about two-thirds of its usual speed; with two copies, at about a third.2 The A1298C variant has a milder effect. Methylfolate is the finished product of that last machine, so it skips the step entirely.

How common is MTHFR in India?

The Short Answer

How common is MTHFR in India?

The milder A1298C variant is common in India: in a South Indian study, about 4 in 10 copies of the gene carried it. The stronger C677T variant is less common than in Europe or East Asia: about 11% of gene copies in North India, with only about 1 in 100 people carrying two copies. Low B12 is a bigger everyday factor in India.

MTHFR gene variants: effect on the enzyme and how common they are in India
VariantWhat it does, and how common it is in India
C677T, one copyEnzyme works at about two-thirds speed; carried by roughly 1 in 5 people in North India
C677T, two copiesEnzyme works at about one-third speed; about 1 in 100 people in North India
A1298CMilder slowing; about 40% of gene copies in a South Indian study, and linked with higher homocysteine in an Indian study

In a study of 1,000 healthy adults in eastern Uttar Pradesh, about 11% of MTHFR gene copies carried C677T, and about 1% of people carried two copies.3 In South India, the A1298C variant was found in about 40% of gene copies,4 and an Indian study linked it with higher homocysteine.5 Add India’s lack of folic acid–fortified flour and widespread low B12, and getting enough active folate and B12 matters more than the gene result itself.13

Folic acid vs methylfolate: what’s the difference?

The Short Answer

What is the difference between folic acid and methylfolate?

Folic acid is a man-made form of folate used in supplements and fortified foods. The body has to convert it in several steps, including the MTHFR step, before cells can use it. Methylfolate (5-MTHF) is the active form already found in your blood, so it needs no conversion and works the same whatever your MTHFR genes.

Folic acid and methylfolate (5-MTHF) compared
FeatureFolic acidMethylfolate (5-MTHF)
What it isA man-made, stable form of folateThe active form of folate found in your blood
Steps before your cells can use itSeveral, including the slow DHFR step in the liver and the MTHFR stepNone: already active
Depends on your MTHFR genesYes, for the final stepNo
Unmetabolised folic acid in the bloodCan appear at higher dosesDoes not create it
Raises red blood cell folateYesYes; more than folic acid in a 24-week trial in women
Proven to prevent neural tube defects in trialsYes, the form used in the landmark trialsRaises folate levels as well; not tested in those trials
On a label“Folic acid” or “pteroylmonoglutamic acid”“L-5-MTHF”, “L-methylfolate”, “(6S)-5-methyltetrahydrofolate”

In a 24-week trial in 144 women of childbearing age, methylfolate raised red blood cell folate more than folic acid.14 Reviews describe 5-MTHF as the form that avoids the conversion steps folic acid needs.8 Folate contributes to normal homocysteine metabolism, normal blood formation and normal psychological function.1 Read folic acid vs folate vs methylfolate, explained simply.

Unmetabolised folic acid (UMFA): why folic acid can build up

The Short Answer

Why does folic acid build up in the blood?

Folic acid must first pass through an enzyme in the liver called DHFR, which works slowly in humans. When more folic acid arrives than it can handle, some stays in the blood unchanged, called unmetabolised folic acid. This happens to many people taking folic acid, whatever their MTHFR genes. Methylfolate does not create it.

In a study of 105 women after menopause, unmetabolised folic acid was found in 78% of fasting blood samples, and women who had it showed lower activity of natural killer cells, a type of immune cell.6 In a randomised trial in breastfeeding women, methylfolate led to less unmetabolised folic acid in breast milk than the same dose of folic acid.7 Whether this matters for health is still being studied, but it is one reason many people prefer the active form.

Folate and vitamin B12: partners in the same cycle

The Short Answer

Should I take methylfolate with vitamin B12?

Yes. Methylfolate hands its methyl group to vitamin B12 to recycle homocysteine, so the two work as a pair. If B12 is low, folate gets stuck in an unusable form. High doses of folic acid can also hide the anaemia of B12 deficiency while nerve damage continues, so check B12 too.

Folate and B12 meet in the same step: methylfolate passes its methyl group to B12, which uses it to turn homocysteine back into a useful amino acid. Without enough B12, folate is trapped, homocysteine rises, and the body behaves as if it is short of folate even when intake is good.9 That matters in India, where about half of adults are low in B12.13 Vitamins B6, B12 and folate each contribute to normal homocysteine metabolism.1 The active form methylcobalamin pairs naturally with methylfolate. Read our vitamin B12 guide.

Should you get an MTHFR test?

The Short Answer

Should I get an MTHFR test?

For most people, a homocysteine, folate and vitamin B12 blood test is more useful than the gene test, because it shows how well your folate cycle is working right now. Medical genetics guidelines do not advise routine MTHFR testing. If your doctor recommends one, it is available at major diagnostic labs in India.

The gene test tells you what you were born with; it does not tell you whether you are short of folate or B12 today. That is why the American College of Medical Genetics advises against routine MTHFR testing, including for blood clots or pregnancy loss, and suggests checking homocysteine instead when needed.10 Many labs treat homocysteine above about 15 µmol/L as high. High homocysteine is most often due to low B12, folate or B6, kidney problems or some medicines, and it usually comes down when the missing vitamins are replaced.9

MTHFR, folate and pregnancy

The Short Answer

Can I take methylfolate during pregnancy?

Yes, methylfolate is a safe, active form of folate, and many prenatal supplements use it. The World Health Organization advises 400 mcg of folic acid a day from before conception until 12 weeks of pregnancy. Whichever form you take, start at least three months before trying to conceive and follow your gynaecologist’s dose.

Folate helps build the baby’s brain and spine in the first weeks of pregnancy, often before a woman knows she is pregnant, and contributes to maternal tissue growth during pregnancy.1,11 India’s daily folate need rises from 220 mcg to 570 mcg in pregnancy.12 If you carry an MTHFR variant, methylfolate gives you the active form directly; if you have been prescribed a specific dose, keep to it. Read our guide to multivitamins for women.

Folate foods in an Indian diet

The Short Answer

Which foods are high in folate?

Dals and pulses such as rajma, chana, moong and masoor are the best Indian sources, along with leafy greens like spinach (palak) and methi, peanuts, sunflower seeds, broccoli, beetroot, oranges and eggs. Folate is destroyed by long boiling, so steam or cook greens lightly and use the cooking water in dal.

Most of the folate in Indian food is natural folate, which your body turns into methylfolate through the MTHFR step. A daily bowl of dal, a portion of leafy greens and a handful of peanuts go a long way towards India’s daily need of 300 mcg for men and 220 mcg for women.12 Folate is fragile: long boiling and reheating destroy much of it.9

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Check your own label: folic acid or methylfolate?

The Short Answer

How do I check if my multivitamin uses folic acid or methylfolate?

Turn the bottle over and find the folate (Vitamin B9) line. “Folic acid” or “pteroylmonoglutamic acid” is the man-made form. “L-5-MTHF”, “L-methylfolate” or “(6S)-5-methyltetrahydrofolate” is the active form. Then check B12: “methylcobalamin” is active, “cyanocobalamin” is the standard form.

Active folate

Methylfolate

“L-5-MTHF”, “L-methylfolate”, “(6S)-5-methyltetrahydrofolate”, or a branded methylfolate such as Quatrefolic®.

Active B12

Methylcobalamin

The active form that works with methylfolate in the same cycle.

Look for

Amounts in mcg DFE

Dietary folate equivalents let you compare forms fairly against India’s daily needs.

Standard form

Folic acid

“Folic acid” or “pteroylmonoglutamic acid”: effective, but needs conversion and can leave some unmetabolised.

Be wary

High doses without advice

More than 1,000 mcg a day of supplemental folate is above India’s upper limit unless a doctor prescribes it.

What to do: a simple plan

The Short Answer

What should I do if I think I have MTHFR?

Check your supplement label, eat folate-rich dals and greens every day, make sure your B12 is adequate, ask your doctor about a homocysteine, folate and B12 test, and if a pregnancy is possible, start folate three months ahead. Never stop prescribed folic acid without your doctor.

  1. Check your labelFind the folate line and see whether it says folic acid or methylfolate, and check the B12 form too.
  2. Eat folate foods dailyDal, rajma or chana, leafy greens and a handful of peanuts or seeds, cooked lightly.
  3. Look after your B12Milk, curd, paneer or eggs every day, and a B12 test if you are vegetarian or take metformin.
  4. Ask about a homocysteine testA homocysteine, folate and B12 blood test shows how well your folate cycle is working.
  5. Plan ahead for pregnancyStart folate at least three months before trying to conceive, at your gynaecologist’s dose.
  6. Keep prescribed dosesNever stop or change prescribed folic acid without your doctor.
About the studies
  • The enzyme-speed figures come from laboratory measurements of the C677T variant; the A1298C variant has a smaller effect, and most carriers have normal homocysteine when they get enough folate and B12.2
  • The Indian gene figures come from single regional studies (eastern Uttar Pradesh for C677T, South India for A1298C) and may differ across India.3,4
  • The 78% unmetabolised folic acid figure comes from US women, where flour is fortified with folic acid; the immune finding is a link, not proof of harm.6
  • The methylfolate red blood cell trial compared folic acid and methylfolate over 24 weeks in German women.14 Short-term studies found both forms raise blood folate about equally.
  • Folic acid is the form proven in trials to prevent neural tube defects; methylfolate studies measured folate levels, not birth outcomes.11
Questions

MTHFR and methylfolate, answered plainly.

What is the MTHFR gene mutation?

MTHFR is a gene that makes the enzyme methylenetetrahydrofolate reductase, which turns folate into 5-MTHF, the active form your cells use. Common variants, mainly C677T and A1298C, make the enzyme work more slowly. They are very common, usually cause no symptoms, and methylfolate supplies the active form directly.

How common is MTHFR in India specifically?

The milder A1298C variant is common in India, found in about 40% of gene copies in a South Indian study. The stronger C677T variant is less common than in Europe or East Asia: about 11% of gene copies in North India, with about 1 in 100 people carrying two copies. Low B12 is a bigger everyday factor in India.

What is the difference between folic acid and methylfolate?

Folic acid is a man-made form of folate that the body must convert in several steps, including the MTHFR step, before cells can use it. Methylfolate (5-MTHF) is the active form already found in your blood, so it needs no conversion and works the same whatever your MTHFR genes.

Can I test for MTHFR in India?

Yes. MTHFR gene testing is available at major diagnostic labs in India. For most people, a homocysteine, folate and vitamin B12 blood test is more useful, because it shows how well your folate cycle is working now. Medical genetics guidelines do not advise routine MTHFR testing. Ask your doctor which test suits you.

Why does folic acid build up in the blood for some people?

Folic acid must first pass through an enzyme in the liver called DHFR, which works slowly in humans. When more folic acid arrives than it can handle, some stays in the blood unchanged, called unmetabolised folic acid. In one study it was found in 78% of fasting blood samples. Methylfolate does not create it.

What is Quatrefolic® and why is it different from generic methylfolate?

Quatrefolic® is a branded methylfolate, the (6S)-5-MTHF glucosamine salt, made by Gnosis by Lesaffre, who describe it as a fourth-generation folate. Its maker reports far higher water solubility and good stability compared with the older calcium salt. In the body, it delivers the same active methylfolate.

Is folate the same thing as folic acid?

No. Folate (Vitamin B9) is the family name for all forms of the vitamin, including the natural folate in dal and leafy greens and the active methylfolate in your blood. Folic acid is one man-made member of the family, used in supplements and fortified foods.

Should I stop taking folic acid if I have MTHFR?

Never stop prescribed folic acid without your doctor, especially before or during pregnancy. Folic acid still works for most people with MTHFR variants. Methylfolate is a good alternative because it supplies the active form directly, so ask your doctor whether switching suits you.

How do I check if my current multivitamin uses folic acid or methylfolate?

Find the folate (Vitamin B9) line on the label. “Folic acid” or “pteroylmonoglutamic acid” is the man-made form. “L-5-MTHF”, “L-methylfolate” or “(6S)-5-methyltetrahydrofolate” is the active form. Also check B12: “methylcobalamin” is active and “cyanocobalamin” is the standard form.

What are the symptoms of MTHFR?

Most people with MTHFR variants have no symptoms. Problems come from what can follow when folate or B12 is low, such as high homocysteine, anaemia, tiredness, mouth ulcers or tingling. A blood test for homocysteine, folate and B12 shows whether that is happening.

Can MTHFR cause fatigue or brain fog?

Not by itself. Tiredness and poor focus are more often linked to low B12, low iron, low vitamin D, poor sleep or thyroid problems. If you feel tired for weeks, ask for a blood count, ferritin, B12, folate, vitamin D and thyroid test.

What is the best folate supplement for MTHFR?

Methylfolate (L-5-MTHF), because it is already the active form and skips the MTHFR step. Choose one that states the amount in mcg DFE, pairs it with vitamin B12 (ideally methylcobalamin), and keeps the dose close to your daily need unless your doctor advises more.

How much methylfolate should I take?

India’s daily folate need is 300 mcg for men and 220 mcg for women, rising to 570 mcg in pregnancy. Before pregnancy, the WHO advises 400 mcg of folic acid a day. Stay below 1,000 mcg a day from supplements unless a doctor prescribes more.

Is methylfolate safe?

Yes, at normal daily doses methylfolate is safe and well tolerated. Keep total supplemental folate below 1,000 mcg a day unless prescribed, and make sure your vitamin B12 is adequate, because folate and B12 work together.

Can I take methylfolate during pregnancy?

Yes. Methylfolate is an active form of folate and is used in many prenatal supplements. Start folate at least three months before trying to conceive, keep taking it through early pregnancy, and follow your gynaecologist’s choice of form and dose.

Does MTHFR cause miscarriage?

Studies have not shown a clear link, and medical genetics guidelines do not recommend MTHFR testing after pregnancy loss. If you have had miscarriages, your gynaecologist will look at the full range of causes and may check homocysteine, folate and B12.

Should I take methylfolate with vitamin B12?

Yes. Methylfolate passes its methyl group to vitamin B12 to recycle homocysteine, so the two work as a pair. If B12 is low, folate gets stuck. About half of Indian adults are low in B12, so check it, especially if you are vegetarian.

What level of homocysteine is high?

Many labs treat fasting homocysteine above about 15 µmol/L as high. The most common causes are low B12, folate or B6, kidney problems and some medicines. Folate, B6 and B12 contribute to normal homocysteine metabolism, and levels usually fall when the missing vitamins are replaced.

Which foods are high in folate?

Dals and pulses such as rajma, chana, moong and masoor, leafy greens like spinach and methi, peanuts, sunflower seeds, broccoli, beetroot, oranges and eggs. Cook greens lightly, because long boiling destroys folate.
Sources

Studies behind this guide

  1. Commission Regulation (EU) No 432/2012 — authorised health claims: folate (normal homocysteine metabolism, blood formation, psychological function, maternal tissue growth during pregnancy); vitamins B6 and B12 (normal homocysteine metabolism).
  2. Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10(1):111–3.
  3. Yadav U, Kumar P, Gupta S, Rai V. Distribution of MTHFR C677T gene polymorphism in healthy North Indian population and an updated meta-analysis. Indian J Clin Biochem. 2017;32(4) — 1,000 adults, eastern Uttar Pradesh; T allele about 11%, TT about 1%. PMC5634971
  4. Radha Rama Devi A, Govindaiah V, Ramakrishna G, Naushad SM. Prevalence of methylene tetrahydrofolate reductase polymorphism in South Indian population. Curr Sci. 2004;86(3):440–3 — 608 people; A1298C C allele about 0.40.
  5. Kumar J, Das SK, Sharma P, et al. Homocysteine levels are associated with MTHFR A1298C polymorphism in Indian population. J Hum Genet. 2005;50(12):655–63. PMID 16244782
  6. Troen AM, Mitchell B, Sorensen B, et al. Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr. 2006;136(1):189–94. PMID 16365081
  7. Cochrane KM, et al. Randomised trial of (6S)-5-methyltetrahydrofolic acid vs folic acid in lactating women: unmetabolised folic acid in human milk. Sci Rep. 2023.
  8. Scaglione F, Panzavolta G. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica. 2014;44(5):480–8. PMID 24494987
  9. NIH Office of Dietary Supplements. Folate — Fact Sheet for Health Professionals (metabolism, B12 interaction, homocysteine, food sources and cooking losses, upper limit). ods.od.nih.gov
  10. Hickey SE, Curry CJ, Toriello HV. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2013;15(2):153–6.
  11. World Health Organization. e-Library of Evidence for Nutrition Actions (eLENA): Periconceptional folic acid supplementation to prevent neural tube defects — 400 µg daily from before conception until 12 weeks of pregnancy.
  12. ICMR–National Institute of Nutrition. Nutrient Requirements for Indians, 2020 — folate RDA 300 mcg men, 220 mcg women, 570 mcg pregnancy, 330 mcg lactation; tolerable upper limit 1,000 mcg. nin.res.in
  13. Singla R, Garg A, Surana V, et al. Vitamin B12 deficiency is endemic in Indian population: a perspective from North India. Indian J Endocrinol Metab. 2019;23(2):211–4. PMID 31161105
  14. Lamers Y, Prinz-Langenohl R, Brämswig S, Pietrzik K. Red blood cell folate concentrations increase more after supplementation with [6S]-5-methyltetrahydrofolate than with folic acid in women of childbearing age. Am J Clin Nutr. 2006;84(1):156–61.
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