# MTHFR — Methylenetetrahydrofolate reductase
URL: https://genohealth.app/genes/mthfr
Category: Methylation & B-vitamins
Chromosome: 1p36.22
Key variants: rs1801133 (C677T), rs1801131 (A1298C)
Last reviewed: 2026-04-25

## Summary
MTHFR encodes the enzyme that converts folate into its active form, methylfolate. Variants like C677T (rs1801133) and A1298C (rs1801131) reduce enzyme efficiency and influence how you process B-vitamins, homocysteine and neurotransmitters.

## What it does
MTHFR turns dietary folate (and synthetic folic acid) into 5-methyltetrahydrofolate (5-MTHF) — the form your body actually uses to make DNA, recycle homocysteine into methionine, and produce neurotransmitters like serotonin, dopamine and norepinephrine. When the enzyme works at reduced capacity, the entire methylation cycle slows down, homocysteine accumulates, and cells receive less of the methyl groups they need for gene regulation.

## Why it matters
Reduced MTHFR activity is associated with elevated homocysteine, lower red-cell folate, increased neural-tube-defect risk in pregnancy, a poorer response to standard folic-acid supplementation, and (in some studies) increased risk of cardiovascular disease, depression and migraine with aura. C677T is one of the most-studied SNPs in nutrigenomics with hundreds of clinical associations.

## Variants
- rs1801133 (C677T (Ala222Val)) — risk allele T; Thermolabile enzyme; ~35% activity reduction per T allele. (frequency: T allele ≈30% in Europeans, 10% in West Africans, 50%+ in some Mexican populations.)
- rs1801131 (A1298C (Glu429Ala)) — risk allele C; Mild activity reduction; clinically significant mainly when combined with C677T. (frequency: C allele ≈30% globally.)

## Genotypes
- **CC (wild type)** (~50% of Europeans): Full enzyme activity (~100%). → No special action needed beyond a folate-rich diet.
- **CT (heterozygous)** (~40% of Europeans): Activity reduced ~30-35%. → Favor food folate (leafy greens, legumes) and consider 400 mcg/day L-methylfolate if homocysteine >9 µmol/L.
- **TT (homozygous)** (~10-15% of Europeans): Activity reduced ~60-70%; thermolabile. → Use 400-1000 mcg/day L-methylfolate (5-MTHF), pair with B12 (methylcobalamin) and B6, and test serum homocysteine annually.
- **Compound heterozygous (C677T + A1298C)** (~15-20%): Activity reduced ~40-50%. → Treat similarly to TT — methylfolate plus methylated B-complex.

## Conditions
- **Hyperhomocysteinemia** — Increased risk: TT carriers have ~25% higher fasting homocysteine on average; methylfolate + B12 + B6 typically normalizes it.
- **Neural tube defects** — Increased risk: Maternal TT genotype + low folate intake substantially raises NTD risk; preconception 5-MTHF supplementation is protective.
- **Cardiovascular disease** — Modest association: Mostly mediated by homocysteine; benefit of B-vitamin therapy on hard cardiac endpoints is debated.
- **Depression** — Modifies treatment response: L-methylfolate is FDA-recognized as adjunct to SSRIs in MTHFR-variant carriers with treatment-resistant depression.
- **Migraine with aura** — Increased risk: TT carriers have higher migraine-with-aura prevalence; riboflavin (B2, 400 mg/day) is well-studied prophylaxis.

## Diet
Rationale: Food folate is delivered as polyglutamates the gut converts efficiently; synthetic folic acid requires DHFR conversion that competes with the impaired MTHFR pathway and can leave unmetabolized folic acid in circulation in TT carriers.
Prioritize: Dark leafy greens (spinach, romaine, kale); Lentils, chickpeas, black beans; Asparagus, broccoli, brussels sprouts; Avocado; Liver (1-2x/month); Pasture-raised eggs
Limit: Fortified cereals/breads using folic acid (synthetic); Energy drinks fortified with folic acid; Excess alcohol (depletes folate)

## Lifestyle
- Test homocysteine annually — target <8 µmol/L.
- If planning pregnancy, start 5-MTHF (not folic acid) at least 3 months pre-conception.
- Avoid nitrous-oxide anesthesia where possible (depletes B12, stresses methylation).
- Limit alcohol to <7 drinks/week (alcohol antagonizes folate).

## Supplements
- **L-methylfolate (5-MTHF)** — 400-1000 mcg/day, form: Quatrefolic or Metafolin (5-MTHF), NOT folic acid. Start low (400 mcg) — too much too fast can cause irritability or anxiety in slow-COMT individuals.
- **Methylcobalamin (B12)** — 500-1000 mcg/day sublingual, form: Methylcobalamin or hydroxocobalamin, not cyanocobalamin. Required to recycle homocysteine; deficiency masks MTHFR symptoms.
- **Pyridoxal-5-phosphate (B6)** — 25-50 mg/day, form: P5P (active form). Supports CBS pathway downstream of MTHFR.
- **Riboflavin (B2)** — 100-400 mg/day, form: Riboflavin-5-phosphate. Cofactor for MTHFR enzyme; especially useful in TT migraine sufferers.
- **Trimethylglycine (TMG / betaine)** — 500-3000 mg/day with meals, form: Anhydrous betaine. Provides alternative methyl donor; lowers homocysteine when B-vitamins alone are insufficient.

## Contraindications
- High-dose methylfolate (>1 mg) without B12 testing — can mask B12 deficiency neuropathy.
- Pre-existing bipolar disorder — methyl donors can sometimes precipitate hypomania.
- Known cancer — discuss folate supplementation with oncologist (folate-dependent tumors).

## FAQ
**Q: Is MTHFR C677T the same as A1298C?**
A: No. They are two distinct variants in the same gene. C677T (rs1801133) has a stronger effect on enzyme activity. Many people carry one, both (compound heterozygous), or neither.

**Q: Should everyone with MTHFR take methylfolate?**
A: People who are CT or TT for C677T typically benefit, especially if homocysteine is >9 µmol/L. Wild-type CC carriers can use food folate. Always start with 400 mcg and titrate; discuss high doses with a clinician.

**Q: What is the best methylfolate dose for MTHFR TT?**
A: Most evidence supports 400-1000 mcg/day of L-5-MTHF for general health, with 7.5-15 mg/day reserved for FDA-recognized adjunct treatment of depression under clinician supervision.

**Q: Can MTHFR cause anxiety?**
A: Indirectly, yes. Impaired methylation can disrupt serotonin and dopamine production. However, over-methylating (too much methylfolate too fast) can also cause anxiety, especially in people with slow COMT — titrate slowly.

**Q: Should I avoid folic acid completely if I have MTHFR?**
A: Many practitioners recommend choosing 5-MTHF over synthetic folic acid for TT carriers, since unmetabolized folic acid can accumulate. Avoiding fortified foods entirely is impractical and unnecessary; just don't add a folic-acid multivitamin on top.

**Q: Does MTHFR affect pregnancy?**
A: Yes. Maternal MTHFR variants combined with low folate intake increase neural-tube-defect risk. Preconception 5-MTHF (400-800 mcg/day) starting 3 months before conception is recommended.

## Citations
- Frosst et al., Nat Genet 1995 (PMID 7647779): Original discovery of the C677T variant and its thermolabile effect on MTHFR activity.
- Liew & Gupta, Eur J Med Genet 2015 (PMID 25449138): Comprehensive review of MTHFR C677T and A1298C clinical associations.
- Papakostas et al., Am J Psychiatry 2012 (PMID 23212058): L-methylfolate 15 mg/day augmentation improved SSRI response in treatment-resistant depression.

Disclaimer: Informational only — not medical advice.