MTHFR mutation: what it is and what it does to your health

MTHFR (methylenetetrahydrofolate reductase) is the enzyme that converts folate to its active 5-MTHF form. Two common variants — C677T and A1298C — can reduce enzyme activity by 30–70%. But the clinical meaning is more nuanced than internet forums claim.

What MTHFR does

The enzyme converts folic acid/folate into 5-methyltetrahydrofolate (5-MTHF), which drives homocysteine metabolism, DNA methylation and neurotransmitter synthesis. Reduced activity can raise homocysteine, a cardiovascular risk factor.

Common variants

• C677T homozygous (TT): ~30% enzyme activity, ~10% of Europeans
• C677T heterozygous (CT): ~65% activity, ~40%
• A1298C homozygous (CC): ~60% activity, smaller effect
• Compound heterozygous (C677T + A1298C): ~50% activity

What current science actually says

The 2013 ACMG practice guideline (Hickey et al.) explicitly states that routine MTHFR genotyping is NOT recommended: the variant's association with disease risk is clinically insignificant when homocysteine is normal. It is the homocysteine level that matters, not the genotype.

When to test homocysteine

• Family history of early cardiovascular disease (< 55 men, < 65 women)
• Recurrent miscarriage
• Deep vein thrombosis at a young age
• Fatigue + depression + high homocysteine

What to do if you carry a variant

Action depends on homocysteine, not genotype alone. If homocysteine > 10 μmol/L: 5-MTHF (methylfolate) 400–800 μg + methylcobalamin (B12) 500 μg + P5P (B6) 20 mg daily. Limit alcohol and excess coffee. Emphasise leafy greens — the natural folate source.