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.