MTHFR Gene Explained: What Your C677T and A1298C Results Mean
Separating science from supplement-industry hype
By GenomeInsight Science Team
Key Takeaways
- MTHFR C677T (TT) reduces enzyme activity to ~30%, but this is often compensated by adequate dietary folate
- The most actionable step is checking your homocysteine level — if normal, MTHFR status is largely irrelevant
- ACMG recommends AGAINST routine MTHFR testing — most claims about MTHFR are overhyped
- If homocysteine IS elevated, methylfolate (5-MTHF) + B12 + B6 can bring it down
- All women planning pregnancy should take 400-800 mcg folate regardless of MTHFR status
What is MTHFR?
MTHFR (methylenetetrahydrofolate reductase) is an enzyme that converts folate (vitamin B9) into its active form, 5-methyltetrahydrofolate (5-MTHF). This active folate is essential for a process called methylation — a biochemical reaction that happens billions of times per second in your body.
Methylation is involved in:
- •DNA repair and synthesis — building and maintaining your genetic material
- •Homocysteine metabolism — converting the amino acid homocysteine back to methionine
- •Neurotransmitter production — making serotonin, dopamine, and norepinephrine
- •Detoxification — processing and eliminating toxins
- •Gene expression — turning genes on and off (epigenetics)
Two common variants in the MTHFR gene — C677T (rs1801133) and A1298C (rs1801131) — can reduce enzyme activity, affecting how efficiently your body processes folate.
The Two Key MTHFR Variants
C677T (rs1801133) — The More Significant Variant
| Genotype | Enzyme Activity | Population Frequency |
|---|---|---|
| CC (normal) | 100% | ~45% of population |
| CT (heterozygous) | ~65% activity | ~42% of population |
| TT (homozygous) | ~30% activity | ~13% of population |
The TT genotype significantly reduces enzyme function, leading to higher homocysteine levels — especially if dietary folate is low.
A1298C (rs1801131) — The Less-Studied Variant
| Genotype | Enzyme Activity | Effect |
|---|---|---|
| AA (normal) | 100% | — |
| AC (heterozygous) | ~80-85% activity | Mild reduction |
| CC (homozygous) | ~60-70% activity | Moderate reduction |
A1298C has a smaller effect on enzyme activity. The combination of C677T heterozygous + A1298C heterozygous (compound heterozygous) has effects similar to being C677T homozygous.
What Does This Mean for Your Health?
Elevated Homocysteine
- •Increased cardiovascular disease risk (1.2-1.6× per 5 μmol/L increase)
- •Slightly increased risk of neural tube defects in pregnancy
- •Potential association with recurrent pregnancy loss (evidence is mixed)
What the science does NOT support:
- •❌ MTHFR variants do NOT cause "methylation disorders" as a disease entity
- •❌ MTHFR testing is NOT recommended by ACMG for thrombophilia evaluation
- •❌ Most people with MTHFR variants have perfectly normal homocysteine levels
- •❌ Having an MTHFR variant does NOT mean you need expensive methylfolate supplements
The American College of Medical Genetics (ACMG) Position: In 2013, ACMG explicitly recommended AGAINST clinical testing for MTHFR variants, stating that common MTHFR polymorphisms should not be included in thrombophilia panels or recurrent pregnancy loss workups.
Evidence-Based Recommendations
If you have MTHFR TT (rs1801133):
1. Get your homocysteine checked — a simple blood test. If it's normal (<12 μmol/L), no action needed. 2. Ensure adequate folate intake — 400-800 mcg/day from food and/or supplements. Leafy greens, legumes, and fortified foods are excellent sources. 3. Consider methylfolate — if your homocysteine IS elevated, methylfolate (5-MTHF) bypasses the MTHFR enzyme. But standard folic acid works fine for most people too. 4. B12 and B6 — these are cofactors in the methylation cycle. Ensure adequate intake (~2.4 mcg B12/day, ~1.3 mg B6/day). 5. Pregnancy — all women planning pregnancy should take 400-800 mcg folate regardless of MTHFR status. Those with TT may benefit from methylfolate form specifically.
If you have CT (heterozygous):
- •Your enzyme activity is only mildly reduced (~65%). This is very common and rarely clinically significant.
- •Standard dietary folate intake is almost always sufficient.
- •No special supplements needed unless homocysteine is elevated.
Bottom line: MTHFR variants are extremely common (nearly half the population carries at least one copy of C677T). For most people, eating a balanced diet with adequate folate is all that's needed.
Medical Disclaimer: This article is for educational purposes only and does not constitute medical advice. Genetic information should be interpreted in the context of your full medical history by a qualified healthcare provider. Never change medications without consulting your doctor.
References
- [1]Hickey SE et al. (2013). ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 15(2):153-6.PubMed
- [2]Frosst P et al. (1995). A candidate genetic risk factor for vascular disease. Nat Genet. 10(1):111-3.PubMed
- [3]Homocysteine Studies Collaboration (2002). Homocysteine and risk of ischemic heart disease and stroke. JAMA. 288(16):2015-22.PubMed
- [4]Liew SC, Gupta ED (2015). Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism. J Med Genet. 52(1):1-16.
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