Gene guide
MTHFR gene: what C677T and A1298C mean for folate and homocysteine
MTHFR makes the enzyme that turns folate into its active form, methylfolate. Two common variants, C677T and A1298C, slow the enzyme down. They are very common, often harmless, and easy to check in 23andMe or AncestryDNA raw data.
- Full name
- Methylenetetrahydrofolate reductase
- Chromosome
- 1 (1p36.22)
- Role
- Makes 5-methyltetrahydrofolate (methylfolate), the folate form used to recycle homocysteine into methionine
- Common variants
- C677T (rs1801133) and A1298C (rs1801131)
- In raw DNA data
- Both variants are on 23andMe, AncestryDNA and most other consumer chips
What does the MTHFR gene do?
MTHFR (methylenetetrahydrofolate reductase) carries out one step in the folate cycle: it converts 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate, usually called methylfolate. Methylfolate then hands its methyl group to homocysteine, with vitamin B12 as a helper, turning it back into the amino acid methionine. Methionine becomes SAMe, the body's main methyl donor, used for making neurotransmitters, phospholipids and creatine and for regulating genes.
The enzyme needs riboflavin (vitamin B2), in the form of FAD, to work. That detail matters for the most common variant, as explained below.
MTHFR C677T and A1298C
C677T (rs1801133) changes one amino acid (alanine to valine at position 222) and makes the enzyme less stable, or "thermolabile". In the study that first described it, people with one copy had about 65% of normal enzyme activity and people with two copies (the TT genotype) about 30%, and TT carriers had higher homocysteine levels (Frosst 1995). Roughly 10–15% of people of European descent, and more in some Hispanic populations, are TT.
A1298C (rs1801131) has a milder effect on its own. It matters most in combination: people with one copy of each variant (compound heterozygotes) show lower enzyme activity than either variant alone (van der Put 1998).
Having one or both variants is common and is not a disease. What it changes is how much the folate cycle depends on a good supply of folate, riboflavin and vitamin B12.
MTHFR and health: what the evidence says
The best-established effect is on homocysteine: TT carriers tend to have higher levels, especially when folate intake is low. Mild elevations of homocysteine have been linked with cardiovascular disease, and the C677T variant has been studied as a risk factor for neural tube defects when the mother carries it.
Many other claims online go further than the evidence. MTHFR variants on their own are not considered a cause of blood clots, and major medical groups advise against MTHFR testing to explain clotting or recurrent pregnancy loss (Moll and Varga 2015). Your MTHFR genotype is best read alongside an actual homocysteine blood test, not instead of one.
What people with MTHFR variants can do
- Get folate from food. Leafy greens, legumes and liver are rich in natural folate. Fortified foods and standard folic acid supplements still work for most people with MTHFR variants.
- Consider methylfolate. Some people prefer methylfolate (5-MTHF) because it skips the MTHFR step. Discuss the dose with your doctor, especially in pregnancy.
- Check riboflavin. In people with the TT genotype, a low dose of riboflavin (1.6 mg a day) lowered homocysteine, while it had no effect in other genotypes (McNulty 2006).
- Keep B12 adequate. The same reaction that uses methylfolate needs vitamin B12.
- Test, don't guess. A homocysteine blood test tells you whether your folate cycle is actually under strain.
How to check your MTHFR status
If you have tested with 23andMe, AncestryDNA, MyHeritage or a similar service, your raw data file already contains both MTHFR variants. Upload it to NutraHacker and the free Detoxification and Methylation Report shows your C677T and A1298C genotypes, what each means and possible mitigation strategies, alongside other methylation genes such as MTR, MTRR, COMT and CBS. If you haven't downloaded your file yet, see how to download 23andMe raw data or AncestryDNA raw data.
Key MTHFR variants
| Variant | Also called | What it does |
|---|---|---|
| rs1801133 | C677T, A222V | Less stable enzyme. Two copies (TT) leave about 30% of normal activity and tend to raise homocysteine, especially with low folate or riboflavin. |
| rs1801131 | A1298C, E429A | Milder reduction in activity. Most relevant combined with one copy of C677T. |
NutraHacker reports that include MTHFR
- Complete Mutation Nutrition Report
- Histamine/Allergy Panel
- Fitness and Injury Report
- Lactation Report
Every raw DNA upload also gets a free Detoxification and Methylation Report, genome imputation and a Superhuman traits report. See what you can do with raw DNA data.
Related reading
- MTHFR C677T (rs1801133): complete guide
- MTHFR A1298C (rs1801131)
- Folic acid in NutraPedia
- Vitamin B2 (riboflavin) in NutraPedia
- Vitamin B12 in NutraPedia
- MTHFD1, another folate-cycle gene
- Free MTHFR analysis from your raw DNA data
- Free methylation report compared
Frequently asked questions
What is an MTHFR mutation?
Usually it means one of two common variants, C677T or A1298C, that make the MTHFR enzyme work more slowly. They are inherited, very common and are not a disease in themselves.
Is MTHFR C677T bad?
Two copies (TT) reduce enzyme activity to roughly 30% of normal and tend to raise homocysteine when folate or riboflavin intake is low. Many TT carriers have normal homocysteine with a good diet. A blood test shows whether it affects you.
Should I take methylfolate if I have an MTHFR variant?
Folic acid works for most people, but some prefer methylfolate because it does not need the MTHFR step. Ask your doctor, particularly if you are pregnant or planning a pregnancy, and make sure vitamin B12 is adequate too.
Can I find my MTHFR status in 23andMe data?
Yes. Both rs1801133 (C677T) and rs1801131 (A1298C) are in 23andMe and AncestryDNA raw data. NutraHacker's free methylation report reads them for you.
Do MTHFR variants cause blood clots?
Not on their own. Current guidance says MTHFR variants are not a meaningful clotting risk factor and testing them to explain clots is not recommended.
References
- Frosst P, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10(1):111-3. PubMed 7647779
- van der Put NM, et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet. 1998;62(5):1044-51. PubMed 9545395
- McNulty H, et al. Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphism. Circulation. 2006;113(1):74-80. PubMed 16380544
- Moll S, et al. Homocysteine and MTHFR Mutations. Circulation. 2015;132(1):e6-9. PubMed 26149435