MTHFR Variants and Folate: What Testing Does and Does Not Show
Many people carry an MTHFR gene variant. What the gene does, what the American College of Medical Genetics said about testing, and what is and is not known about methylfolate.
Content last updated . This page has not been medically reviewed.
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Having an MTHFR variant is common and, on its own, does not mean you are ill or need a special supplement. If a test report or a seller tells you otherwise, ask your clinician or a genetic counselor to explain what it means for you. This page is information only. It does not tell anyone to start, stop or change a medicine or supplement, and it does not replace the folic acid advice given to people who could become pregnant (see Folic acid and folate before and during pregnancy).What the MTHFR gene does
MedlinePlus Genetics (US National Library of Medicine) explains that the MTHFR gene makes an enzyme that converts one form of folate into 5-methyltetrahydrofolate, the primary form of folate found in blood. [1] That form is needed to turn the amino acid homocysteine into methionine. [1]Common variants
The two best-studied variants are called 677C>T and 1298A>C. They can reduce the enzyme's activity and cause a mild rise in blood homocysteine. [1] MedlinePlus says the 677C>T variant is common: an estimated 25 percent of Hispanics and 10 to 15 percent of North American whites have it in both copies of the gene. [1] Rare, severe changes in the gene have been found in people with a different condition, homocystinuria, in which the body cannot process homocysteine and methionine properly. [1]What testing does and does not show
| Question | What the source found | Strength of evidence |
|---|---|---|
| Should MTHFR testing be part of a routine clot (thrombophilia) work-up? | The American College of Medical Genetics and Genomics (ACMG, 2013) said testing has minimal clinical utility and should not be ordered as part of a routine evaluation for thrombophilia. [2] | Professional-body statement |
| Heart disease, clots, pregnancy loss | The ACMG said meta-analyses had disproven links between mild high homocysteine and coronary heart disease, and between MTHFR status and venous thromboembolism. [2] MedlinePlus says studies of other conditions have had mixed results. [1] | Mixed |
| Neural tube defects | Some studies found a small increased risk, but most people with the variants do not have affected children. [1] | Small association |
| Does knowing your result change what to take? | Proper evidence not found (see below). | None found |
| Methylfolate blood levels compared with folic acid | A single-dose crossover study in 677TT patients with coronary artery disease found higher bioavailability of 5-MTHF than folic acid, whatever the genotype. [3] This is a blood-level result, not a health outcome. | Biomarker only |
| Treatment-resistant depression | A 2026 systematic review found a potential link with some variants but conflicting evidence across studies. [4] | Mixed |
Proper evidence not found: for trials showing that choosing methylfolate instead of folic acid because of an MTHFR result improves health outcomes in people without a rare enzyme disorder. We searched PubMed for MTHFR with methylfolate, 5-MTHF and folic acid, genotype and supplementation, and found pharmacokinetic and condition-specific studies only. A genetic counseling review describes a wide spectrum of purported clinical implications for the variants and the prevalence of these polymorphisms. [5]
Related pages
L-methylfolate (5-MTHF) and Folate vs folic acid vs methylfolate.Frequently asked questions
Do I need an MTHFR test?
The ACMG said testing has minimal clinical utility and should not be a routine part of a thrombophilia work-up. [2] A clinician decides whether you have another reason.
Is an MTHFR variant rare?
No. MedlinePlus estimates about 25 percent of Hispanics and 10 to 15 percent of North American whites carry two copies of 677C>T. [1]
Does a variant mean I should take methylfolate instead of folic acid?
Proper evidence not found that this improves outcomes. One study showed higher blood levels from 5-MTHF than folic acid, which is not the same as a health benefit. [3]
Does it cause miscarriage or heart disease?
The ACMG said meta-analyses had disproven some links, and MedlinePlus describes mixed results for others. [2][1]
What if I am planning a pregnancy?
Ask your midwife or doctor. Official advice applies to everyone who could become pregnant. [6]
More details: evidence, limits and cautions
The details behind this page: cautions, limits of the evidence and where sources disagree. Open any note to read it.
How to read the evidence labels
Labels used on this page: established nutritional role, mixed, insufficient evidence, marketing claim and Proper evidence not found.
Cautions
- Do not stop folic acid if you are planning a pregnancy because of a test result. Official advice names all people who could become pregnant, not only those with certain genes. [6]
- Consumer and mail-order panels may report MTHFR as a "risk" or a reason to buy a product. Ask a clinician or genetic counselor what a label like that means for you; a product claim is a marketing claim, not a diagnosis.
- Homocysteine and vitamin B12 or folate blood levels can be checked by a clinician, but see Deficiency testing and its limits for why results need context.
- Quality varies between products: see Quality testing and certifications.
References
- MedlinePlus Genetics, US National Library of Medicine. MTHFR gene. Read 2026-10-23.
- Hickey SE, Curry CJ, Toriello HV. ACMG practice guideline: lack of evidence for MTHFR polymorphism testing. Genet Med 2013;15(2):153-156.
- Willems FF, et al. Pharmacokinetic study on the utilisation of 5-methyltetrahydrofolate and folic acid in patients with coronary artery disease. Br J Pharmacol 2004;141(5):825-830.
- Systematic review of MTHFR 677C>T and 1298A>C variants and treatment-resistant depression. Complex Psychiatry 2026;12.
- Levin BL, Varga E. MTHFR: addressing genetic counseling dilemmas using evidence-based literature. J Genet Couns 2016;25(5):901-911.
- US Preventive Services Task Force. Folic acid supplementation to prevent neural tube defects: reaffirmation recommendation statement. JAMA 2023;330(5):454-459.