What is MTHFR?
MTHFR stands for MethyleneTetraHydroFolate Reductase which is an enzyme that helps your body use folate. MTHFR gives your body instructions to make the MTHFR enzyme. Genes are the instructions for our cells to do all their jobs. Folate is a type of Vitamin B that is needed for healthy cell growth and function. Folate is also important for early pregnancy when the spine and brain develop. The recommended daily amount of folate for adults is 400 micrograms (mcg). People who are planning pregnancy or could become pregnant should get 400 to 800 mcg of folic acid a day. In the United States, the FDA requires food companies to add folic acid, a synthetic form of folate, to most grain products like bread and cereal. Most adults do not need extra supplementation unless advised by a provider.
Common MTHFR Variants
The MTHFR gene is like the recipe for the MTHFR enzyme. We have two copies of every gene, one from one parent and one from the other parent. Sometimes we have spelling changes in these genes. Most of the time these spelling changes, or variants, do not cause disease. They are changes that make us unique humans. Sometimes these variants can change the recipe so much that your body can no longer make the enzyme or enough of the enzyme. When this happens, we can see disease in people.
There are two common variants in the MTHFR gene. The C677T MTHFR variant is extremely common in the United States. About one third of White or Hispanic people have at least one copy of this variant. Another common variant is the A1298C variant. Approximately one in three people have at least one copy of this variant. You may have one or two of these variants. Most people with common MTHFR variants are healthy and do not develop disease because of these variants alone. Research has explored possible links between MTHFR variants and several conditions, but results are inconsistent, and these conditions have many causes. However, these common variants may slightly increase health risks, especially when combined with poor nutrition, chronic inflammation, stress on the body, or environmental factors.
Medical Conditions and MTHFR
Individuals with MTHFR common variants, especially when two C677T variants are present, may have an increased risk for heart disease and stroke, particularly when additional risk factors are present (e.g., smoking, hypertension, diabetes, vitamin B12 or folate deficiency). These variants do not cause heart or blood vessel disease by themselves, but they may make it easier for other risk factors to lead to disease. Other conditions such as diabetes, autism, Alzheimer’s, and pregnancy complications have been associated with these common variants. However, these conditions are best understood as one small part of how metabolism and inflammation affect health, rather than a single main cause.
Rare MTHFR-Related Disease
There are very rare cases of individuals with homocystinuria due to having two pathogenic variants in the MTHFR gene. Pathogenic variants are gene changes that are known to cause disease. They change the gene, or recipe, enough so that it no longer functions properly. When this happens, the body cannot make a working MTHFR enzyme, which leads to a build-up of a substance called homocysteine. People with homocystinuria have high levels of homocysteine in their blood and urine, and can have seizures, psychiatric manifestations, intellectual disability, motor abnormalities, and other neurological symptoms. The two common MTHFR variants are not associated with homocystinuria.
Why do people get tested?
Many health organizations such as American College of Obstetricians and Gynecologists (ACOG), American Academy of Family Physicians (AAFP), American College of Medical Genetics and Genomics (ACMG), and National Society of Genetic Counselors (NSGC) do not recommended testing for variants in the MTHFR gene unless homocystinuria is suspected. This type of testing cannot predict who will develop complex conditions that have many causes. For most people, knowing their MTHFR status does not change their health or medical care. A healthy diet, routine care, and addressing known risk factors remain the most important steps.
Some people get tested as part of functional medicine. Because functional medicine takes a holistic approach to health, knowing your genetic MTHFR status may be helpful for your provider. Some people with the common C677T and A1298C variants may feel better with additional folate in their diet. Testing can also be used in identifying patients who may benefit from closer monitoring of homocysteine, folate, and vitamin B12 status, and from targeted nutritional or preventive strategies. Genetic testing should always be interpreted by a trained medical provider.
Other individuals chose to pursue testing via direct-to-consumer testing. These results may be unclear or misleading without medical guidance. If you are interested in MTHFR testing, we recommend working with a healthcare provider who can offer personalized advice.
References
American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins–Obstetrics (2018). ACOG Practice Bulletin No. 197: Inherited Thrombophilias in Pregnancy. Obstetrics and gynecology, 132(1), e18–e34. https://journals.lww.com/00006250-201807000-00055
Araszkiewicz, A. F., Jańczak, K., Wójcik, P., Białecki, B., Kubiak, S., Szczechowski, M., & Januszkiewicz-Lewandowska, D. (2025). MTHFR Gene Common variants: A Single Gene with Wide-Ranging Clinical Implications-A Review. Genes, 16(4), 441. https://www.mdpi.com/2073-4425/16/4/441
Baglin, T., Gray, E., Greaves, M., Hunt, B. J., Keeling, D., Machin, S., Mackie, I., Makris, M., Nokes, T., Perry, D., Tait, R. C., Walker, I., Watson, H., & British Committee for Standards in Haematology (2010). Clinical guidelines for testing for heritable thrombophilia. British journal of haematology, 149(2), 209–220. https://doi.org/10.1111/j.1365-2141.2009.08022.x
Don’t test women for MTHFR mutations. American Academy of Family Physicians. (2020, March 30). https://www.aafp.org/afp/collections/choosing-wisely/412
Hickey, S. E., Curry, C. J., & Toriello, H. V. (2013). ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genetics in medicine : official journal of the American College of Medical Genetics, 15(2), 153–156. https://linkinghub.elsevier.com/retrieve/pii/S1098360021009163
Levin, B.L. and Varga, E. (2016), MTHFR: Addressing Genetic Counseling Dilemmas Using Evidence-Based Literature. J Genet Counsel, 25: 901-911. https://onlinelibrary.wiley.com/doi/10.1007/s10897-016-9956-7
Nefic, H., Mackic-Djurovic, M., & Eminovic, I. (2018). The Frequency of the 677C>T and 1298A>C Common variants in the Methylenetetrahydrofolate Reductase (MTHFR) Gene in the Population. Medical archives (Sarajevo, Bosnia and Herzegovina), 72(3), 164–169. https://doi.org/10.5455/medarh.2018.72.164-169
Umair M, Alfadhel M. Homocystinuria due to Deficiency of N(5,10)-Methylenetetrahydrofolate Reductase Activity. 2025 May 29 [Updated 2025 Dec 4]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK615089/
About the Author
Margaret Erpelding, CGC
Margaret Erpelding, CGC, is a Certified Genetic Counselor at Minnesota Women’s Care, specializing in reproductive, prenatal, and cancer genetics. She provides personalized, patient-centered guidance to help individuals and families better understand genetic risks, screening results, and testing options.
Margaret works closely with patients during pregnancy planning, following abnormal screening results, and when evaluating family history of genetic conditions. She is known for her clear, compassionate approach, helping patients feel informed and confident in their decisions.
If you or someone you know is interested in genetic counseling or has questions about genetic testing, call 651-600-3035 or click Book Now.