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What is MTHFR?

October 15, 2023

MTHFR stands for methylenetetrahydrofolate reductase. It is an enzyme that plays a critical role in folate metabolism and DNA methylation.

The Science Behind MTHFR

Folate, also known as vitamin B9, is an essential nutrient that is obtained through the diet. Folate is critical for DNA synthesis and methylation reactions. Methylation is a process that attaches methyl groups to DNA, proteins, lipids and other molecules. This impacts gene expression, protein function, hormone balance and detoxification[1].

MTHFR converts 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate. 5-methyltetrahydrofolate is the primary circulating form of folate in the body and the primary methyl donor for the vitamin B12-dependent remethylation of homocysteine to methionine[2].

Methionine is converted into S-adenosylmethionine (SAMe), which is involved in over 200 methylation reactions, including DNA methylation. Therefore, MTHFR plays a key role in linking folate status to DNA methylation status[3].

MTHFR Mutations

The MTHFR gene provides instructions for making the MTHFR enzyme. Certain mutations in the MTHFR gene can decrease MTHFR enzyme activity, resulting in reduced 5-methyltetrahydrofolate and increased homocysteine levels[4].

The two most clinically relevant MTHFR mutations are:

  • C677T – This mutation results in 30-50% reduced MTHFR enzyme activity[5]. Individuals with one copy of the mutation (heterozygous) have slightly elevated homocysteine levels. Individuals with two copies (homozygous) have significantly elevated homocysteine[6].
  • A1298C – This mutation results in 30-40% reduced MTHFR activity, but does not affect homocysteine levels[7]. Compound heterozygotes (one copy of each mutation) have an estimated 60% reduced MTHFR activity[8].

Effects of MTHFR Mutations

MTHFR mutations can potentially impact health in several ways:

  • DNA hypomethylation – Lower MTHFR activity reduces methyl groups available for DNA methylation. This can lead to altered gene expression[9].
  • Increased homocysteine – (with C677T mutation) Elevated homocysteine is a risk factor for cardiovascular disease and pregnancy complications[10].
  • Altered folate distribution – The C677T mutation results in more folate being converted to tetrahydrofolate rather than 5-methyltetrahydrofolate[11]. This reduces availability of 5-methyltetrahydrofolate.
  • Increased risk for certain conditions – MTHFR mutations have been associated with increased risk for neural tube defects, psychiatric disorders, cancer, pregnancy complications and cardiovascular disease[12]. However, results have been inconsistent across studies.

Testing for MTHFR Mutations

Genetic testing can identify MTHFR mutations. This may be beneficial for those with a personal or family history of related health conditions. However, the presence of MTHFR mutations does not necessarily mean an individual will develop health problems. Lifestyle and environmental factors also play a key role[13].

If MTHFR mutations are identified, steps can be taken to minimize potential risks, such as optimizing folate status, reducing homocysteine levels and ensuring adequate intake of other B vitamins involved in one-carbon metabolism[14]. Genetic counseling is recommended to interpret test results and determine the best course of action.


MTHFR is a critical enzyme involved in folate metabolism and DNA methylation. Mutations in the MTHFR gene can impact enzyme activity and are associated with certain health conditions. Genetic testing can identify such mutations, allowing for targeted nutritional interventions to help mitigate potential risks. However, more research is needed to fully establish the effects of MTHFR mutations on long-term health outcomes.


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