When a baby is conceived, they inherit 2 copies of every gene; one from each parent. MTHFR is the name of one particular gene, out of thousands, that each person has 2 copies of. The gene codes for an enzyme called “methylenetetrahydrofolate reductase”, which is responsible for the conversion of dietary folate (vitamin B-9 or folic acid) into its biologically active form, L-methylfolate, to be used by your cells.

There is a certain version of this genetic code that makes the right amount of working enzyme so that every time folate or folic acid (the synthetic version of folate often in supplements or added to fortified foods) is consumed, cells convert it to L-methylfolate and continue their biological processes efficiently.

Unfortunately, many people have a slight change to the code in either one or both copies of their MTHFR gene. A difference in a code for a certain gene is known as a “mutation”, “variant”, or “polymorphism” depending on the context.

Even if only one nucleotide in the MTHFR gene code is different, the enzyme may either be produced incorrectly or be produced in such a low abundance that the normal, downstream biological processes cannot continue at a healthy rate.

The severity of this biological hold-up depends on where in the gene code the difference occurs, and whether the person has inherited one or two copies of a dysfunctional gene [1].

Some of these changes to the code are more common than others. At least 40 different rare mutations have been documented in the MTHFR gene, but there are 2 variants that are strikingly common [2].

The C677T mutation is the most common, commonly studied, and thought to be very biologically important, due to the number of diseases and defects it has been associated with [1].

C677T and another variant, A1298C, have both been implicated in MTHFR enzyme deficiency associated with hyperhomocysteinemia (too-high homocysteine levels in the blood) (link here to the high homocysteine article), which has been previously implicated as a risk factor for cardiovascular disease, among other maladies [3].

Furthermore, the presence of both of these variants, with and without elevated homocysteine levels, have been studied in relation to multifactorial disorders:

  • Cardiovascular disease
  • Thrombosis
  • Pregnancy complications or recurrent pregnancy loss
  • Neural tube defects
  • Cancer risk
  • Psychiatric disease
  • Neurodevelopmental disorders [3].

Studies also suggest that women with two copies of the C677T gene variant (homozygous) are twice as likely to have a child with a neural tube defect [2].

Who is affected by MTHFR?

Interestingly, although variations in the MTHFR gene are quite common, they are not uniformly distributed worldwide. Certain regions of the world see far more cases of MTHFR-related deficiencies than others.

It has been estimated that about 50% of people carry at least one copy of a less-effective MTHFR gene variant [4]. And although more than 40 different polymorphisms of the gene have been identified, 24% of the global population is likely to carry the C677T mutation specifically.

Continentally speaking, C677T is least common in Africans (at a frequency of 10.3%) and more common in North Americans and Europeans (31.2% and 34%, respectively), with South America, Asia, and Australia falling in between.

An example of such was demonstrated in a study that stated the level of UV radiation in a region was a stronger predictor of C677T than latitude [6]. We also know that environmental toxins can have epigenetic effects on methylation and MTHFR expression.

It is important to remember that these factors may play a significant role in the health repercussions of MTHFR polymorphisms, depending on where and how you live.


  1. Yadav, Upendra, et al. “Distribution of MTHFR C677T gene polymorphism in healthy North Indian population and an updated meta-analysis.” Indian Journal of Clinical Biochemistry 32.4 (2017): 399-410.
  2. NIH. MTHFR gene variant. Genetic and Rare Diseases Information Center. Accessed May 6, 2019. https://rarediseases.info.nih.gov/diseases/10953/mthfr-gene-mutation
  3. Levin, Brooke Levenseller, and Elizabeth Varga. “MTHFR: addressing genetic counseling dilemmas using evidence-based literature.” Journal of genetic counseling 25.5 (2016): 901-911.
  4. Kaiser Permanente. “Basic Information About the MTHFR Gene.” The Permanente Medical Group, Inc. Copyright 2015, last reviewed 2018. https://mydoctor.kaiserpermanente.org/ncal/Images/GEN_MTHFR_tcm63-938252.pdf
  5. Contreras-Cubas, Cecilia, et al. “Heterogenous distribution of MTHFR gene variants among Mestizos and diverse Amerindian groups from Mexico.” PloS one 11.9 (2016): e0163248.
  6. Yafei, Wang, et al. “Is the prevalence of MTHFR C677T polymorphism associated with ultraviolet radiation in Eurasia?.” Journal of human genetics 57.12 (2012): 780.