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MTHFR

methylenetetrahydrofolate reductase

The MTHFR gene provides instructions for an enzyme essential in processing folate and amino acids, influencing key metabolic pathways related to health. The MTHFR gene encodes the methylenetetrahydrofolate reductase enzyme, which is critical for converting one form of folate into another.

Chromosome 1p36.22 Polygenic HGNC:7436 Tier B
MTHFR 1p36.22 p arm q arm 1

MTHFR is located on the short (p) arm of chromosome 1, at band 1p36.22. Arm ratio per GRCh38 - banding schematic.

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Clinical tests that include this

Carrier Screening panel
MTHFR is 1 of 1,008 genes on this panel
Expanded carrier screening for recessive and X-linked conditions

Overview

The MTHFR gene, or methylenetetrahydrofolate reductase, is a fundamental component of human metabolism. It directs the production of an enzyme that is indispensable for the folate cycle, a series of biochemical reactions that process vitamin B9, also known as folate [PMID:10484769]. This enzyme's proper function is necessary for a range of bodily processes, including DNA synthesis and repair, as well as the metabolism of certain amino acids.

Variations within the MTHFR gene can influence the efficiency of this enzyme, potentially affecting an individual's metabolic capacity [PMID:11139242]. Due to its central role in folate metabolism, the MTHFR gene is of interest in discussions surrounding conditions where folate pathways are implicated.

What the gene does

The MTHFR gene is responsible for synthesising the enzyme methylenetetrahydrofolate reductase. This enzyme plays a crucial role in the metabolism of amino acids, which are the fundamental building blocks of proteins. Specifically, the methylenetetrahydrofolate reductase enzyme is involved in a key chemical reaction within the folate pathway, which relies on vitamin B9 (folate).

This enzyme facilitates a biochemical transformation where 5,10-methylenetetrahydrofolate is changed into 5-methyltetrahydrofolate [PMID:9399936]. The converted compound becomes the main folate variant present in circulation. This active folate form is then necessary for the multi-step enzymatic process that transforms the amino acid homocysteine into another essential amino acid, methionine. Methionine is subsequently utilised by the body for the construction of proteins and the creation of other vital biological compounds.

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Chromosome location

The MTHFR gene is situated on chromosome 1 at position 1p36.22. This chromosomal address indicates its precise location within the human genome.

Protein structure

The MTHFR protein consists of 656 amino acids. Structural analysis indicates a Disordered (Region) spanning amino acids 1-44. This region, lacking a fixed three-dimensional structure, may be involved in protein-protein interactions or regulatory functions, allowing for flexibility in its interactions with other molecules.

Key variants

Genetic changes within the MTHFR gene can alter the efficiency of the methylenetetrahydrofolate reductase enzyme. These variations, which include single nucleotide polymorphisms (SNPs), can impact the enzyme's ability to process folate and metabolise homocysteine [PMID:11992261]. Polymorphisms within the MTHFR gene may modify or diminish the activity of the methylenetetrahydrofolate reductase. The 677C>T polymorphism is one of the most widely studied and common variants.

965
Total variants catalogued in ClinVar
View all on ClinVar →
200 Pathogenic / Likely pathogenic 238 Uncertain significance 488 Benign / Likely benign 39 Conflicting or other

Sample of pathogenic variants

10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.

Variant (HGVS) Protein change Classification Evidence Associated condition
c.1011del
Deletion
 p.Met338fs Pathogenic/Likely pathogenic ★★☆☆ Homocystinuria due to methylene tetrahydrofolate reductase deficiency
c.1013T>C
single nucleotide variant
 p.Met338Thr Pathogenic/Likely pathogenic ★★☆☆ Homocystinuria due to methylene tetrahydrofolate reductase deficiency
c.1015T>G
single nucleotide variant
 p.Trp339Gly Pathogenic/Likely pathogenic ★★☆☆ Homocystinuria due to methylene tetrahydrofolate reductase deficiency
c.1033C>T
single nucleotide variant
 p.Arg345Cys Pathogenic/Likely pathogenic ★★☆☆ Homocystinuria due to methylene tetrahydrofolate reductase deficiency
c.1069C>T
single nucleotide variant
 p.Arg357Cys Pathogenic/Likely pathogenic ★★☆☆ Neural tube defects, folate-sensitive
c.1070G>A
single nucleotide variant
 p.Arg357His Pathogenic/Likely pathogenic ★★☆☆ Homocystinuria due to methylene tetrahydrofolate reductase deficiency
c.1072C>T
single nucleotide variant
 p.Arg358Ter Pathogenic ★★☆☆ Homocystinuria due to methylene tetrahydrofolate reductase deficiency
c.1121dup
Duplication
 p.Tyr374Ter Pathogenic/Likely pathogenic ★★☆☆ Homocystinuria due to methylene tetrahydrofolate reductase deficiency
c.1130G>A
single nucleotide variant
 p.Arg377His Pathogenic/Likely pathogenic ★★☆☆ Homocystinuria due to methylene tetrahydrofolate reductase deficiency
c.1142G>A
single nucleotide variant
 p.Trp381Ter Pathogenic ★★☆☆ Neural tube defects, folate-sensitive

Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.

Associated conditions

Genetic variations in the MTHFR gene have been linked to a spectrum of health conditions, primarily those related to impaired folate metabolism. The MTHFR C677T (homozygous) variant is recognised in databases. Furthermore, some studies indicate that MTHFR polymorphisms are associated with a slightly increased risk of neural tube defects, which are birth defects affecting the brain and spinal cord [PMID:10484769]. These associations underscore the importance of the MTHFR enzyme in maintaining normal physiological processes.

UK clinical status

In the UK, the MTHFR gene is included in several NHS Genomic Medicine Service panels, indicating its recognised clinical relevance. It is part of panels for Cerebral folate deficiency, DDG2P, Early onset or syndromic epilepsy, Intellectual disability, Leukodystrophy, adult onset (under an R62 sub-panel), and Likely inborn error of metabolism (under an R98 sub-panel). Additionally, it is reviewed within the Undiagnosed metabolic disorders panel, reflecting its role in metabolic pathways and associated disorders.

Green-listed
High evidence · clinically actionable in NHS testing
Included in NHS GMS signed-off panels
Leukodystrophy, adult onset · R62 NHS GMS → Likely inborn error of metabolism · R98 NHS GMS → DDG2P NHS GMS → Early onset or syndromic epilepsy NHS GMS → Intellectual disability NHS GMS →
NHS Genomic Medicine Service Jeen carrier screening

Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory

Diet & lifestyle considerations

Research suggests that certain lifestyle factors can interact with MTHFR gene variants, particularly concerning folate status. Maintaining a balanced diet rich in natural folate sources, such as leafy green vegetables, legumes, and fortified grains, is generally recommended for the population [PMID:11139242]. Some studies indicate that adequate dietary folate intake may help support metabolic pathways influenced by MTHFR enzyme activity. However, specific dietary recommendations should always be discussed with a healthcare professional.

Supplement considerations

Due to the MTHFR enzyme's role in folate metabolism, some individuals with specific MTHFR variants may consider folate supplementation. It is crucial to consult with a healthcare provider before starting any supplementation, as they can provide personalised advice based on an individual's specific health needs and genetic profile. There is no conclusive evidence that folate supplements prevent neural tube defects or other MTHFR-associated conditions.

Frequently asked questions

What is the MTHFR gene?

The MTHFR gene provides instructions for creating the methylenetetrahydrofolate reductase enzyme. This enzyme is crucial for processing folate (vitamin B9) and plays a key role in converting homocysteine to methionine, an essential amino acid.

What does the MTHFR enzyme do?

The MTHFR enzyme converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. This conversion is vital for the body's ability to process homocysteine and produce methionine, which is used for protein synthesis and other important biological functions.

Are MTHFR variants common?

Some MTHFR gene variants, such as MTHFR C677T, are relatively common in the general population. These variants can influence the efficiency of the MTHFR enzyme, potentially affecting an individual's metabolic capacity for folate.

What conditions are associated with MTHFR gene variants?

MTHFR gene variants have been associated with various conditions, including MTHFR C677T (homozygous) and an increased risk of neural tube defects. These associations are often linked to impaired folate metabolism caused by reduced enzyme activity.

Should I take folate supplements if I have an MTHFR variant?

While MTHFR variants can affect folate metabolism, any decision regarding folate supplementation should be made in consultation with a healthcare professional. They can provide advice tailored to your individual health status and genetic profile.

References

  1. ACOG Practice Bulletin No. 197 Summary: Inherited Thrombophilias in Pregnancy. Obstetrics and gynecology. 2018. PMID: 29939934
  2. Liu F, Silva D, Malone MV. MTHFR A1298C and C677T Polymorphisms Are Associated with Increased Risk of Venous Thromboembolism: A Retrospective Chart Review Study. Acta haematologica. 2017. PMID: 29212064
  3. Levin BL, Varga E. MTHFR: Addressing Genetic Counseling Dilemmas Using Evidence-Based Literature. Journal of genetic counseling. 2016. PMID: 27130656
  4. Yadav U, Kumar P, Yadav SK. "Polymorphisms in folate metabolism genes as maternal risk factor for neural tube defects: an updated meta-analysis". Metabolic brain disease. 2015. PMID: 25005003
  5. Kumar A, Kumar P, Prasad M. Association of C677T polymorphism in the methylenetetrahydrofolate reductase gene (MTHFR gene) with ischemic stroke: a meta-analysis. Neurological research. 2015. PMID: 25591425
  6. Xie SZ, Liu ZZ, Yu JH. Association between the MTHFR C677T polymorphism and risk of cancer: evidence from 446 case-control studies. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 2015. PMID: 26081619
  7. Moll S, Varga EA. Homocysteine and MTHFR Mutations. Circulation. 2015. PMID: 26149435
  8. Trimmer EE. Methylenetetrahydrofolate reductase: biochemical characterization and medical significance. Current pharmaceutical design. 2013. PMID: 23116396
  9. Hickey SE, Curry CJ, Toriello HV. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genetics in medicine : official journal of the American College of Medical Genetics. 2013. PMID: 23288205
  10. Zhang T, Lou J, Zhong R. Genetic variants in the folate pathway and the risk of neural tube defects: a meta-analysis of the published literature. PloS one. 2013. PMID: 23593147
  11. Bhargava S, Ali A, Parakh R. Higher incidence of C677T polymorphism of the MTHFR gene in North Indian patients with vascular disease. Vascular. 2012. PMID: 22375042
  12. Yan L, Zhao L, Long Y. Association of the maternal MTHFR C677T polymorphism with susceptibility to neural tube defects in offsprings: evidence from 25 case-control studies. PloS one. 2012. PMID: 23056169
  13. Urreizti R, Moya-García AA, Pino-Ángeles A. Molecular characterization of five patients with homocystinuria due to severe methylenetetrahydrofolate reductase deficiency. Clinical genetics. 2010. PMID: 20236116
  14. Khandanpour N, Willis G, Meyer FJ. Peripheral arterial disease and methylenetetrahydrofolate reductase (MTHFR) C677T mutations: A case-control study and meta-analysis. Journal of vascular surgery. 2009. PMID: 19157768
  15. Trabetti E. Homocysteine, MTHFR gene polymorphisms, and cardio-cerebrovascular risk. Journal of applied genetics. 2008. PMID: 18670064
  16. Sibani S, Christensen B, O'Ferrall E. Characterization of six novel mutations in the methylenetetrahydrofolate reductase (MTHFR) gene in patients with homocystinuria. Human mutation. 2000. PMID: 10679944
  17. Botto LD, Yang Q. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. American journal of epidemiology. 2000. PMID: 10791559
⚠ Draft content. This page has been flagged for manual clinical review and may contain gaps or inaccuracies. Speak with a qualified healthcare professional before acting on any information here.
Educational content. This page is not medical or genetic advice, is not individually reviewed by a clinician for each reader, and should not replace a consultation with a qualified healthcare professional or genetic counsellor. If you are considering genetic testing or acting on a test result, book a consultation.
Data sources Last updated 16 August 2026. Content compiled from HGNC · MedlinePlus Genetics · ClinGen · Genomics England PanelApp · NHS National Genomic Test Directory · ClinVar · UniProt · AlphaFold .