What you carry at this position in your DNA and what research says about it.
Folate Processing: 10/10 evidence, 153 publications.
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Sample genotype (not yours): G/G
Typical Folate Processing and Homocysteine Levels
This genotype is associated with normal MTHFR enzyme activity and efficient folate metabolism. Homocysteine levels are typically kept within a healthy, normal range.
What this genotype means: Normal MTHFR enzyme activity; Typical homocysteine levels; Standard response to methotrexate.
Sample genotype (not yours): A/A
Significantly Reduced Folate Processing and Higher Homocysteine
Carrying two copies of the variant reduces MTHFR enzyme efficiency to about 30 percent. This is linked to elevated homocysteine levels, lower folate, and increased medication sensitivity.
What this genotype means: MTHFR enzyme efficiency reduced to 30 percent; Elevated blood homocysteine levels; High risk of methotrexate toxicity.
Sample genotype (not yours): G/A
Slightly Reduced Folate Processing Efficiency
Carrying one copy of the variant reduces MTHFR enzyme efficiency to about 65 percent. This can lead to slightly lower folate levels and a mild increase in homocysteine.
What this genotype means: MTHFR enzyme efficiency reduced to 65 percent; Slightly elevated homocysteine risk; Moderate risk of methotrexate side effects.
Gene function and biological role
Gene Function: The MTHFR gene provides instructions for making methylenetetrahydrofolate reductase, a critical enzyme in folate metabolism [1]. This enzyme converts a form of folate into 5-methyltetrahydrofolate, the primary active form of folate in the body [2]. This active folate is essential for converting the amino acid homocysteine into methionine, a building block for proteins and other vital compounds [1]. Methionine is further used to produce S-adenosylmethionine, which acts as the primary methyl donor for DNA methylation and cellular reactions [2]. Proper MTHFR function is therefore vital for maintaining healthy homocysteine levels and supporting overall cellular methylation [1].
Variant Impact: This variant, also known as C677T or Ala222Val, changes the amino acid alanine to valine at position 222 of the MTHFR enzyme [1]. This single-letter change alters the enzyme's structure, making it less stable and significantly reducing its activity [1]. The variant allele is highly common worldwide, with frequencies varying widely across different ancestries [3]. Individuals carrying this variant process folate less efficiently, which can lead to a buildup of homocysteine in the blood [1]. It is also widely studied for its impact on sensitivity to certain medications like methotrexate [3].
Key Insight: The MTHFR C677T variant reduces enzyme activity by up to 70 percent, yet its health impacts can often be completely managed or bypassed simply by ensuring adequate intake of active folate.
Location: MTHFR. Chromosome 1 · 1p36.22 · 11.8 Mb
Estimated prevalence by population
Global 53.9%; European 43.9%; African 78.9%; East Asian 48.8%; South Asian 72.6%; Americas 30.9%; Ashkenazi 29.1%; Finnish 58.4%; Middle Eastern 50.5%; Amish 26.7%.
Estimated GG genotype frequency.
Global 37.2%; European 44.7%; African 19.9%; East Asian 42.1%; South Asian 25.2%; Americas 49.4%; Ashkenazi 49.7%; Finnish 36.0%; Middle Eastern 41.1%; Amish 49.9%.
Estimated GA genotype frequency.
Global 9.0%; European 11.4%; African 1.2%; East Asian 9.1%; South Asian 2.2%; Americas 19.7%; Ashkenazi 21.2%; Finnish 5.5%; Middle Eastern 8.4%; Amish 23.4%.
Estimated AA genotype frequency.
Showing effects for G/G genotype
Nutrition & Metabolism
Vitamin & Mineral Metabolism
Folate Levels. Evidence: 10/10. Source: PMID 30339177. Typical Levels.
Blood Chemistry & Metabolites
Homocysteine Levels. Evidence: 10/10. Source: PMID 20031578. Typical Levels.
Pharmacogenomics
Immunosuppressant & Biologic Response
Methotrexate Toxicity. Evidence: 8/10. Source: PMID 40430876. Typical Risk.
Cardiovascular & Metabolic
Hypertension
Diastolic Blood Pressure. Evidence: 8/10. Source: PMID 39048560. Typical.
Blood Cell & Iron Traits
Deficiency Anemia. Evidence: 8/10. Source: PMID 39024449. Typical Risk.
Showing effects for A/A genotype
Folate Levels. Evidence: 10/10. Source: PMID 30339177. Significantly Lower.
Homocysteine Levels. Evidence: 10/10. Source: PMID 20031578. Significantly Elevated.
Methotrexate Toxicity. Evidence: 8/10. Source: PMID 40430876. High Risk.
Diastolic Blood Pressure. Evidence: 8/10. Source: PMID 39048560. Higher.
Deficiency Anemia. Evidence: 8/10. Source: PMID 39024449. Increased Risk.
Showing effects for G/A genotype
Folate Levels. Evidence: 10/10. Source: PMID 30339177. Slightly Lower.
Homocysteine Levels. Evidence: 10/10. Source: PMID 20031578. Slightly Elevated.
Methotrexate Toxicity. Evidence: 8/10. Source: PMID 40430876. Increased Risk.
Diastolic Blood Pressure. Evidence: 8/10. Source: PMID 39048560. Slightly Higher.
Deficiency Anemia. Evidence: 8/10. Source: PMID 39024449. Slightly Higher Risk.
What this genotype means for the people who carry it
Sample genotype: GG (Homozygous)
Carrying two copies of the reference allele ensures that the MTHFR enzyme functions at full capacity [1]. This allows the body to efficiently convert dietary folate and folic acid into its active, usable form [1]. Consequently, the conversion of homocysteine to methionine proceeds smoothly, maintaining low and healthy blood homocysteine levels [2]. This typical enzyme activity provides natural protection against vascular issues and neural tube defects associated with high homocysteine [3]. Additionally, individuals with this genotype show typical tolerance to folate-pathway medications like methotrexate, with a lower risk of drug-induced toxicity [4]. No dietary or supplemental adjustments are typically needed based on this genetic profile. Maintaining a balanced diet rich in natural folates is sufficient to support optimal methylation.
Normal MTHFR enzyme activity; Typical homocysteine levels; Standard response to methotrexate.
Sample genotype: AA (Homozygous)
Having two copies of the variant allele significantly compromises the stability of the MTHFR enzyme, reducing its activity to approximately 30 percent of normal [1]. This dramatic reduction impairs the body's ability to process folate, leading to lower active folate levels in the blood [2]. As a result, the conversion of homocysteine to methionine is slowed, which frequently causes elevated blood homocysteine levels [3]. High homocysteine is a recognized risk factor for cardiovascular issues and pregnancy complications, including neural tube defects [4]. This genotype is also strongly associated with a high risk of severe toxicity and side effects from methotrexate and other chemotherapy drugs [5].
MTHFR enzyme efficiency reduced to 30 percent; Elevated blood homocysteine levels; High risk of methotrexate toxicity; Increased risk of folate-deficiency anemia.
Sample genotype: GA (Heterozygous)
Having one copy of the variant allele means the MTHFR enzyme operates at a slightly reduced capacity [1]. While this reduction is generally mild, it can result in slightly lower circulating folate levels compared to the typical genotype [2]. Blood homocysteine levels may be slightly elevated, though they usually remain within or near the normal range unless dietary folate intake is very low [3]. This genotype also carries a moderately increased risk of side effects when taking folate-disrupting medications such as methotrexate [4]. Most individuals with this genotype do not experience obvious health issues, but ensuring adequate dietary folate from leafy greens is beneficial. It is a very common genetic pattern that rarely requires aggressive supplementation. Simple dietary awareness is usually the most practical approach to supporting methylation.
MTHFR enzyme efficiency reduced to 65 percent; Slightly elevated homocysteine risk; Moderate risk of methotrexate side effects.
Variants with shared genetic architecture
rs17367504 · MTHFR Gene · Chr 1 · Blood Pressure
rs1801131 · MTHFR Gene · Chr 1 · Folate Metabolism
rs2274976 · MTHFR Gene · Chr 1 · Cleft Lip Risk
Impact of Pharmacogenetics on High-Dose Methotrexate Toxicity in Pediatric Oncology.
Content updated August 2026.
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