What you carry at this position in your DNA and what research says about it.
Folate Metabolism: 7/10 evidence, 90 publications.
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Sample genotype (not yours): T/T
Typical Folate Metabolism
Standard enzyme activity supports optimal folate processing and methylation. This genotype is associated with a lower risk of side effects from several common medications.
What this genotype means: Standard MTHFR enzyme activity; Lower risk of chemotherapy toxicity; Typical response to methotrexate.
Sample genotype (not yours): G/G
Reduced Folate Metabolism
Enzyme activity is moderately decreased, which can affect folate processing and raise the risk of side effects from specific medications.
What this genotype means: Moderately reduced MTHFR activity; Higher risk of methotrexate side effects; Increased risk of chemotherapy toxicity.
Sample genotype (not yours): T/G
Slightly Reduced Folate Metabolism
Enzyme efficiency is mildly decreased but generally remains within a healthy functional range. Medication response and toxicity risks are typical or only slightly altered.
What this genotype means: Mildly reduced MTHFR activity; Typical baseline homocysteine levels; Intermediate medication sensitivity.
Gene function and biological role
Gene Function: The MTHFR gene provides instructions for making methylenetetrahydrofolate reductase, a critical enzyme in the folate-mediated one-carbon metabolism pathway [1]. This enzyme converts 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate, which is the primary active form of folate used in the body [2]. Active folate is essential for converting the amino acid homocysteine into methionine, a building block for proteins and a precursor to the body's universal methyl donor, S-adenosylmethionine [3]. Through this methylation cycle, the enzyme supports DNA synthesis, gene regulation, and neurotransmitter production [4]. Proper functioning of this pathway is vital for cardiovascular, neurological, and reproductive health.
Variant Impact: The rs1801131 variant, commonly known as A1298C or E429A, is a missense mutation in exon 7 of the MTHFR gene [4]. This genetic change replaces the nucleotide adenine with cytosine at position 1298 of the mRNA, resulting in the substitution of glutamate with alanine at amino acid position 429 of the enzyme [1]. This substitution occurs in the C-terminal regulatory domain of the protein rather than the catalytic domain [2]. While it reduces the overall stability and activity of the MTHFR enzyme, its biochemical impact is generally milder than that of the well-known C677T variant [3]. The alteration slightly decreases the enzyme's efficiency in recycling tetrahydrobiopterin, which can influence neurotransmitter synthesis.
Key Insight: Unlike the more famous C677T variant, the A1298C change affects the regulatory region of the enzyme rather than its main active site, resulting in a much milder reduction in folate processing.
Location: MTHFR. Chromosome 1 · 1p36.22 · 11.8 Mb
Estimated prevalence by population
Global 54.8%; European 46.8%; African 69.3%; East Asian 60.7%; South Asian 35.1%; Americas 62.9%; Ashkenazi 49.4%; Finnish 45.2%; Middle Eastern 41.4%; Amish 60.9%.
Estimated TT genotype frequency.
Global 37.8%; European 43.2%; African 27.9%; East Asian 34.4%; South Asian 48.3%; Americas 32.8%; Ashkenazi 41.8%; Finnish 44.1%; Middle Eastern 45.9%; Amish 34.2%.
Estimated TG genotype frequency.
Global 7.5%; European 10.0%; African 2.8%; East Asian 4.9%; South Asian 16.6%; Americas 4.3%; Ashkenazi 8.8%; Finnish 10.7%; Middle Eastern 12.7%; Amish 4.8%.
Estimated GG genotype frequency.
Showing effects for T/T genotype
Nutrition & Metabolism
Vitamin & Mineral Metabolism
Folate Metabolism. Evidence: 4/10. Source: PMID 11742092. Typical.
Pharmacogenomics
Immunosuppressant & Biologic Response
Methotrexate Toxicity. Evidence: 6/10. Source: PMID 23652803. Lower Toxicity Risk.
Chemotherapy Response
Chemotherapy Toxicity. Evidence: 6/10. Source: PMID 25331073. Lower Toxicity Risk.
Antidepressant & Psychiatric Drug Response
Antipsychotic Weight Gain. Evidence: 5/10. Source: PMID 24725652. Typical Risk.
Cardiovascular & Metabolic
Obesity & Body Composition
Hip Circumference. Evidence: 7/10. Source: PMID 34021172. Typical.
Cancer & Oncology
Brain & Nervous System Cancers
Brain Tumor. Evidence: 3/10. Source: PMID 28915669. Typical Risk.
Showing effects for G/G genotype
Folate Metabolism. Evidence: 4/10. Source: PMID 11742092. Moderately Reduced.
Methotrexate Toxicity. Evidence: 6/10. Source: PMID 23652803. Higher Toxicity Risk.
Chemotherapy Toxicity. Evidence: 6/10. Source: PMID 25331073. Higher Toxicity Risk.
Antipsychotic Weight Gain. Evidence: 5/10. Source: PMID 24725652. Higher Risk.
Hip Circumference. Evidence: 7/10. Source: PMID 34021172. Larger.
Brain Tumor. Evidence: 3/10. Source: PMID 28915669. Slightly Increased.
Showing effects for T/G genotype
Folate Metabolism. Evidence: 4/10. Source: PMID 11742092. Slightly Reduced.
Methotrexate Toxicity. Evidence: 6/10. Source: PMID 23652803. Typical Toxicity Risk.
Chemotherapy Toxicity. Evidence: 6/10. Source: PMID 25331073. Typical Toxicity Risk.
Hip Circumference. Evidence: 7/10. Source: PMID 34021172. Slightly Larger.
What this genotype means for the people who carry it
Sample genotype: TT (Homozygous)
Standard MTHFR enzyme activity is maintained with this genotype, ensuring efficient conversion of folate into its active form [1]. Optimal folate processing helps regulate homocysteine levels and supports essential cellular methylation processes [2]. Because the enzyme functions at full capacity, the body can efficiently synthesize DNA and regulate gene expression. When undergoing chemotherapy with fluorouracil or capecitabine, this genotype is associated with a significantly lower risk of severe drug toxicity [3]. Similarly, patients treated with methotrexate for rheumatoid arthritis or leukemia experience fewer adverse events compared to those with variant alleles [4]. There is also no elevated risk of antipsychotic-induced weight gain when taking medications like olanzapine [5]. Maintaining typical enzyme function also means there is no genetic predisposition to elevated homocysteine from this specific locus. This baseline stability provides a reliable foundation for cardiovascular and neurological health.
Standard MTHFR enzyme activity; Lower risk of chemotherapy toxicity; Typical response to methotrexate.
Sample genotype: GG (Homozygous)
Two copies of the variant allele result in a moderate reduction of MTHFR enzyme activity, operating at approximately 60% to 70% of typical capacity [1]. This reduction can impair folate metabolism, particularly when dietary folate intake is insufficient [2]. While not a direct cause of disease, this genotype is linked to a significantly higher risk of toxicity and side effects from medications like methotrexate [3]. Patients taking fluoropyrimidine chemotherapies, such as capecitabine or fluorouracil, also face an increased risk of adverse events and reduced survival rates [4]. Additionally, individuals prescribed antipsychotics like olanzapine or clozapine may experience a higher likelihood of drug-induced weight gain [5]. This metabolic bottleneck can lead to slightly elevated homocysteine levels if folate and vitamin B12 levels are low. Ensuring adequate intake of natural folates and active B vitamins can help support optimal methylation pathways. Consulting a healthcare provider before starting any of the associated medications is highly recommended to manage potential side effects.
Moderately reduced MTHFR activity; Higher risk of methotrexate side effects; Increased risk of chemotherapy toxicity.
Sample genotype: TG (Heterozygous)
A single copy of the variant allele leads to a mild reduction in MTHFR enzyme activity, estimated at roughly 80% to 85% of normal levels [1]. This slight decrease is generally well-tolerated and does not significantly alter baseline homocysteine levels under normal dietary folate intake [2]. However, when combined with other MTHFR variants like C677T, it may contribute to a slightly increased susceptibility to certain conditions [3]. In pharmacogenomics, this genotype is associated with intermediate risks of side effects during methotrexate therapy [4]. Some studies also suggest a slightly better clinical response to certain chemotherapy regimens like oxaliplatin compared to the typical genotype [5]. For most individuals, this mild reduction has no noticeable impact on daily health or well-being. Standard dietary intake of folate from green leafy vegetables is usually sufficient to offset any minor enzyme inefficiency. No special dietary interventions or high-dose supplements are typically recommended based on this genotype alone.
Mildly reduced MTHFR activity; Typical baseline homocysteine levels; Intermediate medication sensitivity.
Variants with shared genetic architecture
rs1801133 · MTHFR Gene · Chr 1 · Folate Processing
rs17367504 · MTHFR Gene · Chr 1 · Blood Pressure
rs2274976 · MTHFR Gene · Chr 1 · Cleft Lip Risk
Folate metabolism genetic polymorphisms and meningioma and glioma susceptibility in adults.
Content updated August 2026.
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