What you carry at this position in your DNA and what research says about it.
Meningioma Risk: 6/10 evidence, 38 publications.
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Sample genotype (not yours): A/A
Typical Meningioma Risk
This genotype is associated with typical MTRR enzyme function and baseline risk for meningioma. It also correlates with a better reduction in migraine disability when taking B-vitamin supplements.
What this genotype means: Typical B12 recycling efficiency; Standard risk of meningioma; Favorable response to migraine B-vitamin therapy.
Sample genotype (not yours): A/G
Carrying one copy of the variant allele does not significantly alter the risk of developing meningiomas. However, it may slightly influence how the body processes certain medications like methotrexate.
What this genotype means: Standard risk of meningioma; Slightly altered sensitivity to methotrexate; Favorable response to migraine B-vitamin therapy.
Sample genotype (not yours): G/G
Elevated Meningioma Risk
Having two copies of the variant allele is linked to a modest increase in the risk of developing meningiomas. It also reduces the efficiency of B12 recycling, which can elevate homocysteine levels when B-vitamin intake is low.
What this genotype means: Reduced B12 recycling efficiency; Approximately 1.4x higher risk of meningioma; Increased risk of methotrexate side effects.
Gene function and biological role
Gene Function: The MTRR gene encodes methionine synthase reductase, an essential enzyme in the folate and methionine metabolic pathways [1]. This enzyme plays a critical role in maintaining the active state of methionine synthase by recycling its vital cofactor, vitamin B12 [2]. Methionine synthase is responsible for converting homocysteine into methionine, a building block for proteins and a precursor for major cellular methylation reactions [3]. When MTRR function is compromised, homocysteine can accumulate, potentially impacting cardiovascular health, prenatal development, and DNA methylation [1]. Proper enzyme activity is highly dependent on adequate dietary intake of folate, vitamin B12, and other B-complex vitamins [4].
Variant Impact: The rs1801394 variant, commonly known as A66G or Ile22Met, represents a missense mutation in the MTRR gene that swaps the amino acid isoleucine for methionine at position 22 of the protein. This molecular alteration reduces the enzyme's binding affinity for methionine synthase, leading to less efficient reactivation of vitamin B12 [2]. Although the functional impact of this single change is relatively modest on its own, its effects can compound when paired with other folate pathway variants or during periods of low B-vitamin intake [1]. Researchers have investigated this variant across a wide range of conditions, including neural tube defects, cognitive development, and susceptibility to certain cancers [5]. It also influences how the body processes folate-depleting medications like methotrexate [6].
Key Insight: The G/G genotype is associated with a 1.4x higher risk of meningiomas, but its impact on B12 recycling can often be managed with proper nutrition.
Location: MTRR. Chromosome 5 · 5p15.31 · 7.9 Mb
Estimated prevalence by population
Global 31.9%; European 19.6%; African 51.7%; East Asian 51.4%; South Asian 22.2%; Americas 40.1%; Ashkenazi 29.6%; Finnish 17.8%; Middle Eastern 38.1%; Amish 10.5%.
Estimated AA genotype frequency.
Global 46.2%; European 49.3%; African 40.4%; East Asian 40.6%; South Asian 49.8%; Americas 46.4%; Ashkenazi 49.6%; Finnish 48.8%; Middle Eastern 47.3%; Amish 43.8%.
Estimated AG genotype frequency.
Global 21.9%; European 31.1%; African 7.9%; East Asian 8.0%; South Asian 28.0%; Americas 13.4%; Ashkenazi 20.8%; Finnish 33.4%; Middle Eastern 14.7%; Amish 45.7%.
Estimated GG genotype frequency.
Showing effects for A/A genotype
Cancer & Oncology
Brain & Nervous System Cancers
Meningioma. Evidence: 4/10. Source: PMID 28915669. Typical Risk.
Nutrition & Metabolism
Vitamin & Mineral Metabolism
B12 Recycling. Evidence: 4/10. Source: PMID 12416982. Typical Efficiency.
Neurology & Mental Health
Headache & Migraine
Migraine Supplement Response. Evidence: 5/10. Source: PMID 22926161. Better Pain Relief.
Pharmacogenomics
Immunosuppressant & Biologic Response
Methotrexate Toxicity. Evidence: 6/10. Source: PMID 18368069. Typical Response.
Showing effects for A/G genotype
Methotrexate Toxicity. Evidence: 6/10. Source: PMID 18368069. Increased Risk.
Showing effects for G/G genotype
Meningioma. Evidence: 4/10. Source: PMID 28915669. ~1.4x Higher Risk.
B12 Recycling. Evidence: 4/10. Source: PMID 12416982. Reduced Efficiency.
Migraine Supplement Response. Evidence: 5/10. Source: PMID 22926161. Typical Response.
What this genotype means for the people who carry it
Sample genotype: AA (Homozygous)
Typical enzyme function is maintained by this genotype, ensuring efficient recycling of vitamin B12 to support the methylation cycle [1]. Maintaining this baseline activity helps keep homocysteine levels within a normal range under typical dietary conditions [1]. Clinical studies indicate that this genetic profile does not carry the elevated risk for primary brain tumors, such as meningiomas, observed with other variants [2]. Additionally, research suggests that individuals with this genotype experience a more pronounced reduction in migraine disability when supplementing with B-complex vitamins [3]. When undergoing medical treatments involving folate-pathway drugs like methotrexate, this profile is generally associated with standard drug metabolism and a lower risk of treatment-limiting toxicities [4]. Ensuring adequate daily intake of folate and vitamin B12 remains beneficial for overall cellular health and DNA maintenance.
Typical B12 recycling efficiency; Standard risk of meningioma; Favorable response to migraine B-vitamin therapy.
Sample genotype: AG (Heterozygous)
Standard enzyme efficiency is largely preserved with one copy of the reference allele, allowing for adequate recycling of vitamin B12 under normal circumstances [1]. This heterozygous profile is considered normal and is not associated with an increased risk of developing meningiomas or other primary brain tumors [2]. However, the presence of one variant allele may slightly alter cellular responses to certain medications that target the folate pathway [3]. For instance, some clinical studies of methotrexate therapy show a slightly altered risk profile for drug-related toxicities, such as liver irritation or mucositis, compared to the reference genotype [3]. Supplementation with B-complex vitamins, including folic acid, has been shown to help manage migraine-related pain and disability in individuals with this genetic makeup [4]. Maintaining balanced nutrition with sufficient B-vitamins supports optimal methylation and keeps homocysteine levels stable.
Standard risk of meningioma; Slightly altered sensitivity to methotrexate; Favorable response to migraine B-vitamin therapy.
Sample genotype: GG (Homozygous)
Reduced enzyme efficiency characterizes this genotype, as the altered MTRR protein has a lower affinity for its target enzyme and reactivates vitamin B12 less effectively [1]. This metabolic bottleneck can lead to a modest accumulation of homocysteine, particularly when dietary intake of folate or vitamin B12 is insufficient [2]. Meta-analyses have linked this specific genetic profile to an approximate 1.4-fold increase in the risk of developing meningiomas, a type of primary brain tumor [3]. The altered folate metabolism associated with this genotype also influences how the body processes chemotherapeutic and immunosuppressive drugs like methotrexate, potentially increasing the risk of side effects like mucositis [4]. Unlike carriers of the reference allele, individuals with this genotype may not experience the same degree of migraine relief from standard B-vitamin supplementation [5]. Ensuring consistent, high-quality sources of active B-vitamins can help bypass this metabolic bottleneck and support healthy methylation.
Reduced B12 recycling efficiency; Approximately 1.4x higher risk of meningioma; Increased risk of methotrexate side effects.
Variants with shared genetic architecture
rs1532268 · MTRR Gene · Chr 5 · Folate and Methylation
rs1801198 · TCN2 Gene · Chr 22 · Vitamin B12 Transport
rs1801133 · MTHFR Gene · Chr 1 · Folate Processing
Folate metabolism genetic polymorphisms and meningioma and glioma susceptibility in adults.
Content updated August 2026.
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