What you carry at this position in your DNA and what research says about it.
Folate Metabolism: 6/10 evidence, 8 publications.
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Sample genotype (not yours): C/C
Typical Folate Processing and Standard Drug Response
Standard enzyme activity supports typical folate metabolism and a baseline response to related medications. Standard risk levels are observed for folate-related developmental conditions.
What this genotype means: Typical baseline risk for neural tube defects; Standard tolerability profile for methotrexate therapy; Favorable cellular response to folic acid supplementation.
Sample genotype (not yours): C/G
Slightly Higher Risk of Drug Side Effects and Developmental Sensitivity
A single copy of the variant allele slightly alters enzyme structure, which may elevate the risk of methotrexate side effects. A minor increase in susceptibility to folate-related developmental risks is also observed.
What this genotype means: Slightly elevated risk of methotrexate-induced side effects; Minor increase in genetic susceptibility to spina bifida; Standard cellular response to folic acid supplementation.
Sample genotype (not yours): G/G
Higher Risk of Drug Toxicity and Folate-Related Developmental Sensitivity
Two copies of the variant allele alter enzyme structure, increasing the risk of side effects from methotrexate. This genotype is also linked to a higher genetic susceptibility to neural tube defects.
What this genotype means: Increased risk of adverse side effects during methotrexate therapy; Higher genetic susceptibility to neural tube defects like spina bifida; Potentially reduced cellular response to standard folic acid supplementation.
Gene function and biological role
Gene Function: The ATIC gene encodes a bifunctional enzyme crucial for the de novo purine biosynthesis pathway, which is essential for DNA synthesis and cellular replication. This enzyme catalyzes the final two steps of the pathway, converting AICAR into inosine monophosphate. Because of its central role in nucleotide synthesis, it is a primary intracellular target of antifolate medications like methotrexate. Variations in this gene can alter folate processing and influence how cells respond to folate-depleting therapies [1]. Consequently, genetic differences in this pathway are studied for their impact on developmental risks and drug tolerability [2].
Variant Impact: The rs2372536 variant represents a missense mutation in exon 5 of the ATIC gene, changing the nucleotide from cytosine to guanine. This molecular alteration results in a threonine-to-serine substitution at amino acid position 116 of the enzyme. The structural change can subtly modify the enzyme's catalytic efficiency and its sensitivity to folate pathway inhibitors. Researchers actively study this specific amino acid substitution to understand individual differences in medication side effects and embryonic development.
Key Insight: A single amino acid change in this metabolic enzyme can simultaneously influence how the body processes a common rheumatoid arthritis medication and alter early embryonic development risks.
Location: ATIC. Chromosome 2 · 2q35 · 215.3 Mb
Estimated prevalence by population
Global 56.1%; European 45.5%; African 82.5%; East Asian 53.0%; South Asian 27.9%; Americas 48.9%; Ashkenazi 42.4%; Finnish 53.2%; Middle Eastern 47.2%; Amish 34.2%.
Estimated CC genotype frequency.
Global 36.0%; European 43.9%; African 16.7%; East Asian 39.6%; South Asian 49.8%; Americas 42.0%; Ashkenazi 45.5%; Finnish 39.5%; Middle Eastern 43.0%; Amish 48.6%.
Estimated CG genotype frequency.
Global 7.9%; European 10.6%; African 0.8%; East Asian 7.4%; South Asian 22.3%; Americas 9.0%; Ashkenazi 12.2%; Finnish 7.3%; Middle Eastern 9.8%; Amish 17.3%.
Estimated GG genotype frequency.
Showing effects for C/C genotype
Rare Genetic Disorders
Congenital Malformations
Spina Bifida. Evidence: 3/10. Source: PMID 22140583. Typical Risk.
Pharmacogenomics
Immunosuppressant & Biologic Response
Methotrexate Toxicity. Evidence: 6/10. Source: PMID 38071832. Typical Risk.
Nutrition & Metabolism
Vitamin & Mineral Metabolism
Folic Acid Response. Evidence: 6/10. Source: PMID 16947783. Stronger Response.
Showing effects for C/G genotype
Spina Bifida. Evidence: 3/10. Source: PMID 22140583. Slightly Higher Risk.
Methotrexate Toxicity. Evidence: 6/10. Source: PMID 38071832. Slightly Higher Risk.
Folic Acid Response. Evidence: 6/10. Source: PMID 16947783. Typical Response.
Showing effects for G/G genotype
Spina Bifida. Evidence: 3/10. Source: PMID 22140583. Higher Risk.
Methotrexate Toxicity. Evidence: 6/10. Source: PMID 38071832. Higher Risk.
What this genotype means for the people who carry it
Sample genotype: CC (Homozygous)
Standard cellular processing of folate is maintained by the typical threonine-containing enzyme. Clinical studies indicate that this baseline genetic profile is associated with a standard response to folic acid supplementation [1]. When undergoing treatment with methotrexate for autoimmune conditions, individuals with this genotype generally experience standard rates of drug-related side effects compared to those carrying the variant guanine allele [2]. Furthermore, genetic analysis of developmental pathways shows no elevated risk for neural tube defects like spina bifida associated with this baseline genotype [3]. Maintaining adequate dietary folate intake remains important for overall cellular health and DNA synthesis.
Typical baseline risk for neural tube defects; Standard tolerability profile for methotrexate therapy; Favorable cellular response to folic acid supplementation.
Sample genotype: CG (Heterozygous)
Enzymatic efficiency in the purine synthesis pathway is subtly altered by the presence of one serine-encoding variant allele. This structural shift can influence how cells metabolize folate-inhibiting medications. Clinical research suggests that patients with this intermediate profile may have a slightly elevated likelihood of experiencing adverse events, such as gastrointestinal or liver sensitivity, during methotrexate therapy [1]. In developmental genetics, family-based studies have noted a modest association between this variant and an increased risk of neural tube defects like spina bifida [2]. Ensuring optimal folate levels before and during pregnancy is a widely recommended strategy to mitigate these pathway-specific developmental risks.
Slightly elevated risk of methotrexate-induced side effects; Minor increase in genetic susceptibility to spina bifida; Standard cellular response to folic acid supplementation.
Sample genotype: GG (Homozygous)
Cellular processing of folate and related medications is significantly impacted by having two copies of the serine-encoding variant allele. This altered enzyme structure is consistently linked to a higher incidence of adverse side effects, including gastrointestinal distress and elevated liver enzymes, during methotrexate treatment [1] [2]. In the context of embryonic development, genetic studies have identified this homozygous variant as a risk factor for neural tube defects, specifically spina bifida, due to altered folate pathway dynamics [3]. Adequate folate status is particularly critical for individuals with this genetic profile to support healthy cellular replication. Discussing these metabolic tendencies with a healthcare provider can help optimize treatment strategies if folate-depleting medications are prescribed.
Increased risk of adverse side effects during methotrexate therapy; Higher genetic susceptibility to neural tube defects like spina bifida; Potentially reduced cellular response to standard folic acid supplementation.
Variants with shared genetic architecture
rs4673993 · ATIC Gene · Chr 2 · Methotrexate Response
rs1051266 · SLC19A1 Gene · Chr 21 · Folate and Drug Response
rs1801131 · MTHFR Gene · Chr 1 · Folate Metabolism
ATIC missense variant affects response to methotrexate treatment in rheumatoid arthritis patients.
A genetic signature of spina bifida risk from pathway-informed comprehensive gene-variant analysis.
Content updated August 2026.
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