What you carry at this position in your DNA and what research says about it.
Folate and Drug Response: 8/10 evidence, 67 publications.
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Sample genotype (not yours): T/T
Altered Drug Response and Higher Toxicity Risk
Two copies of the T allele are linked to better response to methotrexate but a higher risk of drug-induced side effects. This genotype also correlates with altered cellular folate levels.
What this genotype means: Better response to methotrexate; Higher risk of liver toxicity; Altered blood folate levels.
Sample genotype (not yours): C/C
Typical Drug Response and Lower Toxicity Risk
Two copies of the C allele are associated with lower cellular uptake of methotrexate, leading to a reduced risk of drug toxicity but potentially lower efficacy.
What this genotype means: Lower risk of drug toxicity; Potentially reduced methotrexate efficacy; Stable baseline folate transport.
Sample genotype (not yours): T/C
Intermediate Drug Response and Moderate Toxicity Risk
Carrying one T and one C allele results in moderate drug transport efficiency, balancing therapeutic response and side effect risks.
What this genotype means: Moderate response to methotrexate; Moderate risk of side effects; Typical folate levels.
Gene function and biological role
Gene Function: The SLC19A1 gene encodes the reduced folate carrier 1, a membrane protein that acts as the primary gateway for importing folate into cells. Folate is a crucial B-vitamin required for DNA synthesis, cell division, and chemical methylation pathways. Because this carrier is the main transporter of folate, variations in this gene directly impact how efficiently cells can absorb this essential nutrient. This transporter is also responsible for taking up folate-like medications, such as the chemotherapy and immunosuppressant drug methotrexate.
Variant Impact: The rs1051266 variant represents a single nucleotide change from T to C in the SLC19A1 gene, resulting in an amino acid substitution from histidine to arginine at position 27. This structural change alters the transport efficiency of the reduced folate carrier 1 protein. The T allele is associated with altered cellular uptake of both natural folates and folate-antagonist drugs [1]. Consequently, this variant is one of the most widely studied pharmacogenomic markers for methotrexate efficacy and toxicity [2].
Key Insight: This single genetic letter change affects how your cells import both essential B-vitamins and critical medications like methotrexate, influencing both drug efficacy and the risk of side effects.
Location: SLC19A1. Chromosome 21 · 21q22.3 · 45.5 Mb
Estimated prevalence by population
Global 23.9%; European 18.3%; African 37.2%; East Asian 27.9%; South Asian 16.5%; Americas 18.6%; Ashkenazi 15.9%; Finnish 20.4%; Middle Eastern 25.7%; Amish 9.9%.
Estimated TT genotype frequency.
Global 48.6%; European 49.0%; African 47.6%; East Asian 49.8%; South Asian 48.2%; Americas 49.1%; Ashkenazi 47.9%; Finnish 49.5%; Middle Eastern 50.0%; Amish 43.1%.
Estimated TC genotype frequency.
Global 27.5%; European 32.7%; African 15.2%; East Asian 22.2%; South Asian 35.3%; Americas 32.3%; Ashkenazi 36.2%; Finnish 30.1%; Middle Eastern 24.3%; Amish 47.1%.
Estimated CC genotype frequency.
Showing effects for T/T genotype
Pharmacogenomics
Immunosuppressant & Biologic Response
Methotrexate Response. Evidence: 8/10. Source: PMID 18322994. Increased Efficacy.
Methotrexate Toxicity. Evidence: 6/10. Source: PMID 17180579. Higher Toxicity Risk.
Mercaptopurine Toxicity. Evidence: 6/10. Source: PMID 18458567. Higher Toxicity Risk.
Nutrition & Metabolism
Vitamin & Mineral Metabolism
Folate Levels. Evidence: 5/10. Source: PMID 19172696. Altered Folate.
Showing effects for C/C genotype
Methotrexate Response. Evidence: 8/10. Source: PMID 18322994. Poorer Efficacy.
Methotrexate Toxicity. Evidence: 6/10. Source: PMID 17180579. Lower Toxicity Risk.
Mercaptopurine Toxicity. Evidence: 6/10. Source: PMID 18458567. Lower Toxicity Risk.
Folate Levels. Evidence: 5/10. Source: PMID 19172696. Typical Folate.
Showing effects for T/C genotype
Methotrexate Response. Evidence: 8/10. Source: PMID 18322994. Moderate Efficacy.
Methotrexate Toxicity. Evidence: 6/10. Source: PMID 17180579. Moderate Risk.
Mercaptopurine Toxicity. Evidence: 6/10. Source: PMID 18458567. Moderate Risk.
What this genotype means for the people who carry it
Sample genotype: TT (Homozygous)
Cellular uptake of methotrexate is highly efficient in individuals carrying two copies of the T allele [1]. This increased uptake often translates to a significantly better therapeutic response to methotrexate in conditions like rheumatoid arthritis [2]. However, the accumulation of the drug inside cells also increases the likelihood of experiencing adverse events. Studies have noted a higher incidence of liver damage, vomiting, and bone marrow suppression during treatment [3]. Additionally, this genotype is associated with reduced plasma folate levels but higher red blood cell folate concentrations [4]. When undergoing maintenance therapy with other drugs like mercaptopurine, there is also an elevated risk of anemia and treatment interruptions [5].
Better response to methotrexate; Higher risk of liver toxicity; Altered blood folate levels.
Sample genotype: CC (Homozygous)
Cellular uptake of methotrexate is lowest in individuals carrying two copies of the C allele [1]. While this lower uptake can sometimes result in a poorer or slower therapeutic response to the drug, it offers a protective benefit against severe side effects [2]. Individuals with this genotype are less likely to experience methotrexate-induced liver damage, severe gastrointestinal toxicity, or bone marrow suppression [3]. Typical plasma folate levels are generally maintained, as the transport of natural dietary folates remains stable [4]. In the context of other treatments like mercaptopurine, the risk of bone marrow toxicity is also significantly lower compared to T allele carriers [5].
Lower risk of drug toxicity; Potentially reduced methotrexate efficacy; Stable baseline folate transport.
Sample genotype: TC (Heterozygous)
Intermediate transport of folate and folate-like medications occurs in individuals with one copy of each allele. This moderate transport rate generally provides a reasonable therapeutic response to methotrexate, though it may not be as pronounced as in those with the T/T genotype [1]. The risk of experiencing drug-related toxicities, such as gastrointestinal discomfort or mild liver enzyme elevation, is also moderate [2]. Folate levels in the blood typically remain within the standard range, as the single C allele helps maintain baseline transport capacity [3]. If taking immunosuppressants or chemotherapy agents, discussing these intermediate characteristics with a healthcare provider can help tailor monitoring protocols [4].
Moderate response to methotrexate; Moderate risk of side effects; Typical folate levels.
Variants with shared genetic architecture
rs2372536 · ATIC Gene · Chr 2 · Folate Metabolism
rs4673993 · ATIC Gene · Chr 2 · Methotrexate Response
rs1801131 · MTHFR Gene · Chr 1 · Folate Metabolism
Reduced folate carrier polymorphism determines methotrexate uptake by B cells and CD4+ T cells.
Content updated August 2026.
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