TPMT rs1800460: What Your Genotype Means
The rs1800460 single nucleotide polymorphism is a missense variant located within the TPMT gene that plays a central role in thiopurine drug metabolism. It defines the reduced-function TPMT*3B allele and, when present alongside rs1142345, forms the prominent non-functional TPMT*3A haplotype. Individuals carrying this variant produce a less stable enzyme, placing them at increased risk for severe adverse effects when taking standard doses of thiopurine medications.
What each genotype means
Typical TPMT enzyme baseline
You carry two reference copies at this position in the TPMT gene, which does not confer the reduced function associated with the TPMT*3B or TPMT*3A alleles. Overall thiopurine metabolism also depends on other genetic loci within TPMT and NUDT15. If thiopurine medications such as azathioprine or mercaptopurine are ever prescribed, discuss full pharmacogenomic profiling and dosing with your clinician or pharmacist.
Carried by approximately 90% to 95% of individuals in European and American populations, and over 98% of individuals in East Asian and African ancestries.
Intermediate TPMT activity risk
You carry one copy of the non-functional A allele, which defines TPMT*3B on its own or forms the compound TPMT*3A haplotype when inherited alongside rs1142345. Carriers typically have reduced thiopurine methyltransferase activity, putting them at elevated risk of bone marrow suppression when receiving conventional doses of thiopurine drugs. Consult your physician or pharmacist regarding dosage adjustments and monitoring before starting medications like azathioprine, mercaptopurine, or thioguanine.
Found in approximately 6% to 10% of European and American cohorts, but occurs in fewer than 2% of individuals of East Asian descent.
Severely reduced TPMT activity
You carry two copies of the loss-of-function A allele, indicating deficient or negligible thiopurine methyltransferase enzymatic activity. Standard doses of thiopurine medications are associated with severe, potentially life-threatening myelosuppression due to cytotoxic metabolite buildup in individuals with this genotype. Always alert your clinician or pharmacist to this result so substantial dose reductions or alternative medications can be evaluated prior to treatment.
Very rare across all global populations, present in approximately 1 in 400 to 1 in 1,000 individuals of European descent and extremely rare in Asian populations.
What Is rs1800460 and Where Is It Located?
The single nucleotide polymorphism rs1800460 is an alteration located on chromosome 6 in the coding region of the human TPMT gene. Specifically, it represents a nucleotide exchange denoted as c.460G>A in exon 6, which replaces the standard amino acid alanine with threonine at codon 154 (p.Ala154Thr). In pharmacogenomic nomenclature, the presence of the A allele alone defines the star allele known as TPMT*3B. However, rs1800460 frequently co-occurs in cis on the same chromosome with a second variant, rs1142345 (c.719A>G), in which case the combined haplotype is designated as TPMT*3A. Both *3B and *3A alleles are functionally compromised. Because modern genotyping assays often read each site independently, clinical pharmacogenomics platforms carefully evaluate rs1800460 alongside surrounding markers to reconstruct diplotypes accurately.
The Biological Role of the TPMT Gene
The TPMT gene encodes thiopurine S-methyltransferase, a cytosolic enzyme expressed throughout the body, including in red blood cells, the liver, and the kidney. This enzyme catalyzes the S-methylation of thiopurine compounds, effectively inactivating them. Clinically important thiopurines include azathioprine, 6-mercaptopurine, and 6-thioguanine, which are widely prescribed as immunosuppressants for autoimmune conditions such as inflammatory bowel disease and as chemotherapeutic agents for acute lymphoblastic leukemia. When TPMT activity is normal, these drugs are safely channeled into both active and inactive metabolites in a balanced manner. When TPMT function is reduced, the parent drug is routed toward alternative metabolic cascades, causing an accumulation of active thioguanine nucleotides (TGNs). These cytotoxic nucleotides incorporate into cellular DNA and RNA, which can lead to profound, dose-dependent bone marrow suppression.
Clinical Evidence and Pharmacogenomic Impact
Evidence evaluating the association between rs1800460 and thiopurine toxicity is classified as strong by international consortia, including the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG). Carriers of one non-functional allele—such as those with TPMT*1/*3A or *1/*3B diplotypes—are classified as intermediate metabolizers and display roughly 50% reduced enzymatic capacity. Individuals with two non-functional alleles are considered poor metabolizers and have nearly absent enzyme activity. If treated with conventional, unadjusted thiopurine dosages, intermediate and poor metabolizers face a heightened risk of life-threatening myelosuppression, neutropenia, and systemic toxicity. Consequently, professional clinical guidelines explicitly recommend pre-therapeutic genetic screening or functional enzymatic assays to guide substantial dosage reductions or alternative medication selections.
Population Frequency and Diversity Patterns
The distribution of the rs1800460 variant varies considerably across global ancestries according to large genomic repositories such as gnomAD. In populations of European and Latino or Admixed American ancestry, the minor A allele typically exhibits a frequency between 3% and 5%, primarily traveling as part of the TPMT*3A haplotype. The isolated TPMT*3B allele without the accompanying rs1142345 variant is relatively uncommon across all populations, occurring at frequencies below 0.5%. In contrast, the rs1800460 A allele is rare in East Asian and African populations, often observed at frequencies lower than 1%. In these East Asian cohorts, alternative pharmacogenomic loci such as NUDT15 play a more dominant role in predicting thiopurine toxicity, illustrating the necessity of considering ancestry-informed panel testing.
Using This Genetic Information Responsibly
Knowing your rs1800460 genotype provides valuable educational insight into how your body may process certain medications, but it is not a clinical diagnosis. This variant does not cause symptoms on its own, nor does it impact day-to-day health in the absence of thiopurine drugs. If you carry one or two copies of the minor allele and are prescribed azathioprine, mercaptopurine, or thioguanine, do not adjust, stop, or start any medications independently. Always share your complete genetic laboratory results with your prescribing physician or a clinical pharmacist. They will evaluate your overall pharmacogenomic profile, including TPMT and NUDT15 status, alongside standard blood monitoring protocols to determine safe and effective therapy.
How common is this variant?
The minor A allele occurs at a frequency of approximately 3% to 5% in European and Admixed American populations, where it predominantly travels within the TPMT*3A haplotype. It is rare in East Asian and African ancestries, typically appearing at frequencies under 1% in gnomAD.
Frequently asked questions
What is the difference between TPMT*3A and TPMT*3B?
The rs1800460 variant alone defines the TPMT*3B allele. When rs1800460 occurs on the exact same chromosome in cis with a second variant, rs1142345, the combination forms the TPMT*3A haplotype, which is the most common non-functional TPMT allele in Europeans.
Does carrying the rs1800460 variant mean I have a disease?
No, carrying rs1800460 is not a disease and causes no health issues or symptoms during normal daily life. It is strictly a pharmacogenomic marker that influences how your body metabolizes specific immunosuppressive and antineoplastic medications.
Which medications are affected by TPMT rs1800460?
The primary medications affected are thiopurine drugs, including azathioprine, 6-mercaptopurine, and 6-thioguanine. These medications are used to treat conditions like inflammatory bowel disease, rheumatoid arthritis, and certain childhood leukemias.
What should I do if my test shows I carry the A allele?
If you carry the A allele, inform your physician or clinical pharmacist prior to starting any thiopurine therapy. They can consult CPIC guidelines to safely adjust your dosing or choose an alternative drug while monitoring your blood counts.
Sources & further reading
Educational information only, last refreshed 9/10/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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Defines the TPMT*4 splice-site mutation (c.414+1G>A) causing complete inactivation of thiopurine methyltransferase and severe toxicity.
A rare variant in the TPMT gene associated with metabolic processing.
Defines the non-functional TPMT*2 missense allele (c.238G>C, p.Ala80Pro), which confers significantly impaired thiopurine metabolism and heightened risk of life-threatening myelosuppression with azathioprine or mercaptopurine.
The TPMT*3C variant is a major determinant of thiopurine metabolism, associated with reduced enzyme activity.
This missense variant in the TPMT gene is associated with altered thiopurine metabolism and is considered a rare variant in global populations.
Variant in TPMT associated with thiopurine metabolism; clinical testing is recommended for patients starting thiopurine therapy.