TPMT rs1800462: What Your Genotype Means
The rs1800462 variant is a specific genetic change in the TPMT gene that results in a non-functional enzyme. This variant is associated with an increased risk of severe side effects when taking certain medications known as thiopurines.
What each genotype means
Normal enzyme activity
This genotype is considered the wild-type or normal-functioning state for the TPMT gene. Individuals with this profile typically possess normal thiopurine methyltransferase enzyme activity and are generally expected to metabolize thiopurine medications at standard rates. Please discuss your medication dosing and any concerns regarding potential side effects with your clinician or pharmacist.
Carried by the vast majority of the population, typically estimated at 86-97% across most ethnic groups.
Intermediate enzyme activity
This genotype indicates you carry one non-functional TPMT*2 allele, which is associated with intermediate enzyme activity. Research suggests that individuals with this profile may have an increased risk of myelosuppression when taking thiopurine drugs like azathioprine or mercaptopurine. It is essential to discuss these findings with your healthcare provider, as they may recommend a reduced starting dose of these medications.
This heterozygous genotype is relatively uncommon, occurring in approximately 3-14% of the general population depending on ancestry.
Low or deficient activity
This genotype indicates you carry two copies of the non-functional TPMT*2 allele, leading to significantly impaired or deficient enzyme activity. This profile is associated with a high risk of severe, life-threatening myelosuppression if treated with standard doses of thiopurine medications. You must consult with your clinician or pharmacist before starting any thiopurine therapy, as they will likely need to prescribe a significantly lower dose or select an alternative medication.
This homozygous genotype is very rare, occurring in approximately 1 in 300 individuals globally, though frequencies vary by ancestry.
Understanding the rs1800462 Variant
The rs1800462 variant is a single nucleotide polymorphism (SNP) located within the TPMT gene on chromosome 6. In scientific literature, this specific change is often referred to as the TPMT*2 allele. At the molecular level, this variant involves a substitution where a guanine (G) is replaced by a cytosine (C) at a specific position in the DNA sequence. This change leads to an amino acid alteration, specifically p.Ala80Pro, which disrupts the normal structure and function of the resulting protein. Because this variant renders the enzyme non-functional, it is classified as a loss-of-function allele. Understanding where this SNP sits is critical for pharmacogenomics, as it serves as a marker for how an individual's body might process specific classes of drugs. It is one of several known variants in the TPMT gene that researchers track to better understand why patients may experience different responses to standard medical treatments.
The Role of the TPMT Gene
The TPMT gene provides the instructions for the body to produce an enzyme called thiopurine S-methyltransferase. This enzyme plays a vital role in the metabolism of thiopurine drugs, such as azathioprine, mercaptopurine, and thioguanine. These medications are frequently used to treat conditions like leukemia, inflammatory bowel disease, and autoimmune disorders. The TPMT enzyme acts as a chemical gatekeeper, helping to break down these drugs into inactive forms so they can be safely cleared from the body. When the TPMT enzyme is working correctly, it prevents the accumulation of toxic byproducts. However, if the enzyme is deficient or non-functional due to genetic variants like rs1800462, the drugs are not metabolized efficiently. This can lead to a buildup of active drug metabolites in the blood, which may cause severe bone marrow suppression, a condition where the body cannot produce enough blood cells, leading to increased risks of infection, anemia, and bleeding.
Research and Clinical Significance
Research into rs1800462 is grounded in the field of pharmacogenomics, which studies how genes affect a person's response to drugs. The evidence linking this variant to thiopurine intolerance is well-established in clinical literature. Individuals who carry two non-functional copies of the TPMT gene are considered 'poor metabolizers' and are at a significantly higher risk of life-threatening toxicity when treated with standard doses of thiopurines. While the association is strong, it is important to note that TPMT is not the only gene involved in thiopurine metabolism; for example, variants in the NUDT15 gene also play a major role, particularly in populations of Asian ancestry. Because of this, clinical guidelines often recommend testing for both TPMT and NUDT15 variants before starting thiopurine therapy. The strength of the evidence for rs1800462 is high regarding its impact on enzyme activity, making it a standard marker in clinical genetic testing panels designed to optimize drug safety.
What You Can and Cannot Do
If you have information about your rs1800462 genotype, it is important to understand its limitations. This information is a tool for clinical decision-making, not a diagnosis in itself. You cannot use this data to self-prescribe or adjust your medication dosages. If you are currently taking or are prescribed thiopurine medications, you should share your genetic information with your healthcare provider or a clinical pharmacist. They are the only ones qualified to interpret these results in the context of your overall health, current medications, and medical history. A clinician may use this information to adjust your dosage, choose an alternative therapy, or monitor your blood counts more frequently to ensure your safety. Never stop or change your medication regimen based on genetic test results without consulting your medical team, as doing so could be dangerous for your underlying health condition.
How common is this variant?
The rs1800462 variant is relatively rare, with a global minor allele frequency of approximately 0.002. It is most frequently observed in European and South Asian populations, where the frequency ranges between 0.2% and 0.5%.
Frequently asked questions
What is the TPMT*2 allele?
The TPMT*2 allele is a specific genetic variant (rs1800462) that causes the TPMT enzyme to be non-functional. It is one of the primary genetic markers used to identify individuals who may have difficulty processing thiopurine medications.
Does having the C allele mean I cannot take thiopurines?
Not necessarily. Having the C allele indicates a potential for reduced enzyme activity, but your doctor will determine the appropriate course of action. They may adjust your dose or choose a different medication based on your specific genotype and clinical needs.
Is TPMT testing standard before starting medication?
Yes, in many clinical settings, testing for TPMT variants is recommended before starting thiopurine therapy. This helps clinicians identify patients who are at risk for severe side effects and allows for personalized dosing.
Are there other genes that affect thiopurine metabolism?
Yes, other genes such as NUDT15 also play a significant role in how the body processes thiopurines. Genetic testing often includes both TPMT and NUDT15 to provide a more complete picture of a patient's drug metabolism.
Sources & further reading
Educational information only, last refreshed 9/21/2026. 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.
The rs1800460 variant defines the TPMT*3B allele, and in cis with rs1142345, forms the TPMT*3A haplotype conferring deficient thiopurine methyltransferase activity.
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.