TPMT rs72552758: The TPMT*3D Pharmacogenomic Variant
The rs72552758 variant is an ultra-rare single nucleotide polymorphism located in the thiopurine S-methyltransferase (TPMT) gene. It defines the non-functional TPMT*3D allele, which leads to markedly reduced or absent TPMT enzymatic activity. Individuals carrying this variant have a significantly elevated risk of severe drug toxicity, such as life-threatening bone marrow suppression, when administered standard doses of thiopurine medications.
What each genotype means
Normal enzyme activity
This genotype represents the wild-type or normal function for this specific position in the TPMT gene. Individuals with this result do not carry the non-functional TPMT*3D variant at this location. Please discuss all medication plans and potential side effects with your clinician or pharmacist.
This is the most common genotype globally, as the TPMT*3D variant is an ultra-rare null allele.
Reduced enzyme activity
This genotype indicates you carry one copy of the non-functional TPMT*3D allele. This variant is associated with marked thiopurine S-methyltransferase deficiency, which may increase the risk of toxicity when taking thiopurine medications. You should consult your healthcare provider or pharmacist before starting any thiopurine therapy to discuss appropriate dosing or alternative treatments.
This genotype is extremely rare, with a global minor allele frequency of less than 0.001.
Deficient enzyme activity
This genotype indicates you carry two copies of the non-functional TPMT*3D allele, which is linked to severe thiopurine S-methyltransferase deficiency. Individuals with this profile are at a significantly higher risk for severe toxicity if treated with standard doses of thiopurine drugs. It is critical to discuss this result with your clinician or a pharmacist before initiating any medication.
This genotype is exceptionally rare in all known human populations.
Genetic Identity and Molecular Location
The single nucleotide polymorphism rs72552758 is positioned within the TPMT gene on the short arm of chromosome 6. At the cDNA level, this genetic variation is characterized as c.616A>G, causing an amino acid change from methionine to valine at residue position 206 (p.Met206Val). In pharmacogenomic nomenclature established by international curations such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) and PharmGKB, this alteration forms the defining marker for the TPMT*3D star allele. While common functional changes in the TPMT coding sequence, such as TPMT*3A or *3C, are widespread across various global groups, rs72552758 represents an extremely rare missense substitution that directly alters the core structure and thermal stability of the encoded thiopurine methyltransferase protein.
Biological Role of the TPMT Enzyme
The TPMT gene encodes thiopurine S-methyltransferase, a cytosolic metabolic enzyme responsible for the S-methylation of aromatic and heterocyclic sulfhydryl compounds. Clinically, TPMT plays an indispensable role in the catabolism of thiopurine medications, including azathioprine, 6-mercaptopurine, and thioguanine. These medications are widely utilized as immunosuppressive agents in autoimmune conditions, inflammatory bowel disease, and organ transplantation, as well as core antimetabolites in treating childhood acute lymphoblastic leukemia. Under normal metabolic conditions, functional TPMT diverts thiopurines away from cytotoxic active pathways. However, when the enzyme is defective or absent due to disruptive missense alterations like p.Met206Val, excess drug substrates are preferentially converted via alternative enzymatic cascades into active thioguanine nucleotides (TGNs).
Clinical Implications and Research Evidence
The accumulation of cytotoxic thioguanine nucleotides secondary to deficient TPMT activity disrupts DNA synthesis and repair in rapidly proliferating cells. As a direct consequence, individuals receiving conventional doses of thiopurines who carry non-functional TPMT alleles face high risks of severe, potentially fatal hematopoietic myelosuppression, including profound leukopenia, neutropenia, and thrombocytopenia. Because rs72552758 is classified as the null TPMT*3D allele, it confers total loss of enzyme function. While clinical evidence explicitly studying rs72552758 in large prospective trials is limited due to its ultra-rare status, the mechanistic understanding of TPMT deficiency is well-validated. Pharmacogenomic guidelines, such as those published by CPIC, assign non-functional status to TPMT*3D and recommend substantial preemptive dosage reductions or alternative therapeutic choices for patients carrying null alleles.
Global Prevalence and Ancestry Considerations
Unlike the more prevalent loss-of-function alleles such as TPMT*2 (rs1800462), TPMT*3B (rs1800460), and TPMT*3C (rs1142345), rs72552758 is categorized as an ultra-rare null variant. Public population genomic repositories, including the Genome Aggregation Database (gnomAD), show that the minor allele frequency (MAF) of the G allele is less than 0.001 globally. In fact, large-scale cohorts often detect zero or only a handful of heterozygous carriers across worldwide ancestries. Because of this extreme scarcity, standard commercial or targeted clinical genotyping arrays frequently omit rs72552758, meaning that individuals carrying this variant may only discover it through broad clinical whole-exome or whole-genome sequencing panels.
Navigating Results and Next Steps
Finding rs72552758 in personal genetic data should always be interpreted within a formal clinical and diagnostic framework. Consumers must recognize that pharmacogenomic markers do not diagnose illnesses or predict everyday physiological wellbeing in the absence of drug exposure. Rather, they serve as predictive tools for pharmacological metabolism. If a clinical report identifies the presence of the rs72552758 variant, it is vital to discuss the findings directly with a licensed physician, clinical geneticist, or pharmacist before starting or adjusting medications such as azathioprine or 6-mercaptopurine. Healthcare teams can combine genetic results with baseline erythrocyte TPMT enzyme activity tests or concurrent NUDT15 sequencing to design a safe, tailored treatment regimen.
How common is this variant?
The minor G allele of rs72552758 is an ultra-rare null variant with a minor allele frequency (MAF) of less than 0.001 globally across all major biogeographical populations in gnomAD. Homozygous variant individuals are virtually undetectable in routine population screens.
Frequently asked questions
What is the primary risk associated with the TPMT rs72552758 variant?
The primary clinical concern associated with the rs72552758 variant is severe thiopurine drug toxicity. When individuals carrying this non-functional TPMT*3D allele take standard doses of medications like azathioprine or mercaptopurine, their bodies cannot properly clear the medication, leading to toxic accumulation that can trigger life-threatening bone marrow suppression.
Does having the rs72552758 variant cause any medical symptoms on its own?
No, having this genetic variant does not cause an active medical disorder or baseline health symptoms in everyday life. Its health effects only manifest if you are prescribed specific thiopurine medications that rely on the TPMT enzyme for safe metabolism and clearance.
Why is rs72552758 often missing from standard direct-to-consumer DNA tests?
Direct-to-consumer genetic panels typically prioritize common variants that appear frequently across diverse populations. Because rs72552758 is an ultra-rare variant with an allele frequency below 0.1%, it is rarely included on targeted genotyping chips and is generally only detected through comprehensive clinical exome or whole-genome sequencing.
What should I do if my test shows that I carry the rs72552758 G allele?
You should share your genetic test results with your physician or a pharmacogenomics pharmacist before taking any thiopurine drugs. Your medical provider can confirm the result, evaluate your overall TPMT phenotype, and make personalized adjustments to drug choices and dosages to avoid toxicity.
Sources & further reading
Educational information only, last refreshed 9/8/2026. 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 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.