TPMT rs112339338: What Your Genotype Means
The rs112339338 variant is a rare genetic change in the TPMT gene that results in an amino acid substitution in the thiopurine methyltransferase enzyme. This variant is currently being researched for its potential impact on how the body processes thiopurine medications used to treat conditions like leukemia and inflammatory bowel disease.
What each genotype means
Normal enzyme activity
This genotype represents the most common form of the TPMT gene. Individuals with this profile typically have normal thiopurine methyltransferase enzyme activity and are not expected to have an increased risk of hematopoietic toxicity related to thiopurine medications based on this variant alone. Always discuss medication dosing and potential side effects with your clinician or pharmacist.
This is the most common genotype observed in global populations.
Rare variant genotype
This genotype includes a rare variant in the TPMT gene. Because this is a rare missense variant, its specific impact on enzyme activity and thiopurine metabolism is not fully established in clinical literature. You should discuss the implications of this finding with your healthcare provider or a clinical pharmacist before starting any thiopurine-based therapy.
This genotype is considered rare based on global allele frequency data from gnomAD.
Rare variant genotype
This genotype indicates the presence of a rare variant on both copies of the TPMT gene. The clinical significance of this specific homozygous state is not well-defined in current research, and evidence regarding its effect on enzyme function remains limited. Please consult with your clinician to determine if this information is relevant to your medical management.
This genotype is extremely rare in global populations.
What is the rs112339338 Variant?
The variant known as rs112339338 is a single nucleotide polymorphism (SNP) located in the TPMT gene on chromosome 6. It is classified as a missense mutation, meaning the DNA sequence change results in a different amino acid being incorporated into the TPMT protein. Specifically, this variant is often referred to as p.Arg163Cys, indicating that the amino acid arginine at position 163 has been replaced by cysteine. Because this variant occurs in the coding region of the gene, it has the potential to alter the structure, stability, or function of the resulting enzyme. Researchers categorize this as a rare variant because it appears at a very low frequency in global human populations. While common TPMT variants—such as those defining the well-known *2, *3A, *3B, and *3C alleles—are responsible for the majority of known enzyme deficiencies, rs112339338 represents a less common genetic finding that continues to be investigated in the context of personalized medicine.
The Role of the TPMT Gene
The TPMT gene provides the essential instructions for creating the thiopurine S-methyltransferase (TPMT) enzyme. This enzyme performs a critical role in the liver by helping to break down, or metabolize, a class of drugs known as thiopurines. Thiopurines, such as azathioprine, mercaptopurine, and thioguanine, are powerful medications used to suppress the immune system in patients with autoimmune disorders like inflammatory bowel disease or rheumatoid arthritis, and they are also foundational in treating childhood acute lymphoblastic leukemia. The TPMT enzyme functions by adding a methyl group to these drugs, which inactivates them and prevents them from becoming overly toxic to healthy cells. When an individual has normal TPMT enzyme activity, they can typically process standard doses of these medications effectively. However, if the enzyme is missing or functions poorly, the body may accumulate high levels of active drug metabolites. This accumulation can lead to significant side effects, most notably myelosuppression, a condition where the bone marrow fails to produce enough blood cells.
Research and Evidence Strength
The evidence linking rs112339338 to altered drug metabolism is currently considered limited. While major TPMT variants are well-established as markers for thiopurine toxicity, rarer variants like rs112339338 are not as extensively documented in large clinical trials. Because it is rare, it is difficult for researchers to gather enough patient data to definitively quantify the exact change in enzyme activity or the precise increase in risk for side effects compared to the more common variants. Scientific literature often identifies this variant in the context of the TPMT*33 allele, though its functional consequences—whether it causes a complete loss of enzyme activity or merely a partial reduction—are still being mapped. Computational tools and in vitro studies have sometimes predicted it to be deleterious or probably damaging to the protein, but clinical observation remains the gold standard. Consequently, while it is recognized by the pharmacogenomic community as a variant of interest, it is not yet as universally actionable in standard clinical guidelines as the most frequent TPMT variants.
What You Can Do With This Information
If you have received a report indicating you carry the rs112339338 variant, it is important to remember that this information is intended for educational purposes and should not be used to make independent medical decisions. Genetic variants in pharmacogenes are complex, and the way they affect your body can depend on a variety of factors, including other genetic variants, your specific medical condition, and other medications you may be taking. Always discuss your genetic findings with your clinician or pharmacist. They can help interpret how this variant—or any other genetic information—might be relevant to your health, especially if you are ever prescribed thiopurine medications. Your healthcare provider can determine if additional testing, such as measuring actual TPMT enzyme activity in your blood, is appropriate to help guide safe and effective treatment planning.
How common is this variant?
The rs112339338 variant is classified as rare across global populations, with data from large-scale genomic databases indicating an allele frequency well below 0.1% in most ancestral groups.
Frequently asked questions
Does having a rare TPMT variant mean I have a disease?
No, a TPMT variant is not a disease in itself. It is simply a genetic difference that describes how your body might process certain medications, specifically thiopurines.
Can this variant tell me if a drug will work for me?
This variant is associated with how you metabolize specific drugs, not whether they will treat your condition effectively. It is primarily used to assess the risk of side effects so that doctors can choose the safest starting dose.
If I have this variant, will I definitely have side effects?
Not necessarily. Many factors influence how you respond to medication, including your overall health, other genes, and the dosage prescribed. Genetic information is only one piece of the puzzle that doctors use to manage your care.
Should I be tested for other TPMT variants?
Routine pharmacogenetic testing often covers the most common variants that cause low enzyme activity. Your doctor is the best person to decide if additional testing for rare variants is clinically necessary based on your specific health history.
Sources & further reading
Educational information only, last refreshed 9/15/2026. 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.
Variant in TPMT associated with thiopurine metabolism; clinical testing is recommended for patients starting thiopurine therapy.