TPMT rs11558494: Understanding the TPMT*4 Variant
The rs11558494 variant is a rare genetic change in the TPMT gene that defines the TPMT*4 allele. This variant is associated with the complete loss of thiopurine methyltransferase enzyme activity, which can lead to severe toxicity when patients are treated with standard doses of thiopurine medications.
What each genotype means
Normal thiopurine metabolism
You carry two copies of the standard G allele at this splice junction, which is not associated with the TPMT*4 loss-of-function variation. Research indicates standard TPMT activity from this specific locus, although overall thiopurine metabolism also depends on other TPMT alleles and NUDT15 variants. If you are prescribed thiopurine medications such as azathioprine or 6-mercaptopurine, consult your clinician or pharmacist regarding comprehensive pharmacogenetic testing and proper dosing.
Carried by more than 99.9% of individuals across all major global populations.
Reduced enzyme activity
You carry one copy of the rare A allele defining the non-functional TPMT*4 splice-site mutation alongside one standard allele. Clinical studies show that carrying one completely inactive TPMT allele typically leads to intermediate thiopurine methyltransferase activity, elevating the risk of myelosuppression with standard thiopurine drug doses. Because evidence for this specific rare variant is limited to clinical pedigrees and cohorts, discuss thiopurine dosing and monitoring closely with your healthcare provider or pharmacist.
Extremely rare globally, identified in fewer than 1 in 5,000 individuals across surveyed populations.
Complete enzyme deficiency
You carry two copies of the TPMT*4 splice-site mutation, which completely prevents the generation of functional thiopurine methyltransferase enzyme. Published research shows that individuals with complete TPMT deficiency face a severe, potentially life-threatening risk of bone marrow suppression when exposed to standard doses of azathioprine or 6-mercaptopurine. If thiopurine therapy is being considered, you must immediately discuss these results with your clinician or pharmacist to explore alternative medications or drastic dose reductions.
Exceedingly rare, with a estimated prevalence far below 1 in 1,000,000 individuals globally.
What is the rs11558494 Variant?
The rs11558494 variant, also known as c.414+1G>A, is a specific genetic alteration located within the TPMT gene. In the context of pharmacogenomics, this variant is classified as a splice-site mutation. Splice-site mutations are significant because they interfere with the cellular machinery responsible for correctly processing messenger RNA, the template used to build proteins. When this specific G-to-A change occurs at the splice junction, it typically results in the production of a non-functional or unstable protein. Because this variant leads to the complete inactivation of the enzyme, it is categorized as a 'no-function' allele. In the standardized nomenclature used by researchers, this specific genetic change is designated as the TPMT*4 allele. Understanding such variants is a primary focus of pharmacogenomics, a field that studies how an individual's genetic makeup influences their response to specific medications.
The Role of the TPMT Gene
The TPMT gene provides instructions for making an enzyme called thiopurine S-methyltransferase. This enzyme plays a critical role in the body by breaking down, or metabolizing, a class of drugs known as thiopurines, which include mercaptopurine, azathioprine, and thioguanine. These medications are frequently used to treat conditions such as acute lymphoblastic leukemia, inflammatory bowel disease, and various autoimmune disorders. By methylating these drugs, the TPMT enzyme converts them into inactive forms, effectively regulating the amount of active drug circulating in the body. When the TPMT enzyme is absent or has significantly reduced activity, these medications can accumulate to toxic levels. This accumulation can lead to severe side effects, most notably myelosuppression, a condition where the bone marrow fails to produce enough blood cells, which can be life-threatening if not managed appropriately.
Clinical Significance and Research Evidence
Research into TPMT variants is robust, particularly regarding their impact on drug safety. Clinical guidelines, such as those provided by the Clinical Pharmacogenetics Implementation Consortium (CPIC), emphasize that patients with low or absent TPMT activity are at a much higher risk of experiencing severe adverse reactions to standard thiopurine doses. While the most common low-activity alleles are TPMT*3A and TPMT*3C, the TPMT*4 allele (rs11558494) is recognized as a cause of complete enzyme deficiency. The evidence linking this specific variant to toxicity is strong in the context of its functional impact on the enzyme. However, because the variant is extremely rare, large-scale clinical studies are limited compared to more common variants. Clinicians often use both genotype testing and direct enzyme activity assays to assess a patient's metabolic status, ensuring that medication dosages are adjusted to prevent toxicity while maintaining therapeutic efficacy.
Population Frequency
The rs11558494 variant is considered rare on a global scale. According to data from the Genome Aggregation Database (gnomAD), the minor allele frequency is very low, typically reported as less than 0.0002. Because of this rarity, it is not commonly encountered in the general population. While genetic variants in the TPMT gene are present in all world populations, their specific frequencies and the prevalence of different alleles vary significantly by ancestry. For example, while certain alleles are more common in European populations, others are more prevalent in Asian or African populations. Due to the low frequency of rs11558494, it is often not included in standard, limited-scope pharmacogenetic screening panels, which typically focus on the most common variants that account for the majority of observed enzyme deficiency cases.
Managing Your Genetic Information
If you have received information about your TPMT genotype, it is important to understand that this data is a tool for personalized medicine, not a diagnosis in itself. Genetic testing for TPMT is typically performed to guide medication dosing before starting thiopurine therapy. If you are prescribed a thiopurine medication, your healthcare provider may use your genotype to determine if a dose reduction is necessary. You should never make changes to your medication regimen based on genetic test results without consulting your doctor or pharmacist. They are the only ones who can interpret these results in the context of your overall health, other medications you may be taking, and your specific clinical needs. If you are concerned about your risk for thiopurine toxicity, discuss the possibility of TPMT testing or enzyme activity monitoring with your clinical team.
How common is this variant?
The rs11558494 variant is rare globally, with a minor allele frequency of less than 0.0002 in gnomAD.
Frequently asked questions
What does it mean to have a TPMT deficiency?
TPMT deficiency means your body lacks the enzyme needed to break down thiopurine drugs. This can lead to a buildup of the medication in your system, increasing the risk of severe side effects like bone marrow suppression.
Is TPMT testing required before taking thiopurines?
Many clinical guidelines recommend testing for TPMT genotype or enzyme activity before starting thiopurine therapy. You should discuss with your doctor whether this testing is appropriate for your specific treatment plan.
Can I change my medication dose based on my genotype?
No, you should never change your medication dose on your own. Any adjustments to your treatment must be made by your healthcare provider based on your genetic results and clinical status.
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. Clinicians often consider both TPMT and NUDT15 status when determining safe dosing.
Sources & further reading
Educational information only, last refreshed 10/28/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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A rare variant in the TPMT gene associated with metabolic processing.
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The TPMT*3C variant is a major determinant of thiopurine metabolism, associated with reduced enzyme activity.
The rs1800460 variant defines the TPMT*3B allele, and in cis with rs1142345, forms the TPMT*3A haplotype conferring deficient thiopurine methyltransferase 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.