TPMT rs11558494: Splice Variant and Thiopurine Safety
The genetic variant rs11558494 is an uncommon splice-site alteration located within the TPMT gene on chromosome 6. It defines the pharmacogenetic TPMT*4 allele, which disrupts proper pre-mRNA processing and abolishes normal thiopurine methyltransferase enzyme activity. Carrying this variant is associated with an elevated risk of severe, dose-dependent bone marrow toxicity when taking thiopurine immunosuppressant or chemotherapeutic 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 rs11558494 and Where Is It Located?
The single nucleotide polymorphism designated rs11558494 represents a single base transition (c.414+1G>A) within the human TPMT gene, located on chromosome 6. Specifically, this variant alters an invariant guanine nucleotide at the splice-donor consensus site at the intron-exon boundary. In standard pharmacogenetic nomenclature curated by resources such as PharmGKB, this sequence change definitively characterizes the TPMT*4 star allele. The human cellular splicing machinery depends on precise boundary motifs to accurately remove non-coding introns during messenger RNA (mRNA) maturation. Because this mutation damages the canonical junction, the cell is forced to either skip normal splicing cues or activate cryptic, alternate splice sites. This disruption results in aberrant mRNA transcripts that harbor frame-shifts or include extensive premature intronic sequences. Consequently, translation yields truncated, non-functional proteins or transcripts marked for rapid nonsense-mediated decay, entirely inactivating the enzyme produced from this mutant copy of the gene.
The Biological Role of the TPMT Enzyme
The TPMT gene encodes thiopurine S-methyltransferase, an essential cytosolic enzyme expressed in many human tissues, including circulating erythrocytes and the liver. TPMT is primarily responsible for the S-methylation—and thus enzymatic deactivation—of thiopurine compounds. These therapeutic agents include azathioprine, 6-mercaptopurine, and 6-thioguanine, which are widely prescribed as immunosuppressants for autoimmune conditions like Crohn's disease and rheumatoid arthritis, as well as essential chemotherapy for acute lymphoblastic leukemia. Under normal metabolic conditions, TPMT converts these cytotoxic parent drugs and intermediate metabolites into inactive methylated products. When TPMT function is defective, unmethylated drug precursors are shunted preferentially into an alternative metabolic pathway catalyzed by hypoxanthine phosphoribosyltransferase. This alternative cascade generates cytotoxic thioguanine nucleotides (TGNs). When incorporated into cellular DNA and RNA, elevated TGN concentrations induce systemic cell death and profound hematopoietic myelosuppression.
Strength of Clinical Evidence and Drug Response Associations
In pharmacogenomics, TPMT variation is among the most well-characterized predictors of adverse drug reactions, with evidence curated by consortia like the Clinical Pharmacogenetics Implementation Consortium (CPIC). However, the specific evidence base for rs11558494 itself is classified as limited in population catalogs primarily because of its extreme rarity, rather than uncertainty about its biochemical consequence. Classic pedigree investigations published in the Journal of Clinical Investigation demonstrated that kindreds carrying this specific splice disruption exhibit complete loss of TPMT activity and autosomal recessive patterns of inheritance. Individuals who carry one non-functional allele (intermediate metabolizers) or two non-functional alleles (poor metabolizers) experience dramatically heightened risks of life-threatening leukopenia, neutropenia, and infection if prescribed conventional thiopurine dosages. While more common alleles like TPMT*3A account for the vast majority of cases, rs11558494 represents a fully inactivating null allele when encountered.
What Readers Should Do With This Information
Genetic data regarding rs11558494 provide educational insight into individual metabolic pathways, but they should never be interpreted as an independent medical diagnosis. Possessing a non-functional TPMT variant causes no known baseline symptoms or health complications during ordinary life; clinical vulnerabilities emerge strictly upon exposure to thiopurine pharmaceuticals. A non-carrier finding on a consumer test also does not guarantee normal drug clearance, as standard consumer panels do not evaluate all low-activity TPMT alleles or alternative thiopurine-processing genes such as NUDT15. Patients who are preparing for or currently undergoing treatment with azathioprine or mercaptopurine should never alter, stop, or adjust their prescribed dose based on raw genetic reports. Any medication concerns must be reviewed with a qualified physician or clinical pharmacologist, who can order comprehensive Clinical Laboratory Improvement Amendments (CLIA)-certified genotyping or measure baseline erythrocyte TPMT enzyme activity directly.
How common is this variant?
The rs11558494 variant is an extremely rare allele globally, with a minor allele frequency documented at under 0.0002 in broad population databases such as gnomAD. Almost all individuals worldwide carry the homozygous wild-type GG genotype.
Frequently asked questions
What is rs11558494?
The rs11558494 SNP is a rare genetic variant situated in the TPMT gene that defines the TPMT*4 allele. It disrupts a vital RNA splicing junction, preventing normal production of the functional thiopurine methyltransferase enzyme.
Does having this variant cause everyday health problems?
No. Inheriting rs11558494 is not linked to any spontaneous health conditions, symptoms, or physical impairments in daily life. Its clinical significance appears only when an individual is prescribed specific thiopurine medications.
Which medications are affected by the TPMT gene?
The TPMT enzyme metabolizes thiopurine immunosuppressive and antineoplastic drugs, including azathioprine, 6-mercaptopurine, and 6-thioguanine. These medications are commonly prescribed for autoimmune disorders and certain leukemias.
Should I change my medication if I have this variant?
No, you should never alter, adjust, or discontinue your prescribed medication on your own. Always consult your prescribing physician or clinical pharmacist, who can order validated diagnostic testing to confirm drug metabolism safely.
Sources & further reading
Educational information only, last refreshed 9/9/2026. Not medical advice — these associations describe population statistics, not individual predictions.
Curious what your genotype is for rs11558494?
Upload a raw DNA file from 23andMe, AncestryDNA, MyHeritage, or FamilyTreeDNA and see this variant — plus thousands more — interpreted in your full report.
Get my report — $29