NUDT15 rs11689614: What Your Genotype Means
The genetic variant rs11689614 is a well-characterized missense substitution in the NUDT15 gene, historically defining the non-functional NUDT15*3 allele. Carrying this variant leads to reduced or absent enzyme activity, preventing the normal inactivation of cytotoxic thiopurine metabolites. Consequently, individuals with this variant face a significantly elevated risk of severe, potentially life-threatening thiopurine-induced bone marrow suppression (leukopenia).
What each genotype means
Normal enzyme activity
This genotype is considered the wild-type or normal-functioning state for this variant. Individuals with this profile typically have standard metabolic capacity for thiopurine medications. Please discuss your medication dosing and any concerns regarding potential side effects with your clinician or pharmacist.
This is the most common genotype globally, found in the vast majority of individuals across all ancestral populations.
Intermediate enzyme activity
This genotype indicates you carry one copy of the variant allele, often referred to in literature as the *3 allele (p.Arg139Cys). Research suggests this may lead to reduced enzyme activity, which can increase the risk of thiopurine-induced leukopenia compared to those with the CC genotype. You should discuss your specific medication dosing and monitoring requirements with your healthcare provider or pharmacist.
This genotype is carried by approximately 10-15% of East Asian populations and 6-8% of Hispanic populations, but is found in less than 1% of individuals of European ancestry.
Poor enzyme activity
This genotype indicates you carry two copies of the variant allele, which is associated with severely reduced or absent NUDT15 enzyme activity. This profile confers a high risk of life-threatening thiopurine-induced leukopenia, as the body cannot properly metabolize these drugs. It is critical that you discuss this result with your clinician or pharmacist before starting or continuing any thiopurine therapy.
This genotype is rare, occurring most frequently in populations with higher frequencies of the *3 allele, such as those of East Asian or Hispanic descent.
What Is rs11689614 and Where Is It Located?
The single nucleotide polymorphism rs11689614 is located in exon 3 of the NUDT15 gene on chromosome 13. At the molecular level, it represents a single base transition (c.415C>T) that leads to an amino acid substitution of arginine to cysteine at codon 139 (p.Arg139Cys). In pharmacogenetic nomenclature, this variant is the defining polymorphism of the star allele NUDT15*3. The NUDT15 gene encodes an enzyme belonging to the Nudix hydrolase family. Under normal circumstances, this enzyme hydrolyzes active thiopurine nucleoside diphosphates and triphosphates (such as TGTP and TdGTP) into their less toxic monophosphate forms. The p.Arg139Cys substitution severely destabilizes the resulting protein structure, causing rapid cellular degradation and leading to a near-total loss of functional enzymatic activity in affected tissues.
The Biological Role of NUDT15 in Thiopurine Clearance
Thiopurine medications—including 6-mercaptopurine, azathioprine, and thioguanine—are widely used immunosuppressants and antimetabolites prescribed for acute lymphoblastic leukemia, autoimmune conditions, and inflammatory bowel disease. Once absorbed, these prodrugs are converted into thioguanine nucleotides (TGNs). When incorporated into cellular DNA and RNA, these metabolites trigger cell cycle arrest and apoptosis. NUDT15 acts as a vital negative regulator of this pathway: it cleanses the cell of toxic nucleotide forms by hydrolyzing thioguanine triphosphate back into thioguanine monophosphate. When NUDT15 enzymatic function is impaired by the rs11689614 variant, these active cytotoxic metabolites accumulate unchecked within hematopoietic cells. This leads to premature cell death of bone marrow precursors, resulting in severe myelosuppression and systemic leukopenia.
Research Evidence and Clinical Actionability
Initially discovered in genome-wide association studies evaluating thiopurine sensitivity in pediatric leukemia and inflammatory bowel disease patients, rs11689614 is one of the most clinically validated pharmacogenomic variants. Multiple international studies have confirmed that carriers experience dose-dependent adverse drug reactions, including acute hair loss (alopecia) and severe neutropenia within weeks of beginning therapy. The Clinical Pharmacogenetics Implementation Consortium (CPIC) assigns NUDT15*3 a definitive 'no function' status. CPIC guidelines explicitly advise adjusting the starting doses of azathioprine, mercaptopurine, or thioguanine based on NUDT15 and TPMT status. Intermediate and poor metabolizers typically require substantially reduced starting doses or alternative therapeutic agents to avert severe hematologic toxicity.
Ancestry and Population Frequency Variations
The allele frequency of rs11689614 varies dramatically across global ancestral groups. The variant allele (T) is most prevalent in East Asian populations, where its frequency reaches approximately 10% to 15%, leading to roughly 1% to 2% of individuals carrying two non-functional copies (poor metabolizers). It is also frequently detected among individuals of Hispanic or Latino ethnicity—particularly those with significant Native American (Amerindian) genetic admixture—where allele frequencies range between 6% and 8%. In contrast, the variant is rare in European populations, occurring at an allele frequency of less than 1%, and is similarly infrequent in individuals of African ancestry. This stark divergence highlights the essential role of ancestry-aware pharmacogenetic testing.
Interpreting Your Results and Next Steps
Discovering an altered genotype at rs11689614 does not denote an active disease or cause everyday health symptoms; the variant is strictly pharmacogenetic and dormant in the absence of thiopurine drug exposure. If you carry one or two copies of the T allele and require treatment with thiopurine medications, personalized dosing can significantly reduce your risk of adverse reactions. However, genetic data should never prompt self-directed changes in medication. Always provide your complete pharmacogenomic report to your physician, oncologist, or clinical pharmacist, who can interpret your results in the context of your overall regimen, organ function, and concurrent TPMT status.
How common is this variant?
The rs11689614 variant allele is common in East Asian (10-15%) and Hispanic/Amerindian populations (6-8%), while remaining rare (<1%) among individuals of European and African descent.
Frequently asked questions
What is the NUDT15 rs11689614 variant?
The rs11689614 variant is a genetic change in the NUDT15 gene (p.Arg139Cys) that eliminates the function of the NUDT15 enzyme. It defines the NUDT15*3 allele, which is strongly linked to thiopurine drug intolerance.
Does having rs11689614 mean I have a disease?
No, carrying this variant is not an illness and causes no physical symptoms during regular day-to-day life. It only becomes medically significant if you are prescribed thiopurine medications such as azathioprine or mercaptopurine.
Which medications are affected by NUDT15 variations?
NUDT15 variants primarily affect thiopurine drugs, including mercaptopurine, azathioprine, and thioguanine. These medications are commonly prescribed for childhood leukemia, inflammatory bowel disease (Crohn's and ulcerative colitis), and autoimmune disorders.
How does NUDT15 differ from TPMT?
Both TPMT and NUDT15 enzymes break down toxic thiopurine metabolites, but they operate through different biochemical pathways. TPMT variants are common in European populations, whereas NUDT15 variants are far more frequent in individuals of East Asian and Hispanic descent.
What should I do if my test shows I carry the T allele?
You should share this genetic report directly with your prescribing physician or pharmacist before starting any thiopurine therapy. They can calculate tailored dosages or choose alternative treatments to protect you from severe medication side effects.
Sources & further reading
Educational information only, last refreshed 9/7/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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This variant is often confused with the primary NUDT15*3 (p.Arg139Cys) variant, which is rs116855232. rs116822326 is a distinct NUDT15 variant.
Missense variant (p.Val18Ile) defining the NUDT15*2 haplotype, associated with reduced thiopurine tolerance.
Splice/intronic regulatory modifier in NUDT15 associated with reduced enzyme level and enhanced susceptibility to thiopurine-induced severe leukopenia.
NUDT15 c.55_56insGAGTCG (p.Val18_Gly19insGlyVal) defining the NUDT15*6 allele, associated with reduced enzyme activity and increased risk of thiopurine-induced leukopenia.
This variant is a defining marker for NUDT15 star alleles (*2, *6, *9) which are critical for predicting thiopurine-induced toxicity.
This variant (NUDT15 *3) is the primary predictor of severe, life-threatening bone marrow toxicity when taking thiopurine drugs.