What you carry at this position in your DNA and what research says about it.
Thiopurine Toxicity Risk: 9/10 evidence, 9 publications.
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Sample genotype (not yours): C/C
Normal Thiopurine Metabolism
Standard doses of thiopurine medications are typically processed normally without an elevated risk of severe bone marrow toxicity. This genotype represents the standard, fully functional enzyme activity.
What this genotype means: Normal thiopurine drug metabolism; Standard starting doses of thiopurines typically tolerated.
Sample genotype (not yours): C/T
High Thiopurine Toxicity Risk
One copy of the variant allele substantially reduces NUDT15 enzyme activity, which is associated with a higher risk of severe white blood cell depletion during thiopurine therapy. NUDT15 is one of the genes clinical guidelines take into account for these medicines.
What this genotype means: Reduced thiopurine drug metabolism; Increased risk of early-onset leukopenia; Lower starting doses of thiopurines recommended.
Sample genotype (not yours): T/T
Extreme Thiopurine Toxicity Risk
Two copies of the variant allele cause a complete loss of NUDT15 enzyme activity, leading to life-threatening bone marrow toxicity and severe hair loss if standard thiopurine doses are used. Severely reduced tolerance to thiopurine medications. This is a well-established, clinically actionable finding to raise with your prescriber before treatment.
What this genotype means: Complete loss of NUDT15 enzyme activity; Extreme risk of life-threatening bone marrow toxicity; Extreme risk of early-onset severe hair loss.
Gene function and biological role
Gene Function: The NUDT15 gene encodes an enzyme called nudix hydrolase 15, which plays a critical role in cleaning up damaged or toxic nucleotides within cells [1]. Specifically, this enzyme acts as a safeguard by dephosphorylating active, cytotoxic thiopurine metabolites, preventing them from being mistakenly incorporated into DNA [2]. When these toxic metabolites are successfully cleared, cells are protected from unintended DNA damage and programmed cell death [2]. However, genetic variations that reduce or eliminate NUDT15 enzyme activity allow these toxic compounds to build up, leading to severe cellular damage, particularly in bone marrow cells [1] [2].
Variant Impact: The rs116855232 variant represents a missense mutation in the NUDT15 gene, resulting in the replacement of the amino acid arginine with cysteine at position 139 of the protein [1]. This specific amino acid change, often referred to as the NUDT15*3 allele, dramatically destabilizes the enzyme's structure and disrupts its active binding pocket [1] [2]. As a result, the variant enzyme exhibits a near-complete loss of its ability to break down active thiopurine drug metabolites [2]. This loss of function leads to an excessive accumulation of active, toxic drug compounds in the body, which can trigger severe bone marrow suppression and other adverse reactions when standard doses of thiopurines are administered [1] [2].
Key Insight: While genetic testing for thiopurine sensitivity historically focused almost exclusively on the TPMT gene, research has revealed that NUDT15 variants are actually the primary driver of thiopurine toxicity in East Asian and Hispanic populations.
Location: NUDT15. Chromosome 13 · 13q14.2 · 48.0 Mb
Estimated prevalence by population
Global 97.6%; European 99.4%; African 99.8%; East Asian 80.8%; South Asian 86.3%; Americas 93.0%; Ashkenazi 99.4%; Finnish 95.7%; Middle Eastern 99.3%; Amish 100.0%.
Estimated CC genotype frequency.
Global 2.4%; European 0.6%; African 0.2%; East Asian 18.2%; South Asian 13.2%; Americas 6.9%; Ashkenazi 0.6%; Finnish 4.2%; Middle Eastern 0.7%; Amish 0.0%.
Estimated CT genotype frequency.
Global 0.1%; European < 0.1%; African < 0.1%; East Asian 1.0%; South Asian 0.5%; Americas 0.1%; Ashkenazi < 0.1%; Finnish < 0.1%; Middle Eastern < 0.1%; Amish 0.0%.
Estimated TT genotype frequency.
Showing effects for C/C genotype
Pharmacogenomics
Immunosuppressant & Biologic Response
Thiopurine Sensitivity. Evidence: 9/10. Source: PMID 25108385. Typical Sensitivity.
Mercaptopurine Toxicity. Evidence: 9/10. Source: PMID 25624441. Normal Tolerance.
Cardiovascular & Metabolic
Blood Cell & Iron Traits
White Blood Cell Drop. Evidence: 9/10. Source: PMID 25108385. Typical Risk.
Organ Systems
Pigmentation & Appearance
Hair Loss. Evidence: 9/10. Source: PMID 26076924. Typical Risk.
Showing effects for C/T genotype
Thiopurine Sensitivity. Evidence: 9/10. Source: PMID 25108385. High Sensitivity.
Mercaptopurine Toxicity. Evidence: 9/10. Source: PMID 25624441. Reduced Tolerance.
White Blood Cell Drop. Evidence: 9/10. Source: PMID 25108385. Increased Risk.
Hair Loss. Evidence: 9/10. Source: PMID 26076924. Increased Risk.
Showing effects for T/T genotype
Thiopurine Sensitivity. Evidence: 9/10. Source: PMID 25108385. Extreme Sensitivity.
Mercaptopurine Toxicity. Evidence: 9/10. Source: PMID 25624441. Severely Low Tolerance.
White Blood Cell Drop. Evidence: 9/10. Source: PMID 25108385. Extreme Risk.
Hair Loss. Evidence: 9/10. Source: PMID 26076924. Extreme Risk.
What this genotype means for the people who carry it
Sample genotype: CC (Homozygous)
Standard processing of thiopurine medications like azathioprine and mercaptopurine is expected with this genotype, as both copies of the NUDT15 gene produce fully functional enzymes [1]. Because the enzyme successfully breaks down active, cytotoxic drug metabolites, the risk of severe, early-onset white blood cell depletion is not elevated [1] [2]. Clinical guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC) suggest that individuals with this normal-functioning genotype can typically start thiopurine therapies at standard, full doses [2]. While other genes like TPMT also influence how these medications are processed, having two normal copies of NUDT15 avoids the specific risk of extreme toxicity associated with this locus [1] [2]. It is still important for healthcare providers to monitor blood counts during therapy, but standard dosing is the typical starting point [2].
Normal thiopurine drug metabolism; Standard starting doses of thiopurines typically tolerated.
Sample genotype: CT (Heterozygous)
An intermediate level of enzyme activity results from possessing one copy of the NUDT15*3 variant allele, as only one copy of the gene produces a fully functional enzyme [1]. This partial loss of function leads to a reduced ability to clear active thiopurine drug metabolites, which can accumulate and cause bone marrow toxicity [1] [2]. Clinical studies show that individuals with this genotype have a significantly higher risk of developing early-onset leukopenia, a dangerous drop in white blood cells, when treated with standard doses of azathioprine or mercaptopurine [2] [3]. This variant is particularly common in East Asian and Hispanic populations [2] [3].
Reduced thiopurine drug metabolism; Increased risk of early-onset leukopenia; Lower starting doses of thiopurines recommended.
Sample genotype: TT (Homozygous)
A complete loss of NUDT15 enzyme activity occurs when two copies of the NUDT15*3 variant allele are present, leaving the body unable to degrade active thiopurine metabolites [1]. Standard doses of medications like azathioprine, mercaptopurine, or thioguanine will lead to a rapid, life-threatening accumulation of toxic compounds in the bone marrow [1] [2]. This accumulation causes extreme myelosuppression, characterized by a profound drop in white blood cells, and can also trigger severe, early-onset hair loss [2] [3]. Because the risk of severe adverse events is nearly universal for this genotype under standard dosing, identifying this genetic status before starting treatment is critical [2] [3]. This variant is most frequently observed in individuals of East Asian and South Asian descent, where its prevalence is highest [1] [2].
Complete loss of NUDT15 enzyme activity; Extreme risk of life-threatening bone marrow toxicity; Extreme risk of early-onset severe hair loss; Severely reduced tolerance to thiopurines.
Variants with shared genetic architecture
rs1800462 · TPMT Gene · Chr 6 · Thiopurine Drug Sensitivity
rs1127354 · ITPA Gene · Chr 20 · Thiopurine Drug Sensitivity
rs1142345 · TPMT Gene · Chr 6 · Thiopurine Drug Sensitivity
NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity.
A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia.
Content updated August 2026.
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