NUDT15 rs746071566: What Your Genotype Means
The rs746071566 variant is a specific genetic marker located within the NUDT15 gene. It is recognized as a defining component of certain star alleles that influence how the body processes thiopurine medications, which are often used to treat leukemia and autoimmune conditions.
What each genotype means
Normal enzyme activity
This genotype represents the typical sequence for the NUDT15 gene. Individuals with this profile are generally expected to have normal NUDT15 enzyme activity, which is involved in the metabolism of thiopurine medications. Please discuss your medication plan and any potential side effects with your clinician or pharmacist.
This is the most common genotype observed across all global populations.
Reduced enzyme activity
This genotype includes one copy of the variant (c.50_55dup), which is a defining marker for NUDT15 star alleles such as *6. Research indicates that this variant can lead to reduced NUDT15 enzyme activity, potentially increasing the risk of thiopurine-induced toxicity. Please consult your healthcare provider or pharmacist regarding appropriate dosing if you are prescribed thiopurine medications.
This genotype is found at low frequencies, with higher prevalence observed in certain East Asian populations compared to others.
Significantly reduced enzyme activity
This genotype includes two copies of the variant, which is associated with significantly decreased or absent NUDT15 enzyme function. Individuals with this profile may be at a substantially higher risk for severe hematopoietic toxicity when taking thiopurine drugs. It is essential to discuss this genetic finding with your clinician or pharmacist before starting or continuing any thiopurine therapy.
This genotype is rare in the general population.
Understanding the rs746071566 Variant
The rs746071566 variant is a genetic alteration involving a small insertion of six base pairs (often described as 36GGAGTC) within the NUDT15 gene. In the context of genomics, this is classified as an in-frame insertion. The NUDT15 gene is located on chromosome 13 and provides instructions for creating the Nudix hydrolase 15 enzyme. This enzyme plays a critical role in "nucleotide sanitation," a process that helps maintain cellular health by breaking down potentially harmful or excess nucleotide metabolites. Because of its specific location and functional impact, rs746071566 is used by researchers and clinicians as a diagnostic marker to identify specific NUDT15 star alleles, such as *6, which are associated with altered enzyme function.
The Role of NUDT15 in Drug Metabolism
Thiopurines, such as azathioprine and mercaptopurine, are potent medications used to manage conditions like acute lymphoblastic leukemia and inflammatory bowel disease. These drugs work by interfering with DNA synthesis in rapidly dividing cells. The NUDT15 enzyme acts as a metabolic regulator by dephosphorylating the active metabolites of these drugs, effectively preventing them from accumulating to toxic levels in the body. When an individual carries variants like rs746071566 that reduce the activity of this enzyme, the body may struggle to clear the drug metabolites efficiently. This can lead to an accumulation of the active drug, which significantly increases the risk of severe side effects, most notably myelosuppression, a condition where bone marrow activity decreases and blood cell counts drop dangerously low.
Research and Clinical Significance
Scientific research has established a strong link between NUDT15 variants and thiopurine-induced toxicity. Studies, including those published in journals like Human Genomics, have demonstrated that specific NUDT15 star alleles containing this variant can result in a 74% to 100% loss of enzymatic function compared to the wild-type (normal) version of the gene. The evidence strength for these associations is considered moderate to high in the field of pharmacogenomics. Because of these findings, clinical guidelines from organizations like the Clinical Pharmacogenetics Implementation Consortium (CPIC) emphasize the importance of NUDT15 testing. By identifying these variants before starting treatment, clinicians can adjust dosages to minimize the risk of toxicity while maintaining therapeutic efficacy. This is a hallmark example of how genetic information can be used to personalize medical treatment.
Population Frequency and Distribution
The frequency of NUDT15 variants varies significantly across different global populations. While the rs746071566 variant is generally considered rare, its presence is more notable in specific ancestral groups. Research indicates that NUDT15 deficiency is most common among East Asian, South Asian, and certain Native American populations. For instance, while some high-risk alleles are relatively abundant in parts of East Asia, they are much less common in European populations. Understanding these population-specific frequencies is essential for clinicians, as it helps determine which patients might benefit most from pre-treatment genetic screening. Because the distribution is not uniform, genetic testing provides a more accurate assessment of an individual's specific risk profile than relying on population averages alone.
What You Can Do With This Information
If you have received results regarding your NUDT15 genotype, it is important to understand that this information is primarily intended for clinical decision-making regarding specific medications. You cannot use this information to diagnose yourself or to make changes to your current medication regimen. If you are prescribed thiopurines, you should discuss your genetic status with your physician or pharmacist. They are the only ones qualified to interpret these results in the context of your overall health and to determine if a dosage adjustment is necessary. Always keep your healthcare provider informed about any genetic testing you have undergone, as this data can be a valuable tool in ensuring your treatment plan is both safe and effective for your unique genetic makeup.
How common is this variant?
The rs746071566 variant is generally rare, though specific NUDT15 variants are more prevalent in East Asian, South Asian, and Native American populations compared to European populations.
Frequently asked questions
What is the NUDT15 gene?
The NUDT15 gene provides instructions for making an enzyme that helps break down thiopurine drugs. This process is essential for preventing the buildup of toxic drug levels in the body.
Why is NUDT15 testing important?
Testing helps identify individuals who may be at a higher risk for severe side effects from thiopurine medications. This allows doctors to adjust dosages to keep patients safe.
Does having a NUDT15 variant mean I cannot take thiopurines?
Not necessarily. Having a variant often means your doctor may need to start you on a lower dose or monitor your blood counts more closely to ensure the medication is safe for you.
Is NUDT15 testing standard for everyone?
It is not standard for everyone, but it is frequently recommended for patients who are about to start thiopurine therapy, especially in populations where these variants are more common.
Where can I get tested for NUDT15?
NUDT15 testing is typically ordered by a specialist, such as a gastroenterologist or oncologist, through a clinical laboratory. You should speak with your doctor if you believe this test is relevant to your treatment.
Sources & further reading
Educational information only, last refreshed 10/7/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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This variant (NUDT15 *3) is the primary predictor of severe, life-threatening bone marrow toxicity when taking thiopurine drugs.
This rare variant in the NUDT15 gene is investigated for its potential impact on thiopurine-induced leukopenia in pediatric acute lymphoblastic leukemia patients.
A recurring low-frequency missense variant (p.Val18Ile) defining the NUDT15*2 haplotype, reducing thiopurine tolerance in pediatric leukemia patients.
Splice/intronic regulatory modifier in NUDT15 associated with reduced enzyme level and enhanced susceptibility to thiopurine-induced severe leukopenia.
This missense change (NUDT15 p.Arg139Cys, defining the *3 allele) substantially reduces enzyme activity and confers high risk of life-threatening thiopurine-induced leukopenia.
NUDT15 c.55_56insGAGTCG intermediate-activity allele (defining NUDT15*6), associated with severe thiopurine-induced leukopenia in Asian and Hispanic populations.