DPYD rs75017182: Fluoropyrimidine Toxicity and HapB3
The rs75017182 variant is a deep intronic single nucleotide polymorphism in the DPYD gene, historically identified as the functional driver of the HapB3 haplotype. Carrying the altered allele is linked to reduced activity of dihydropyrimidine dehydrogenase (DPD), an enzyme critical for breaking down fluoropyrimidine chemotherapies like 5-fluorouracil and capecitabine. Individuals who carry this variant are classified as having decreased enzyme activity and face an elevated risk of severe or life-threatening drug-induced toxicity.
What each genotype means
Normal enzyme activity
You carry two reference copies at this position and do not carry the deep intronic HapB3 risk allele. Individuals with this genotype typically have standard dihydropyrimidine dehydrogenase (DPD) function from this site, though other genetic markers can still alter metabolism. If fluoropyrimidine-based chemotherapy is ever considered, discuss full DPYD screening and dosing considerations with your physician or pharmacist.
Carried by approximately 96% to 98% of people of European descent and nearly 100% of individuals of East Asian ancestry.
Reduced enzyme activity
You carry one copy of the c.1129-5923C>G (HapB3) variant, which is associated with partially reduced dihydropyrimidine dehydrogenase (DPD) enzymatic activity. Research shows that carriers treated with standard doses of fluoropyrimidine drugs such as capecitabine or 5-fluorouracil face an increased risk of severe, potentially life-threatening drug toxicity. If you are ever prescribed fluoropyrimidine chemotherapy, discuss this finding with your oncologist or pharmacist, as clinical guidelines recommend dose reductions.
Carried by approximately 2% to 4% of individuals of European ancestry, but it is rare or absent in East Asian populations.
Severely reduced enzyme activity
You carry two copies of the c.1129-5923C>G (HapB3) variant, which is associated with significantly decreased dihydropyrimidine dehydrogenase (DPD) enzymatic capacity. Population research indicates that individuals with severe DPD deficiency have a substantial risk of severe to fatal toxicity if exposed to standard doses of fluoropyrimidine chemotherapies. If treatment with 5-fluorouracil or capecitabine is ever considered, immediately consult your physician or pharmacist regarding alternative medications or substantial dose modifications.
Extremely rare across all ancestral populations, occurring in fewer than 1 in 2,500 individuals globally.
What Is rs75017182 and Where Is It Located?
The genetic variant rs75017182 is located within intron 10 of the DPYD gene on chromosome 1, designated at the cDNA level as c.1129-5923C>G. Because it lies thousands of base pairs away from coding exons, it is classified as a deep intronic variant. For many years, pharmacogenomic arrays did not sequence deep into introns and instead tagged the underlying HapB3 haplotype using a linked synonymous exonic variant, c.1236G>A (rs56038477). Functional molecular studies revealed that rs75017182 is itself the causative variant. The single base substitution creates a cryptic splice donor site in pre-mRNA processing, leading to the mis-splicing of an aberrant 44-base-pair pseudo-exon into the mature messenger RNA. This aberrant insertion disrupts the reading frame, producing a truncated, nonfunctional enzyme subunit and significantly lowering the overall cellular pool of active dihydropyrimidine dehydrogenase.
The Biological Role of the DPYD Gene
The DPYD gene provides instructions for creating dihydropyrimidine dehydrogenase (DPD), a rate-limiting metabolic enzyme primarily active in liver tissue. DPD is responsible for the catabolism of endogenous pyrimidines, uracil and thymine, breaking them down into inactive metabolites. In oncology, this same pathway is essential because DPD processes and eliminates more than 80% of an administered dose of fluoropyrimidine chemotherapies, which include 5-fluorouracil (5-FU) and its oral prodrug, capecitabine. When DPD enzyme activity is compromised, the clearance of these active cytotoxic compounds slows down dramatically. As a result, active metabolites accumulate in normal tissues, leading to severe cellular damage across rapidly dividing compartments such as the bone marrow and the mucosal lining of the gastrointestinal tract.
Clinical Research and Evidence on Drug Toxicity
Carriers of the rs75017182 risk allele exhibit approximately a 25% to 35% reduction in overall DPD functional capacity per copy. Clinical pharmacogenetic bodies, including the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG), evaluate rs75017182 as a decreased-function allele with an assigned activity score of 0.5. Large clinical cohorts demonstrate that cancer patients carrying this variant face a significantly increased risk of grade 3 or higher toxicities when receiving standard full-dose fluoropyrimidines. Common manifestations include profound neutropenia, thrombocytopenia, severe diarrhea, mucositis, hand-foot syndrome, and dehydration. While some clinical trials have reported variable hazard ratios depending on tumor site and polychemotherapy regimens, broad international consensus classifies this variant as clinically actionable, recommending pre-emptive dose reductions to prevent severe adverse outcomes.
Population Frequency and Ancestry Patterns
The prevalence of the rs75017182 minor allele varies substantially across global populations. It is most frequently detected in individuals of European ancestry, where the minor allele frequency typically ranges between 1% and 2.6%, meaning roughly 2% to 4% of European individuals are heterozygous carriers. Similar carrier rates are observed in certain admixed Latin American populations, such as southern Brazilian cohorts. In contrast, rs75017182 is exceedingly rare or virtually absent in East Asian and African populations, where alternative DPYD variants or distinct genetic risk factors may predominate. South Asian cohorts exhibit intermediate frequencies that are higher than East Asian groups but often lower than Western European populations. Because variant distributions are ancestry-dependent, commercial testing panels tailored strictly to European markers may not capture risk alleles in other backgrounds.
Practical Implications and Next Steps for Patients
Discovering an rs75017182 carrier genotype on a personal genomic report does not signify illness or mean that cancer treatments cannot be used. Under normal circumstances, partial DPD deficiency causes no noticeable symptoms or health problems in day-to-day life. However, if chemotherapy with 5-fluorouracil, capecitabine, or related antimetabolite agents is ever considered, this genetic information becomes critically important. Major medical guidelines recommend that intermediate metabolizers receive an upfront chemotherapy dose reduction—frequently starting at 50% of the normal dosage—followed by close clinical monitoring and subsequent dose titration. Readers should never alter prescribed medical treatments or assume medical risk independently; instead, bring these genetic results to an oncologist, medical geneticist, or specialized pharmacotherapy pharmacist for comprehensive clinical evaluation.
How common is this variant?
The minor allele frequency for rs75017182 is roughly 0.01 to 0.02 in populations of European ancestry, resulting in a carrier frequency of about 2% to 4%, while it is extremely rare or undetectable in East Asian and African cohorts.
Frequently asked questions
What does a positive rs75017182 test mean for my health?
In daily life, carrying this variant causes no symptoms and does not affect your health or lifespan. Its significance appears almost exclusively if you ever require treatment with fluoropyrimidine chemotherapy drugs such as capecitabine or 5-fluorouracil. In that specific setting, it indicates a lower ability to break down the medicine, raising the risk of severe side effects.
What is the HapB3 haplotype in DPYD testing?
HapB3 is a specific genetic haplotype in the DPYD gene that was originally linked to the synonymous marker c.1236G>A (rs56038477). Modern research demonstrated that the deep intronic variant rs75017182 (c.1129-5923C>G) is the true functional driver of HapB3, altering mRNA splicing and reducing active DPD enzyme levels. Many commercial clinical panels now directly test rs75017182 to evaluate this risk.
Can people with this variant still receive chemotherapy?
Yes, carrying this variant does not mean you cannot receive cancer treatment. International clinical guidelines from groups like CPIC advise starting fluoropyrimidines at a substantially reduced dose (often around 50%) for heterozygous carriers. Clinicians then monitor drug tolerance and blood counts closely, adjusting doses upward as tolerated.
Should my family members be tested for rs75017182?
Routine population screening for healthy family members is generally not recommended unless an individual has been diagnosed with a cancer that requires fluoropyrimidine therapy. Because this variant is inherited, first-degree relatives have a 50% chance of carrying it, making targeted pre-treatment testing helpful if they ever face chemotherapy decisions.
Sources & further reading
Educational information only, last refreshed 9/13/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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This intronic variant is a marker for reduced DPYD enzyme activity, increasing the risk of severe toxicity from fluoropyrimidine-based chemotherapies.
This variant is linked to decreased dihydropyrimidine dehydrogenase activity, increasing the risk of severe toxicity during fluoropyrimidine chemotherapy.
Defines the DPYD*7 variant (p.Leu311Phe) associated with impaired pyrimidine metabolism and potential fluoropyrimidine toxicity.
Constitutes the DPYD*13 variant (p.Ile560Thr), associated with significantly reduced DPYD enzyme activity and increased risk of severe fluoropyrimidine toxicity.
Also designated as DPYD c.557A>G (p.Tyr186Cys), this variant significantly decreases dihydropyrimidine dehydrogenase activity and predisposes patients to severe fluoropyrimidine toxicity.
Causes the c.2846A>T (p.Asp949Val) missense change in DPYD, associated with reduced enzyme activity and increased risk of fluoropyrimidine-associated toxicity.