DPYD rs11558498: Fluoropyrimidine Toxicity Risk
The rs11558498 variant is a single nucleotide polymorphism in the DPYD gene, which encodes the dihydropyrimidine dehydrogenase (DPD) enzyme responsible for metabolizing fluoropyrimidine chemotherapy drugs. Also known as c.2194G>A or p.Val732Ile, this missense change has been investigated for potential reductions in enzymatic function and mild increases in chemotherapy toxicity risk. Current evidence for its standalone clinical impact remains limited and mixed compared to major DPYD risk alleles.
What each genotype means
Normal enzyme activity
This genotype represents the most common form of the DPYD gene, often referred to as the wild-type or normal function state. Individuals with this profile typically possess standard dihydropyrimidine dehydrogenase enzyme activity, which is responsible for breaking down fluoropyrimidine medications like 5-fluorouracil and capecitabine. While this is considered the standard profile, you should always discuss any planned chemotherapy with your oncologist or pharmacist to ensure appropriate dosing.
This is the most common genotype, found in the vast majority of individuals across all global populations.
Reduced enzyme activity
This genotype includes one copy of the c.2194G>A variant, also known as the DPYD*6 allele. Research suggests this variant may be associated with decreased dihydropyrimidine dehydrogenase enzyme activity, which can potentially lead to an increased risk of severe toxicity when taking fluoropyrimidine-based chemotherapy. Because the evidence for this specific variant is considered limited compared to other DPYD mutations, you should discuss this result with your clinician or a pharmacist to determine if it impacts your specific treatment plan.
This genotype is carried by approximately 8% to 12% of individuals in European and Hispanic populations, though it is less common in other ancestral groups.
Likely reduced enzyme activity
This genotype indicates that both copies of your DPYD gene carry the c.2194G>A (p.Val732Ile) variant. This state is associated with a higher likelihood of reduced dihydropyrimidine dehydrogenase enzyme activity compared to those with the G/G genotype. If you are prescribed fluoropyrimidine medications, this may increase your risk of experiencing severe drug-related side effects; it is essential to consult with your healthcare provider or a clinical pharmacist before starting any such treatment.
This genotype is rare, occurring in less than 1% of the general population.
Genetic Identity and Molecular Characteristics
The single nucleotide polymorphism rs11558498 (frequently co-referenced in clinical literature alongside rs1801160 within the DPYD*6 allele definitions) represents a substitution of guanine (G) to adenine (A) at coding position 2194 (c.2194G>A) of the DPYD gene on chromosome 1. This change produces a missense mutation replacing valine with isoleucine at amino acid position 732 (p.Val732Ile). Because valine and isoleucine share similar nonpolar, branched-chain chemical structures, this amino acid substitution causes a relatively subtle structural modification to the dihydropyrimidine dehydrogenase protein rather than causing an overt truncation or loss of structural folding. As a result, its individual molecular impact on cellular protein stability is milder than that of classical canonical splice-site or frameshift disruptions.
Biological Function of the DPYD Gene
The DPYD gene provides instructions for making dihydropyrimidine dehydrogenase (DPD), an essential liver enzyme that performs the initial, rate-limiting step in pyrimidine catabolism. In endogenous metabolism, DPD breaks down uracil and thymine into inactive metabolites. In oncology, DPD serves a critical pharmacogenomic role by inactivating over 80% of administered fluoropyrimidine-based chemotherapies, primarily 5-fluorouracil (5-FU) and its oral prodrug capecitabine. If DPD enzymatic capacity is diminished, active cytotoxic fluoropyrimidine metabolites accumulate to toxic concentrations in the bloodstream. This systemic accumulation damages rapidly dividing non-cancerous tissues, leading to severe adverse drug reactions including neutropenia, thrombocytopenia, mucositis, and life-threatening gastrointestinal diarrhea.
Research Associations and Strength of Evidence
The Clinical Pharmacogenetics Implementation Consortium (CPIC) and European guidelines recognize four primary actionable DPYD variants (such as DPYD*2A, c.2846A>T, and HapB3) that unambiguously require dose reductions. In contrast, the evidence surrounding rs11558498 is categorized as limited or controversial. Some retrospective analyses and observational cohort studies report that carriers of the minor A allele exhibit modestly decreased DPD activity or an elevated odds ratio for grade 3 or higher fluoropyrimidine toxicity. However, other large clinical trials have failed to confirm a strong independent predictive effect once high-risk alleles are accounted for. Because its functional deficit is slight compared to fully inactivating alleles, experts consider its standalone predictive power for chemotherapy toxicity to be weak or uncertain.
Population Distribution and Ancestral Patterns
Unlike high-penetrance DPYD null alleles that are exceptionally rare, rs11558498 is relatively common across several ancestral groups. Population genomics datasets such as gnomAD show that the minor A allele occurs at an estimated minor allele frequency (MAF) of approximately 4% to 6% among populations of European and Hispanic ancestry, while it is observed at lower frequencies in individuals of East Asian and African descent. Because a non-trivial portion of the population carries at least one copy of this variant, understanding its true functional contribution is essential to avoid inappropriately withholding standard first-line chemotherapy regimens from individuals who may actually tolerate normal or near-normal fluoropyrimidine dosing.
Clinical Interpretation and Limitations
Genetic data regarding rs11558498 cannot be used in isolation to diagnose dihydropyrimidine dehydrogenase deficiency or to independently guide medical treatment. Established clinical prescribing guidelines by CPIC do not recommend automatic dose reductions based purely on the rs11558498 A allele alone. Patients planning to undergo chemotherapy with 5-fluorouracil or capecitabine should discuss their complete pharmacogenomic profile, including validated high-risk DPYD alleles, with their treating oncologist or clinical pharmacist. A clinician may also evaluate complementary phenotypic metrics, such as baseline plasma uracil concentrations, alongside clinical indicators, rather than relying on an ambiguous or low-penetrance single-nucleotide variant.
How common is this variant?
The minor A allele occurs at an estimated minor allele frequency of approximately 0.04 to 0.06 (4% to 6%) in European and Hispanic populations, while it is detected at lower frequencies across other global ancestries.
Frequently asked questions
Does carrying rs11558498 mean I am allergic to 5-FU?
No, carrying this variant is not an allergy. It reflects a variation in the DPYD gene that may modestly influence how efficiently your body breaks down fluoropyrimidine medications like 5-fluorouracil and capecitabine.
Will my oncologist reduce my chemotherapy dose if I have rs11558498?
Current CPIC and regulatory guidelines do not mandate dose modifications based solely on rs11558498, because evidence linking it to severe toxicity is limited compared to established high-risk DPYD markers. Your oncology team will evaluate your full genetic test results, renal and liver function, and overall health to determine your optimal dosing plan.
Is rs11558498 the same as the DPYD*2A variant?
No, they are distinct variants within the DPYD gene. DPYD*2A (c.1905+1G>A) causes a severe splice disruption resulting in an inactive enzyme with high clinical risk, whereas rs11558498 (c.2194G>A) causes a conservative amino acid substitution with much milder and less definitive functional consequences.
Can rs11558498 cause symptoms if I am not taking chemotherapy?
No. In individuals who are not receiving fluoropyrimidine drugs, carrying rs11558498 has no known health consequences or symptoms, as baseline pyrimidine degradation remains sufficient for normal biological function.
Sources & further reading
Educational information only, last refreshed 9/8/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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This variant is located in the DPYD gene, which is critical for the metabolism of fluoropyrimidine chemotherapy drugs.
This intronic variant is a well-established marker for reduced DPYD enzyme activity, significantly increasing the risk of severe toxicity when patients are treated with fluoropyrimidine-based chemotherapies like 5-fluorouracil.
This variant is linked to decreased dihydropyrimidine dehydrogenase activity, increasing the risk of severe toxicity during fluoropyrimidine chemotherapy.
A rare but high-risk variant for severe adverse reactions to chemotherapy.
Dramatically increases risk of life-threatening toxicity from 5-FU chemotherapy.
Associated with significantly reduced metabolism of fluoropyrimidine drugs.