CYP2C9 rs28371686: Understanding the CYP2C9*5 Variant
The single nucleotide polymorphism rs28371686 is a missense variant in the CYP2C9 gene that defines the star allele CYP2C9*5. This genetic alteration results in an amino acid substitution (p.Asp360Glu) that leads to significantly decreased enzymatic activity. As a result, individuals carrying this allele may clear certain narrow-therapeutic-index drugs, such as warfarin and phenytoin, more slowly than normal metabolizers.
What each genotype means
Normal enzyme activity
You carry two copies of the C allele, which is considered the reference version of this variant. Research indicates that individuals with this genotype typically have normal CYP2C9 enzyme activity, meaning your body is generally expected to metabolize medications like warfarin at standard rates.
This is the most common genotype worldwide, found in the vast majority of individuals across all ancestral backgrounds.
Reduced enzyme activity
You carry one copy of the C allele and one copy of the G allele, which defines the CYP2C9*5 allele. This genotype is associated with decreased CYP2C9 enzyme activity, which may result in a slower breakdown of certain medications; please discuss this result with your clinician or pharmacist.
Carried by approximately 1–2% of people with African ancestry and is rare in other populations.
Significantly reduced enzyme activity
You carry two copies of the G allele, known as the CYP2C9*5 allele. Research associates this genotype with a more pronounced reduction in CYP2C9 enzyme activity, which could influence how your body responds to therapy; discuss this genotype with your healthcare provider before starting or adjusting any medication metabolized by CYP2C9.
This genotype is very rare, appearing primarily in populations of African ancestry.
Genetic Location and Molecular Mechanism
The rs28371686 polymorphism sits within exon 7 of the CYP2C9 gene on human chromosome 10. At the molecular level, it represents a single base substitution where cytosine is replaced by guanine (c.1080C>G). This nucleotide change alters codon 360, exchanging the standard amino acid aspartic acid for glutamic acid (p.Asp360Glu). Within pharmacogenetic nomenclature established by the Pharmacogene Variation Consortium (PharmVar) and curated by the [Pharmacogenomics Knowledge Base (PharmGKB)](https://www.pharmgkb.org/gene/PA126), this specific missense variation defines the CYP2C9*5 allele. Alterations in this region modify the protein's conformational stability, impairing the catalytic pocket and reducing the rate at which the hepatic enzyme can process its physiological and pharmaceutical substrates.
The Biological Role of the CYP2C9 Enzyme
The CYP2C9 gene encodes Cytochrome P450 Family 2 Subfamily C Member 9, a vital phase I drug-metabolizing enzyme primarily expressed in the liver. CYP2C9 is responsible for the biotransformation and clearance of roughly fifteen to twenty percent of all clinically prescribed medications. Its substrates include oral anticoagulants like S-warfarin, anti-epileptics such as phenytoin, antidiabetic sulfonylureas, and various nonsteroidal anti-inflammatory drugs (NSAIDs) like celecoxib and ibuprofen. Under typical physiological conditions, standard CYP2C9 enzymes break down these substances into inactive metabolites for excretion. When genetic variants impede this metabolic pathway, medications can accumulate in the bloodstream, leading to prolonged drug exposure, unexpected pharmacological potency, and an increased risk of adverse toxic reactions.
Clinical Evidence and Pharmacogenomic Impact
The Clinical Pharmacogenetics Implementation Consortium ([CPIC](https://cpicpgx.org/genes-drugs/)) and the Association for Molecular Pathology classify CYP2C9*5 as a Tier 1 decreased-function allele. Because rs28371686 significantly curtails substrate clearance, carriers require lower maintenance doses of oral anticoagulants like warfarin to achieve therapeutic anticoagulation without provoking serious bleeding events. Similar effects have been observed with phenytoin, where decreased metabolism elevates the risk of central nervous system toxicity. While the overarching functional impact of CYP2C9 impairment is thoroughly established, observational evidence explicitly evaluating CYP2C9*5 outcomes remains categorized as limited to moderate compared to the more universally studied *2 and *3 alleles, largely because *5 has historically been omitted from standard commercial screening panels.
Population Distribution and Ancestry Patterns
The distribution of rs28371686 exhibits distinct biogeographical patterns across global human populations. Research documented across public repositories such as [dbSNP](https://www.ncbi.nlm.nih.gov/snp/rs28371686) shows that the variant G allele occurs almost exclusively in individuals of African ancestry, where it reaches an estimated minor allele frequency of approximately 1% to 1.2%. In contrast, rs28371686 is extremely rare or entirely absent in cohorts of European, East Asian, and Native American descent (typically well below 0.1%). Because common Caucasian-derived alleles such as CYP2C9*2 and *3 account for only a small fraction of reduced enzyme activity in African descendants, including rs28371686 in multiethnic genotyping panels is critical to avoid underestimating altered drug clearance in diverse populations.
Interpreting Your Genetic Results Safely
Discovering an altered genotype at rs28371686 offers personal biological context, but it is not a diagnostic verdict or an acute health risk on its own. Non-genetic factors such as age, kidney function, liver health, diet, and interacting medications can cause phenoconversion, altering effective enzyme activity regardless of DNA sequence. If you carry one or more copies of the variant G allele, you must never self-adjust, discontinue, or initiate any prescription medication on your own. Instead, share your laboratory report with a physician or clinical pharmacologist. Healthcare providers can interpret this genetic information alongside validated dosing algorithms and routine blood monitoring (such as International Normalized Ratio testing for warfarin) to personalize medical care safely.
How common is this variant?
The rs28371686 G allele exhibits a minor allele frequency of approximately 1% to 1.2% in populations of African descent, while remaining exceptionally rare (<0.1%) in European and Asian cohorts.
Frequently asked questions
Does carrying the rs28371686 G allele mean I cannot take warfarin?
No, it does not mean you cannot take warfarin. It indicates that your body may metabolize warfarin more slowly than average, which often translates to needing a lower daily dose to avoid bleeding risks. Dosing adjustments should always be determined by your doctor using clinical testing.
Can rs28371686 affect how I respond to over-the-counter pain medications?
Yes, CYP2C9 is partially responsible for clearing several common nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and celecoxib. Individuals with decreased-function alleles may retain these medications in their system longer, potentially raising the likelihood of gastrointestinal or renal side effects with prolonged use.
Why is the CYP2C9*5 allele more common in people of African ancestry?
Human genetic variation naturally varies across ancestral lineages due to human demographic history, genetic drift, and geographic isolation. While CYP2C9*2 and *3 predominate in European groups, alleles like *5, *6, *8, and *11 represent the predominant loss-of-function variants in African lineages.
What is the difference between an intermediate and a poor metabolizer for CYP2C9?
An intermediate metabolizer typically has one normal-function allele paired with a decreased- or no-function allele, leading to moderately reduced drug clearance. A poor metabolizer possesses two decreased- or no-function alleles, resulting in substantially slower drug clearance and a higher risk of adverse reactions.
Sources & further reading
Educational information only, last refreshed 9/5/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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Get my report — $29Related variants in CYP2C9
Rare variant in the CYP2C9 gene potentially impacting enzyme activity and drug metabolism; clinical significance requires further validation.
Coding variant conferring the CYP2C9*3 allele (often mislabeled as *4 in older literature) with decreased enzymatic activity affecting clearance of drugs such as warfarin and phenytoin.
A rare variant in the CYP2C9 gene that may impact the metabolism of various clinical drugs.
The CYP2C9*2 variant (p.Arg144Cys) results in reduced enzymatic activity, significantly impacting the metabolism and required dosing of substrates such as warfarin and irbesartan.
Defining the CYP2C9*3 (p.Ile359Leu) allele, this variant markedly decreases enzymatic activity, requiring reduced dosages for warfarin and phenytoin to prevent toxicity.
The CYP2C9*3 allele significantly reduces enzyme activity, necessitating dose adjustments for warfarin and phenytoin.