CYP2C9 rs1057912: Pharmacogenomics of the *4 Allele
The rs1057912 variant is a rare missense single nucleotide polymorphism located in the CYP2C9 gene on chromosome 10, defining the pharmacogenetic CYP2C9*4 star allele. It leads to an isoleucine-to-threonine substitution (p.Ile359Thr) that reduces the catalytic efficiency of the CYP2C9 drug-metabolizing enzyme. Because it alters enzymatic clearance, it has been linked to slower metabolism of substrates like warfarin and phenytoin, although clinical evidence remains limited due to its low frequency.
What each genotype means
Normal enzyme activity profile
This is the most common genotype, often referred to as the wild-type or *1/*1 state. It is generally associated with standard CYP2C9 enzyme activity and typical metabolism of drugs processed by this enzyme. Please discuss your medication dosing and any therapeutic concerns with your clinician or pharmacist.
This is the most frequent genotype found in nearly all human populations.
Potential reduced enzyme activity
This genotype indicates you carry one copy of the variant allele, sometimes associated with the CYP2C9*4 haplotype, and one reference allele. Research suggests this may be associated with decreased enzyme activity, which could impact how your body processes certain medications like warfarin or phenytoin. Please discuss these findings with your clinician or pharmacist, as they can determine if your current medication dosing is appropriate.
This genotype is very rare, typically appearing in less than 1% of the population, with slightly higher observed frequencies in specific European and South Asian cohorts.
Likely reduced enzyme activity
This genotype indicates you carry two copies of the variant allele. Research suggests individuals with this profile may have more pronounced reductions in CYP2C9 enzyme activity, which can significantly affect the clearance of drugs that rely on this pathway. It is important to discuss this result with your clinician or pharmacist before starting or adjusting any medications metabolized by CYP2C9.
This genotype is exceptionally rare, with a frequency significantly below 0.001 globally.
What is rs1057912 and Where Is It Located?
The single nucleotide polymorphism rs1057912 is a coding sequence variant located on the short arm of human chromosome 10 within exon 7 of the CYP2C9 gene. At the nucleotide level, the variant typically involves a change from thymine (T) to cytosine (C) on the forward coding strand (c.1076T>C). This point mutation alters codon 359, resulting in an amino acid substitution from isoleucine to threonine (p.Ile359Thr). In pharmacogenomic nomenclature coordinated by PharmVar and the Clinical Pharmacogenetics Implementation Consortium (CPIC), this specific nucleotide transition defines the CYP2C9*4 allele. Unlike more widespread variations like CYP2C9*2 and *3, which also cause non-synonymous amino acid changes, the *4 allele sits at the very same codon position as the canonical *3 variant (p.Ile359Leu, rs1057910), highlighting codon 359 as a critical structural site for enzymatic fidelity. However, because rs1057912 is far less common in the general population, researchers historically categorized it as an infrequent variant of interest.
The Biological Role of the CYP2C9 Enzyme
The CYP2C9 gene encodes a member of the cytochrome P450 superfamily of monooxygenases, primarily anchored to the membrane of the hepatic endoplasmic reticulum. In human physiology, CYP2C9 is one of the most critical phase I drug-metabolizing enzymes, responsible for the metabolic clearance and bio-transformation of an estimated 15% to 20% of clinically prescribed medications. Its primary substrates include therapeutic agents with narrow therapeutic windows, such as the anticoagulant warfarin, the anticonvulsant phenytoin, and oral sulfonylurea antidiabetics like glipizide, as well as common nonsteroidal anti-inflammatory drugs (NSAIDs) such as celecoxib and ibuprofen. Functionally, the wild-type enzyme carries out oxidative reactions that render hydrophobic molecules more polar, facilitating safe excretion through bile or urine. When structural mutations alter the enzyme's active binding site or disrupt its folding, substrate binding affinity and catalytic turnaround decrease, resulting in impaired metabolic clearance and prolonged systemic drug exposure.
Research Associations and Evidence Strength
Experimental and functional characterization studies demonstrate that the CYP2C9*4 allele conferred by rs1057912 produces an enzyme with diminished catalytic activity relative to the fully functional wild-type allele (CYP2C9*1). In vitro kinetic models using recombinant proteins reveal reduced intrinsic clearance (Vmax/Km) toward model probe substrates, including tolbutamide and phenytoin. In clinical pharmacogenomics, carriers of reduced-function CYP2C9 alleles face a heightened risk of drug accumulation, potentially increasing adverse effects such as bleeding complications during warfarin initiation or neurotoxicity with phenytoin. However, peer-reviewed clinical data specific to rs1057912 remain categorized as limited in evidence strength. Because the allele appears at extremely low prevalence in broad clinical trials, direct in vivo pharmacokinetic measurements derive mostly from small case studies or extrapolated functional assays rather than large randomized prospective cohorts. Consequently, expert consortia treat CYP2C9*4 as a reduced-function allele, while emphasizing that statistical confidence intervals regarding exact dose adjustments remain wider than those for well-characterized alleles like *2 and *3.
Population Frequency and Ethnogeographic Distribution
Global sequencing resources, including gnomAD and the 1000 Genomes Project, indicate that rs1057912 is a rare variant worldwide, with an aggregate minor allele frequency (MAF) well below 0.005 (0.5%). Ethnogeographic studies identify the variant predominantly in specific cohorts of European and South Asian ancestry, whereas it is virtually undetected or exceptionally rare in East Asian and African-descended populations. Even within European and South Asian cohorts, the vast majority of people carry the reference genotype, with heterozygous carriers appearing in only a small fraction of a percent of individuals. Homozygous carriers of the C allele are exceptionally rare in published sequencing databases. This pronounced ethnic and geographic disparity reflects the complex background of pharmacogenetic architecture, demonstrating that while core pharmacogenes are universally vital, rarer variants like rs1057912 exhibit localized patterns that standard small-scale genotyping panels often overlook.
Navigating Pharmacogenomic Results and Limitations
Understanding a personal genotype at rs1057912 requires recognizing what commercial or exploratory genetic testing can and cannot achieve. Identifying a minor allele indicates a biological predisposition toward slower CYP2C9-mediated metabolism, but genetics represents only one component of medication response. Factors such as patient age, kidney and liver function, co-administered medications that inhibit or induce cytochrome enzymes, and dietary intake of vitamin K all exert major influences on drug safety and efficacy. Genetic results should never be treated as a standalone clinical diagnosis or a mandate to alter drug therapy independently. Patients who carry atypical CYP2C9 alleles must consult their attending physician, cardiologist, or clinical pharmacologist before initiating, adjusting, or stopping any prescribed pharmacotherapy. Professional healthcare providers utilize validated clinical guidelines, comprehensive medication reviews, and therapeutic drug monitoring to integrate genetic insights safely into personalized patient care.
How common is this variant?
The rs1057912 minor allele is rare globally, exhibiting a frequency below 0.005 (<0.5%), and has been observed predominantly at low frequencies within European and South Asian populations while remaining nearly absent in East Asian and African groups.
Frequently asked questions
What is the rs1057912 variant in the CYP2C9 gene?
The rs1057912 variant is a rare single nucleotide polymorphism in exon 7 of the CYP2C9 gene that causes an amino acid substitution (p.Ile359Thr). In pharmacogenetics, this change defines the CYP2C9*4 allele, which is associated with reduced metabolic clearance of various medications.
Does carrying the rs1057912 variant affect warfarin dosing?
Laboratory studies suggest the variant reduces CYP2C9 activity, which could slow warfarin clearance and potentially elevate bleeding risks if standard doses are given. However, because the variant is rare, direct clinical trial data are limited, and any dosing considerations should be managed directly by your doctor or pharmacist.
How common is the CYP2C9*4 allele in the general population?
It is an uncommon variant with an overall global minor allele frequency well under 0.5%. It is observed mostly in small subsets of individuals of South Asian and European ancestry, and is virtually absent in most other global ancestries.
Should I change my medication if I test positive for this variant?
No, you should never stop, start, or change the dose of any prescription medication based on personal genetic results alone. Discuss your results with a qualified healthcare provider who can evaluate your complete medical history, lab results, and concurrent prescriptions.
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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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.