{"gene":{"symbol":"CYP2C9","name":"Cytochrome P450 Family 2 Subfamily C Member 9","protein":"Cytochrome P450 2C9","ncbi_gene_id":"1559","locus":"10q23.33","summary":"CYP2C9 is a hepatic cytochrome P450 enzyme that clears the anticoagulant warfarin, phenytoin, several NSAIDs and some sulfonylureas. People with reduced-function alleles break warfarin down slowly, need much lower doses and face a higher bleeding risk while their dose is found. Together with the drug-target gene VKORC1, CYP2C9 explains a large share of why the right warfarin dose varies so widely between people.","function":"CYP2C9 inactivates a set of narrow-therapeutic-window drugs. Its headline substrate is S-warfarin, the more potent enantiomer of warfarin; it also metabolizes phenytoin, NSAIDs such as celecoxib, ibuprofen and flurbiprofen, several sulfonylureas used for type 2 diabetes, losartan and the multiple-sclerosis drug siponimod. Because these drugs are inactivated by CYP2C9, a reduced-function genotype means the parent drug is cleared slowly and accumulates: for warfarin a lower dose requirement and higher early bleeding risk; for phenytoin a risk of dose-dependent neurotoxicity; for NSAIDs greater exposure and gastrointestinal risk. Warfarin is special because two genes act together: CYP2C9 controls how fast the drug is cleared, while VKORC1, which encodes warfarin's target enzyme, controls sensitivity to it. CPIC dosing algorithms combine CYP2C9 star alleles, the VKORC1 -1639 variant and sometimes CYP4F2, alongside age and weight, to estimate a starting dose.","category":"pharmacogene","key_variants":[{"rsid":null,"name":"*1 (reference)","alleles":"Wild-type haplotype","effect":"Normal enzyme activity; reference for phenotype scoring.","frequency_note":null},{"rsid":"rs1799853","name":"*2 (R144C, Arg144Cys)","alleles":"Plus strand, GRCh37 (as in 23andMe raw data): C reference, T variant (Arg144Cys), which defines *2.","effect":"Reduced activity; lowers warfarin metabolism. One *2 allele modestly reduces warfarin dose requirement.","frequency_note":"~12–15% in Europeans, rarer in East Asians."},{"rsid":"rs1057910","name":"*3 (I359L, Ile359Leu)","alleles":"Plus strand, GRCh37 (as in 23andMe raw data): A reference, C variant (Ile359Leu), which defines *3.","effect":"Strongly reduced activity, larger effect than *2. *3 carriers need substantially lower warfarin doses.","frequency_note":"~7% in Europeans, ~4% in East Asians."},{"rsid":null,"name":"*5, *6, *8, *11 (African-ancestry alleles)","alleles":null,"effect":"Reduced- or no-function alleles more common in people of African ancestry. Omitting them is a known source of inaccuracy in warfarin algorithms built mainly on *2 and *3.","frequency_note":"More common in people of African ancestry."}],"phenotypes":["Normal metabolizer (NM): two normal-function alleles (*1/*1)","Intermediate metabolizer (IM): activity score 1.0–1.5 (e.g. *1/*2, *1/*3, *2/*2)","Poor metabolizer (PM): activity score 0–0.5 (e.g. *2/*3, *3/*3); lower warfarin dose requirement and higher early bleeding risk"],"clinical_relevance":"CYP2C9 has formal dosing guidelines from CPIC and DPWG, and the FDA warfarin label includes a pharmacogenomic dosing table. Warfarin: CPIC's guideline combines CYP2C9 genotype with VKORC1 (and CYP4F2) to recommend a starting dose; poor metabolizers and VKORC1-sensitive patients need markedly lower doses, and in one large randomized trial (GIFT), genotype-guided initial dosing reduced a combined outcome of major bleeding, INR of 4 or more, venous thromboembolism or death. Phenytoin: CPIC recommends the usual first or loading dose, then about 25% lower maintenance doses for intermediate metabolizers with activity score 1.0 and about 50% lower for poor metabolizers, and recommends against phenytoin for HLA-B*15:02 carriers who have not taken it before (skin-reaction risk). NSAIDs (celecoxib, ibuprofen, flurbiprofen, meloxicam): CPIC suggests reduced doses or alternatives for poor metabolizers to limit exposure and gastrointestinal risk. Siponimod: the label contraindicates the drug in CYP2C9 *3/*3 poor metabolizers. A raw file is never a substitute for INR monitoring; warfarin dosing is a clinical decision made with lab monitoring and a validated algorithm.","consumer_array_caveat":"CYP2C9 is relatively array-friendly: rs1799853 (*2) and rs1057910 (*3) are usually genotyped, and warfarin's partner variant rs9923231 (VKORC1 -1639G>A) is often genotyped too. The limits are not symmetric across ancestries: consumer chips frequently miss the *5, *6, *8 and *11 alleles that matter in people of African ancestry, so a 'normal' raw-data readout can be falsely reassuring.","drugs":[{"drug":"warfarin","guideline":"CPIC","level":"CPIC A","summary":"CPIC guideline (Johnson et al. 2017) combines CYP2C9 genotype with VKORC1 (and CYP4F2) to recommend a starting dose; poor metabolizers and VKORC1-sensitive patients need markedly lower doses. The FDA warfarin label includes a pharmacogenomic dosing table. Dosing remains a clinical decision with INR monitoring."},{"drug":"phenytoin","guideline":"CPIC","level":"CPIC A","summary":"CPIC recommends against phenytoin for HLA-B*15:02 carriers who have not taken it before (SJS/TEN risk). For CYP2C9, it recommends the usual first or loading dose, then about 25% lower maintenance doses for intermediate metabolizers with activity score 1.0 and about 50% lower for poor metabolizers, adjusted by drug-level monitoring. Reduced clearance raises the risk of dose-related toxicity."},{"drug":"celecoxib","guideline":"CPIC","level":"CPIC A","summary":"NSAID inactivated by CYP2C9. CPIC recommends 25–50% of the lowest recommended starting dose, or an alternative, for poor metabolizers, and the lowest recommended starting dose with monitoring of blood pressure and kidney function for intermediate metabolizers with activity score 1.0."},{"drug":"ibuprofen","guideline":"CPIC","level":"CPIC A","summary":"NSAID inactivated by CYP2C9. CPIC recommends 25–50% of the lowest recommended starting dose, or an alternative, for poor metabolizers, and the lowest recommended starting dose with monitoring of blood pressure and kidney function for intermediate metabolizers with activity score 1.0."},{"drug":"flurbiprofen","guideline":"CPIC","level":"CPIC A","summary":"NSAID inactivated by CYP2C9. CPIC recommends 25–50% of the lowest recommended starting dose, or an alternative, for poor metabolizers, and the lowest recommended starting dose with monitoring of blood pressure and kidney function for intermediate metabolizers with activity score 1.0."},{"drug":"meloxicam","guideline":"CPIC","level":"CPIC A","summary":"NSAID inactivated by CYP2C9, with a long half-life. CPIC recommends an alternative (a drug not metabolized by CYP2C9 or a shorter-acting NSAID) for poor metabolizers, and 50% of the lowest recommended starting dose, or an alternative, for intermediate metabolizers with activity score 1.0."},{"drug":"siponimod","guideline":"drug label","level":"CPIC A (provisional)","summary":"The siponimod label contraindicates the drug in CYP2C9 *3/*3 poor metabolizers."},{"drug":"piroxicam","guideline":"CPIC","level":"CPIC A","summary":"NSAID inactivated by CYP2C9, with a long half-life. CPIC recommends an alternative (a drug not metabolized by CYP2C9 or a shorter-acting NSAID) for poor metabolizers and for intermediate metabolizers with activity score 1.0."},{"drug":"lornoxicam","guideline":"CPIC","level":"CPIC A","summary":"NSAID inactivated by CYP2C9. CPIC recommends 25–50% of the lowest recommended starting dose, or an alternative, for poor metabolizers, and the lowest recommended starting dose with monitoring of blood pressure and kidney function for intermediate metabolizers with activity score 1.0."},{"drug":"tenoxicam","guideline":"CPIC","level":"CPIC A","summary":"NSAID inactivated by CYP2C9, with a long half-life. CPIC suggests an alternative (a drug not metabolized by CYP2C9 or a shorter-acting NSAID) for poor metabolizers and for intermediate metabolizers with activity score 1.0. CPIC classifies these tenoxicam recommendations as optional."},{"drug":"fosphenytoin","guideline":"CPIC","level":"CPIC A","summary":"Prodrug converted to phenytoin, so the phenytoin guideline applies. CPIC recommends against phenytoin and fosphenytoin for HLA-B*15:02 carriers who have not taken it before (SJS/TEN risk). For CYP2C9, it recommends the usual first or loading dose, then about 25% lower maintenance doses for intermediate metabolizers with activity score 1.0 and about 50% lower for poor metabolizers, adjusted by drug-level monitoring."},{"drug":"fluvastatin","guideline":"CPIC","level":"CPIC A","summary":"Statin cleared mainly by CYP2C9. CPIC 2022, with normal SLCO1B1 function: a starting dose of ≤40 mg/day for intermediate metabolizers and ≤20 mg/day for poor metabolizers (moderate), considering an alternative statin or combination therapy if a higher dose is needed. When decreased or poor SLCO1B1 function is also present, CPIC lowers these limits or suggests an alternative statin (optional)."}],"sources":[{"label":"CPIC — CYP2C9 gene page","url":"https://cpicpgx.org/gene/cyp2c9/"},{"label":"PharmGKB CYP2C9 (PA126)","url":"https://www.pharmgkb.org/gene/PA126"},{"label":"PharmVar CYP2C9","url":"https://www.pharmvar.org/gene/CYP2C9"},{"label":"NCBI Gene 1559","url":"https://www.ncbi.nlm.nih.gov/gene/1559"},{"label":"Johnson et al., Clin Pharmacol Ther 2017 (CPIC warfarin guideline)","url":"https://pubmed.ncbi.nlm.nih.gov/28198005/"},{"label":"Karnes et al., Clin Pharmacol Ther 2021 (CPIC CYP2C9 and HLA-B phenytoin guideline, 2020 update)","url":"https://pubmed.ncbi.nlm.nih.gov/32779747/"},{"label":"Theken et al., Clin Pharmacol Ther 2020 (CPIC CYP2C9 and NSAID guideline)","url":"https://pubmed.ncbi.nlm.nih.gov/32189324/"},{"label":"FDA label, Mayzent (siponimod) (contraindicated in CYP2C9*3/*3)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=44492772-5aed-4627-bd85-e8e89f308bb3"},{"label":"FDA label, Jantoven (warfarin sodium) (Table 1: expected maintenance doses by CYP2C9 and VKORC1 genotype)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=19a69a72-ac5d-45d5-a94d-a5aaecbe4730"},{"label":"Gage et al., JAMA 2017 (GIFT randomized trial of genotype-guided warfarin dosing)","url":"https://pubmed.ncbi.nlm.nih.gov/28973620/"}],"related_blog":"/blog/pharmacogenomics-europe-guide/","disclaimer":"Educational information only, not medical advice or diagnosis. Consult a clinician before acting on genetic information."},"meta":{"disclaimer":"Educational information only, not medical advice or diagnosis. Consult a clinician before acting on genetic information.","api_version":"2026-09-20","docs":"https://deepdna.ai/docs/","status":"live","data_as_of":"2026-10-25T21:32:19.251Z","freshness":"https://deepdna.ai/api/v1/freshness"}}