CYP2C9 Cytochrome P450 2C9
CYP2C9 clears warfarin (the active S-enantiomer), phenytoin, celecoxib and most other NSAIDs, and several sulfonylureas.
What does CYP2C9 do?
CYP2C9 clears warfarin (the active S-enantiomer), phenytoin, celecoxib and most other NSAIDs, and several sulfonylureas. The two common decreased-function alleles, *2 and *3, slow clearance enough that carriers need lower warfarin doses and are more prone to bleeding during the first weeks of therapy; together with VKORC1 they explain a large share of the dose variation between patients.
What do the CYP2C9 metaboliser phenotypes mean?
Each person carries two CYP2C9 alleles. Each allele has a function and an activity score; the two scores are added and the total is mapped to a phenotype as follows.
| Phenotype | How it is assigned | What it means |
|---|---|---|
| Normal Metabolizer | activity score ≥ 1.5 (*1/*1) | Full enzyme activity. |
| Intermediate Metabolizer | activity score 1 (one *2 or *3) | Reduced clearance of CYP2C9 substrates. |
| Poor Metabolizer | activity score ≤ 0.5 (*2/*3, *3/*3 and similar) | Markedly reduced clearance. |
Which CYP2C9 star alleles are there, and how common are they?
| Allele | Function | Activity score | Defining variants | Frequency (EUR / EAS / AFR / SAS / AMR) | Note |
|---|---|---|---|---|---|
| *1 | normal function | 1 | reference | 65.0% / 90.0% / 80.0% / 75.0% / 70.0% | Wild-type/reference allele. Normal enzyme activity. |
| *2 | decreased function | 0.5 | rs1799853 430C>T (R144C) | 13.0% / 0.1% / 3.0% / 5.0% / 8.0% | Decreased function allele. Common in Europeans (~13%), rare in East Asians. Reduces warfarin metabolism by ~40%. |
| *3 | decreased function | 0.5 | rs1057910 1075A>C (I359L) | 7.0% / 4.0% / 1.0% / 8.0% / 5.0% | Decreased function allele. Reduces warfarin metabolism by ~80%. More severe effect than *2. |
| *5 | decreased function | 0.5 | rs28371686 1080C>G (D360E) | 0.1% / 0.1% / 2.0% / 0.5% / 0.5% | Decreased function allele. Rare overall but more common in African populations. |
| *6 | no function | 0 | rs9332131 818delA (frameshift) | 0.1% / 0.1% / 1.0% / 0.1% / 0.5% | Loss-of-function allele. Frameshift mutation. More common in African populations. |
| *8 | decreased function | 0.5 | rs7900194 449G>A (R150H) | 0.1% / 0.1% / 6.0% / 0.5% / 1.0% | Decreased function allele. Common in African populations (~6%). Important for warfarin dosing in African Americans. |
| *11 | decreased function | 0.5 | rs28371685 1003C>T (R335W) | 0.5% / 0.1% / 0.5% / 0.5% / 0.5% | Decreased function allele. Rare. |
| *12 | decreased function | 0.5 | rs9332239 1465C>T (P489S) | 0.1% / 0.1% / 0.1% / 0.1% / 0.1% | Decreased function allele. Rare. |
Which drugs does CYP2C9 affect?
- Warfarin Anticoagulant CPIC level A
- CYP2C9 clears S-warfarin, the more potent enantiomer. Carriers of *2 or *3 clear it slowly, need lower maintenance doses, take longer to reach a stable INR and bleed more often during initiation. VKORC1 genotype is the other half of the picture.
- Phenytoin Anticonvulsant CPIC level A
- Phenytoin is cleared by CYP2C9 and has a narrow therapeutic index. Reduced-function carriers reach toxic concentrations at standard doses; HLA-B*15:02 separately predicts severe skin reactions.
- Celecoxib NSAID (COX-2 inhibitor) CPIC level B
- Celecoxib is almost entirely cleared by CYP2C9. Poor metabolisers have a much longer half-life and higher exposure, with more gastrointestinal, cardiovascular and renal risk.
- Flurbiprofen/NSAIDs NSAID CPIC level B
- Flurbiprofen, ibuprofen, meloxicam, piroxicam and other NSAIDs are CYP2C9 substrates. Reduced clearance raises exposure and the risk of bleeding and kidney injury, particularly for the longer-acting drugs.
Can a 23andMe or AncestryDNA file tell you your CYP2C9 type?
The *2 (rs1799853) and *3 (rs1057910) variants are on the major consumer chips, so the common CYP2C9 phenotypes are called with good confidence. Rarer alleles such as *5, *6, *8 and *11, which matter most in people of African ancestry, are usually not genotyped.
Upload your 23andMe, AncestryDNA or WeGene raw file → · Ask G2: “What is my CYP2C9 metaboliser status and which of my medicines does it affect?”
Genetic associations describe risk across populations, not a diagnosis for any one person. Most variants shift risk modestly and act alongside lifestyle, environment and other genes. Consumer DNA chips do not read every position and can be wrong at any single one. For general education only; talk to a clinician or genetic counsellor before acting on anything here, and never change a prescribed medicine without your prescriber.