rs1057910 — CYP2C9 *3

No-function CYP2C9 variant with major warfarin implications

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CYP2C9*3 - The Severe Warfarin Metabolism Variant

The CYP2C9*3 allele11 rs1057910 has a more severe impact on enzyme function than *2. While *2 reduces activity to about 50%, *3 reduces it to approximately 5-15% of normal. This makes *3 the most clinically impactful CYP2C9 variant for warfarin dosing.

The Mechanism

The *3 variant causes an isoleucine-to-leucine substitution at position 35922 Amino acid change: isoleucine to leucine at position 359 (I359L), which is located in the substrate recognition site of the enzyme. This dramatically reduces the enzyme's ability to bind and metabolize its substrates. The residual activity is so low (approximately 5-15% of normal33 5-15% of normal
Pharmacogenomics of CYP2C9 review) that *3 is sometimes classified as a no-function allele in clinical guidelines. Unlike *2, the *3 allele is found across multiple ancestry groups, with highest frequencies in South Asian populations (about 11%).

The Warfarin Connection

Patients carrying CYP2C9*3 require substantially lower warfarin doses. A patient who is *1/*3 (heterozygous) typically needs about 30-40% less warfarin than a *1/*1 patient. Those who are *3/*3 (homozygous) or compound heterozygous (*2/*3) may need only a fraction of the typical dose. The risk of over-anticoagulation and bleeding is significantly higher during warfarin initiation in these patients.

Combined CYP2C9 + VKORC1

Warfarin dosing is determined by both CYP2C9 (metabolism) and VKORC1 (drug target sensitivity). The combination of CYP2C9*3 with the VKORC1 -1639A allele44 rs9923231 creates the most extreme dosing scenario - these patients may need only 1-2mg of warfarin daily, compared to the typical 5mg starting dose. Pharmacogenomic-guided dosing is especially valuable for these individuals.

Practical Implications

If you carry *3, even in heterozygous form, this is clinically significant information. In the event you ever need warfarin therapy, your CYP2C9 genotype should be communicated to your prescribing physician and included in your medical record. The growing availability of direct oral anticoagulants (DOACs like apixaban and rivaroxaban) that do not require CYP2C9-guided dosing provides alternatives in many clinical scenarios. Note that siponimod (for multiple sclerosis) is contraindicated in CYP2C9*3/*3 individuals55 contraindicated in CYP2C9*3/*3 individuals
FDA siponimod label due to extremely elevated plasma levels.

Drug Interactions

warfarin increased_toxicity CPIC
phenytoin increased_toxicity CPIC
celecoxib increased_toxicity CPIC
ibuprofen increased_toxicity CPIC
flurbiprofen increased_toxicity CPIC
meloxicam increased_toxicity CPIC
piroxicam increased_toxicity CPIC
tenoxicam dose_adjustment DPWG
glipizide dose_adjustment literature
tolbutamide dose_adjustment literature
siponimod contraindicated FDA
losartan reduced_efficacy literature

Genotype Interpretations

What each possible genotype means for this variant.

AA Normal Metabolizer Normal

Normal CYP2C9 activity at *3 position

No reduced function variant at this position. About 88% of Europeans share this genotype. Standard dosing for CYP2C9-metabolized drugs applies.

AC Intermediate Metabolizer Intermediate

Intermediate CYP2C9 metabolizer

You carry one copy of the CYP2C9*3 variant. About 11% of Europeans share this genotype. Combined with your *2 status (rs1799853), this determines your overall CYP2C9 metabolizer phenotype. Even one copy of *3 significantly reduces CYP2C9 activity to about 30-40% for that allele.

CC Poor Metabolizer Poor

Poor CYP2C9 metabolizer

You have two copies of the CYP2C9*3 no-function variant. About 1% of the population shares this genotype. This severely impacts warfarin metabolism, reducing enzyme activity to approximately 5-10% of normal.