rs67807361 — CYP2C9 p.Leu19Ile

Rare CYP2C9 N-terminal missense variant of uncertain functional significance in a CYP2C9 substrate metabolizer gene

See your personal result for CYP2C9

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

CYP2C9 p.Leu19Ile — A Rare Variant in the Enzyme's Membrane Anchor

CYP2C9 is one of the most clinically important liver enzymes, responsible for metabolizing roughly 15% of all prescription drugs. It sits in the wall of the endoplasmic reticulum11 endoplasmic reticulum
Endoplasmic reticulum: the intracellular membrane system where CYP450 enzymes reside and where drug oxidation occurs and carries out oxidative biotransformation of warfarin, phenytoin, many NSAIDs, and several oral hypoglycemics. Variants that impair its activity require dose adjustments to avoid toxicity. This variant, p.Leu19Ile, sits at the very N-terminus of the protein in the membrane-anchoring region — an extremely rare change with no assigned star allele and no published ClinVar classification.

The Mechanism

Position 19 falls within or immediately adjacent to the N-terminal signal-anchor sequence22 N-terminal signal-anchor sequence
Signal-anchor: a short hydrophobic stretch at the start of CYP450 proteins that lodges the enzyme in the ER membrane of CYP2C9 (approximately residues 3–23). This region does not participate directly in substrate binding or catalysis; its job is to embed the enzyme in the ER membrane so that the catalytic domain is correctly positioned in the ER lumen. The variant substitutes leucine for isoleucine at position 19 — a conservative change33 conservative change
Conservative change: both Leu and Ile are aliphatic, hydrophobic amino acids with very similar physicochemical properties between two aliphatic, hydrophobic residues. Ensemble VEP rates the impact as MODERATE with SIFT "tolerated_low_confidence" (score 0.05, borderline), and PolyPhen data are insufficient. This is consistent with the absence of any ClinVar submission despite the variant having been observed in large sequencing cohorts.

The Evidence

The massively parallel CYP2C9 variant study by Amorosi et al.44 massively parallel CYP2C9 variant study by Amorosi et al.
Amorosi CJ et al. Massively parallel characterization of CYP2C9 variant enzyme activity and abundance. Am J Hum Genet, 2021 measured enzymatic activity for 6,142 CYP2C9 missense variants and found that almost two-thirds showed decreased activity. Position 19 was among variants assayed in that high-throughput screen; however, the specific activity score for p.Leu19Ile was not highlighted in published reports. The Daly et al. review55 Daly et al. review
Daly AK et al. Pharmacogenomics of CYP2C9: Functional and Clinical Considerations. J Pers Med, 2017 notes that rare variants of uncertain significance are increasingly detected by exome and genome sequencing and require systematic functional cataloging before clinical application. There are no published case reports, association studies, or CPIC classifications specifically addressing rs67807361. The variant has been observed at a frequency of approximately 0.002% globally (gnomAD v4), with marginal enrichment in South/East Asian populations (~0.02%) relative to European (~0.001%).

Practical Context

Because this variant has no established functional classification, it is best treated as a variant of uncertain significance (VUS) within the CYP2C9 pharmacogenomic framework. If you carry this variant alongside a well-characterized reduced-function allele (*2 or *3), the combined phenotype is determined primarily by those established alleles. Without functional evidence, prescribers should apply standard CYP2C9 clinical annotations from well-characterized alleles. If you are being assessed for warfarin or phenytoin therapy, the CPIC guidelines for CYP2C9 remain the authoritative reference — and this variant should be flagged for the prescribing pharmacogeneticist as unclassified.

Interactions

This variant sits in the same gene as the well-characterized *2 (rs1799853) and *3 (rs1057910) alleles. If rs67807361 were to reduce CYP2C9 expression or activity, compound heterozygosity with *2 or *3 could produce a more pronounced intermediate or poor metabolizer phenotype. However, without direct functional evidence, this potential interaction remains speculative.

Drug Interactions

warfarin dose_adjustment literature
phenytoin dose_adjustment literature
celecoxib dose_adjustment literature
ibuprofen dose_adjustment literature

Genotype Interpretations

What each possible genotype means for this variant.

CC Reference Genotype Normal

Wild-type CYP2C9 at the p.Leu19 position

You carry the common reference allele at this position. No variant is present at codon 19 of CYP2C9. This genotype is present in essentially all individuals (~99.98% globally), including nearly all Europeans. Your CYP2C9 metabolizer status for warfarin, NSAIDs, and phenytoin is determined by your genotype at the well-characterized *2 (rs1799853) and *3 (rs1057910) positions.

AC Uncertain Variant Carrier Intermediate

One copy of the rare CYP2C9 p.Leu19Ile variant — functional significance unknown

Position 19 of CYP2C9 lies within the short N-terminal signal-anchor sequence responsible for embedding the enzyme in the ER membrane. A leucine-to-isoleucine substitution here is chemically conservative — both are aliphatic, nonpolar residues — but changes in the hydrophobic core of a membrane-spanning domain can occasionally affect protein topology or expression levels even when SIFT predicts tolerance. Without in vitro kinetic data or clinical pharmacokinetic studies specifically for this variant, its effect on warfarin, phenytoin, or NSAID metabolism cannot be determined. This variant should be reported as a CYP2C9 variant of uncertain significance in any pharmacogenomic workup.

AA Homozygous VUS Reduced

Two copies of the rare CYP2C9 p.Leu19Ile variant — very rare, functional significance unknown

Homozygosity for rs67807361 is vanishingly rare given the extremely low allele frequency (~0.002% globally). No homozygous case has been published in the clinical or pharmacogenomics literature. Any interpretation of this genotype must be treated as highly speculative. The conservative Leu→Ile substitution in the membrane anchor region may affect CYP2C9 expression levels in two-copy carriers, but without functional studies this cannot be determined. This variant should be promptly referred to a clinical pharmacogeneticist for comprehensive evaluation, particularly before any warfarin or phenytoin therapy.