rs67807361 — CYP2C9 p.Leu19Ile

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.