rs3758581 — CYP2C19 Ile331Val (CYP2C19*1B)

CYP2C19 Ile331Val — The *1B Background Marker

CYP2C19 is one of the most pharmacogenomically important enzymes in the human body, metabolizing drugs as diverse as the antiplatelet agent clopidogrel, antifungals like voriconazole, proton pump inhibitors (PPIs), and multiple antidepressants. The rs3758581 variant encodes an isoleucine-to-valine substitution at position 331 ¹¹ p.Ile331Val, c.991A>G and defines part of the CYP2C19*1B allele classification. Understanding this variant requires recognizing that most people carry the Val331 form (G allele), while the ancestral Ile331 form (A allele) is the rarer variant found predominantly in South Asian populations and in backgrounds that include loss-of-function haplotypes.

The Mechanism

The Ile331Val substitution occurs in a substrate-binding region of the CYP2C19 protein. Val331 (the G allele, *1B-associated) represents the common population form and is associated with normal enzyme function. The rarer Ile331 form (A allele) frequently co-occurs on haplotypes that carry other loss-of-function variants, most notably CYP2C19*2 (rs4244285)²² CYP2C19*2 (rs4244285) — the splice-site variant that abolishes enzyme activity. As noted by Yaşar (2018)³³ Yaşar (2018)
Yaşar Ü. The role of pharmacogenetics of cytochrome P450s in phenytoin-induced DRESS syndrome. Cent Eur J Immunol, 2018, rs3758581 "may be present in 40 different haplotypes of CYP2C19 including *2 and *17," which is why full haplotyping — not this single variant alone — gives the definitive metabolizer phenotype.

The Evidence

Cardiovascular pharmacogenomics: CYP2C19 metabolizer status is most clinically impactful for clopidogrel, the antiplatelet prodrug. The 2022 CPIC guideline update for clopidogrel⁴⁴ 2022 CPIC guideline update for clopidogrel
Lee CR et al. CPIC guideline for CYP2C19 and clopidogrel. Clin Pharmacol Ther, 2022 documents that intermediate metabolizers (one reduced-function allele) have elevated risk of major adverse cardiovascular events, and recommends considering alternative antiplatelet agents such as prasugrel or ticagrelor.

Acid suppression: For proton pump inhibitors, the CPIC PPI guideline⁵⁵ CPIC PPI guideline
Lima JJ et al. CPIC guideline for CYP2C19 and PPI dosing. Clin Pharmacol Ther, 2021 recommends genotype-guided dosing, with dose increases for rapid/ultrarapid metabolizers and dose considerations for poor metabolizers taking chronic PPI therapy.

Antifungal therapy: Voriconazole trough concentrations vary up to 10-fold based on CYP2C19 genotype. The CPIC voriconazole guideline⁶⁶ CPIC voriconazole guideline
Moriyama B et al. CPIC guidelines for CYP2C19 and voriconazole. Clin Pharmacol Ther, 2017 recommends dose adjustment and therapeutic drug monitoring across all non-normal metabolizer phenotypes.

Antidepressants: CYP2C19 metabolizes citalopram, escitalopram, sertraline, and other SSRIs. The 2023 CPIC antidepressant guideline⁷⁷ 2023 CPIC antidepressant guideline
Bousman CA et al. CPIC guideline for CYP2C19 and serotonin reuptake inhibitors. Clin Pharmacol Ther, 2023 provides genotype-guided selection and dosing recommendations.

Population context: rs3758581 was significantly associated with warfarin weekly dose⁸⁸ significantly associated with warfarin weekly dose
Ammari MA et al. Pharmacogenomics J, 2023 in 786 Saudi patients, highlighting population-specific pharmacogenomic implications.

Practical Actions

Because the A allele at this position frequently marks haplotypes carrying the *2 loss-of-function allele (rs4244285), carriers of the A allele — particularly homozygous AA individuals — benefit from comprehensive CYP2C19 haplotyping before starting any CYP2C19-substrate drug. The clinical management decisions ultimately depend on the full metabolizer phenotype (normal, intermediate, or poor), not this single variant in isolation.

Interactions

This variant sits in the same gene as CYP2C19*2 (rs4244285) and CYP2C19*3 (rs4986893), which are the primary loss-of-function alleles, and CYP2C19*17 (rs12248560), the gain-of-function promoter variant. The rs3758581 A allele is in linkage disequilibrium with *2-containing haplotypes in many populations, meaning a homozygous AA individual is more likely than chance to also carry *2. Full diplotype testing resolves this ambiguity. CYP2C8 variants (e.g. rs1934953) also influence drug metabolism in the same chromosomal region and can compound pharmacogenomic effects.