rs3758581 — CYP2C19 Ile331Val (CYP2C19*1B)

Common CYP2C19 missense variant defining the *1B allele; the G (Val331) allele is the population-major normal-function form, while the rare A (Ile331) allele marks loss-of-function haplotype backgrounds

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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.

Drug Interactions

clopidogrel reduced_efficacy CPIC
omeprazole dose_adjustment CPIC
pantoprazole dose_adjustment CPIC
lansoprazole dose_adjustment CPIC
esomeprazole dose_adjustment CPIC
voriconazole dose_adjustment CPIC
citalopram dose_adjustment CPIC
escitalopram dose_adjustment CPIC
sertraline dose_adjustment CPIC
warfarin dose_adjustment literature

Genotype Interpretations

What each possible genotype means for this variant.

GG Normal *1B Homozygote Normal

Common CYP2C19 Val331 — normal enzyme function

The GG genotype represents homozygosity for the Val331 form, which is the population-major allele at ~93.7% globally and up to 98.8% in African populations. CYP2C19 *1B is a normal-function allele designation, meaning the Val331 substitution itself does not impair enzyme activity compared to the reference *1A allele. Your overall CYP2C19 metabolizer phenotype depends on the full complement of functional and non-functional alleles across both chromosomes (the diplotype). Standard dosing for CYP2C19 substrates applies unless other CYP2C19 variants (such as *2 or *17) are also present.

AG Intermediate Haplotype Carrier Intermediate

One rare A allele — possible loss-of-function haplotype background

The AG genotype carries one A allele (Ile331), which is the ancestral form and tends to mark haplotype backgrounds containing other variants, including CYP2C19*2 (rs4244285), the most common loss-of-function allele. A 2018 pharmacogenetics letter noted that rs3758581 appears in 40 different CYP2C19 haplotypes, including both *2 (reduced function) and *17 (increased function), so the A allele alone is not diagnostic. However, population data show enrichment of the A allele in intermediate metabolizer contexts. If you are about to start clopidogrel, voriconazole, or an SSRI, request full CYP2C19 genotyping to resolve your diplotype phenotype before prescribing decisions are made.

AA Rare Ile331 Homozygote Reduced

Rare homozygous A allele — high likelihood of loss-of-function haplotype background

The AA genotype is rare globally (~0.4%) but reaches ~1.2% in South Asian populations, where the A allele frequency is highest (~11%). Because the A allele is enriched on loss-of-function haplotype backgrounds (*2 being the most common), homozygous AA individuals have a substantially elevated probability of being intermediate or poor metabolizers when their full CYP2C19 diplotype is assessed. The CPIC guidelines for clopidogrel (2022 update), PPIs (2021), voriconazole (2017), and SSRIs (2023) all provide clear dose modification or alternative drug recommendations for intermediate and poor CYP2C19 metabolizers. A Sri Lankan pharmacogenomics study (2025) found rs3758581 classified among markers for poor/intermediate metabolizer status with a 9.7% MAF in that South Asian population, consistent with enriched loss-of-function background. Full CYP2C19 diplotyping is essential to confirm phenotype and guide clinical decisions.