rs4986893 — CYP2C19 *3

CYP2C19*3 — The East Asian No-Function Allele

CYP2C19*3¹¹ rs4986893 — the second most common CYP2C19 loss-of-function allele after *2 is a single-base G-to-A change (c.636G>A) that replaces the tryptophan codon at position 212 with a premature stop codon (p.Trp212Ter, historically written W212X). The truncated protein lacks the heme-binding domain and has essentially zero catalytic activity — classifying any carrier as having a no-function allele for the purpose of CPIC phenotype assignment.

While *2 (rs4244285) gets most of the clinical attention, *3 is clinically just as important in populations where it's common. In East Asians, the *3 allele frequency is ~7–8%, meaning ~14% of East Asian individuals carry at least one copy. Missing *3 from a pharmacogenomic workup systematically under-diagnoses poor metabolizer status in East Asian patients — the exact population where *3 matters most.

The Mechanism

CYP2C19 is a hepatic cytochrome P450 enzyme that oxidizes about 10% of clinically used drugs. The *3 variant introduces a single-nucleotide change in exon 4 that converts the codon TGG (tryptophan) to TGA (stop). Because the stop codon appears near the middle of the protein sequence, the truncated CYP2C19 polypeptide never folds into a functional enzyme and is rapidly degraded. No residual activity remains from the affected allele — unlike some missense variants that retain partial function.

Carriers of one *3 allele (heterozygous) have approximately half-normal CYP2C19 activity and are classified as intermediate metabolizers unless they also carry a second no-function allele. Homozygotes or compound heterozygotes (e.g. *2/*3) are poor metabolizers with effectively no CYP2C19 activity.

The Clopidogrel Problem

Clopidogrel (Plavix) is a prodrug²² An inactive compound that must be metabolized by the liver into its active form that depends on CYP2C19 to generate its active antiplatelet metabolite. Poor metabolizers who take clopidogrel after coronary stenting, stroke, or acute coronary syndrome get little to no antiplatelet effect, and have significantly higher rates of stent thrombosis, recurrent myocardial infarction, and cardiovascular death. The Mega et al. 2009 meta-analysis³³ Mega et al. 2009 meta-analysis
Mega JL et al. Cytochrome P-450 polymorphisms and response to clopidogrel. NEJM, 2009 pooled data across multiple trials and confirmed that both *2 and *3 carriers had increased cardiovascular events — the FDA black-box warning⁴⁴ FDA black-box warning
Clopidogrel (Plavix) prescribing label, FDA on clopidogrel explicitly covers poor metabolizers regardless of which no-function alleles they carry.

The CPIC clopidogrel guideline⁵⁵ CPIC clopidogrel guideline
Scott SA et al. CPIC guideline for CYP2C19 genotype and clopidogrel therapy. Clin Pharmacol Ther, 2013 recommends prasugrel or ticagrelor (which do not require CYP2C19 for activation) as alternatives for any CYP2C19 poor metabolizer undergoing percutaneous coronary intervention. This recommendation applies identically to *3 carriers as to *2 carriers.

Proton Pump Inhibitors

CYP2C19 is also the major pathway for clearing proton pump inhibitors (PPIs) such as omeprazole, esomeprazole, lansoprazole, and pantoprazole. In poor metabolizers the drug clears much more slowly, plasma levels stay higher for longer, and acid suppression is correspondingly stronger. This is typically a benefit — a standard PPI dose works better — but the CPIC PPI guideline⁶⁶ CPIC PPI guideline
Lima JJ et al. CPIC guideline for CYP2C19 and proton pump inhibitor dosing. Clin Pharmacol Ther, 2021 recommends considering a 50% dose reduction for chronic PPI therapy (>12 weeks) in poor metabolizers to minimize the long-term risks of over-suppression (hypergastrinemia, low magnesium, bone loss, increased enteric infection risk).

Antidepressants

CYP2C19 clears several SSRIs and tricyclic antidepressants. For citalopram and escitalopram, the CPIC SSRI guideline⁷⁷ CPIC SSRI guideline
Bousman CA et al. CPIC guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A and serotonin reuptake inhibitor antidepressants. Clin Pharmacol Ther, 2023 recommends a 50% starting dose reduction in poor metabolizers, or switching to an antidepressant not primarily metabolized by CYP2C19 (fluoxetine, paroxetine, fluvoxamine, or a non-SSRI). Higher plasma citalopram is associated with QT prolongation — a real safety concern, not a theoretical one. For tricyclics (amitriptyline, clomipramine, imipramine, doxepin, trimipramine), the CPIC TCA guideline⁸⁸ CPIC TCA guideline
Hicks JK et al. CPIC guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther, 2017 recommends a 50% dose reduction or alternative drug selection.

Voriconazole

Voriconazole is a triazole antifungal used for invasive aspergillosis and other serious fungal infections. In CYP2C19 poor metabolizers, voriconazole plasma concentrations can be several-fold higher than expected, dramatically increasing the risk of hepatotoxicity, QT prolongation, and neurotoxicity (visual disturbances, hallucinations, encephalopathy). The CPIC voriconazole guideline⁹⁹ CPIC voriconazole guideline
Moriyama B et al. CPIC guideline for CYP2C19 and voriconazole therapy. Clin Pharmacol Ther, 2017 recommends choosing an alternative antifungal (isavuconazole, posaconazole, liposomal amphotericin B) for poor metabolizers rather than attempting dose reduction, because the pharmacokinetic variability is too wide to dose safely.

Ancestry Context

CYP2C19*3 is predominantly an East Asian variant. Allele frequency is ~7–8% in East Asian populations (highest in Japanese, Korean, and Chinese cohorts), falling to ~0.4–0.5% in Europeans, ~0.03% in Africans, and ~1% in South Asians. A clopidogrel pharmacogenomic panel that tests only *2 misses roughly 15% of East Asian poor metabolizers — the exact population subset where CYP2C19-guided antiplatelet therapy has the biggest impact.

Interactions

CYP2C19*3 interacts with the other two CYP2C19 variants in the GeneOps catalog. Compound heterozygotes who carry both *2 (rs4244285) and *3 (rs4986893) are classified as poor metabolizers — even though neither SNP alone would place them in that category. The *3 allele also interacts with the *17 gain-of-function variant (rs12248560): a *3/*17 diplotype is generally classified as intermediate metabolizer, though the clinical behavior depends on the specific drug. Both combinations matter most for clopidogrel, the PPIs, and the SSRI/TCA antidepressants.