rs4244285 — CYP2C19 *2

No-function CYP2C19 variant affecting PPIs, clopidogrel, and some antidepressants

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CYP2C19*2 - The Clopidogrel Gene

CYP2C19 is a drug-metabolizing enzyme with enormous clinical significance, particularly for the antiplatelet drug clopidogrel (Plavix). The *2 allele11 rs4244285 is the most common loss-of-function variant, rendering the enzyme completely non-functional. This variant carries an FDA black-box warning22 FDA black-box warning
Clopidogrel (Plavix) prescribing label, FDA on the clopidogrel label - one of the clearest examples of pharmacogenomics directly affecting prescribing decisions.

The Mechanism

The CYP2C19*2 variant is a synonymous change (G>A at position 681 in exon 5) that creates an aberrant splice site33 Despite being synonymous at the protein level, this variant disrupts normal mRNA splicing, producing a truncated, non-functional protein. Although the nucleotide change itself does not alter the encoded amino acid (Pro227=), it introduces a cryptic splice site that shifts the reading frame, leading to a premature stop codon. Homozygous carriers (AA) have no CYP2C19 activity and are classified as poor metabolizers.

The Clopidogrel Crisis

Clopidogrel is a prodrug44 A prodrug is inactive until the body converts it to its active form that REQUIRES CYP2C19 to be converted to its active antiplatelet metabolite. Poor metabolizers who take clopidogrel after coronary stent placement have significantly higher rates of stent thrombosis, heart attack, and cardiovascular death. A landmark study by Mega et al.55 landmark study by Mega et al.
Mega JL et al. Reduced-function CYP2C19 genotype and risk of cardiovascular events. JAMA, 2010 confirmed this association across multiple trials, leading to the FDA black-box warning66 FDA black-box warning
Clopidogrel (Plavix) prescribing label, FDA.

Beyond Clopidogrel

CYP2C19 also metabolizes proton pump inhibitors (PPIs like omeprazole and pantoprazole), certain antidepressants (citalopram, escitalopram, sertraline), and antifungal agents (voriconazole). For PPIs, poor metabolizers actually benefit because the drug stays active longer, providing better acid suppression. For antidepressants, poor metabolizers may need dose reductions.

What You Should Do

If you are a poor metabolizer (AA), the clopidogrel information is potentially life-saving. If you ever need antiplatelet therapy (after a stent, stroke, or peripheral vascular disease), you MUST use an alternative like prasugrel or ticagrelor. Share this information with your cardiologist and keep it in your medical records.

Drug Interactions

clopidogrel ineffective CPIC
prasugrel dose_adjustment literature
voriconazole increased_toxicity CPIC
citalopram increased_toxicity CPIC
escitalopram increased_toxicity CPIC
sertraline dose_adjustment CPIC
amitriptyline increased_toxicity CPIC
clomipramine increased_toxicity CPIC
imipramine increased_toxicity CPIC
doxepin increased_toxicity CPIC
trimipramine increased_toxicity CPIC
omeprazole dose_adjustment CPIC
pantoprazole dose_adjustment CPIC
lansoprazole dose_adjustment CPIC
dexlansoprazole dose_adjustment CPIC
diazepam dose_adjustment DPWG
brivaracetam dose_adjustment DPWG

Genotype Interpretations

What each possible genotype means for this variant.

GG Normal Metabolizer Normal

Normal CYP2C19 activity at *2 position

No loss-of-function variant at this position. About 72% of Europeans share this genotype, though the frequency varies by ancestry -- it is less common in East Asian and South Asian populations where the *2 allele is more prevalent.

AG Intermediate Metabolizer Intermediate

Intermediate CYP2C19 metabolizer

You carry one no-function CYP2C19*2 allele, giving you intermediate metabolizer status. This affects medications like clopidogrel (Plavix), PPIs (omeprazole, pantoprazole), and some antidepressants.

For clopidogrel, you may have reduced antiplatelet effect.

AA Poor Metabolizer Poor

Poor CYP2C19 metabolizer - clopidogrel ineffective

You are a CYP2C19 poor metabolizer. About 3% of Europeans share this genotype, with higher frequencies in East Asian populations. This has critical implications:

CLOPIDOGREL (PLAVIX) WILL NOT WORK FOR YOU. This antiplatelet medication needs CYP2C19 to convert it to its active form. If you need antiplatelet therapy after stent placement or for stroke prevention, you need an alternative.

PPIs like omeprazole will actually work BETTER for you since they won't be broken down as quickly.