rs4244285 — CYP2C19 *2

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

Established Risk Factor

Details

Gene: CYP2C19
Chromosome: 10
Risk allele: A
Consequence: Synonymous
Inheritance: Codominant
Clinical: Risk Factor
Evidence: Established
Chip coverage: v3 v4 v5

Population Frequency

72%

25%

Ancestry Frequencies

south_asian

32%

east_asian

30%

african

18%

european

15%

latino

10%

Related SNPs

rs12248560 (CYP2C19)

External

SNPedia ClinVar dbSNP

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 Caution

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 Critical

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.