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CYP2C19 c.681G>A Is not in Complete Linkage Disequilibrium With c.332-23A>G: Implications for Pharmacogenetic Testing
Amy J Turner1, Erin C Boone2, Cyrine E Haidar3
1RPRD Diagnostics LLC, Milwaukee, Wisconsin, USA.
Clinical and Translational Science
|July 31, 2026
Summary
The CYP2C19*2 allele definition is revised to solely include the c.681G>A variant. This change impacts genetic testing interpretation for drug metabolism, particularly for medications like clopidogrel.
Area of Science:
- Pharmacogenetics
- Genetics
- Clinical Pharmacology
Background:
- CYP2C19 is crucial for metabolizing numerous medications, including clopidogrel, voriconazole, SSRIs, TCAs, and PPIs.
- Clinical Pharmacogenetics Implementation Consortium guidelines highlight CYP2C19 genotype-guided therapy for optimized patient outcomes.
- The previous definition of the no-function CYP2C19*2 allele included three variants: c.332-23A>G, c.681G>A, and c.991A>G.
Purpose of the Study:
- To report the discovery of new haplotypes challenging the traditional definition of CYP2C19*2.
- To explain the revision of the CYP2C19*2 core allele definition by PharmVar.
- To discuss the implications of these changes for genetic testing and interpretation.
Main Methods:
- Identification and characterization of novel CYP2C19 haplotypes.
- Utilizing PharmVar nomenclature for variant designation.
- Analysis of variant frequencies across diverse populations.
Main Results:
- Two new haplotypes, CYP2C19*2.018 and *2.019, were identified, containing only c.681G>A or both c.681G>A and c.991A>G, respectively.
- The CYP2C19*2 core allele definition was revised to be solely based on the c.681G>A variant.
- Rare instances of CYP2C19*2/*35 poor metabolizer diplotypes (variants in trans) may occur instead of CYP2C19*1/*2 intermediate metabolizer diplotypes (variants in cis).
- CYP2C19*2 alleles lacking c.332-23A>G but containing c.681G>A have an estimated frequency of 0.03% across populations.
Conclusions:
- The revised CYP2C19*2 definition necessitates adjustments in genetic testing, interpretation, and reporting.
- Accurate diplotype determination is critical for precise pharmacogenetic assessments.
- These findings enhance the understanding of CYP2C19 genetic variations and their clinical relevance.
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