Global spectrum of population-specific common missense variation in cytochrome P450 pharmacogenes

Hum Mutat. 2021 Sep;42(9):1107-1123. doi: 10.1002/humu.24243. Epub 2021 Jun 29.


Next-generation sequencing technology has afforded the discovery of many novel variants that are of significance to inheritable pharmacogenomics (PGx) traits but a large proportion of them have unknown consequences. These include missense variants resulting in single amino acid substitutions in cytochrome P450 (CYP) proteins that can impair enzyme function, leading to altered drug efficacy and toxicity. While most unknown variants are rare, an overlooked minority are variants that are collectively rare but enriched in specific populations. Here, we analyzed sequence variation data in 141,456 individuals from across eight study populations in gnomAD for 38 CYP genes to identify such variants in addition to common variants. By further comparison with data from two PGx-specific databases (PharmVar and PharmGKB) and ClinVar, we identified 234 missense variants in 35 CYP genes, of which 107 were unknown to these databases. Most unknown variants (n = 83) were population-specific common variants and several (n = 7) were found in important CYP pharmacogenes (CYP2D6, CYP4F2, and CYP2C19). Overall, 29% (n = 31) of 107 unknown variants were predicted to affect CYP enzyme function although further biochemical characterization is necessary. These variants may elucidate part of the unexplained interpopulation differences observed in drug response.

Keywords: common missense variants; cytochrome P450; gnomAD; pharmacogenomics; population-specific common variants; single-nucleotide variant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytochrome P-450 CYP2D6* / genetics
  • Cytochrome P-450 Enzyme System* / genetics
  • High-Throughput Nucleotide Sequencing / methods
  • Humans
  • Pharmacogenetics / methods
  • Phenotype


  • Cytochrome P-450 Enzyme System
  • Cytochrome P-450 CYP2D6