A comprehensive overview of common polymorphic variants that cause missense mutations in human CYPs and UGTs

Abstract Genetic polymorphisms in cytochrome P450 (CYP) or UDP-glucuronosyltransferase (UGT) genes can lead to changes in endocrine regulation or drug metabolism. Based on the recently published allele frequency data of the Exome Aggregation Consortium (ExAC), we extracted all common SNP variants that lead to missense mutations in CYPs and UGTs or in their helping proteins CPR, AdR, Adx, and UGDH. With a total of 737 alleles from 83 genes we provide the most comprehensive overview of missense variation distributions in drug metabolizing enzymes published to date. In all variants the most common allele was always considered to be the wild-type (WT), even if it was not identical to the *1-allele and/or the reference standard sequence of the RefSeq project. Surprisingly, in 15 cases (AdR, CYP2A7, CYP2C19, CYP2D6, CYP4A22, CYP4F11, CYP4F12, CYP4V2, CYP8B1, CYP20A1, UGT1A3, UGT1A7, UGT2A3, UGT2B7, and UGT2B15), the WT protein sequences were found to differ from reference standard sequences in up to four amino acids. We expect that these findings will have an impact on the definition of reference sequence standards for these genes, on the corresponding naming of alleles, and on the definition of reference standard activities.