EBM Consult

Pharmacogenetics: CYP2D6 Genetic Polymorphisms

     Allele Population
    Single Nucleotide


     General Population Wild-type; 5,139bp
    Extensive metabolizer
    CYP2D6*2xn Ethiopians/Saudi
    Arabian 10-16%
    Caucasians 1-5%
      Asians 0-2%
    Gene duplication
    C2983T (R296C)
    G4268C (S486T)
    Exon 6
    Exon 9

    Ultra-rapid or extensive

     CYP2D6*3 Asians 0%
    1-bp deletion 2637A
    or (aka., 2549A)
    Exon 5
    Poor metabolizer due
    to frame shift mutation
     CYP2D6*4 African Americans 2%
    G1934A Junction
    of Intron 3
    & Exon 4
     absent Poor to no metabolic
    activity due to a
    splicing defect
     CYP2D6*5 Caucasians 0.04%
    African Americans 4%
    11.5-kb deletion
    on gene
    On allele absent
    No 2D6 enzyme
    present in liver
    Caucasians 1.8%
    Deletion of T-1795
    causing a premature
    stop codon
    Exon 3

    Poor metabolizer non-
    functioning variant

     NR AGA deletion at
    2613-2615 (K281)
    Poor metabolizer
     Asians 39-51%
    African American 6%
    Caucasians 1-2%
    C188T; also seen as
    C100T (P34S)
    Exon 1

    Intermediate metabolizer
     Asian 2.2%
    Exon 3
    Poor metabolizer; non-
    functional enzyme
     African Americans
    C111T (T107I)
    C2938T (R296S)
    G4268C (S486T)
    Intron 1

    Altered affinity for
    substrates of 2D6
     Black Africans 20%

    Poor metabolizer
     Caucasians 8-10%
    African American 11%
    Japanese 2.6%
    Intron 6

    Intermediate metabolizer
    due to aberrant splicing

    The letters  before and after the numbers represent the single nucleotides that make up the DNA sequence and codons to code for an amino acid (A = adenine, C = cytosine, G = guanine, T = thymine). Amino acids represented:(C = cysteine, G = glycine, K = lysine, P = proline, R = arginine, S = serine, T = threonine, V = valine). NR = not reported.


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    6. Gough AC, Miles JS, Spurr NK et al. Identification of the primary gene defect at the cytochrome P450 CYP2D locus.  Nature 1990;347:773-776.  PubMed
    7. Hanioka N, Kimura S, Meyer UA et al. The human CYP2D locus associated with a common genetic defect in drug oxidation: a G(1934)-to-A base change in intron 3 of a mutant CYP2D6 allele results in an aberrant 3-prime splice recognition site.  Am J Hum Genet. 1990;47:994-1001.  PubMed
    8. Gaedigk A, Blum M, Gaedigk R et al. Deletion of the entire cytochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphism.  Am J Hum Genet 1991;48:943-950.  PubMed
    9. Nelson DR, Koymans L, Kamataki T et al. Cytochrome P450 superfamily: update on new sequences, gene mapping, accession numbers, and nomenclature.  Pharmacogenetics 1996;6:1-42.  PubMed
    10. Steen VM, Molven A, Aarskog NK et al.  Homologous unequal cross-over involving a 2.8 kb direct repeat as a mechanism for the generation of allelic variants of the human cytochrome P450 CYP2D6 gene.  Hum Molec Genet  1995;4:2251-2257.  PubMed
    11. Saxena R, Shaw GL, Relling MV et al. Identification of a new variant CYP2D6 allele with a single base deletion in exon 3 and its association with the poor metabolizer phenotype.  Hum Molec Genet 1994;3:923-926.  PubMed
    12. Tyndale R, Aoyama T, Broly F et al.  Identification of a new variant CYP2D6 allele lacking the codon encoding Lys-281: possible association with the poor metabolizer phenotype.  Pharmacogenetics 1991;1:26-32.  PubMed
    13. Kagimoto M, Heim M, Kagimoto K et al. Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine: study of the functional significance of individual mutations by expression of chimeric genes.  J Biol Chem 1990;265:17209-17214.  PubMed
    14. Wang SL, Lai MD, Huang JD.  G169R mutation diminishes the metabolic activity of CYP2D6 in chinese.  Drug Metab Dispos 1999;27:385-8.  PubMed
    15. Masimirembwa C, Persson I, Bertilsson L et al.  A novel mutant variant of the CYP2D6 gene (CYP2D6*17) common in a black African population: association with diminished debrisoquine hydroxylase activity.  Br J Clin Pharmacol  1996;42:713-9.  PubMed
    16. Wennerholm A, Johansson I, Hidestrand M et al.  Characterization of the CYP2D6*29 allele commonly present in a black Tanzanian population causing reduced catalytic activity.  Pharmacogenetics  2001;11:417-27.  PubMed
    17. Ikenaga Y, Fukuda T, Fukuda K et al.  The frequency of candidate alleles for CYP2D6 genotyping in the Japanese population with an additional respect to the -1584C to G substitution.  Drug Metab Pharmacokinet 2005;20:113-6.  PubMed
    18. Raimundo S, Toscano C, Klein K et al.  A novel intronic mutation, 2988G>A, with predictivity for impaired function of cytochrome P450 2D6 in white subjects.  Clin Pharmacol Ther  2004;76:128-38.  PubMed

Editors & Reviewers

  • Editors:  Anthony J. Busti, MD, PharmD, FNLA, FAHA
    Last Reviewed:  June 2015

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