CYP2D6

The 25-percent enzyme.

CYP2D6 is a hepatic cytochrome P450 enzyme that performs oxidative metabolism — typically hydroxylation or demethylation — on a long list of drug substrates. For some drugs it converts an inactive prodrug into the active form (codeine → morphine, tramadol → O-desmethyltramadol, tamoxifen → endoxifen). For others it inactivates the parent drug (most SSRIs, many tricyclic antidepressants, metoprolol). Risperidone is converted to 9-hydroxyrisperidone, which is also active.

The clinical implication runs in opposite directions depending on the drug class. A poor metabolizer taking codeine experiences little analgesia (no conversion to morphine) but a poor metabolizer taking a tricyclic antidepressant accumulates the drug and risks toxicity. An ultra-rapid metabolizer of codeine can develop life-threatening opioid toxicity from a standard dose because they over-produce morphine — this is the basis for the FDA's boxed warning on ultra-rapid metabolism and life-threatening respiratory depression in children. The label also states that breastfeeding is not recommended during codeine treatment.

Because the gene sits in a duplication-prone region of chromosome 22, copy number variation matters as much as point mutations. Some people carry zero functional copies; others carry three, four, or more — and the dose multiplies the enzyme activity correspondingly.

Star alleles, not single SNPs.

CYP2D6 is described using star-allele haplotype nomenclature rather than individual rsIDs. Each star allele is a combination of SNPs and structural variants that produces a defined enzyme activity. The most clinically relevant alleles globally:

Each person carries two alleles. Adding their activity scores produces a phenotype:

• Poor metabolizer (PM) — activity score 0. Two no-function alleles.
• Intermediate metabolizer (IM) — activity score 0.25 to < 1.25.
• Normal metabolizer (NM) — activity score 1.25 to 2.25.
• Ultra-rapid metabolizer (UM) — activity score > 2.25, typically driven by gene duplication.

The strongest pharmacogenomic evidence in the genome.

Unlike most pharmacogenes, CYP2D6 has formal, peer-reviewed dosing guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG). These are clinical recommendations, not speculation. Examples:

• Codeine and tramadol: CPIC recommends avoiding both in poor metabolizers (diminished analgesia) and in ultra-rapid metabolizers (risk of toxicity).
• Tamoxifen: CPIC recommends alternative hormonal therapy such as an aromatase inhibitor for poor metabolizers and considering it for intermediate metabolizers, because their active metabolite (endoxifen) levels are lower.
• Tricyclic antidepressants (amitriptyline, nortriptyline): CPIC recommends avoiding them in poor and ultra-rapid metabolizers; if one is used, a 50% lower starting dose for poor metabolizers or a higher target dose with drug-level monitoring for ultra-rapid metabolizers.
• SSRIs (paroxetine, fluvoxamine): CPIC provides phenotype-based guidance: for paroxetine, an alternative drug for ultra-rapid metabolizers and a lower dose for poor metabolizers; for fluvoxamine, guidance for poor metabolizers only.
• Antipsychotics (risperidone, aripiprazole): DPWG recommends a lower dose of either for poor metabolizers, and an alternative drug or dose titration of risperidone for ultra-rapid metabolizers.

ClinVar lists hundreds of CYP2D6 variants, and the variant-to-star-allele mapping is maintained by the Pharmacogene Variation Consortium (PharmVar). For clinical decisions, a CPIC-aware pharmacogenomic report (which integrates copy number, star alleles, and the resulting phenotype) is the standard — not a single SNP readout.

Primary sources: ClinVar — CYP2D6 entries; CPIC — CYP2D6 gene page; PharmVar CYP2D6; Caudle et al., Clin Transl Sci 2020 (CYP2D6 genotype-to-phenotype translation); Crews et al., Clin Pharmacol Ther 2021 (CPIC opioids); Goetz et al., Clin Pharmacol Ther 2018 (CPIC tamoxifen); Hicks et al., Clin Pharmacol Ther 2017 (CPIC tricyclics); Bousman et al., Clin Pharmacol Ther 2023 (CPIC SSRIs/SNRIs); Beunk et al., Eur J Hum Genet 2024 (DPWG antipsychotics); FDA label, codeine sulfate; FDA label, Risperdal.

What consumer arrays do — and don't — tell you about CYP2D6.

This is the gene where consumer SNP arrays struggle most. CYP2D6 lives in a region with:

• A nearby pseudogene (CYP2D7) with very high sequence similarity, which causes alignment ambiguity.
• Frequent gene duplications, deletions, and hybrid CYP2D6/CYP2D7 fusion alleles that array genotyping cannot directly detect.
• Population-specific star alleles that may not be represented on a chip designed primarily for European samples.

What you can usually look up in raw data:

• rs3892097 (*4 marker) — usually genotyped. Two T alleles at this position are consistent with two *4 alleles, but a chip cannot see CYP2D6 deletions, duplications or hybrid genes, so it cannot give a diplotype or a metabolizer status.
• rs1065852 (*10 marker) — usually genotyped. Important in East Asian populations.
• rs28371706 (*17 marker) — sometimes genotyped, important in African populations.

What you typically cannot determine from a consumer chip alone: copy number variation (*5 deletion or *2×N duplications), some rare star alleles, and the precise haplotype phase. For clinical decisions about codeine, tamoxifen, or antidepressants, a dedicated pharmacogenomic test (typically a panel-based assay or targeted sequencing with CNV calling) is the appropriate tool — not a raw consumer file.