{"gene":{"symbol":"CYP2D6","name":"Cytochrome P450 Family 2 Subfamily D Member 6","protein":"Cytochrome P450 2D6","ncbi_gene_id":"1565","locus":"22q13.2","summary":"CYP2D6 is a hepatic cytochrome P450 enzyme that metabolizes roughly 25% of clinically used drugs, including codeine, tramadol, tamoxifen, many antidepressants, antipsychotics and beta blockers. It is the most polymorphic CYP450 enzyme in humans, with more than 100 named star alleles, and copy-number variation matters as much as point mutations. The same dose can lead to very different drug levels across CYP2D6 phenotypes, which is why CPIC and DPWG publish phenotype-based guidelines.","function":"CYP2D6 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 to morphine, tramadol to O-desmethyltramadol, tamoxifen to endoxifen); for others it inactivates the parent drug (most SSRIs, many tricyclic antidepressants, metoprolol), and it converts risperidone to 9-hydroxyrisperidone, which is also active. The clinical implication therefore runs in opposite directions by drug class: a poor metabolizer taking codeine gets little analgesia, while a poor metabolizer taking a tricyclic accumulates the drug and risks toxicity; an ultra-rapid metabolizer of codeine can develop life-threatening opioid toxicity from a standard dose, the basis of the FDA 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, some people carry zero functional copies and others three, four or more, with enzyme activity multiplying accordingly.","category":"pharmacogene","key_variants":[{"rsid":null,"name":"*1 (reference)","alleles":"Wild-type haplotype","effect":"Normal function; activity value 1.0. Reference for phenotype scoring.","frequency_note":null},{"rsid":"rs3892097","name":"*4 (1846G>A)","alleles":"Plus strand, GRCh37 (as in 23andMe raw data): C reference, T variant. CYP2D6 is on the minus strand, so T here is the A of the splice change known as 1846G>A, which defines *4. A diplotype needs phasing, and consumer chips cannot see CYP2D6 deletions, duplications or hybrid genes.","effect":"Splice defect, no functional enzyme; activity value 0. CPIC classifies *4/*4 as poor metabolizer; two T alleles at rs3892097 alone do not establish *4/*4.","frequency_note":"The most common loss-of-function allele in Europeans (~20% frequency)."},{"rsid":"rs1065852","name":"*10 (100C>T)","alleles":"Plus strand, GRCh37 (as in 23andMe raw data): G reference, A variant. CYP2D6 is on the minus strand, so A here is the T of c.100C>T (Pro34Ser). A is carried by *10 and by many other alleles, *4 among them, so it can't be read as *10 on its own: read it together with rs3892097.","effect":"Decreased function; activity value 0.25.","frequency_note":"~40% in East Asians, where it is the dominant intermediate-activity variant. Rare in Europeans."},{"rsid":"rs28371706","name":"*17","alleles":"Plus strand, GRCh37 (as in 23andMe raw data): G reference, A variant. CYP2D6 is on the minus strand, so A here is the T of c.320C>T (Thr107Ile). A defines *17; rarer alleles (*40, *58 and *64 among them) also carry it.","effect":"Decreased function; activity value 0.5.","frequency_note":"The most common reduced-activity allele in sub-Saharan African populations (~20%)."},{"rsid":null,"name":"*2xN (gene duplication)","alleles":"Whole-gene duplication or multiplication of a functional allele","effect":"Activity value 2.0 or more for the duplicated allele; CPIC classifies a total activity score above 2.25 as ultra-rapid, so the other allele matters too.","frequency_note":"~3% of Europeans, up to 30% in some Ethiopian and Saudi Arabian populations."},{"rsid":null,"name":"*5 (whole-gene deletion)","alleles":"Complete deletion of CYP2D6","effect":"Loss of function; activity value 0.","frequency_note":"Present at 4–6% frequency in most populations."}],"phenotypes":["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"],"clinical_relevance":"CYP2D6 has formal, peer-reviewed dosing guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG). CPIC recommends avoiding codeine and tramadol in poor metabolizers (diminished analgesia) and in ultra-rapid metabolizers (risk of toxicity); recommends alternative hormonal therapy such as an aromatase inhibitor instead of tamoxifen for poor metabolizers and considering it for intermediate metabolizers, because endoxifen is lower; recommends avoiding the tricyclic antidepressants amitriptyline and nortriptyline 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); and provides phenotype-based dosing guidance for the SSRIs paroxetine and fluvoxamine. DPWG recommends a lower dose of risperidone and aripiprazole 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 PharmVar. For clinical decisions the standard is a CPIC-aware pharmacogenomic report integrating copy number, star alleles and the resulting phenotype, not a single-SNP readout.","consumer_array_caveat":"CYP2D6 is the gene where consumer SNP arrays struggle most: a nearby pseudogene (CYP2D7) with very high sequence similarity causes alignment ambiguity; frequent gene duplications, deletions and hybrid CYP2D6/CYP2D7 fusion alleles cannot be directly detected by array genotyping; and population-specific star alleles may not be represented on chips designed primarily for European samples. Usually genotyped: rs3892097 (*4 marker), rs1065852 (*10 marker); sometimes genotyped: rs28371706 (*17 marker). Typically not determinable from a consumer chip: copy number variation (*5 deletion or *2xN duplications), some rare star alleles, and the precise haplotype phase. For clinical decisions about codeine, tamoxifen or antidepressants, a dedicated pharmacogenomic test (panel-based assay or targeted sequencing with CNV calling) is the appropriate tool.","drugs":[{"drug":"codeine","guideline":"CPIC","level":"CPIC A","summary":"Prodrug converted to morphine by CYP2D6. CPIC recommends avoiding codeine in poor metabolizers (diminished analgesia) and in ultra-rapid metabolizers (risk of serious toxicity). The FDA label carries a boxed warning on ultra-rapid metabolism and life-threatening respiratory depression in children, contraindicates codeine under 12 years, and states that breastfeeding is not recommended during treatment."},{"drug":"tramadol","guideline":"CPIC","level":"CPIC A","summary":"Prodrug converted to O-desmethyltramadol by CYP2D6. CPIC recommends avoiding tramadol in poor metabolizers (diminished analgesia) and ultra-rapid metabolizers (risk of toxicity)."},{"drug":"tamoxifen","guideline":"CPIC","level":"CPIC A","summary":"CYP2D6 converts tamoxifen to its active metabolite endoxifen, which is lower in poor and intermediate metabolizers. CPIC recommends alternative hormonal therapy such as an aromatase inhibitor for poor metabolizers (strong) and considering it for intermediate metabolizers (moderate); if aromatase inhibitors are contraindicated, a higher FDA-approved tamoxifen dose can be considered. Lower endoxifen was linked to higher recurrence risk in some studies."},{"drug":"amitriptyline","guideline":"CPIC","level":"CPIC A","summary":"Tricyclic antidepressant inactivated by CYP2D6. CPIC recommends avoiding amitriptyline in poor and ultra-rapid metabolizers; if it is used, CPIC suggests considering a 50% lower starting dose for poor metabolizers or a higher target dose for ultra-rapid metabolizers, with drug-level monitoring, and a 25% lower starting dose for intermediate metabolizers. CYP2C19 phenotype also changes the recommendation."},{"drug":"nortriptyline","guideline":"CPIC","level":"CPIC A","summary":"Tricyclic antidepressant inactivated by CYP2D6. CPIC recommends avoiding nortriptyline in poor and ultra-rapid metabolizers; if it is used, CPIC suggests considering a 50% lower starting dose for poor metabolizers or a higher target dose for ultra-rapid metabolizers, with drug-level monitoring, and a 25% lower starting dose for intermediate metabolizers."},{"drug":"paroxetine","guideline":"CPIC","level":"CPIC A","summary":"SSRI metabolized by CYP2D6. CPIC recommends an alternative drug not mainly metabolized by CYP2D6 for ultra-rapid metabolizers, and suggests considering a 50% lower starting dose, slower titration and a 50% lower maintenance dose for poor metabolizers."},{"drug":"fluvoxamine","guideline":"CPIC","level":"CPIC B","summary":"SSRI metabolized by CYP2D6. CPIC guidance applies to poor metabolizers only: a 25–50% lower starting dose with slower titration, or an alternative drug not mainly metabolized by CYP2D6. CPIC makes no recommendation for ultra-rapid metabolizers."},{"drug":"risperidone","guideline":"DPWG","level":"CPIC B (provisional)","summary":"Antipsychotic converted by CYP2D6 to 9-hydroxyrisperidone, which is also active. DPWG recommends a lower dose for poor metabolizers and an alternative drug or dose titration for ultra-rapid metabolizers."},{"drug":"aripiprazole","guideline":"DPWG","level":"CPIC B (provisional)","summary":"Antipsychotic metabolized by CYP2D6. DPWG recommends a lower dose for poor metabolizers and no adjustment for other CYP2D6 phenotypes."},{"drug":"atomoxetine","guideline":"CPIC","level":"CPIC A","summary":"ADHD medicine cleared mainly by CYP2D6; poor metabolizers reach much higher drug levels, with more side effects but also a better response in those who tolerate it. For poor metabolizers and intermediate metabolizers with activity score below 1.0, CPIC recommends the usual starting dose with slower titration, a drug-level check if response is inadequate and a lower dose if side effects are unacceptable. For other phenotypes it recommends the usual titration, with a drug-level check if there is no response; based on very limited data, ultra-rapid metabolizers are unlikely to reach adequate levels at standard doses."},{"drug":"clomipramine","guideline":"CPIC","level":"CPIC B","summary":"Tricyclic antidepressant metabolized by CYP2D6 to less active compounds. CPIC extrapolates its amitriptyline and nortriptyline recommendations to clomipramine, noting fewer supporting data, and classifies them as optional except the usual starting dose for normal metabolizers (strong). Assuming CYP2C19 normal metabolism, CPIC suggests avoiding clomipramine in poor and ultra-rapid metabolizers; if it is used, considering a 50% lower starting dose for poor metabolizers or a higher target dose for ultra-rapid metabolizers, and a 25% lower starting dose for intermediate metabolizers, with drug-level monitoring. These recommendations apply to the higher doses used for depression, and other CYP2C19 phenotypes change them."},{"drug":"imipramine","guideline":"CPIC","level":"CPIC B","summary":"Tricyclic antidepressant metabolized by CYP2D6 to less active compounds. CPIC extrapolates its amitriptyline and nortriptyline recommendations to imipramine, noting fewer supporting data, and classifies them as optional except the usual starting dose for normal metabolizers (strong). Assuming CYP2C19 normal metabolism, CPIC suggests avoiding imipramine in poor and ultra-rapid metabolizers; if it is used, considering a 50% lower starting dose for poor metabolizers or a higher target dose for ultra-rapid metabolizers, and a 25% lower starting dose for intermediate metabolizers, with drug-level monitoring. These recommendations apply to the higher doses used for depression, and other CYP2C19 phenotypes change them."},{"drug":"doxepin","guideline":"CPIC","level":"CPIC B","summary":"Tricyclic antidepressant metabolized by CYP2D6 to less active compounds. CPIC extrapolates its amitriptyline and nortriptyline recommendations to doxepin, noting fewer supporting data, and classifies them as optional except the usual starting dose for normal metabolizers (strong). Assuming CYP2C19 normal metabolism, CPIC suggests avoiding doxepin in poor and ultra-rapid metabolizers; if it is used, considering a 50% lower starting dose for poor metabolizers or a higher target dose for ultra-rapid metabolizers, and a 25% lower starting dose for intermediate metabolizers, with drug-level monitoring. These recommendations apply to the higher doses used for depression, and other CYP2C19 phenotypes change them."},{"drug":"trimipramine","guideline":"CPIC","level":"CPIC B","summary":"Tricyclic antidepressant metabolized by CYP2D6 to less active compounds. CPIC extrapolates its amitriptyline and nortriptyline recommendations to trimipramine, noting fewer supporting data, and classifies them as optional except the usual starting dose for normal metabolizers (strong). Assuming CYP2C19 normal metabolism, CPIC suggests avoiding trimipramine in poor and ultra-rapid metabolizers; if it is used, considering a 50% lower starting dose for poor metabolizers or a higher target dose for ultra-rapid metabolizers, and a 25% lower starting dose for intermediate metabolizers, with drug-level monitoring. These recommendations apply to the higher doses used for depression, and other CYP2C19 phenotypes change them."},{"drug":"desipramine","guideline":"CPIC","level":"CPIC B","summary":"Tricyclic antidepressant (secondary amine) metabolized by CYP2D6 to less active compounds, without major CYP2C19 metabolism. CPIC extrapolates its amitriptyline and nortriptyline recommendations to desipramine, noting fewer supporting data, and classifies them as optional except the usual starting dose for normal metabolizers (strong). CPIC suggests avoiding a tricyclic in poor and ultra-rapid metabolizers and considering an alternative not metabolized by CYP2D6; if one is used, considering a 50% lower starting dose for poor metabolizers or a higher target dose for ultra-rapid metabolizers, and a 25% lower starting dose for intermediate metabolizers, with drug-level monitoring. These recommendations apply to the higher doses used for depression."},{"drug":"vortioxetine","guideline":"CPIC","level":"CPIC A","summary":"Antidepressant inactivated by CYP2D6, covered by CPIC's 2023 serotonin reuptake inhibitor guideline. For poor metabolizers, who have higher drug levels, CPIC recommends a 50% lower starting dose with a maximum dose of 10 mg, or an alternative antidepressant not predominantly metabolized by CYP2D6 (moderate). For ultra-rapid metabolizers it suggests an alternative not predominantly metabolized by CYP2D6, noting that a higher maintenance dose may be needed if vortioxetine is used (optional). For intermediate and normal metabolizers CPIC recommends the usual starting dose (moderate and strong, respectively)."},{"drug":"venlafaxine","guideline":"CPIC","level":"CPIC B","summary":"SNRI antidepressant converted by CYP2D6 to its active metabolite O-desmethylvenlafaxine (desvenlafaxine). For poor metabolizers CPIC suggests considering an alternative antidepressant not predominantly metabolized by CYP2D6 (optional); it notes that the clinical impact of their altered metabolism is unclear, but that the poor-metabolizer genotype has been associated with adverse effects. For intermediate and ultra-rapid metabolizers CPIC recommends no action based on genotype because of minimal evidence; for normal metabolizers, the usual starting dose (strong)."},{"drug":"metoprolol","guideline":"CPIC","level":"CPIC B","summary":"Beta-blocker metabolized by CYP2D6. CPIC notes that poor metabolizers have markedly higher drug levels and greater heart-rate and blood-pressure reductions, although the effect on clinical outcomes is unclear. For them CPIC recommends the lowest recommended starting dose with careful upward titration and closer monitoring for bradycardia, or another beta-blocker (moderate). For intermediate and normal metabolizers it recommends standard dosing (moderate and strong, respectively); it makes no recommendation for ultra-rapid metabolizers because of insufficient evidence."},{"drug":"hydrocodone","guideline":"CPIC","level":"CPIC B","summary":"Opioid converted by CYP2D6 to its active metabolite hydromorphone. CPIC notes that there is insufficient evidence on whether lower conversion in poor metabolizers reduces pain relief or changes side effects. For poor and intermediate metabolizers it suggests the label's age- or weight-specific dosing and, if there is no response and an opioid is still warranted, considering an opioid other than codeine or tramadol (optional). For normal metabolizers it recommends the label's dosing (strong); it makes no recommendation for ultra-rapid metabolizers because of minimal evidence."}],"sources":[{"label":"ClinVar — CYP2D6 entries","url":"https://www.ncbi.nlm.nih.gov/clinvar/?term=CYP2D6%5Bgene%5D"},{"label":"CPIC — CYP2D6 gene page","url":"https://cpicpgx.org/gene/cyp2d6/"},{"label":"PharmVar CYP2D6","url":"https://www.pharmvar.org/gene/CYP2D6"},{"label":"PharmGKB CYP2D6 (PA128)","url":"https://www.pharmgkb.org/gene/PA128"},{"label":"NCBI Gene 1565","url":"https://www.ncbi.nlm.nih.gov/gene/1565"},{"label":"Caudle et al., Clin Transl Sci 2020 (CPIC/DPWG consensus on CYP2D6 genotype-to-phenotype translation and activity scores)","url":"https://pubmed.ncbi.nlm.nih.gov/31647186/"},{"label":"Crews et al., Clin Pharmacol Ther 2021 (CPIC guideline: CYP2D6, OPRM1, COMT and opioids)","url":"https://pubmed.ncbi.nlm.nih.gov/33387367/"},{"label":"FDA label, codeine sulfate tablets (DailyMed: boxed warning, contraindications, lactation)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=010905f9-3bcb-4b50-9fe8-a3ad0010f14c"},{"label":"Goetz et al., Clin Pharmacol Ther 2018 (CPIC guideline: CYP2D6 and tamoxifen)","url":"https://pubmed.ncbi.nlm.nih.gov/29385237/"},{"label":"Hicks et al., Clin Pharmacol Ther 2017 (CPIC guideline: CYP2D6, CYP2C19 and tricyclic antidepressants)","url":"https://pubmed.ncbi.nlm.nih.gov/27997040/"},{"label":"Bousman et al., Clin Pharmacol Ther 2023 (CPIC guideline: CYP2D6, CYP2C19, CYP2B6, SLC6A4, HTR2A and SSRI/SNRI antidepressants)","url":"https://pubmed.ncbi.nlm.nih.gov/37032427/"},{"label":"Beunk et al., Eur J Hum Genet 2024 (DPWG guideline: CYP2D6, CYP3A4, CYP1A2 and antipsychotics)","url":"https://pubmed.ncbi.nlm.nih.gov/37002327/"},{"label":"FDA label, Risperdal (DailyMed: clinical effect from risperidone plus its major metabolite 9-hydroxyrisperidone)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e117c7e-02fc-4343-92a1-230061dfc5e0"}],"related_blog":"/blog/pharmacogenomics-europe-guide/","disclaimer":"Educational information only, not medical advice or diagnosis. Consult a clinician before acting on genetic information."},"meta":{"disclaimer":"Educational information only, not medical advice or diagnosis. Consult a clinician before acting on genetic information.","api_version":"2026-09-20","docs":"https://deepdna.ai/docs/","status":"live","data_as_of":"2026-10-25T21:32:19.251Z","freshness":"https://deepdna.ai/api/v1/freshness"}}