{"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. Two people taking the same dose can have plasma concentrations that differ by 50x because of CYP2D6 genotype alone.","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, risperidone). 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 black-box warning against codeine in nursing mothers. 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. Two *4 copies = poor metabolizer.","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; two or more copies give an ultra-rapid metabolizer.","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 (no analgesia) and in ultra-rapid metabolizers (risk of opioid toxicity); notes reduced endoxifen production from tamoxifen in poor and intermediate metabolizers, with clinical implications still debated although several oncology guidelines consider CYP2D6 status; recommends dose reductions of tricyclic antidepressants for poor metabolizers and dose increases or alternative drugs for ultra-rapid metabolizers; and provides phenotype-based dosing guidance for the SSRIs paroxetine and fluvoxamine. DPWG guidance exists for the antipsychotics risperidone and aripiprazole. 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":null,"summary":"Prodrug converted to morphine by CYP2D6. CPIC recommends avoiding codeine in poor metabolizers (no analgesia) and in ultra-rapid metabolizers (risk of opioid toxicity). FDA black-box warning against codeine in nursing mothers."},{"drug":"tramadol","guideline":"CPIC","level":null,"summary":"Prodrug converted to O-desmethyltramadol by CYP2D6. CPIC recommends avoiding tramadol in poor metabolizers (no analgesia) and ultra-rapid metabolizers (risk of opioid toxicity)."},{"drug":"tamoxifen","guideline":"CPIC","level":null,"summary":"CYP2D6 converts tamoxifen to its active metabolite endoxifen. CPIC notes reduced endoxifen production in poor and intermediate metabolizers; clinical implications remain debated but several oncology guidelines now consider CYP2D6 status."},{"drug":"amitriptyline","guideline":"CPIC","level":null,"summary":"Tricyclic antidepressant inactivated by CYP2D6. CPIC recommends dose reductions for poor metabolizers and dose increases or alternative drug selection for ultra-rapid metabolizers."},{"drug":"nortriptyline","guideline":"CPIC","level":null,"summary":"Tricyclic antidepressant inactivated by CYP2D6. CPIC recommends dose reductions for poor metabolizers and dose increases or alternative drug selection for ultra-rapid metabolizers."},{"drug":"paroxetine","guideline":"CPIC","level":null,"summary":"SSRI; CPIC provides dosing guidance based on CYP2D6 phenotype."},{"drug":"fluvoxamine","guideline":"CPIC","level":null,"summary":"SSRI; CPIC provides dosing guidance based on CYP2D6 phenotype."},{"drug":"risperidone","guideline":"DPWG","level":null,"summary":"Antipsychotic inactivated by CYP2D6; DPWG guidance available."},{"drug":"aripiprazole","guideline":"DPWG","level":null,"summary":"Antipsychotic; DPWG guidance available."}],"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., Genet Med 2020 (standardized phenotype terms)","url":null}],"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"}}