CYP2D6 (Cytochrome P450 2D6) variants and mutations
CYP2D6 (also known as Cytochrome P450 2D6) is a human protein-coding gene encoding a cytochrome P450 2D6 protein. It oxidizes many commonly prescribed drugs, and inherited differences in activity can shift patients from poor to ultrarapid metabolism. This variability can substantially alter drug exposure, efficacy, and toxicity, making CYP2D6 one of the most clinically important pharmacogenes. This analysis covers 1,661 CYP2D6 variants and mutations. Of these, 72% have computational variant effect predictions. Disease context includes response to tramadol, debrisoquine, poor metabolism of, and Abnormality of the skeletal system. Example CYP2D6 variants include G2R, G2V, and G2W.
Variant analysis overview
- Gene: CYP2D6
- Protein: Cytochrome P450 2D6
- UniProt accession: P10635
- Organism: Homo sapiens
- Variants analyzed: 1661
- Variant scope: all variants
- Completed: 2026-08-09
Variant and mutation evidence
- Variant composition: 1,385 unspecified-consequence records; 1 stop retained variant; 3 stop lost; 102 synonymous variants; 116 missense variants; 39 frameshift variants; 6 stop-gained variants; 4 in-frame deletions; 3 splice-region variants; 2 substitution
- Prediction scores: 1,193 variants have prediction scores (72% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: response to tramadol, debrisoquine, poor metabolism of, Abnormality of the skeletal system, Precordial pain, ventricular septal defect, intelligence, schizophrenia, insomnia, mathematical ability, bipolar disorder, reasoning, major depressive disorder.
Protein structure and variant hotspots
- Protein features: 2 binding sites.
Data sources
Evidence in this analysis draws on EBI Proteins Variation, UniProt, gnomAD v4, EuropePMC, 3D Hotspot Analysis, Interaction Network Analysis, Protein Data Bank, AlphaFold DB, gnomAD constraint, Open Targets, MaveDB, LitVar.
Notable CYP2D6 variants
Examples include G2R, G2V, G2W, L3Q, L3R, E4D, E4G, A5G. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- G2R (p.Gly2Arg), Ensembl rs2146945211, CADD 17.90, PolyPhen-2 0.01
- G2V (p.Gly2Val), Ensembl rs2146945202, CADD 15.40, PolyPhen-2 0.01
- G2W (p.Gly2Trp), Ensembl rs2146945211, CADD 20.70, PolyPhen-2 0.42
- L3Q (p.Leu3Gln), Ensembl rs2146945182
- L3R (p.Leu3Arg), Ensembl rs2146945182
- E4D (p.Glu4Asp), Ensembl rs2146945155
- E4G (p.Glu4Gly), Ensembl rs2146945165
- A5G (p.Ala5Gly), ExAC rs773790593, TOPMed rs773790593, CADD 0.00, PolyPhen-2 0.00
- A5P (p.Ala5Pro), TOPMed rs1315104438
- A5S (p.Ala5Ser), TOPMed rs1315104438, CADD 0.00, PolyPhen-2 0.03
- A5T (p.Ala5Thr), TOPMed rs1315104438, CADD 0.01, PolyPhen-2 0.00
- A5V (p.Ala5Val), rs773790593, cosmic curated COSV62243, UniProt VAR 072764, ExAC rs773790593, CADD 0.01, PolyPhen-2 0.00, Benign, in allele CYP2D6*87
- L6Q (p.Leu6Gln), Ensembl rs2146945104, CADD 22.40, PolyPhen-2 1.00
- L6V (p.Leu6Val), 1000Genomes rs199635004, ExAC rs199635004, gnomAD rs199635004
- V7A (p.Val7Ala), rs1602591357, ClinGen CA411776061, ClinVar RCV001029556, Ensembl rs1602591357, CADD 0.01, PolyPhen-2 0.00, drug response, Tramadol response
- V7L (p.Val7Leu), 1000Genomes rs72549358, ESP rs72549358, ExAC rs72549358, TOPMed rs72549358
- V7M (p.Val7Met), cosmic curated COSV99053, 1000Genomes rs72549358, ESP rs72549358, ExAC rs72549358, CADD 0.46, PolyPhen-2 0.00, Likely benign, not provided
- P8A (p.Pro8Ala), gnomAD rs1346961531, CADD 0.00, PolyPhen-2 0.00
- P8H (p.Pro8His), TOPMed rs1275370019, gnomAD rs1275370019, CADD 15.10, PolyPhen-2 0.34
- P8L (p.Pro8Leu), TOPMed rs1275370019, gnomAD rs1275370019, CADD 9.72, PolyPhen-2 0.00
- P8R (p.Pro8Arg), TOPMed rs1275370019, gnomAD rs1275370019
- P8S (p.Pro8Ser), gnomAD rs1346961531, CADD 0.00, PolyPhen-2 0.00
- P8T (p.Pro8Thr), gnomAD rs1346961531
- L9M (p.Leu9Met), gnomAD rs1238780949
- L9P (p.Leu9Pro), Ensembl rs2146945029, CADD 23.30, PolyPhen-2 0.83
- L9Q (p.Leu9Gln), Ensembl rs2146945029
- A10G (p.Ala10Gly), gnomAD rs1447119000, CADD 14.50, PolyPhen-2 0.01
- A10P (p.Ala10Pro), 1000Genomes rs2146945007
- A10S (p.Ala10Ser), 1000Genomes rs2146945007, CADD 14.60, PolyPhen-2 0.21
- A10T (p.Ala10Thr), 1000Genomes rs2146945007, CADD 15.30, PolyPhen-2 0.03
- A10V (p.Ala10Val), gnomAD rs1447119000, CADD 15.50, PolyPhen-2 0.27
- V11E (p.Val11Glu), Ensembl rs2146944956
- V11G (p.Val11Gly), Ensembl rs2146944956, CADD 19.90, PolyPhen-2 0.21
- V11L (p.Val11Leu), 1000Genomes rs769258, ESP rs769258, ExAC rs769258, TOPMed rs769258, CADD 0.00, PolyPhen-2 0.00, Likely benign, in allele CYP2D6*35
- V11M (p.Val11Met), rs769258, ClinGen CA10265379, cosmic curated COSV62244, ClinVar RCV000835751, CADD 0.01, PolyPhen-2 0.02, Likely benign, not provided
- I12K (p.Ile12Lys), Ensembl rs2146944927
- I12L (p.Ile12Leu), gnomAD rs1416532887, CADD 0.89, PolyPhen-2 0.00
- I12M (p.Ile12Met), Ensembl rs2146944915
- I12R (p.Ile12Arg), Ensembl rs2146944927, CADD 1.33, PolyPhen-2 0.01
- I12V (p.Ile12Val), gnomAD rs1416532887
- V13E (p.Val13Glu), Ensembl rs2146944892
- V13G (p.Val13Gly), Ensembl rs2146944892
- V13L (p.Val13Leu), Ensembl rs2146944902, CADD 0.00, PolyPhen-2 0.00
- V13M (p.Val13Met), Ensembl rs2146944902, CADD 0.00, PolyPhen-2 0.01
- A14P (p.Ala14Pro), Ensembl rs2146944870
- A14S (p.Ala14Ser), Ensembl rs2146944870
- A14T (p.Ala14Thr), Ensembl rs2146944870, CADD 1.36, PolyPhen-2 0.01
- A14V (p.Ala14Val), ExAC rs745794582, gnomAD rs745794582, CADD 3.98, PolyPhen-2 0.00
- I15F (p.Ile15Phe), Ensembl rs2146944846
- I15L (p.Ile15Leu), Ensembl rs2146944846
- I15M (p.Ile15Met), Ensembl rs2146944839
- F16L (p.Phe16Leu), gnomAD rs1382290042
- F16S (p.Phe16Ser), Ensembl rs2146944824, CADD 26.00, PolyPhen-2 0.99
- F16V (p.Phe16Val), TOPMed rs1167414191, gnomAD rs1167414191, CADD 24.30
- F16Y (p.Phe16Tyr), Ensembl rs2146944824, CADD 24.80, PolyPhen-2 0.98
- L17P (p.Leu17Pro), Ensembl rs2146944802
- L18F (p.Leu18Phe), TOPMed rs1420797477, gnomAD rs1420797477, CADD 22.80, PolyPhen-2 0.56
- L18H (p.Leu18His), Ensembl rs2146944777
- L18P (p.Leu18Pro), Ensembl rs2146944777, CADD 25.90, PolyPhen-2 0.83
- L18R (p.Leu18Arg), Ensembl rs2146944777
- L18V (p.Leu18Val), TOPMed rs1420797477, gnomAD rs1420797477
- L19P (p.Leu19Pro), Ensembl rs2146944754
- L19Q (p.Leu19Gln), Ensembl rs2146944754
- L19V (p.Leu19Val), TOPMed rs1412157908
- V20L (p.Val20Leu), Ensembl rs2146944735
- V20M (p.Val20Met), Ensembl rs2146944735, CADD 19.50, PolyPhen-2 0.36
- D21A (p.Asp21Ala), Ensembl rs1932030649
- D21E (p.Asp21Glu), Ensembl rs1932030074, CADD 20.80, PolyPhen-2 0.26
- D21G (p.Asp21Gly), Ensembl rs1932030649, CADD 23.20, PolyPhen-2 0.25
- D21H (p.Asp21His), Ensembl rs2146944722
- D21V (p.Asp21Val), Ensembl rs1932030649, CADD 22.80, PolyPhen-2 0.06
- D21Y (p.Asp21Tyr), Ensembl rs2146944722
- L22P (p.Leu22Pro), gnomAD rs1179371370, CADD 24.30, PolyPhen-2 0.96
- L22Q (p.Leu22Gln), cosmic curated COSV10466, gnomAD rs1179371370
- L22R (p.Leu22Arg), gnomAD rs1179371370
- L22V (p.Leu22Val), Ensembl rs2146944692
- M23I (p.Met23Ile), Ensembl rs2146944645, CADD 18.60, PolyPhen-2 0.38
- M23K (p.Met23Lys), gnomAD rs1472562440
- M23R (p.Met23Arg), gnomAD rs1472562440, CADD 23.70, PolyPhen-2 0.93
- H24D (p.His24Asp), Ensembl rs2146944638
- H24L (p.His24Leu), TOPMed rs1358991664, gnomAD rs1358991664
- H24P (p.His24Pro), TOPMed rs1358991664, gnomAD rs1358991664
- H24Q (p.His24Gln), Ensembl rs2146944619, CADD 15.70, PolyPhen-2 0.18
- H24R (p.His24Arg), TOPMed rs1358991664, gnomAD rs1358991664, CADD 22.60, PolyPhen-2 0.70, Uncertain significance, not specified
- H24Y (p.His24Tyr), Ensembl rs2146944638
- R25G (p.Arg25Gly), ExAC rs267608313, TOPMed rs267608313, gnomAD rs267608313
- R25L (p.Arg25Leu), ESP rs138417770, ExAC rs138417770, TOPMed rs138417770, gnomAD rs138417770
- R25P (p.Arg25Pro), ESP rs138417770, ExAC rs138417770, TOPMed rs138417770, gnomAD rs138417770, CADD 23.90, PolyPhen-2 0.95
- R25Q (p.Arg25Gln), rs138417770, UniProt VAR 072765, ESP rs138417770, ExAC rs138417770, CADD 22.30, PolyPhen-2 0.30
- R25W (p.Arg25Trp), cosmic curated COSV10063, ExAC rs267608313, TOPMed rs267608313, gnomAD rs267608313, CADD 20.50, PolyPhen-2 0.17
- R26C (p.Arg26Cys), rs145868402, ClinGen CA10265373, ClinVar RCV004187988, ESP rs145868402, CADD 22.90, PolyPhen-2 0.08, Uncertain significance, not specified
- R26G (p.Arg26Gly), ESP rs145868402, ExAC rs145868402, TOPMed rs145868402, gnomAD rs145868402, Uncertain significance, in allele CYP2D6*21 and allele CYP2D6*46
- R26H (p.Arg26His), rs28371696, cosmic curated COSV62244, UniProt VAR 008367, 1000Genomes rs28371696, CADD 21.80, PolyPhen-2 0.03, Benign, in allele CYP2D6*21 and allele CYP2D6*46
- R26L (p.Arg26Leu), 1000Genomes rs28371696, ESP rs28371696, ExAC rs28371696, TOPMed rs28371696
- R26P (p.Arg26Pro), 1000Genomes rs28371696, ESP rs28371696, ExAC rs28371696, TOPMed rs28371696
- Q27* (p.Gln27Ter), Ensembl rs2146944544
- Q27E (p.Gln27Glu), Ensembl rs2146944544, CADD 4.32, PolyPhen-2 0.10
- Q27H (p.Gln27His), Ensembl rs2146944515
- Q27K (p.Gln27Lys), Ensembl rs2146944544, CADD 1.86, PolyPhen-2 0.01
- Q27L (p.Gln27Leu), Ensembl rs1602590731, Drug response
- Q27P (p.Gln27Pro), Ensembl rs1602590731, CADD 7.60, PolyPhen-2 0.01, Drug response
- Q27R (p.Gln27Arg), rs1602590731, ClinGen CA411775941, ClinVar RCV001029559, Ensembl rs1602590731, CADD 3.26, PolyPhen-2 0.01, drug response, Tramadol response
- R28C (p.Arg28Cys), rs138100349, cosmic curated COSV62242, UniProt VAR 008368, 1000Genomes rs138100349, CADD 12.90, PolyPhen-2 0.02, Benign, in allele CYP2D6*22
- R28G (p.Arg28Gly), 1000Genomes rs138100349, ESP rs138100349, ExAC rs138100349, TOPMed rs138100349
- R28H (p.Arg28His), rs377617003, ESP rs377617003, ExAC rs377617003, TOPMed rs377617003, CADD 15.10, PolyPhen-2 0.01, Variant assessed as somatic; moderate impact., in allele CYP2D6*22
- R28L (p.Arg28Leu), ESP rs377617003, ExAC rs377617003, TOPMed rs377617003, gnomAD rs377617003, CADD 18.80, PolyPhen-2 0.30
- R28P (p.Arg28Pro), ESP rs377617003, ExAC rs377617003, TOPMed rs377617003, gnomAD rs377617003, CADD 20.30, PolyPhen-2 0.67
- R28S (p.Arg28Ser), 1000Genomes rs138100349, ESP rs138100349, ExAC rs138100349, TOPMed rs138100349, CADD 14.10, PolyPhen-2 0.07
- W29* (p.Trp29Ter), Ensembl rs2146944440, CADD 35.00
- W29C (p.Trp29Cys), Ensembl rs2146944440
- W29G (p.Trp29Gly), TOPMed rs1276203971, CADD 24.70, PolyPhen-2 1.00
- W29L (p.Trp29Leu), gnomAD rs1223876546
- W29R (p.Trp29Arg), TOPMed rs1276203971
- W29S (p.Trp29Ser), gnomAD rs1223876546
- A30G (p.Ala30Gly), TOPMed rs1377921514, gnomAD rs1377921514
- A30P (p.Ala30Pro), Ensembl rs2146944429
- A30S (p.Ala30Ser), Ensembl rs2146944429, CADD 7.98, PolyPhen-2 0.30
- A30T (p.Ala30Thr), Ensembl rs2146944429
- A30V (p.Ala30Val), TOPMed rs1377921514, gnomAD rs1377921514, CADD 18.90, PolyPhen-2 0.37
- A31E (p.Ala31Glu), ExAC rs765912784, gnomAD rs765912784, CADD 21.30, PolyPhen-2 0.52
- A31G (p.Ala31Gly), ExAC rs765912784, gnomAD rs765912784
- A31P (p.Ala31Pro), TOPMed rs1282073755, gnomAD rs1282073755
- A31T (p.Ala31Thr), TOPMed rs1282073755, gnomAD rs1282073755, CADD 2.56, PolyPhen-2 0.02
- A31V (p.Ala31Val), ExAC rs765912784, gnomAD rs765912784, CADD 21.90, PolyPhen-2 0.39
- R32C (p.Arg32Cys), rs762378491, ClinGen CA10265366, ClinVar RCV004367933, ExAC rs762378491, CADD 21.10, PolyPhen-2 0.12, Uncertain significance, not specified
- R32G (p.Arg32Gly), ExAC rs762378491, TOPMed rs762378491, gnomAD rs762378491, CADD 22.70, PolyPhen-2 0.81, Uncertain significance
- R32H (p.Arg32His), rs1418365589, TOPMed rs1418365589, gnomAD rs1418365589, CADD 9.64, PolyPhen-2 0.07, Variant assessed as somatic; moderate impact.
- R32L (p.Arg32Leu), TOPMed rs1418365589, gnomAD rs1418365589, CADD 19.60, PolyPhen-2 0.81
- R32P (p.Arg32Pro), TOPMed rs1418365589, gnomAD rs1418365589
- Y33H (p.Tyr33His), Ensembl rs2146944351
- Y33N (p.Tyr33Asn), Ensembl rs2146944351
- Y33S (p.Tyr33Ser), TOPMed rs1932016704, CADD 23.80, PolyPhen-2 0.94
- P34A (p.Pro34Ala), 1000Genomes rs1065852, ESP rs1065852, ExAC rs1065852, TOPMed rs1065852, Likely benign, in allele CYP2D6*10 and allele CYP2D6*14
- P34L (p.Pro34Leu), ESP rs370009591, ExAC rs370009591, TOPMed rs370009591, gnomAD rs370009591, CADD 25.30, PolyPhen-2 0.98
- P34Q (p.Pro34Gln), ESP rs370009591, ExAC rs370009591, TOPMed rs370009591, gnomAD rs370009591, CADD 24.80, PolyPhen-2 0.99
- P34R (p.Pro34Arg), ESP rs370009591, ExAC rs370009591, TOPMed rs370009591, gnomAD rs370009591, CADD 24.90, PolyPhen-2 0.99
- P34S (p.Pro34Ser), rs1065852, ClinGen CA126956, cosmic curated COSV62243, ClinVar RCV000018389, CADD 24.40, PolyPhen-2 0.69, Likely benign; drug response; other, not specified; not provided; Deutetrabenazine response
- P35A (p.Pro35Ala), ExAC rs771774661, TOPMed rs771774661, gnomAD rs771774661
- P35L (p.Pro35Leu), gnomAD rs1258016506, CADD 25.70, PolyPhen-2 0.99
- P35R (p.Pro35Arg), gnomAD rs1258016506
- P35S (p.Pro35Ser), ExAC rs771774661, TOPMed rs771774661, gnomAD rs771774661, CADD 24.40, PolyPhen-2 0.97
- G36C (p.Gly36Cys), NCI-TCGA TCGA novel, Ensembl rs2146944282, Variant assessed as somatic; moderate impact.
- G36D (p.Gly36Asp), TOPMed rs1407786572, CADD 24.30, PolyPhen-2 1.00
- G36R (p.Gly36Arg), Ensembl rs2146944282
- G36S (p.Gly36Ser), Ensembl rs2146944282, CADD 23.10, PolyPhen-2 1.00
- P37A (p.Pro37Ala), gnomAD rs1487241440
- P37H (p.Pro37His), gnomAD rs1288096759, CADD 25.10, PolyPhen-2 1.00
- P37L (p.Pro37Leu), gnomAD rs1288096759
- P37R (p.Pro37Arg), gnomAD rs1288096759
- P37S (p.Pro37Ser), gnomAD rs1487241440, CADD 24.40, PolyPhen-2 1.00
- P37T (p.Pro37Thr), gnomAD rs1487241440
- L38V (p.Leu38Val), gnomAD rs1320662968, CADD 0.00, PolyPhen-2 0.00
- P39A (p.Pro39Ala), Ensembl rs2146944206
- P39L (p.Pro39Leu), TOPMed rs1326543372, gnomAD rs1326543372, CADD 23.30, PolyPhen-2 0.96, Uncertain significance, not specified
- P39R (p.Pro39Arg), TOPMed rs1326543372, gnomAD rs1326543372, Uncertain significance
- P39S (p.Pro39Ser), Ensembl rs2146944206, CADD 15.20, PolyPhen-2 0.39
- P39T (p.Pro39Thr), Ensembl rs2146944206
- L40Q (p.Leu40Gln), ExAC rs770891169, TOPMed rs770891169, gnomAD rs770891169, CADD 23.90, PolyPhen-2 0.92, Uncertain significance, not specified
- L40R (p.Leu40Arg), ExAC rs770891169, TOPMed rs770891169, gnomAD rs770891169
- L40V (p.Leu40Val), Ensembl rs2146944195
- P41A (p.Pro41Ala), ExAC rs749179272, gnomAD rs749179272
- P41L (p.Pro41Leu), 1000Genomes rs373243894, ExAC rs373243894, gnomAD rs373243894, CADD 25.10, PolyPhen-2 1.00
- P41R (p.Pro41Arg), 1000Genomes rs373243894, ExAC rs373243894, gnomAD rs373243894, CADD 24.70, PolyPhen-2 1.00
- P41S (p.Pro41Ser), ExAC rs749179272, gnomAD rs749179272, CADD 24.80, PolyPhen-2 1.00
- P41T (p.Pro41Thr), ExAC rs749179272, gnomAD rs749179272
- G42A (p.Gly42Ala), 1000Genomes rs118203758, ExAC rs118203758, TOPMed rs118203758, gnomAD rs118203758
- G42E (p.Gly42Glu), cosmic curated COSV10591, 1000Genomes rs118203758, ExAC rs118203758, TOPMed rs118203758, CADD 17.90, PolyPhen-2 0.95
- G42R (p.Gly42Arg), rs5030862, ClinGen CA10265355, cosmic curated COSV62243, ClinVar RCV000734609, CADD 21.90, PolyPhen-2 0.94, Likely benign; other, not provided
- G42V (p.Gly42Val), 1000Genomes rs118203758, ExAC rs118203758, TOPMed rs118203758, gnomAD rs118203758
- G42W (p.Gly42Trp), ESP rs5030862, ExAC rs5030862, TOPMed rs5030862, gnomAD rs5030862, CADD 22.50, PolyPhen-2 0.99, Likely benign, in allele CYP2D6*12
- L43P (p.Leu43Pro), ExAC rs750859276, TOPMed rs750859276, gnomAD rs750859276
- L43Q (p.Leu43Gln), ExAC rs750859276, TOPMed rs750859276, gnomAD rs750859276
- L43R (p.Leu43Arg), ExAC rs750859276, TOPMed rs750859276, gnomAD rs750859276, CADD 24.00, PolyPhen-2 0.99
- L43V (p.Leu43Val), ESP rs139638916, ExAC rs139638916, TOPMed rs139638916, gnomAD rs139638916
- G44A (p.Gly44Ala), Ensembl rs2146944064
- G44C (p.Gly44Cys), ESP rs146838345, ExAC rs146838345, TOPMed rs146838345, gnomAD rs146838345
- G44D (p.Gly44Asp), Ensembl rs2146944064, CADD 24.60, PolyPhen-2 1.00
- G44R (p.Gly44Arg), ESP rs146838345, ExAC rs146838345, TOPMed rs146838345, gnomAD rs146838345
- G44S (p.Gly44Ser), ESP rs146838345, ExAC rs146838345, TOPMed rs146838345, gnomAD rs146838345, CADD 25.00, PolyPhen-2 1.00
- G44V (p.Gly44Val), Ensembl rs2146944064
Public CYP2D6 analysis runs
- CYP2D6 analysis run — CYP2D6 (1,661 variants) — completed 2026-08-09