COMT (Catechol O-methyltransferase) variants and mutations
COMT (also known as Catechol O-methyltransferase) is a human protein-coding gene encoding a catechol O-methyltransferase protein. It inactivates catecholamines and catechol-containing drugs through methylation, contributing to dopamine, norepinephrine, and estrogen-metabolite turnover. Common functional variants alter enzyme activity and have modest effects on catecholamine physiology and responses to some medications. This analysis covers 591 COMT variants and mutations. Of these, 84% have computational variant effect predictions. Disease context includes Parkinson disease, response to tramadol, and hair color. Example COMT variants include M1N, P2L, and P2R.
Variant analysis overview
- Gene: COMT
- Protein: Catechol O-methyltransferase
- UniProt accession: P21964
- Organism: Homo sapiens
- Variants analyzed: 591
- Variant scope: all variants
- Completed: 2026-08-19
Variant and mutation evidence
- Variant composition: 359 unspecified-consequence records; 3 splice-region variants; 101 missense variants; 92 synonymous variants; 23 frameshift variants; 10 in-frame deletions; 1 in-frame insertions; 2 stop-gained variants
- Prediction scores: 494 variants have prediction scores (84% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: Parkinson disease, response to tramadol, hair color, type 2 diabetes mellitus, Hepatic failure, internet addiction disorder, Bardet-Biedl syndrome, mathematical ability, restless legs syndrome, schizophrenia, obsessive-compulsive disorder, dilated cardiomyopathy.
Protein structure and variant hotspots
- Protein features: 1 transmembrane segments; 14 binding sites; 1 post-translational modification sites.
- Structural context: 60 variants have structural context.
- PTM context: 1 variants overlap post-translational modification 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 COMT variants
Examples include M1N, P2L, P2R, P2T, P2S, P2A, P2Q, P2P. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- M1N (p.Met1Asn), gnomAD 22-19962526-G-GA, CADD 26.50
- P2L (p.Pro2Leu), 1000Genomes rs551312068, ExAC rs551312068, TOPMed rs551312068, gnomAD rs551312068, REVEL 0.06, CADD 2.02
- P2R (p.Pro2Arg), 1000Genomes rs551312068, ExAC rs551312068, TOPMed rs551312068, gnomAD rs551312068
- P2T (p.Pro2Thr), gnomAD 22-19962530-C-A, REVEL 0.02, MetaLR 0.12
- P2S (p.Pro2Ser), gnomAD 22-19962530-C-T, REVEL 0.05, MetaLR 0.12
- P2A (p.Pro2Ala), gnomAD 22-19962530-C-G, REVEL 0.03, MetaLR 0.11
- P2Q (p.Pro2Gln), gnomAD 22-19962531-C-A, REVEL 0.03, MetaLR 0.12
- P2P (p.Pro2Pro), rs368616155, gnomAD 22-19962532-G-A, CADD 5.32
- E3K (p.Glu3Lys), ExAC rs759181324, gnomAD rs759181324, REVEL 0.09, CADD 21.40
- E3V (p.Glu3Val), gnomAD rs1164904803, REVEL 0.13, CADD 13.40
- E3G (p.Glu3Gly), gnomAD 22-19962534-A-G, REVEL 0.07, MetaLR 0.12
- E3A (p.Glu3Ala), gnomAD 22-19962534-A-C, REVEL 0.11, MetaLR 0.13
- E3E (p.Glu3Glu), gnomAD 22-19962535-G-A, CADD 1.77
- E3D (p.Glu3Asp), gnomAD 22-19962535-G-T, REVEL 0.08, MetaLR 0.13
- A4P (p.Ala4Pro), gnomAD 22-19962536-G-C, REVEL 0.07, MetaLR 0.11
- A4S (p.Ala4Ser), gnomAD 22-19962536-G-T, REVEL 0.04, MetaLR 0.09
- A4V (p.Ala4Val), gnomAD 22-19962537-C-T, REVEL 0.05, MetaLR 0.09
- A4A (p.Ala4Ala), gnomAD 22-19962538-C-A, CADD 5.17
- P5L (p.Pro5Leu), rs1160435070, ClinGen CA410688400, ClinVar RCV001028893, TOPMed rs1160435070, REVEL 0.08, CADD 13.40, drug response, Tramadol response
- P5W (p.Pro5Trp), gnomAD 22-19962534-AGGCC, CADD 25.00
- P5R (p.Pro5Arg), gnomAD 22-19962536-GC-G, CADD 15.70
- P5T (p.Pro5Thr), gnomAD 22-19962539-C-A, REVEL 0.06, MetaLR 0.07
- P5Q (p.Pro5Gln), gnomAD 22-19962540-C-A, REVEL 0.04, MetaLR 0.10
- P5P (p.Pro5Pro), rs561536243, gnomAD 22-19962541-G-C, CADD 0.83
- P6L (p.Pro6Leu), rs1601526877, ClinGen CA410688406, ClinVar RCV001028891, Ensembl rs1601526877, drug response, Tramadol response
- P6T (p.Pro6Thr), gnomAD 22-19962542-C-A, REVEL 0.03, MetaLR 0.14
- P6P (p.Pro6Pro), gnomAD 22-19962544-T-C, CADD 4.49
- L7P (p.Leu7Pro), ExAC rs753302283, TOPMed rs753302283, gnomAD rs753302283, REVEL 0.21, CADD 22.80
- L7R (p.Leu7Arg), ExAC rs753302283, TOPMed rs753302283, gnomAD rs753302283
- L7Q (p.Leu7Gln), gnomAD 22-19962546-T-A, REVEL 0.26, MetaLR 0.22
- L7L (p.Leu7Leu), gnomAD 22-19962547-G-T, CADD 8.73
- L8R (p.Leu8Arg), Ensembl rs1942217599
- L8L (p.Leu8Leu), gnomAD 22-19962548-C-T, CADD 8.76
- L9L (p.Leu9Leu), gnomAD 22-19962551-T-C, CADD 1.05
- L9F (p.Leu9Phe), gnomAD 22-19962553-G-C, REVEL 0.12, MetaLR 0.31
- A10V (p.Ala10Val), TOPMed rs1457049406, REVEL 0.05, CADD 0.85
- A10P (p.Ala10Pro), gnomAD 22-19962554-G-C, REVEL 0.28, MetaLR 0.25
- A11T (p.Ala11Thr), gnomAD rs1360629147, REVEL 0.06, CADD 8.75
- A11V (p.Ala11Val), gnomAD 22-19962558-C-T, REVEL 0.06, MetaLR 0.16
- V12M (p.Val12Met), TOPMed rs1415216107, REVEL 0.32, CADD 0.72
- V12L (p.Val12Leu), gnomAD 22-19962560-G-T, REVEL 0.29, MetaLR 0.12
- V12V (p.Val12Val), gnomAD 22-19962562-G-T, CADD 1.29
- L13F (p.Leu13Phe), ExAC rs764392202, TOPMed rs764392202, gnomAD rs764392202, REVEL 0.15, CADD 0.03
- L13V (p.Leu13Val), rs753820115, gnomAD 22-19962560-G-GT, CADD 9.20
- L13C (p.Leu13Cys), gnomAD 22-19962561-TGTTG, CADD 24.50
- L14L (p.Leu14Leu), gnomAD 22-19962568-G-T, CADD 6.23
- G15A (p.Gly15Ala), TOPMed rs1942218305, REVEL 0.09, CADD 10.50
- G15V (p.Gly15Val), cosmic curated COSV52889, REVEL 0.19, CADD 16.70
- G15C (p.Gly15Cys), gnomAD 22-19962569-G-T, REVEL 0.24, MetaLR 0.22
- G15D (p.Gly15Asp), gnomAD 22-19962570-G-A, REVEL 0.42, MetaLR 0.36
- G15G (p.Gly15Gly), gnomAD 22-19962571-C-T, CADD 9.12
- L16P (p.Leu16Pro), Ensembl rs1942218377, REVEL 0.52, CADD 23.20
- L16L (p.Leu16Leu), gnomAD 22-19962574-G-T, CADD 2.15
- V17M (p.Val17Met), gnomAD 22-19962575-G-A, REVEL 0.11, MetaLR 0.19
- V17L (p.Val17Leu), gnomAD 22-19962575-G-T, REVEL 0.06, MetaLR 0.14
- V17V (p.Val17Val), gnomAD 22-19962577-G-T, CADD 1.74
- L18Q (p.Leu18Gln), Ensembl rs1439513393, REVEL 0.40, CADD 12.10
- L18M (p.Leu18Met), gnomAD 22-19962578-C-A, REVEL 0.14, MetaLR 0.38
- L18L (p.Leu18Leu), gnomAD 22-19962580-G-A, CADD 1.93
- L19M (p.Leu19Met), gnomAD 22-19962581-C-A, REVEL 0.26, MetaLR 0.42
- L19L (p.Leu19Leu), rs1942218865, gnomAD 22-19962581-C-T, CADD 5.97
- V20E (p.Val20Glu), ExAC rs757427295, gnomAD rs757427295
- V20L (p.Val20Leu), TOPMed rs559479480, gnomAD rs559479480, cosmic curated COSV52889, REVEL 0.07, CADD 1.71
- V20M (p.Val20Met), TOPMed rs559479480, gnomAD rs559479480, REVEL 0.07, CADD 10.90
- p.Val20 Leu23del, rs1942218448, gnomAD 22-19962572-CTGGT, CADD 16.00
- V20W (p.Val20Trp), rs755100597, gnomAD 22-19962580-G-GCT, CADD 20.60
- V21L (p.Val21Leu), ExAC rs781461677, TOPMed rs781461677, gnomAD rs781461677, REVEL 0.08, CADD 0.26
- V21M (p.Val21Met), ExAC rs781461677, TOPMed rs781461677, gnomAD rs781461677, REVEL 0.05, CADD 3.01
- V21del (p.Val21del), gnomAD 22-19962581-CTGG-, CADD 13.00
- V21V (p.Val21Val), gnomAD 22-19962589-G-T, CADD 0.39
- L22V (p.Leu22Val), cosmic curated COSV10956
- L22P (p.Leu22Pro), gnomAD 22-19962591-T-C, REVEL 0.18, MetaLR 0.15
- L22L (p.Leu22Leu), gnomAD 22-19962592-G-C, CADD 1.21
- L23P (p.Leu23Pro), cosmic curated COSV99258
- L23Q (p.Leu23Gln), TOPMed rs970645223, gnomAD rs970645223, REVEL 0.23, CADD 12.30
- L23V (p.Leu23Val), Ensembl rs1209323936
- L23A (p.Leu23Ala), rs1443347792, gnomAD 22-19962590-C-CT, CADD 16.70
- L23L (p.Leu23Leu), gnomAD 22-19962595-G-A, CADD 2.84
- L24M (p.Leu24Met), gnomAD rs1203339655
- L24P (p.Leu24Pro), gnomAD 22-19962597-T-C, REVEL 0.44, MetaLR 0.31
- L24L (p.Leu24Leu), rs1241505943, gnomAD 22-19962598-G-C, CADD 0.38
- L25F (p.Leu25Phe), ExAC rs750490382, TOPMed rs750490382, gnomAD rs750490382, REVEL 0.11, CADD 0.00
- L25P (p.Leu25Pro), gnomAD 22-19962600-T-C, REVEL 0.18, MetaLR 0.24
- L26R (p.Leu26Arg), Ensembl rs1942219980
- L26del (p.Leu26del), gnomAD 22-19962587-GTGC-, CADD 5.06
- p.Leu26dup, rs1942219358, gnomAD 22-19962587-G-GTG, CADD 3.00
- L26L (p.Leu26Leu), rs756235784, gnomAD 22-19962602-C-T, CADD 2.23
- R27E (p.Arg27Glu), rs1942220061, gnomAD 22-19962603-T-TA, CADD 22.40
- R27S (p.Arg27Ser), rs1328870779, gnomAD 22-19962605-AG-A, CADD 20.20
- R27W (p.Arg27Trp), gnomAD 22-19962605-A-T, REVEL 0.20, MetaLR 0.19
- H28Q (p.His28Gln), gnomAD 22-19962610-C-A, REVEL 0.14, MetaLR 0.20
- W29S (p.Trp29Ser), TOPMed rs1278178766, REVEL 0.09, CADD 9.23
- W29R (p.Trp29Arg), gnomAD 22-19962611-T-C, REVEL 0.11, MetaLR 0.12
- W29L (p.Trp29Leu), gnomAD 22-19962612-G-T, REVEL 0.14, MetaLR 0.10
- G30A (p.Gly30Ala), gnomAD rs1363253427, REVEL 0.05, CADD 0.75
- G30S (p.Gly30Ser), 1000Genomes rs139227383, TOPMed rs139227383, gnomAD rs139227383, REVEL 0.08, CADD 0.44
- G30D (p.Gly30Asp), gnomAD 22-19962615-G-A, REVEL 0.11, MetaLR 0.15
- W31* (p.Trp31Ter), TOPMed rs931653147, gnomAD rs931653147, CADD 33.00
- W31R (p.Trp31Arg), gnomAD 22-19962617-T-C, REVEL 0.19, MetaLR 0.15
- G32D (p.Gly32Asp), ExAC rs748066830, TOPMed rs748066830, gnomAD rs748066830, REVEL 0.22, CADD 15.90
- G32R (p.Gly32Arg), 1000Genomes rs138628382, ESP rs138628382, ExAC rs138628382, TOPMed rs138628382, REVEL 0.19, CADD 17.30
- G32S (p.Gly32Ser), 1000Genomes rs138628382, ESP rs138628382, ExAC rs138628382, TOPMed rs138628382, REVEL 0.06, CADD 13.30
- G32A (p.Gly32Ala), gnomAD 22-19962617-TG-T, CADD 15.40
- G32V (p.Gly32Val), gnomAD 22-19962621-G-T, REVEL 0.18, MetaLR 0.28
- G32G (p.Gly32Gly), gnomAD 22-19962622-C-A, CADD 7.83
- L33P (p.Leu33Pro), Ensembl rs1942220905, REVEL 0.41, CADD 16.40
- L33M (p.Leu33Met), gnomAD 22-19962623-C-A, REVEL 0.13, MetaLR 0.21
- L33L (p.Leu33Leu), rs1601527054, gnomAD 22-19962623-C-T, CADD 2.65
- L33Q (p.Leu33Gln), gnomAD 22-19962624-T-A, REVEL 0.27, MetaLR 0.27
- C34S (p.Cys34Ser), rs6270, UniProt VAR 013925, Ensembl rs6270
- C34V (p.Cys34Val), rs777507390, gnomAD 22-19962623-C-CT, CADD 19.60
- C34Y (p.Cys34Tyr), gnomAD 22-19962627-G-A, REVEL 0.17, MetaLR 0.19
- C34C (p.Cys34Cys), gnomAD 22-19962628-C-T, CADD 1.27
- L35F (p.Leu35Phe), ExAC rs771850671
- I36L (p.Ile36Leu), ExAC rs777441922, TOPMed rs777441922, gnomAD rs777441922, REVEL 0.19, CADD 5.65
- I36V (p.Ile36Val), gnomAD 22-19962632-A-G, REVEL 0.17, MetaLR 0.16
- I36I (p.Ile36Ile), rs746604009, gnomAD 22-19962634-C-T, CADD 3.10
- I36M (p.Ile36Met), gnomAD 22-19962634-C-G, REVEL 0.14, MetaLR 0.27
- G37C (p.Gly37Cys), cosmic curated COSV52890
- G37R (p.Gly37Arg), ExAC rs770700364, TOPMed rs770700364, gnomAD rs770700364, REVEL 0.24, CADD 0.00
- G37S (p.Gly37Ser), ExAC rs770700364, TOPMed rs770700364, gnomAD rs770700364, REVEL 0.10, CADD 0.00
- G37L (p.Gly37Leu), gnomAD 22-19962634-C-CTT, CADD 10.50
- G37V (p.Gly37Val), gnomAD 22-19962636-G-T, REVEL 0.07, MetaLR 0.11
- G37D (p.Gly37Asp), gnomAD 22-19962636-G-A, REVEL 0.14, MetaLR 0.15
- G37G (p.Gly37Gly), rs776476521, gnomAD 22-19962637-C-T, CADD 3.62
- W38* (p.Trp38Ter), ExAC rs759091417, gnomAD rs759091417, CADD 36.00
- W38R (p.Trp38Arg), gnomAD 22-19962638-T-C, REVEL 0.46, MetaLR 0.45
- N39D (p.Asn39Asp), cosmic curated COSV52889, ExAC rs75012854, TOPMed rs75012854, gnomAD rs75012854, REVEL 0.08, CADD 6.49
- N39K (p.Asn39Lys), 1000Genomes rs74745580, ESP rs74745580, ExAC rs74745580, TOPMed rs74745580, REVEL 0.08, CADD 1.40, Benign
- N39S (p.Asn39Ser), ExAC rs776094728, gnomAD rs776094728
- N39N (p.Asn39Asn), rs74745580, gnomAD 22-19962643-C-T, CADD 0.89
- E40G (p.Glu40Gly), Ensembl rs1942222178
- E40K (p.Glu40Lys), rs984098043, gnomAD rs984098043, REVEL 0.40, CADD 23.10, Variant assessed as somatic; moderate impact.
- E40Q (p.Glu40Gln), gnomAD rs984098043, REVEL 0.28, CADD 22.60
- E40* (p.Glu40Ter), gnomAD 22-19962644-G-T, CADD 37.00
- E40E (p.Glu40Glu), rs1834557494, gnomAD 22-19962646-G-A, CADD 8.43
- I42V (p.Ile42Val), Ensembl rs2146165010, REVEL 0.03, CADD 0.04
- L43P (p.Leu43Pro), gnomAD rs1261617944, REVEL 0.45, CADD 21.40
- p.Leu43 Ile46del, gnomAD 22-19962648-TCATC, CADD 13.30
- Q44K (p.Gln44Lys), gnomAD 22-19962656-C-A, REVEL 0.05, MetaLR 0.13
- Q44H (p.Gln44His), gnomAD 22-19962658-G-T, REVEL 0.18, MetaLR 0.28
- P45P (p.Pro45Pro), gnomAD 22-19962661-C-T, CADD 0.45
- I46M (p.Ile46Met), cosmic curated COSV10633
- I46N (p.Ile46Asn), ExAC rs762297267, gnomAD rs762297267, REVEL 0.31, CADD 22.40
- I46S (p.Ile46Ser), ExAC rs762297267, gnomAD rs762297267, REVEL 0.18, CADD 22.20
- I46V (p.Ile46Val), gnomAD 22-19962662-A-G, REVEL 0.03, MetaLR 0.09
- I46I (p.Ile46Ile), rs1199445620, gnomAD 22-19962664-C-T, CADD 6.32
- H47P (p.His47Pro), NCI-TCGA TCGA novel, REVEL 0.12, CADD 0.03, Variant assessed as somatic; high impact.
- H47Q (p.His47Gln), gnomAD 22-19962667-C-A, REVEL 0.09, MetaLR 0.16
- L49V (p.Leu49Val), TOPMed rs1942222499, gnomAD rs1942222499, REVEL 0.07, CADD 11.50
- L49L (p.Leu49Leu), gnomAD 22-19962671-C-T, CADD 7.61
- L50F (p.Leu50Phe), Ensembl rs2146165053, REVEL 0.07, CADD 3.21
- L50L (p.Leu50Leu), gnomAD 22-19962676-C-T, CADD 12.50
- M51T (p.Met51Thr), Ensembl rs569294134
- G52D (p.Gly52Asp), cosmic curated COSV10802, Ensembl rs1942222832
- G52G (p.Gly52Gly), rs750684179, gnomAD 22-19962682-T-C, CADD 4.13
- D53E (p.Asp53Glu), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- D53N (p.Asp53Asn), cosmic curated COSV52889, REVEL 0.07, CADD 9.03
- T54A (p.Thr54Ala), gnomAD rs1179632437, REVEL 0.07, CADD 22.50
- T54S (p.Thr54Ser), Ensembl rs1942223079
- T54N (p.Thr54Asn), gnomAD 22-19962687-C-A, REVEL 0.14, MetaLR 0.26
- K55M (p.Lys55Met), Ensembl rs2146165115
- K55K (p.Lys55Lys), rs1601527185, gnomAD 22-19962691-G-A, CADD 12.60
- E56K (p.Glu56Lys), TOPMed rs1243773629, gnomAD rs1243773629, REVEL 0.53, CADD 29.10
- Q57* (p.Gln57Ter), ExAC rs756145905, gnomAD rs756145905, CADD 37.00
- Q57K (p.Gln57Lys), ExAC rs756145905, gnomAD rs756145905, REVEL 0.39, CADD 22.40
- Q57R (p.Gln57Arg), Ensembl rs2146165136, REVEL 0.36, CADD 23.70
- R58C (p.Arg58Cys), cosmic curated COSV52889, TOPMed rs1480698560, gnomAD rs1480698560, REVEL 0.64, CADD 28.50
- R58G (p.Arg58Gly), cosmic curated COSV52889
- R58H (p.Arg58His), ExAC rs766469681, TOPMed rs766469681, gnomAD rs766469681, REVEL 0.64, CADD 31.00
- I59T (p.Ile59Thr), gnomAD rs1466865313, REVEL 0.58, CADD 24.10
- I59V (p.Ile59Val), ExAC rs752620960, gnomAD rs752620960, REVEL 0.28, CADD 21.60
- I59S (p.Ile59Ser), gnomAD 22-19962702-T-G, REVEL 0.76, MetaLR 0.47
- I59I (p.Ile59Ile), rs1342715506, gnomAD 22-19962703-C-T, CADD 7.57
- I59M (p.Ile59Met), gnomAD 22-19962703-C-G, REVEL 0.45, MetaLR 0.26
- L60L (p.Leu60Leu), rs758271838, gnomAD 22-19962704-C-T, CADD 11.20
- N61S (p.Asn61Ser), gnomAD 22-19962708-A-G, REVEL 0.06, MetaLR 0.13
- N61K (p.Asn61Lys), gnomAD 22-19962709-C-A, REVEL 0.04, MetaLR 0.09
- N61N (p.Asn61Asn), gnomAD 22-19962709-C-T, CADD 0.32
- H62Y (p.His62Tyr), TOPMed rs1942223864, gnomAD rs1942223864, REVEL 0.07, CADD 0.01
Public COMT analysis runs
- COMT analysis run — COMT (591 variants) — completed 2026-08-19