HTT (Huntingtin) variants and mutations
HTT (also known as Huntingtin) is a human protein-coding gene encoding a huntingtin protein. It participates in intracellular transport, autophagy, synaptic function, and other neuronal processes. Expansion of the CAG repeat produces an abnormally long polyglutamine tract and causes Huntington disease through a toxic gain of function. This analysis covers 3,276 HTT variants and mutations. Of these, 69% have computational variant effect predictions. Disease context includes obsessive-compulsive disorder, major depressive disorder, and depressive disorder. Example HTT variants include A2E, A2S, and A2V.
Variant analysis overview
- Gene: HTT
- Protein: Huntingtin
- UniProt accession: P42858
- Organism: Homo sapiens
- Variants analyzed: 3276
- Variant scope: all variants
- Completed: 2026-08-10
Variant and mutation evidence
- Variant composition: 3,105 unspecified-consequence records; 12 frameshift variants; 1 stop retained variant; 1 stop lost; 43 synonymous variants; 109 missense variants; 2 stop-gained variants; 1 in-frame insertions; 1 substitution
- Prediction scores: 2,249 variants have prediction scores (69% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: obsessive-compulsive disorder, major depressive disorder, depressive disorder, panic disorder, fibromyalgia, anxiety disorder, post-traumatic stress disorder, social phobia, attention deficit-hyperactivity disorder, bipolar disorder, obesity disorder, generalized anxiety disorder.
Protein structure and variant hotspots
- Protein features: 15 post-translational modification sites.
- PTM context: 4 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, gnomAD constraint, Open Targets, MaveDB, LitVar.
Notable HTT variants
Examples include A2E, A2S, A2V, K6M, L7M, M8I, M8L, F11L. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- A2E (p.Ala2Glu), TOPMed rs1311999577, gnomAD rs1311999577
- A2S (p.Ala2Ser), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- A2V (p.Ala2Val), TOPMed rs1311999577, gnomAD rs1311999577, MetaLR 0.09, MetaSVM -1.03
- K6M (p.Lys6Met), 1000Genomes rs2110128543, MetaLR 0.09, MetaSVM -1.07
- L7M (p.Leu7Met), Ensembl rs1712380917, MetaLR 0.09, MetaSVM -1.03
- M8I (p.Met8Ile), TOPMed rs1276350475, gnomAD rs1276350475
- M8L (p.Met8Leu), ExAC rs754144476, TOPMed rs754144476, gnomAD rs754144476, MetaLR 0.02, MetaSVM -0.96
- F11L (p.Phe11Leu), NCI-TCGA TCGA novel, MetaLR 0.03, MetaSVM -1.10, Variant assessed as somatic; moderate impact.
- E12A (p.Glu12Ala), gnomAD rs1461907867, MetaLR 0.04, MetaSVM -1.11
- S13F (p.Ser13Phe), TOPMed rs1200106626, gnomAD rs1200106626
- K15R (p.Lys15Arg), TOPMed rs1712382211, MetaLR 0.03, MetaSVM -1.12
- S16F (p.Ser16Phe), gnomAD rs1291005109
- S16Y (p.Ser16Tyr), gnomAD rs1291005109
- F17L (p.Phe17Leu), Ensembl rs1712382998
- F17S (p.Phe17Ser), Ensembl rs1578474811
- F17Y (p.Phe17Tyr), Ensembl rs1578474811, MetaLR 0.10, MetaSVM -1.02
- Q18H (p.Gln18His), TOPMed rs1224354255, gnomAD rs1224354255
- Q18* (p.Gln18Ter), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- Q18P (p.Gln18Pro), gnomAD rs1254089537
- Q19H (p.Gln19His), Ensembl rs1578474910, MetaLR 0.04, MetaSVM -1.05
- Q20H (p.Gln20His), Ensembl rs1167917936
- Q20L (p.Gln20Leu), TOPMed rs1477471475, gnomAD rs1477471475
- Q20R (p.Gln20Arg), TOPMed rs1477471475, gnomAD rs1477471475, MetaLR 0.04, MetaSVM -1.05
- Q21H (p.Gln21His), Ensembl rs1712388871
- Q21R (p.Gln21Arg), TOPMed rs1712388514, MetaLR 0.04, MetaSVM -1.05
- Q22H (p.Gln22His), Ensembl rs1578474949
- Q22K (p.Gln22Lys), Ensembl rs1712389025, MetaLR 0.02, MetaSVM -1.02
- Q22R (p.Gln22Arg), Ensembl rs1578474941, MetaLR 0.18, MetaSVM -0.89
- Q23* (p.Gln23Ter), gnomAD rs1408045384
- Q23R (p.Gln23Arg), TOPMed rs1712390348, MetaLR 0.03, MetaSVM -1.04
- Q24* (p.Gln24Ter), gnomAD rs1301888922
- Q24R (p.Gln24Arg), TOPMed rs1464706656, MetaLR 0.08, MetaSVM -0.84
- Q25* (p.Gln25Ter), ExAC rs779062371
- Q26P (p.Gln26Pro), TOPMed rs917907941, gnomAD rs917907941
- Q26R (p.Gln26Arg), TOPMed rs917907941, gnomAD rs917907941, MetaLR 0.06, MetaSVM -0.83
- Q27H (p.Gln27His), ExAC rs745920924, gnomAD rs745920924
- Q27P (p.Gln27Pro), rs1712393582, ClinGen CA356074878, ClinVar RCV002808731, TOPMed rs1712393582, AlphaMissense 0.08, MetaLR 0.05, Uncertain significance
- Q29P (p.Gln29Pro), rs1469776724, ClinGen CA2823100, ClinVar RCV002951378, gnomAD rs1469776724, AlphaMissense 0.07, MetaLR 0.02, Uncertain significance, Inborn genetic diseases
- Q30P (p.Gln30Pro), TOPMed rs1560534931, gnomAD rs1560534931
- Q30R (p.Gln30Arg), TOPMed rs1560534931, gnomAD rs1560534931, MetaLR 0.03, MetaSVM -1.02
- Q30Q (p.Gln30Gln), rs879045557, []
- Q31P (p.Gln31Pro), gnomAD rs1560534943, MetaLR 0.03, MetaSVM -1.04, Uncertain significance, Inborn genetic diseases
- Q32P (p.Gln32Pro), gnomAD rs1253122256, MetaLR 0.03, MetaSVM -1.00
- Q33H (p.Gln33His), ExAC rs758426055, gnomAD rs758426055
- Q33P (p.Gln33Pro), rs1302432328, ClinGen CA356075054, ClinVar RCV002674527, gnomAD rs1302432328, AlphaMissense 0.07, MetaLR 0.02, Uncertain significance
- Q34P (p.Gln34Pro), gnomAD rs1448138447
- Q34R (p.Gln34Arg), gnomAD rs1448138447, MetaLR 0.03, MetaSVM -1.04
- Q35P (p.Gln35Pro), rs587777899, ClinGen CA248405, ClinVar RCV000190286, gnomAD rs587777899, AlphaMissense 0.21, MetaLR 0.03, Uncertain significance, Inborn genetic diseases
- Q35R (p.Gln35Arg), gnomAD rs587777899, MetaLR 0.03, MetaSVM -1.04
- Q36* (p.Gln36Ter), TOPMed rs1240431349
- Q36H (p.Gln36His), gnomAD rs756955307
- Q36K (p.Gln36Lys), TOPMed rs1240431349
- Q36P (p.Gln36Pro), ExAC rs746852037, gnomAD rs746852037, MetaLR 0.02, MetaSVM -0.99
- Q37L (p.Gln37Leu), gnomAD rs61792465
- Q37P (p.Gln37Pro), gnomAD rs61792465, MetaLR 0.02, MetaSVM -0.99, not provided
- Q38L (p.Gln38Leu), Ensembl rs61792466
- Q38P (p.Gln38Pro), Ensembl rs61792466, MetaLR 0.03, MetaSVM -1.02, Benign, not specified
- P39Q (p.Pro39Gln), ExAC rs768457728, gnomAD rs768457728
- P40Q (p.Pro40Gln), ExAC rs776374599, gnomAD rs776374599, MetaLR 0.03, MetaSVM -1.02
- P41Q (p.Pro41Gln), rs1261369311, ClinGen CA356075328, ClinVar RCV002961402, gnomAD rs1261369311, AlphaMissense 0.08, MetaLR 0.03, Uncertain significance, Inborn genetic diseases
- P41T (p.Pro41Thr), ExAC rs747806296, gnomAD rs747806296, MetaLR 0.04, MetaSVM -1.01
- P42Q (p.Pro42Gln), ExAC rs772839428, gnomAD rs772839428
- P42T (p.Pro42Thr), gnomAD rs1375537334, MetaLR 0.03, MetaSVM -1.01
- P43Q (p.Pro43Gln), ExAC rs775838708, gnomAD rs775838708, Uncertain significance, Inborn genetic diseases
- P43S (p.Pro43Ser), ExAC rs768111121
- P44Q (p.Pro44Gln), gnomAD rs1248032135
- P44R (p.Pro44Arg), gnomAD rs1248032135
- P44S (p.Pro44Ser), Ensembl rs1712422790, MetaLR 0.04, MetaSVM -1.06
- P45Q (p.Pro45Gln), ExAC rs764556863, gnomAD rs764556863, MetaLR 0.04, MetaSVM -1.08
- P46L (p.Pro46Leu), TOPMed rs1365030065, gnomAD rs1365030065
- P46Q (p.Pro46Gln), TOPMed rs1365030065, gnomAD rs1365030065
- P46S (p.Pro46Ser), gnomAD rs1181979177
- P47Q (p.Pro47Gln), gnomAD rs1162241011
- P47S (p.Pro47Ser), TOPMed rs1422982151, gnomAD rs1422982151, MetaLR 0.04, MetaSVM -1.02
- P48H (p.Pro48His), Ensembl rs1560535378
- P48L (p.Pro48Leu), Ensembl rs1560535378, MetaLR 0.03, MetaSVM -1.02
- P49H (p.Pro49His), Ensembl rs1560535383
- P49S (p.Pro49Ser), TOPMed rs1271648389, gnomAD rs1271648389
- Q50P (p.Gln50Pro), 1000Genomes rs1394673872, gnomAD rs1394673872, MetaLR 0.03, MetaSVM -1.03
- L51F (p.Leu51Phe), TOPMed rs1214832191, gnomAD rs1214832191
- L51H (p.Leu51His), gnomAD rs1224888537
- L51P (p.Leu51Pro), gnomAD rs1224888537, MetaLR 0.03, MetaSVM -1.00
- P52H (p.Pro52His), ExAC rs765371096, TOPMed rs765371096
- P52L (p.Pro52Leu), ExAC rs765371096, TOPMed rs765371096
- P54L (p.Pro54Leu), TOPMed rs1314330024, gnomAD rs1314330024
- P54Q (p.Pro54Gln), TOPMed rs1314330024, gnomAD rs1314330024, MetaLR 0.03, MetaSVM -1.04
- P55Q (p.Pro55Gln), gnomAD rs1249390585
- P55S (p.Pro55Ser), gnomAD rs1224511868, MetaLR 0.03, MetaSVM -0.98
- P56Q (p.Pro56Gln), gnomAD rs1196024813, MetaLR 0.04, MetaSVM -1.07
- Q57H (p.Gln57His), rs1442265763, ClinGen CA356075686, ClinVar RCV003995042, Uncertain significance, not specified
- L61Q (p.Leu61Gln), gnomAD rs1712432491, MetaLR 0.02, MetaSVM -0.99
- L62P (p.Leu62Pro), gnomAD rs1444439801, MetaLR 0.03, MetaSVM -1.00
- P63R (p.Pro63Arg), TOPMed rs1354042335, MetaLR 0.03, MetaSVM -0.99
- Q66E (p.Gln66Glu), TOPMed rs1423242905, MetaLR 0.03, MetaSVM -1.03
- P67R (p.Pro67Arg), gnomAD rs1158883388, MetaLR 0.03, MetaSVM -1.03
- P68A (p.Pro68Ala), TOPMed rs1712434385, gnomAD rs1712434385
- P68L (p.Pro68Leu), gnomAD rs1167429684
- P68S (p.Pro68Ser), TOPMed rs1712434385, gnomAD rs1712434385, MetaLR 0.04, MetaSVM -1.03
- P69L (p.Pro69Leu), rs1461748315, gnomAD rs1461748315, AlphaMissense 0.11, MetaLR 0.03, Variant assessed as somatic; moderate impact.
- P69S (p.Pro69Ser), gnomAD rs1712434908, MetaLR 0.04, MetaSVM -1.07
- P70L (p.Pro70Leu), Ensembl rs375917
- P70Q (p.Pro70Gln), Ensembl rs375917, MetaLR 0.03, MetaSVM -1.04
- P71Q (p.Pro71Gln), TOPMed rs1712436172, MetaLR 0.04, MetaSVM -1.03
- P72S (p.Pro72Ser), TOPMed rs1231836584, gnomAD rs1231836584
- P72T (p.Pro72Thr), TOPMed rs1231836584, gnomAD rs1231836584, MetaLR 0.06, MetaSVM -1.00
- P74L (p.Pro74Leu), TOPMed rs1204540369
- P74R (p.Pro74Arg), TOPMed rs1204540369, MetaLR 0.06, MetaSVM -1.06
- P75L (p.Pro75Leu), 1000Genomes rs1712437349
- P75S (p.Pro75Ser), TOPMed rs1439201204, gnomAD rs1439201204
- P75T (p.Pro75Thr), TOPMed rs1439201204, gnomAD rs1439201204, MetaLR 0.05, MetaSVM -1.03
- P76A (p.Pro76Ala), TOPMed rs921054551, gnomAD rs921054551
- P76L (p.Pro76Leu), Ensembl rs2110129575, MetaLR 0.03, MetaSVM -0.98
- P78A (p.Pro78Ala), TOPMed rs1712438098
- P78Q (p.Pro78Gln), 1000Genomes rs1050799427, TOPMed rs1050799427, gnomAD rs1050799427
- P78R (p.Pro78Arg), 1000Genomes rs1050799427, TOPMed rs1050799427, gnomAD rs1050799427, MetaLR 0.03, MetaSVM -1.08
- A79P (p.Ala79Pro), rs921054551, []
- A81G (p.Ala81Gly), Ensembl rs1712438617, MetaLR 0.01, MetaSVM -1.00
- E83D (p.Glu83Asp), TOPMed rs1372453864, gnomAD rs1372453864, MetaLR 0.01, MetaSVM -1.00
- P84S (p.Pro84Ser), gnomAD rs1379372136, MetaLR 0.01, MetaSVM -1.01
- L85Q (p.Leu85Gln), TOPMed rs1712439468, MetaLR 0.01, MetaSVM -1.04
- H86N (p.His86Asn), gnomAD rs1383511543
- H86P (p.His86Pro), rs868348450, ClinGen CA91430578, ClinVar RCV003434945, 1000Genomes rs868348450, AlphaMissense 0.04, MetaLR 0.01, Likely benign, not provided
- R87* (p.Arg87Ter), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- K89E (p.Lys89Glu), TOPMed rs1713241167, gnomAD rs1713241167
- K89R (p.Lys89Arg), ExAC rs748879296, TOPMed rs748879296, gnomAD rs748879296, MetaLR 0.39, MetaSVM -0.21
- E91* (p.Glu91Ter), NCI-TCGA Cosmic COSV6185, Variant assessed as somatic; high impact.
- E91D (p.Glu91Asp), NCI-TCGA TCGA novel, MetaLR 0.09, MetaSVM -1.07, Variant assessed as somatic; high impact.
- L92R (p.Leu92Arg), NCI-TCGA TCGA novel, MetaLR 0.35, MetaSVM -0.28, Variant assessed as somatic; moderate impact.
- T95I (p.Thr95Ile), Ensembl rs1266392456, MetaLR 0.32, MetaSVM -0.42
- K96Q (p.Lys96Gln), gnomAD rs1428324375
- K96R (p.Lys96Arg), gnomAD rs1171526197, MetaLR 0.37, MetaSVM -0.30
- R99C (p.Arg99Cys), rs770370500, ClinGen CA2823178, ClinVar RCV001923421, ExAC rs770370500, AlphaMissense 0.89, MetaLR 0.44, Uncertain significance, not provided
- R99G (p.Arg99Gly), rs770370500, ClinGen CA356081906, ClinVar RCV002040542, ExAC rs770370500, AlphaMissense 0.89, MetaLR 0.44, Uncertain significance, not provided
- R99H (p.Arg99His), 1000Genomes rs551783257, ExAC rs551783257, TOPMed rs551783257, gnomAD rs551783257, MetaLR 0.44, MetaSVM -0.11
- V100A (p.Val100Ala), NCI-TCGA TCGA novel, Ensembl rs1578486196, MetaLR 0.37, MetaSVM -0.42, Variant assessed as somatic; moderate impact.
- N101K (p.Asn101Lys), Ensembl rs1287551044, MetaLR 0.14, MetaSVM -0.99
- H102P (p.His102Pro), gnomAD rs1713242609, MetaLR 0.43, MetaSVM -0.13
- I106V (p.Ile106Val), TOPMed rs773112263, MetaLR 0.37, MetaSVM -0.42
- C107R (p.Cys107Arg), gnomAD rs1287073928, MetaLR 0.41, MetaSVM -0.15
- N109S (p.Asn109Ser), Ensembl rs1713243495, MetaLR 0.18, MetaSVM -0.90
- I110M (p.Ile110Met), gnomAD rs1279841426
- I110T (p.Ile110Thr), ESP rs370488438, ExAC rs370488438, TOPMed rs370488438, gnomAD rs370488438, MetaLR 0.50, MetaSVM 0.09
- V111E (p.Val111Glu), gnomAD rs1222527408
- V111M (p.Val111Met), TOPMed rs1321049145, gnomAD rs1321049145, MetaLR 0.43, MetaSVM -0.23
- S114A (p.Ser114Ala), TOPMed rs1713244414, MetaLR 0.36, MetaSVM -0.33
- V115I (p.Val115Ile), TOPMed rs1263314404, gnomAD rs1263314404, MetaLR 0.01, MetaSVM -0.96
- R116I (p.Arg116Ile), Ensembl rs2110142105
- S118Y (p.Ser118Tyr), gnomAD rs1489969237
- P119L (p.Pro119Leu), gnomAD rs1247555339
- P119S (p.Pro119Ser), rs745364744, ClinGen CA2823201, ClinVar RCV001957087, ExAC rs745364744, AlphaMissense 0.19, MetaLR 0.40, Uncertain significance, not provided
- F121L (p.Phe121Leu), ESP rs375334095, ExAC rs375334095, TOPMed rs375334095, gnomAD rs375334095, MetaLR 0.43, MetaSVM -0.15
- Q122* (p.Gln122Ter), NCI-TCGA Cosmic COSV6186, Variant assessed as somatic; high impact.
- Q122E (p.Gln122Glu), ExAC rs762329574, gnomAD rs762329574
- Q122H (p.Gln122His), TOPMed rs1315494366, gnomAD rs1315494366, MetaLR 0.41, MetaSVM -0.25
- G126S (p.Gly126Ser), TOPMed rs1714026053, MetaLR 0.36, MetaSVM -0.64
- I127F (p.Ile127Phe), Ensembl rs963369791, MetaLR 0.46, MetaSVM -0.06
- A128T (p.Ala128Thr), rs1160407584, NCI-TCGA Cosmic COSV6187, TOPMed rs1160407584, gnomAD rs1160407584, AlphaMissense 0.74, MetaLR 0.40, Variant assessed as somatic; moderate impact.
- M129I (p.Met129Ile), gnomAD rs1423813185
- M129L (p.Met129Leu), 1000Genomes rs77742164, ExAC rs77742164, TOPMed rs77742164, gnomAD rs77742164, Uncertain significance
- M129V (p.Met129Val), rs77742164, ClinGen CA2823205, ClinVar RCV001888538, 1000Genomes rs77742164, AlphaMissense 0.32, MetaLR 0.26, Uncertain significance, not provided
- E130K (p.Glu130Lys), rs1303509203, NCI-TCGA Cosmic COSV6187, gnomAD rs1303509203, AlphaMissense 0.99, MetaLR 0.48, Variant assessed as somatic; moderate impact.
- L131R (p.Leu131Arg), gnomAD rs1439565558, MetaLR 0.32, MetaSVM -0.41
- L133M (p.Leu133Met), NCI-TCGA Cosmic COSV1007, NCI-TCGA Cosmic COSV6186, MetaLR 0.56, MetaSVM -0.02, Variant assessed as somatic; moderate impact.
- S136G (p.Ser136Gly), ExAC rs766612691, gnomAD rs766612691
- S136I (p.Ser136Ile), gnomAD rs1714028682
- S136T (p.Ser136Thr), gnomAD rs1714028682, MetaLR 0.28, MetaSVM -0.72
- D137G (p.Asp137Gly), rs988441501, ClinGen CA91446273, ClinVar RCV002014242, TOPMed rs988441501, AlphaMissense 0.63, MetaLR 0.21, Uncertain significance, not provided
- D137N (p.Asp137Asn), Ensembl rs1578496958, MetaLR 0.20, MetaSVM -0.91
- A139P (p.Ala139Pro), ExAC rs759582713, TOPMed rs759582713, gnomAD rs759582713
- A139T (p.Ala139Thr), ExAC rs759582713, TOPMed rs759582713, gnomAD rs759582713
- A139V (p.Ala139Val), TOPMed rs1361778147, gnomAD rs1361778147, MetaLR 0.14, MetaSVM -0.88
- E140D (p.Glu140Asp), ESP rs372355130, ExAC rs372355130, TOPMed rs372355130, gnomAD rs372355130, MetaLR 0.25, MetaSVM -0.72
- S141L (p.Ser141Leu), TOPMed rs1714029977, MetaLR 0.47, MetaSVM -0.05
- D142Y (p.Asp142Tyr), ExAC rs752654123, gnomAD rs752654123, MetaLR 0.44, MetaSVM -0.13
- V143I (p.Val143Ile), TOPMed rs1202708405, gnomAD rs1202708405, MetaLR 0.33, MetaSVM -0.50
- M145I (p.Met145Ile), Ensembl rs987425434
- M145L (p.Met145Leu), Ensembl rs953390305, Uncertain significance
- M145V (p.Met145Val), rs953390305, ClinGen CA356088622, ClinVar RCV001864129, Ensembl rs953390305, AlphaMissense 0.67, MetaLR 0.43, Uncertain significance, not provided
- E149K (p.Glu149Lys), rs1440430798, NCI-TCGA Cosmic COSV1044, gnomAD rs1440430798, AlphaMissense 0.98, MetaLR 0.50, Variant assessed as somatic; moderate impact.
- C150Y (p.Cys150Tyr), NCI-TCGA Cosmic COSV6186, MetaLR 0.47, MetaSVM -0.14, Variant assessed as somatic; moderate impact.
Public HTT analysis runs
- HTT analysis run — HTT (3,276 variants) — completed 2026-08-10