ERBB4 (Q15303) variants and mutations
ERBB4 (also known as Q15303) is a human protein-coding gene encoding a receptor tyrosine-protein kinase erbB-4 protein. It transduces neuregulin and other EGF-family signals important for neural, cardiac, and mammary development. Altered signaling or somatic variants occur in several cancers and have also been studied in neurodevelopmental disease. This analysis covers 3,860 ERBB4 variants and mutations. Of these, 47% have computational variant effect predictions. Disease context includes non-small cell lung carcinoma, amyotrophic lateral sclerosis, and neoplasm. Example ERBB4 variants include K2N, P3L, and P3S.
Variant analysis overview
- Gene: ERBB4
- Protein: Q15303
- UniProt accession: Q15303
- Organism: Homo sapiens
- Variants analyzed: 3860
- Variant scope: all variants
- Completed: 2026-08-19
Variant and mutation evidence
- Variant composition: 3,665 unspecified-consequence records; 123 synonymous variants; 60 missense variants; 4 in-frame deletions; 2 in-frame insertions; 3 frameshift variants; 2 splice-region variants; 1 stop-gained variants
- Prediction scores: 1,810 variants have prediction scores (47% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: non-small cell lung carcinoma, amyotrophic lateral sclerosis, neoplasm, cancer, breast cancer, medullary thyroid gland carcinoma, polycystic ovary syndrome, Abnormality of the skeletal system, atrial fibrillation, hereditary disease, lung adenocarcinoma, breast carcinoma.
Protein structure and variant hotspots
- Protein features: 1 transmembrane segments; 1 domains; 4 binding sites; 21 post-translational modification sites.
- Structural context: 781 variants have structural context.
- PTM context: 61 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, ClinGen, MaveDB, LitVar.
Notable ERBB4 variants
Examples include K2N, P3L, P3S, A4E, A4T, A4V, T5A, T5K. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- K2N (p.Lys2Asn), Ensembl rs2106366518, MetaLR 0.05, MetaSVM -1.05
- P3L (p.Pro3Leu), ExAC rs772612441, gnomAD rs772612441, REVEL 0.24, CADD 19.30, Uncertain significance, ERBB4-related disorder
- P3S (p.Pro3Ser), cosmic curated COSV53525, Ensembl rs868365105, REVEL 0.25, CADD 21.50
- A4E (p.Ala4Glu), rs748663394, ClinGen CA2088631, cosmic curated COSV53600, ClinVar RCV001981082, REVEL 0.35, CADD 21.10, Uncertain significance, not provided
- A4T (p.Ala4Thr), NCI-TCGA TCGA novel, Ensembl rs2106366489, Variant assessed as somatic; moderate impact.
- A4V (p.Ala4Val), cosmic curated COSV53498, ExAC rs748663394, TOPMed rs748663394, gnomAD rs748663394, REVEL 0.36, CADD 22.60, Uncertain significance
- T5A (p.Thr5Ala), ESP rs376416471, ExAC rs376416471, gnomAD rs376416471
- T5K (p.Thr5Lys), Ensembl rs1693241398
- T5R (p.Thr5Arg), Ensembl rs1693241398, MetaLR 0.19, MetaSVM -0.95
- G6E (p.Gly6Glu), Ensembl rs2106366406, REVEL 0.24, CADD 18.10
- L7V (p.Leu7Val), Ensembl rs2106366396, REVEL 0.24, CADD 22.90
- W8R (p.Trp8Arg), Ensembl rs2106366380, REVEL 0.41, CADD 22.00
- V9D (p.Val9Asp), Ensembl rs1575106378, MetaLR 0.21, MetaSVM -0.66
- W10C (p.Trp10Cys), Ensembl rs2106366356, MetaLR 0.22, MetaSVM -0.60
- V11G (p.Val11Gly), Ensembl rs2106366347, MetaLR 0.12, MetaSVM -1.03
- S12C (p.Ser12Cys), ExAC rs749688150, TOPMed rs749688150, gnomAD rs749688150, REVEL 0.38, CADD 25.10
- S12I (p.Ser12Ile), ExAC rs755858938, TOPMed rs755858938, gnomAD rs755858938, MetaLR 0.33, MetaSVM -0.40
- S12N (p.Ser12Asn), ExAC rs755858938, TOPMed rs755858938, gnomAD rs755858938, REVEL 0.27, CADD 23.10
- S12R (p.Ser12Arg), rs1478394764, ClinGen CA350784009, ClinVar RCV002993779, TOPMed rs1478394764, REVEL 0.33, CADD 23.60, Uncertain significance, not provided
- L13V (p.Leu13Val), ExAC rs749917244, gnomAD rs749917244, REVEL 0.12, CADD 22.40
- L14P (p.Leu14Pro), NCI-TCGA Cosmic COSV9962, cosmic curated COSV99629, Variant assessed as somatic; moderate impact.
- V15L (p.Val15Leu), ExAC rs751515664, TOPMed rs751515664, gnomAD rs751515664, REVEL 0.16, CADD 7.07
- V15M (p.Val15Met), NCI-TCGA TCGA novel, ExAC rs751515664, TOPMed rs751515664, gnomAD rs751515664, REVEL 0.24, CADD 13.70, Variant assessed as somatic; moderate impact.
- A16V (p.Ala16Val), rs1297962291, NCI-TCGA Cosmic COSV5350, cosmic curated COSV53500, Ensembl rs1297962291, REVEL 0.17, CADD 21.20, Variant assessed as somatic; moderate impact.
- A17E (p.Ala17Glu), ExAC rs201202926, TOPMed rs201202926, gnomAD rs201202926, Likely benign
- A17G (p.Ala17Gly), cosmic curated COSV53545, ExAC rs201202926, TOPMed rs201202926, gnomAD rs201202926, MetaLR 0.07, MetaSVM -1.03, Likely benign
- A17V (p.Ala17Val), rs201202926, ClinGen CA2088621, ClinVar RCV002088147, ClinVar RCV004752151, REVEL 0.24, CADD 23.00, Likely benign, not provided
- G18E (p.Gly18Glu), ExAC rs762676889, TOPMed rs762676889, gnomAD rs762676889, REVEL 0.23, CADD 19.80
- T19A (p.Thr19Ala), cosmic curated COSV53503, Ensembl rs1222629052, REVEL 0.33, CADD 23.90
- T19I (p.Thr19Ile), NCI-TCGA Cosmic COSV5355, cosmic curated COSV53558, TOPMed rs1693238142, gnomAD rs1693238142, REVEL 0.31, CADD 24.30, Variant assessed as somatic; moderate impact.
- T19P (p.Thr19Pro), Ensembl rs1222629052
- T19S (p.Thr19Ser), TOPMed rs1693238142, gnomAD rs1693238142, MetaLR 0.25, MetaSVM -0.79
- V20A (p.Val20Ala), Ensembl rs2106366134, MetaLR 0.16, MetaSVM -1.00
- V20F (p.Val20Phe), ESP rs373308672, ExAC rs373308672, TOPMed rs373308672, gnomAD rs373308672, REVEL 0.27, CADD 19.40
- V20G (p.Val20Gly), Ensembl rs2106366134, REVEL 0.39, CADD 22.90
- V20I (p.Val20Ile), cosmic curated COSV53580, ESP rs373308672, ExAC rs373308672, TOPMed rs373308672, REVEL 0.13, CADD 19.90
- V20L (p.Val20Leu), ESP rs373308672, ExAC rs373308672, TOPMed rs373308672, gnomAD rs373308672, REVEL 0.15, CADD 19.20
- Q21H (p.Gln21His), 1000Genomes rs2229091, ESP rs2229091, ExAC rs2229091, TOPMed rs2229091, REVEL 0.25, CADD 24.50, Conflicting interpretations, not provided; not specified
- Q21L (p.Gln21Leu), Ensembl rs2106366103
- Q21P (p.Gln21Pro), Ensembl rs2106366103
- Q21R (p.Gln21Arg), rs2106366103, ClinGen CA350783962, ClinVar RCV003063746, AlphaMissense 0.10, MetaLR 0.05, Uncertain significance, not provided
- P22H (p.Pro22His), TOPMed rs1300045748, gnomAD rs1300045748, REVEL 0.16, CADD 18.10
- P22L (p.Pro22Leu), TOPMed rs1300045748, gnomAD rs1300045748, REVEL 0.11, CADD 17.30
- P22S (p.Pro22Ser), TOPMed rs930144500, gnomAD rs930144500, REVEL 0.10, CADD 21.20, Uncertain significance, Inborn genetic diseases
- S23N (p.Ser23Asn), Ensembl rs918972978, REVEL 0.11, CADD 21.60
- S23R (p.Ser23Arg), gnomAD rs1407234754, REVEL 0.16, CADD 23.50, Uncertain significance, not provided
- D24H (p.Asp24His), ExAC rs774666639, gnomAD rs774666639
- D24N (p.Asp24Asn), NCI-TCGA Cosmic COSV5357, cosmic curated COSV53576, ExAC rs774666639, gnomAD rs774666639, REVEL 0.15, CADD 21.40, Variant assessed as somatic; moderate impact.
- D24V (p.Asp24Val), Ensembl rs2106366019, MetaLR 0.06, MetaSVM -1.03
- D24Y (p.Asp24Tyr), ExAC rs774666639, gnomAD rs774666639, REVEL 0.26, CADD 23.70
- Q26E (p.Gln26Glu), Ensembl rs1370453674, REVEL 0.22, CADD 21.40
- Q26H (p.Gln26His), Ensembl rs2106365974
- Q26R (p.Gln26Arg), ExAC rs749626683, gnomAD rs749626683, REVEL 0.27, CADD 22.60
- S27* (p.Ser27Ter), Ensembl rs2106365965
- S27L (p.Ser27Leu), NCI-TCGA Cosmic COSV5354, cosmic curated COSV53547, MetaLR 0.05, MetaSVM -1.04, Variant assessed as somatic; moderate impact.
- V28M (p.Val28Met), Ensembl rs2106365945
- C29* (p.Cys29Ter), NCI-TCGA Cosmic COSV5350, cosmic curated COSV53504, NCI-TCGA Cosmic COSV5351, Ensembl rs2125571775, Variant assessed as somatic; high impact.
- C29S (p.Cys29Ser), Ensembl rs2125571794
- C29W (p.Cys29Trp), Ensembl rs2125571775
- C29Y (p.Cys29Tyr), Ensembl rs2125571784, MetaLR 0.36, MetaSVM -0.45
- A30P (p.Ala30Pro), Ensembl rs2125571762
- A30S (p.Ala30Ser), cosmic curated COSV10807, NCI-TCGA Cosmic COSV9961, Variant assessed as somatic; moderate impact.
- A30T (p.Ala30Thr), cosmic curated COSV99616, Ensembl rs2125571762
- A30V (p.Ala30Val), Ensembl rs2125571751, REVEL 0.21, CADD 22.50
- G31E (p.Gly31Glu), cosmic curated COSV53538, Ensembl rs2125571711
- G31R (p.Gly31Arg), Ensembl rs2125571729
- T32M (p.Thr32Met), rs1463950609, NCI-TCGA Cosmic COSV5359, cosmic curated COSV53593, gnomAD rs1463950609, REVEL 0.80, CADD 26.10, Variant assessed as somatic; moderate impact.
- T32R (p.Thr32Arg), gnomAD rs1463950609
- T32S (p.Thr32Ser), Ensembl rs2125571681, MetaLR 0.60, MetaSVM 0.27
- E33* (p.Glu33Ter), Ensembl rs2125571632
- E33D (p.Glu33Asp), Ensembl rs2125571619
- E33K (p.Glu33Lys), NCI-TCGA Cosmic COSV5359, cosmic curated COSV53596, Ensembl rs2125571632, Variant assessed as somatic; moderate impact.
- E33Q (p.Glu33Gln), Ensembl rs2125571632, MetaLR 0.03, MetaSVM -1.08
- N34K (p.Asn34Lys), TOPMed rs2079872814, MetaLR 0.49, MetaSVM 0.01
- K35* (p.Lys35Ter), Ensembl rs2125571598
- K35I (p.Lys35Ile), Ensembl rs2125571585
- K35N (p.Lys35Asn), Ensembl rs2125571574
- L36Q (p.Leu36Gln), Ensembl rs2125571549
- L36V (p.Leu36Val), Ensembl rs2125571559
- S37C (p.Ser37Cys), Ensembl rs2125571525
- S37G (p.Ser37Gly), Ensembl rs2125571525
- S37I (p.Ser37Ile), Ensembl rs2125571517
- S37R (p.Ser37Arg), Ensembl rs2125571508
- S37T (p.Ser37Thr), Ensembl rs2125571517, MetaLR 0.30, MetaSVM -0.63
- S38C (p.Ser38Cys), Ensembl rs2125571504
- L39F (p.Leu39Phe), cosmic curated COSV53542, gnomAD rs1176455587
- L39I (p.Leu39Ile), gnomAD rs1176455587, REVEL 0.28, CADD 24.00
- L39V (p.Leu39Val), gnomAD rs1176455587
- S40C (p.Ser40Cys), Ensembl rs2125571464
- S40F (p.Ser40Phe), cosmic curated COSV53584, Ensembl rs2125571464, MetaLR 0.48, MetaSVM -0.08
- D41A (p.Asp41Ala), TOPMed rs2079872429, gnomAD rs2079872429, REVEL 0.56, CADD 29.50
- D41E (p.Asp41Glu), Ensembl rs2125571426, REVEL 0.40, CADD 24.50
- D41H (p.Asp41His), Ensembl rs2125571445
- D41L (p.Asp41Leu), NCI-TCGA Cosmic COSV5358, Variant assessed as somatic; high impact.
- D41V (p.Asp41Val), TOPMed rs2079872429, gnomAD rs2079872429, MetaLR 0.19, MetaSVM -0.86
- L42P (p.Leu42Pro), NCI-TCGA Cosmic COSV9961, cosmic curated COSV99619, Ensembl rs2125571402, Variant assessed as somatic; moderate impact.
- L42V (p.Leu42Val), ExAC rs745619679, TOPMed rs745619679, gnomAD rs745619679
- E43* (p.Glu43Ter), cosmic curated COSV53539, TOPMed rs965744501, gnomAD rs965744501
- E43D (p.Glu43Asp), Ensembl rs2125571373, REVEL 0.17, CADD 9.93
- E43K (p.Glu43Lys), cosmic curated COSV10459, TOPMed rs965744501, gnomAD rs965744501, REVEL 0.56, CADD 24.70
- E43Q (p.Glu43Gln), cosmic curated COSV10941, TOPMed rs965744501, gnomAD rs965744501, REVEL 0.40, CADD 23.00
- Q44* (p.Gln44Ter), Ensembl rs2125571365
- Q44E (p.Gln44Glu), Ensembl rs2125571365
- Q44H (p.Gln44His), Ensembl rs2125571345
- Q44R (p.Gln44Arg), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- Q45* (p.Gln45Ter), Ensembl rs2125571336
- Q45H (p.Gln45His), ExAC rs776609107, TOPMed rs776609107, gnomAD rs776609107
- Q45K (p.Gln45Lys), Ensembl rs2125571336
- Q45L (p.Gln45Leu), Ensembl rs2125571321
- Q45R (p.Gln45Arg), Ensembl rs2125571321
- Y46* (p.Tyr46Ter), TOPMed rs1238805932, gnomAD rs1238805932
- Y46C (p.Tyr46Cys), NCI-TCGA Cosmic COSV5351, cosmic curated COSV53513, Variant assessed as somatic; moderate impact.
- Y46F (p.Tyr46Phe), Ensembl rs2125571290
- Y46N (p.Tyr46Asn), Ensembl rs2125571296
- R47* (p.Arg47Ter), rs772401914, ClinGen CA2088516, cosmic curated COSV10961, ClinVar RCV002002868, CADD 37.00, Uncertain significance
- R47G (p.Arg47Gly), cosmic curated COSV53497, ExAC rs772401914, TOPMed rs772401914, gnomAD rs772401914, Uncertain significance
- R47L (p.Arg47Leu), NCI-TCGA Cosmic COSV9962, cosmic curated COSV99627, NCI-TCGA Cosmic COSV9963, Variant assessed as somatic; moderate impact.
- R47Q (p.Arg47Gln), rs748447524, ClinGen CA2088515, cosmic curated COSV99633, ClinVar RCV003414155, REVEL 0.18, CADD 22.40, Uncertain significance, ERBB4-related disorder
- A48D (p.Ala48Asp), NCI-TCGA Cosmic COSV5354, cosmic curated COSV53544, Ensembl rs2125571236, REVEL 0.51, CADD 25.10, Variant assessed as somatic; moderate impact.
- A48G (p.Ala48Gly), Ensembl rs2125571236, REVEL 0.39, CADD 24.60
- A48S (p.Ala48Ser), Ensembl rs2125571245
- A48V (p.Ala48Val), Ensembl rs2125571236
- L49F (p.Leu49Phe), TOPMed rs910289291
- L49S (p.Leu49Ser), gnomAD rs1251265863, REVEL 0.86, CADD 29.30
- R50C (p.Arg50Cys), rs372631205, cosmic curated COSV53515, 1000Genomes rs372631205, ESP rs372631205, REVEL 0.57, CADD 31.00, Variant assessed as somatic; moderate impact.
- R50H (p.Arg50His), rs755026855, ClinGen CA2088513, NCI-TCGA Cosmic COSV5350, cosmic curated COSV53501, REVEL 0.42, CADD 24.40, Uncertain significance, not provided
- R50L (p.Arg50Leu), ExAC rs755026855, TOPMed rs755026855, gnomAD rs755026855, REVEL 0.36, CADD 22.80, Uncertain significance
- R50P (p.Arg50Pro), ExAC rs755026855, TOPMed rs755026855, gnomAD rs755026855, Uncertain significance
- K51* (p.Lys51Ter), Ensembl rs2125571164
- K51N (p.Lys51Asn), 1000Genomes rs565068265, ExAC rs565068265, TOPMed rs565068265, gnomAD rs565068265, Benign
- K51R (p.Lys51Arg), Ensembl rs2125571155
- Y52* (p.Tyr52Ter), Ensembl rs2125571119
- Y52D (p.Tyr52Asp), Ensembl rs2125571137
- Y52F (p.Tyr52Phe), cosmic curated COSV10459, Ensembl rs2125571130
- Y52N (p.Tyr52Asn), Ensembl rs2125571137, REVEL 0.33, CADD 22.90
- Y53C (p.Tyr53Cys), rs756650586, ClinGen CA2088510, cosmic curated COSV53552, ClinVar RCV001095444, REVEL 0.95, CADD 31.00, Uncertain significance, Amyotrophic lateral sclerosis
- Y53F (p.Tyr53Phe), cosmic curated COSV10583, ExAC rs756650586, gnomAD rs756650586, Uncertain significance
- Y53H (p.Tyr53His), Ensembl rs2125571111
- Y53N (p.Tyr53Asn), Ensembl rs2125571111
- E54* (p.Glu54Ter), Ensembl rs2125571076
- E54G (p.Glu54Gly), Ensembl rs1559544105, REVEL 0.72, CADD 26.30
- E54K (p.Glu54Lys), cosmic curated COSV53552, Ensembl rs2125571076
- E54Q (p.Glu54Gln), Ensembl rs2125571076
- E54V (p.Glu54Val), Ensembl rs1559544105
- N55D (p.Asn55Asp), Ensembl rs2125571058
- C56* (p.Cys56Ter), Ensembl rs2125571040, CADD 32.00
- C56S (p.Cys56Ser), Ensembl rs2125571050
- C56Y (p.Cys56Tyr), NCI-TCGA Cosmic COSV9961, cosmic curated COSV99613, Ensembl rs2125571050, Variant assessed as somatic; moderate impact.
- E57* (p.Glu57Ter), Ensembl rs2125571023
- E57K (p.Glu57Lys), Ensembl rs2125571023
- V58A (p.Val58Ala), 1000Genomes rs545249326, ExAC rs545249326, TOPMed rs545249326, gnomAD rs545249326, REVEL 0.90, CADD 28.10
- V58D (p.Val58Asp), 1000Genomes rs545249326, ExAC rs545249326, TOPMed rs545249326, gnomAD rs545249326
- V58F (p.Val58Phe), TOPMed rs2079870579
- V58G (p.Val58Gly), 1000Genomes rs545249326, ExAC rs545249326, TOPMed rs545249326, gnomAD rs545249326
- V58I (p.Val58Ile), TOPMed rs2079870579
- V58L (p.Val58Leu), TOPMed rs2079870579
- V59A (p.Val59Ala), Ensembl rs2125570942
- V59D (p.Val59Asp), cosmic curated COSV53551, Ensembl rs2125570942
- V59G (p.Val59Gly), Ensembl rs2125570942
- M60I (p.Met60Ile), TOPMed rs1443958987, gnomAD rs1443958987
- M60K (p.Met60Lys), Ensembl rs2079870377
- M60L (p.Met60Leu), Ensembl rs2125570917
- M60T (p.Met60Thr), Ensembl rs2079870377
- G61A (p.Gly61Ala), Ensembl rs2125570866
- G61C (p.Gly61Cys), gnomAD rs1413385805
- G61D (p.Gly61Asp), cosmic curated COSV10961, Ensembl rs2125570866, REVEL 0.96, CADD 26.40
- G61R (p.Gly61Arg), gnomAD rs1413385805
- G61S (p.Gly61Ser), gnomAD rs1413385805
- G61V (p.Gly61Val), Ensembl rs2125570866
- N62I (p.Asn62Ile), ExAC rs767922354, TOPMed rs767922354, gnomAD rs767922354
- N62K (p.Asn62Lys), TOPMed rs2079869850
- N62S (p.Asn62Ser), ExAC rs767922354, TOPMed rs767922354, gnomAD rs767922354, REVEL 0.77, CADD 26.20, Uncertain significance, not provided
- N62T (p.Asn62Thr), ExAC rs767922354, TOPMed rs767922354, gnomAD rs767922354
- L63P (p.Leu63Pro), cosmic curated COSV53564, Ensembl rs2125570808
- L63Q (p.Leu63Gln), Ensembl rs2125570808
- L63V (p.Leu63Val), Ensembl rs2125570825
- E64* (p.Glu64Ter), Ensembl rs2125570784
- E64D (p.Glu64Asp), Ensembl rs2125570773
- E64K (p.Glu64Lys), Ensembl rs2125570784
- E64Q (p.Glu64Gln), Ensembl rs2125570784
Public ERBB4 analysis runs
- ERBB4 analysis run — ERBB4 (3,860 variants) — completed 2026-08-19