ERBB4

Summary

ERBB4 (erb-b2 receptor tyrosine kinase 4, HGNC:3432) is a protein-coding gene on chromosome 2q34, encoding Receptor tyrosine-protein kinase erbB-4 (Q15303). Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell proliferation, differentiation, migration and a…. In precision oncology, ERBB4 Mutation confers sensitivity to Lapatinib in Melanoma (CIViC Level D); 3 further curated variant–drug associations are listed below.

This gene is a member of the Tyr protein kinase family and the epidermal growth factor receptor subfamily. It encodes a single-pass type I membrane protein with multiple cysteine rich domains, a transmembrane domain, a tyrosine kinase domain, a phosphotidylinositol-3 kinase binding site and a PDZ domain binding motif. The protein binds to and is activated by neuregulins and other factors and induces a variety of cellular responses including mitogenesis and differentiation. Multiple proteolytic events allow for the release of a cytoplasmic fragment and an extracellular fragment. Mutations in this gene have been associated with cancer. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized.

Source: NCBI Gene 2066 — RefSeq curated summary.

At a glance

• Gene–disease (curated): amyotrophic lateral sclerosis type 19 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 66
• Clinical variants (ClinVar): 777 total — 3 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 53
• Druggable target: yes — 47 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 4 curated variant–drug associations
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 10 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_005235

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3432
Approved symbol	ERBB4
Name	erb-b2 receptor tyrosine kinase 4
Location	2q34
Locus type	gene with protein product
Status	Approved
Aliases	ALS19, HER4
Ensembl gene	ENSG00000178568
Ensembl biotype	protein_coding
OMIM	600543
Entrez	2066

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 2 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000260943, ENST00000342788, ENST00000435846, ENST00000436443, ENST00000459774, ENST00000463121, ENST00000484474, ENST00000484594

RefSeq mRNA: 2 — MANE Select: NM_005235 NM_001042599, NM_005235

CCDS: CCDS2394, CCDS42811

Canonical transcript exons

ENST00000342788 — 28 exons

Exon	Start	End
ENSE00000965161	211428408	211428483
ENSE00000965162	211424155	211424301
ENSE00001002878	211420441	211420611
ENSE00001002880	211430945	211431100
ENSE00001002882	211422007	211422104
ENSE00001295501	211561903	211562088
ENSE00001302849	211386853	211387150
ENSE00001329579	211387945	211387992
ENSE00001563494	211375717	211384060
ENSE00003466941	211619177	211619275
ENSE00003471607	211673164	211673257
ENSE00003486501	211701967	211702166
ENSE00003501799	211712050	211712176
ENSE00003512307	211704104	211704194
ENSE00003512540	211750639	211750704
ENSE00003542689	211623922	211624044
ENSE00003543170	211713535	211713648
ENSE00003570459	211947430	211947616
ENSE00003595381	211630462	211630594
ENSE00003600790	212124752	212124903
ENSE00003610472	211679052	211679184
ENSE00003612141	211657754	211657828
ENSE00003620037	211788025	211788159
ENSE00003630686	211725076	211725194
ENSE00003662423	211705318	211705391
ENSE00003676702	211665323	211665477
ENSE00003681368	211722393	211722534
ENSE00003843480	212538449	212538802

Expression profiles

Bgee: expression breadth ubiquitous, 226 present calls, max score 99.06.

FANTOM5 (CAGE): breadth broad, TPM avg 7.3550 / max 325.6449, expressed in 604 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
33507	3.0193	489
33503	1.1758	350
33506	1.1064	280
33508	0.7827	284
33509	0.4210	186
33505	0.2007	103
33487	0.1769	102
33502	0.1663	95
33499	0.0792	48
33504	0.0638	30

Top tissues by expression

282 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.06	gold quality
secondary oocyte	CL:0000655	97.75	gold quality
cranial nerve II	UBERON:0000941	94.75	gold quality
middle temporal gyrus	UBERON:0002771	94.55	gold quality
oocyte	CL:0000023	94.54	gold quality
buccal mucosa cell	CL:0002336	94.32	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.07	gold quality
entorhinal cortex	UBERON:0002728	91.37	gold quality
Brodmann (1909) area 46	UBERON:0006483	91.35	gold quality
orbitofrontal cortex	UBERON:0004167	90.98	gold quality
right uterine tube	UBERON:0001302	90.78	gold quality
corpus callosum	UBERON:0002336	90.14	gold quality
substantia nigra pars reticulata	UBERON:0001966	89.62	gold quality
postcentral gyrus	UBERON:0002581	89.62	gold quality
CA1 field of hippocampus	UBERON:0003881	89.23	gold quality
metanephric glomerulus	UBERON:0004736	89.22	gold quality
parietal lobe	UBERON:0001872	89.15	gold quality
renal glomerulus	UBERON:0000074	89.02	gold quality
superior frontal gyrus	UBERON:0002661	89.00	gold quality
substantia nigra pars compacta	UBERON:0001965	88.85	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	88.26	gold quality
renal medulla	UBERON:0000362	88.08	gold quality
globus pallidus	UBERON:0001875	87.65	gold quality
medial globus pallidus	UBERON:0002477	87.55	gold quality
primary visual cortex	UBERON:0002436	87.23	gold quality
occipital lobe	UBERON:0002021	87.11	gold quality
kidney epithelium	UBERON:0004819	87.11	gold quality
cardiac muscle of right atrium	UBERON:0003379	87.09	gold quality
lateral globus pallidus	UBERON:0002476	86.80	gold quality
Brodmann (1909) area 10	UBERON:0013541	86.37	gold quality

Single-cell (SCXA)

Detected in 18 experiment(s), a significant marker in 16.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	12646.74
E-GEOD-131882	yes	11932.00
E-CURD-119	yes	11857.97
E-HCAD-30	yes	8231.65
E-GEOD-180759	yes	7087.96
E-HCAD-25	yes	6259.30
E-GEOD-109979	yes	2032.22
E-GEOD-93593	yes	1085.94
E-MTAB-7316	yes	725.89
E-GEOD-111727	yes	161.79
E-HCAD-10	yes	29.46
E-MTAB-5061	yes	9.54
E-ANND-3	yes	8.21
E-GEOD-81608	yes	5.84
E-ENAD-27	yes	5.28

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ADAM10, AP1, DLX1, ESR1, WWP1

miRNA regulators (miRDB)

346 targeting ERBB4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3646	100.00	73.56	5283
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-6891-5P	99.98	66.53	1372

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• cleavage by gamma-secretase releases the ErbB-4 intracellular domain from the membrane and facilitates its translocation to the nucleus (PMID:11679632)
• ErbB4 expression was observed through all stages of chondrocytic differentiation in vitro. (PMID:12297288)
• deletion of the PDZ domain recognition motif does abrogate the gamma-secretase cleavage of ErbB-4 (PMID:12454007)
• ErbB4 is specifically associated with neuritic plaques in the hippocampus of Alzheimer disease patients. (PMID:12528817)
• ErbB4 signaling is growth inhibitory and may be coupled to tumor suppression in prostate cells (PMID:12637154)
• Expression of HER4 protein correlates with favourable tumor stage in pancreatic cancer patients. (PMID:12678544)
• YAP is a potential signaling partner of the full-length ErbB4 receptor at the membrane and of the COOH-terminal fragment of ErbB-4 that translocates to the nucleus to regulate transcription (PMID:12807903)
• ErbB-4 characterization of the cleavage site and m80 fragment (PMID:12869563)
• Nuclear localization of the activated p80 fragment of Her-4 is associated with osteosarcoma pathogenesis (PMID:15026342)
• HER4 is involved in a non-proliferative or even protective role in breast cancer. (PMID:15084248)
• betacellulin may play a role as a local growth factor in promoting the differentiated villous trophoblastic function via ErbB-1 in early placentas and in contributing to placental growth through EVT cell function via ErbB-4 in term placentas. (PMID:15248827)
• nuclear localization of STAT5A and stimulation of the beta-casein promoter requires nuclear translocation of the ERBB4 intracellular domain 4ICD; binding of the two proteins at transcription factor target promoters results in activation of gene expression (PMID:15534001)
• ErbB4 is increased by cAMP, a potent inducer of decidualization of the endometrial stroma. (PMID:15562026)
• erbB receptor inactivation by unknown mechanisms results in altered splicing of bcl-x towards enhanced formation of proapoptotic Bcl-xS, thereby contributing to enhanced apoptotic susceptibility of failing human myocardium (PMID:15685397)
• Association of ErbB4 expression with clinical outcome is dependent on the subcellular localization of ErbB4 and that a proteinase-cleavable ErbB4 isoform promotes growth of ER-positive breast cancer and enhances ER-mediated gene transcription. (PMID:15735025)
• proteolytic processing of ERBB4 is a critical event regulating multiple receptor signaling activities (PMID:15746097)
• Absence of HER4 expression is associated with recurrence of ductal carcinoma in situ of the breast (PMID:15788662)
• HB-EGF may play a vital role in regulating luteal growth in a juxtacrine manner and through activating HER4 signalling (PMID:15979989)
• Data show that expression of the ErbB-4 ICD fragment leads to its constitutive association with and tyrosine phosphorylation of Mdm2. (PMID:15985438)
• WWOX antagonizes the function of YAP by competing for interaction with ErbB-4 and other targets and thus affect its transcriptional activity. (PMID:16061658)
• the s80 domain of ErbB-4 may function to phosphorylate substrates in the cytoplasm or nucleus (PMID:16170367)
• Data suggested that alterations of ERBB4-mediated signaling pathway by ERBB4 mutations may contribute to the development of human cancers. (PMID:16187281)
• Results report the 2.4 A crystal structure of the extracellular region of human ErbB4 in the absence of ligand and show that it adopts a tethered conformation similar to inactive forms of ErbB1 and ErbB3. (PMID:16203964)
• Mutation screening of erbB4 in 14 schizophrenics revealed 15 SNPs. (PMID:16249994)
• novel transforming mechanism for the ErbB4 receptor in human breast cancer that is 1) specific for a single receptor isoform and 2) depends on proteinase cleavage and kinase activity but not ligand activation of the receptor (PMID:16251361)
• Results showed a highly significant difference between patient and control groups in three SNPs from one linkage disequilibrium block both in allele and genotype frequencies, as well as a risk haplotype. (PMID:16402353)
• Activation of Rac by heregulin beta1 is mediated not only by ErbB3 and ErbB2 but also by transactivation of EGFR, and it is independent of ErbB4. (PMID:16428439)
• A monoclonal antibody to ErbB-4 showed both an inhibitory effect on growth rate and an increasing apoptotic rate in the cells expressing ErbB-4. (PMID:16463386)
• ErbB4 receptor expression was accompanied with positive regulation of PP2A for phosphorylation of Shc Tyr317 and its downstream ERK phosphorylation in MCF-7 and SK-OV-3 cell lines, but not in LNCaP and PC-3 cells. (PMID:16477370)
• These experiments demonstrate a novel mechanism controlling ErbB receptor activation. Ras induces ErbB4 receptor phosphorylation in a non-autocrine manner and this activation depends on multiple Ras effector pathways and on ErbB4 kinase activity. (PMID:16518842)
• Function of HER4 and its fragments is particularly important, with \the different functions of nuclear and mitochondrial HER4 in breast cancer. (PMID:16606438)
• HER3 and HER4 has been related to a favourable prognosis in bladder cancer. (PMID:16685269)
• ErbB4 has 5 docking sites for Grb2. It is a direct binding partner for STAT5. It functions as control center & integration site for signaling processes, involving stimulation with neuregulin. (PMID:16729043)
• Neurogulin 1 induced activation of erbB4 in the prefrontal cortex in schizophrenia. (PMID:16767099)
• Cytosolic but not membrane ERBB4/4ICD expression in primary human breast tumors was associated with tumor apoptosis, providing a mechanistic explanation for the loss of ERBB4 expression during tumor progression. (PMID:16778220)
• -16 E5 protein can form a complex with ErbB4 via binding to the extracellular and transmembrane domains of ErbB4 (JM-b/CYT-1) (PMID:16819515)
• Down regulation of ERBB4 is associated with brease, prostate and ovarian cancer (PMID:16832345)
• Expression of c-erbB-4 in brain medulloblastoma and its correlation with prognosis. (PMID:16842254)
• low-level hedgehog signalling in human medulloblastoma is associated with the selective maintenance of high ErbB-4 CYT-1 expression, an alteration that exerts tumor-promoting effects (PMID:16878160)
• Contribution of an autocrine ERBB4/estrogen receptor signaling pathway to tumor growth and therapeutic response should be considered when managing patients with ER-positive breast cancer. (PMID:16912174)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	erbb4a	ENSDARG00000063207
danio_rerio	erbb4b	ENSDARG00000089536
danio_rerio	ERBB4	ENSDARG00000090408
mus_musculus	Erbb4	ENSMUSG00000062209
rattus_norvegicus	Erbb4	ENSRNOG00000014248

Paralogs (53): INSRR (ENSG00000027644), MUSK (ENSG00000030304), FLT4 (ENSG00000037280), EPHA3 (ENSG00000044524), ROS1 (ENSG00000047936), LTK (ENSG00000062524), ERBB3 (ENSG00000065361), TIE1 (ENSG00000066056), FGFR2 (ENSG00000066468), FGFR3 (ENSG00000068078), EPHA8 (ENSG00000070886), FGFR1 (ENSG00000077782), EPHA6 (ENSG00000080224), TYRO3 (ENSG00000092445), FLT1 (ENSG00000102755), MET (ENSG00000105976), EPHB6 (ENSG00000106123), PDGFRB (ENSG00000113721), EPHA4 (ENSG00000116106), TEK (ENSG00000120156), FLT3 (ENSG00000122025), KDR (ENSG00000128052), EPHB2 (ENSG00000133216), PDGFRA (ENSG00000134853), EPHA7 (ENSG00000135333), IGF1R (ENSG00000140443), NTRK3 (ENSG00000140538), ERBB2 (ENSG00000141736), EPHA2 (ENSG00000142627), EPHA5 (ENSG00000145242), EGFR (ENSG00000146648), EPHA1 (ENSG00000146904), NTRK2 (ENSG00000148053), MERTK (ENSG00000153208), EPHB1 (ENSG00000154928), KIT (ENSG00000157404), FGFR4 (ENSG00000160867), DDR2 (ENSG00000162733), RYK (ENSG00000163785), MST1R (ENSG00000164078)

Protein

Protein identifiers

Receptor tyrosine-protein kinase erbB-4 — Q15303 (reviewed: Q15303)

Alternative names: Proto-oncogene-like protein c-ErbB-4, Tyrosine kinase-type cell surface receptor HER4, p180erbB4

All UniProt accessions (3): E9PDR1, Q15303, H3BLT0

UniProt curated annotations — full annotation on UniProt →

Function. Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell proliferation, differentiation, migration and apoptosis. Required for normal cardiac muscle differentiation during embryonic development, and for postnatal cardiomyocyte proliferation. Required for normal development of the embryonic central nervous system, especially for normal neural crest cell migration and normal axon guidance. Required for mammary gland differentiation, induction of milk proteins and lactation. Acts as cell-surface receptor for the neuregulins NRG1, NRG2, NRG3 and NRG4 and the EGF family members BTC, EREG and HBEGF. Ligand binding triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Ligand specificity and signaling is modulated by alternative splicing, proteolytic processing, and by the formation of heterodimers with other ERBB family members, thereby creating multiple combinations of intracellular phosphotyrosines that trigger ligand- and context-specific cellular responses. Mediates phosphorylation of SHC1 and activation of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Isoform JM-A CYT-1 and isoform JM-B CYT-1 phosphorylate PIK3R1, leading to the activation of phosphatidylinositol 3-kinase and AKT1 and protect cells against apoptosis. Isoform JM-A CYT-1 and isoform JM-B CYT-1 mediate reorganization of the actin cytoskeleton and promote cell migration in response to NRG1. Isoform JM-A CYT-2 and isoform JM-B CYT-2 lack the phosphotyrosine that mediates interaction with PIK3R1, and hence do not phosphorylate PIK3R1, do not protect cells against apoptosis, and do not promote reorganization of the actin cytoskeleton and cell migration. Proteolytic processing of isoform JM-A CYT-1 and isoform JM-A CYT-2 gives rise to the corresponding soluble intracellular domains (4ICD) that translocate to the nucleus, promote nuclear import of STAT5A, activation of STAT5A, mammary epithelium differentiation, cell proliferation and activation of gene expression. The ERBB4 soluble intracellular domains (4ICD) colocalize with STAT5A at the CSN2 promoter to regulate transcription of milk proteins during lactation. The ERBB4 soluble intracellular domains can also translocate to mitochondria and promote apoptosis.

Subunit / interactions. Monomer in the absence of bound ligand. Homodimer or heterodimer with another ERBB family member upon ligand binding, thus forming heterotetramers. Interacts with EGFR and ERBB2. Interacts with CBFA2T3. Interacts with DLG2 (via its PDZ domain), DLG3 (via its PDZ domain), DLG4 (via its PDZ domain) and SNTB2 (via its PDZ domain). Interacts with MUC1. Interacts (via its PPxy motifs) with WWOX. Interacts (via the PPxY motif 3 of isoform JM-A CYT-2) with YAP1 (via the WW domain 1 of isoform 1). Interacts (isoform JM-A CYT-1 and isoform JM-B CYT-1) with WWP1. Interacts (via its intracellular domain) with TRIM28. Interacts (via the intracellular domains of both CYT-1 and CYT-2 isoforms) with KAP1; the interaction does not phosphorylate KAP1 but represses ERBB4-mediated transcriptional activity. Interacts with PRPU, DDX23, MATR3, RBM15, ILF3, KAP1, U5S1, U2SURP, ITCH, HNRNPU, AP2A1, NULC, LEO1, WWP2, IGHG1, HXK1, GRB7 and SRRT. Interacts (phosphorylated isoform JM-A CYT-1 and isoform JM-B CYT-1) with PIK3R1. Interacts with SHC1. Interacts with GRB2. Interacts (soluble intracellular domain) with STAT5A. Interacts (soluble intracellular domain) with BCL2. Interacts (phosphorylated) with STAT1.

Subcellular location. Cell membrane Nucleus. Mitochondrion.

Tissue specificity. Expressed at highest levels in brain, heart, kidney, in addition to skeletal muscle, parathyroid, cerebellum, pituitary, spleen, testis and breast. Lower levels in thymus, lung, salivary gland, and pancreas. Isoform JM-A CYT-1 and isoform JM-B CYT-1 are expressed in cerebellum, but only the isoform JM-B is expressed in the heart.

Post-translational modifications. Isoform JM-A CYT-1 and isoform JM-A CYT-2 are processed by ADAM17. Proteolytic processing in response to ligand or 12-O-tetradecanoylphorbol-13-acetate stimulation results in the production of 120 kDa soluble receptor forms and intermediate membrane-anchored 80 kDa fragments (m80HER4), which are further processed by a presenilin-dependent gamma-secretase to release a cytoplasmic intracellular domain (E4ICD; E4ICD1/s80Cyt1 or E4ICD2/s80Cyt2, depending on the isoform). Membrane-anchored 80 kDa fragments of the processed isoform JM-A CYT-1 are more readily degraded by the proteasome than fragments of isoform JM-A CYT-2, suggesting a prevalence of E4ICD2 over E4ICD1. Isoform JM-B CYT-1 and isoform JM-B CYT-2 lack the ADAM17 cleavage site and are not processed by ADAM17, precluding further processing by gamma-secretase. Autophosphorylated on tyrosine residues in response to ligand binding. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Ligands trigger phosphorylation at specific tyrosine residues, thereby creating binding sites for scaffold proteins and effectors. Constitutively phosphorylated at a basal level when overexpressed in heterologous systems; ligand binding leads to increased phosphorylation. Phosphorylation at Tyr-1035 is important for interaction with STAT1. Phosphorylation at Tyr-1056 is important for interaction with PIK3R1. Phosphorylation at Tyr-1242 is important for interaction with SHC1. Phosphorylation at Tyr-1188 may also contribute to the interaction with SHC1. Isoform JM-A CYT-2 is constitutively phosphorylated on tyrosine residues in a ligand-independent manner. E4ICD2 but not E4ICD1 is phosphorylated on tyrosine residues. Ubiquitinated. During mitosis, the ERBB4 intracellular domain is ubiquitinated by the APC/C complex and targeted to proteasomal degradation. Isoform JM-A CYT-1 and isoform JM-B CYT-1 are ubiquitinated by WWP1. The ERBB4 intracellular domain (E4ICD1) is ubiquitinated, and this involves NEDD4.

Disease relevance. Amyotrophic lateral sclerosis 19 (ALS19) [MIM:615515] A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Binding of a cognate ligand leads to dimerization and activation by autophosphorylation on tyrosine residues. In vitro kinase activity is increased by Mg(2+). Inhibited by PD153035, lapatinib, gefitinib (iressa, ZD1839), AG1478 and BIBX1382BS.

Miscellaneous. Proteolytical processing generates E4ICD1 (s80Cyt1). Proteolytical processing generates E4ICD2 (s80Cyt2).

Similarity. Belongs to the protein kinase superfamily. Tyr protein kinase family. EGF receptor subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
Q15303-1	JM-A CYT-1	yes
Q15303-2	JM-B CYT-1
Q15303-3	JM-A CYT-2
Q15303-4	JM-B CYT-2

RefSeq proteins (2): NP_001036064, NP_005226* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000494	Rcpt_L-dom	Domain
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR006211	Furin-like_Cys-rich_dom	Domain
IPR006212	Furin_repeat	Repeat
IPR008266	Tyr_kinase_AS	Active_site
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR016245	Tyr_kinase_EGF/ERB/XmrK_rcpt	Family
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR020635	Tyr_kinase_cat_dom	Domain
IPR032778	GF_recep_IV	Domain
IPR036941	Rcpt_L-dom_sf	Homologous_superfamily
IPR049328	TM_ErbB1	Domain
IPR050122	RTK	Family

Pfam: PF00757, PF01030, PF07714, PF14843, PF21314

Enzyme classification (BRENDA):

• EC 2.7.10.1 — receptor protein-tyrosine kinase (BRENDA: 44 organisms, 214 substrates, 574 inhibitors, 11 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0011–0.129	4
AC-DYFE-6-CHLORO-W-NHME	0.0051	1
AC-DYFGW-NHME	0.07	1
YFEW	0.232	1

Catalyzed reactions (Rhea), 1 shown:

• L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) (RHEA:10596)

UniProt features (195 total): strand 61, helix 33, mutagenesis site 26, disulfide bond 23, glycosylation site 11, modified residue 10, turn 7, short sequence motif 5, binding site 4, sequence variant 4, chain 2, topological domain 2, splice variant 2, signal peptide 1, active site 1, transmembrane region 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
2AHX	X-RAY DIFFRACTION	2.4
2R4B	X-RAY DIFFRACTION	2.4
3BCE	X-RAY DIFFRACTION	2.5
3U2P	X-RAY DIFFRACTION	2.57
3BBT	X-RAY DIFFRACTION	2.8
3U7U	X-RAY DIFFRACTION	3.03
8U4L	ELECTRON MICROSCOPY	3.31
8U4I	ELECTRON MICROSCOPY	3.38
3U9U	X-RAY DIFFRACTION	3.42
8U4J	ELECTRON MICROSCOPY	3.7
3BBW	X-RAY DIFFRACTION	4
8U4K	ELECTRON MICROSCOPY	4.27
2L2T	SOLUTION NMR
2LCX	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15303-F1	73.17	0.45

Antibody-complex structures (SAbDab): 1 — 3U9U

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 843 (proton acceptor)

Ligand- & substrate-binding residues (4): 724–732; 751; 797–799; 843–848

Post-translational modifications (10): 875, 1035, 1056, 1150, 1162, 1188, 1202, 1242, 1258, 1284

Disulfide bonds (23): 29–56, 156–186, 189–197, 193–205, 213–221, 217–229, 230–238, 234–246, 249–258, 262–289, 293–304, 308–323, 326–330, 503–512, 507–520, 523–532, 536–552, 555–569, 559–577, 580–589 …

Glycosylation sites (11): 138, 174, 181, 253, 358, 410, 473, 495, 548, 576, 620

Mutagenesis-validated functional residues (26):

Position	Phenotype
646	constitutively activated kinase.
675	abolishes proteolytic processing and nuclear localization.
681–684	abolishes nuclear localization of the erbb4 intracellular domain.
710	strongly reduced autophosphorylation.
721	no effect on kinase activity.
751	abolishes kinase activity. abolishes phosphorylation, proteolytic processing and nuclear localization.
766	strongly reduced autophosphorylation.
773	no effect on kinase activity.
782	no effect on kinase activity.
810	no effect on kinase activity.
843	loss of kinase activity.
854	no effect on kinase activity.
861	loss of kinase activity.
864	strongly reduced autophosphorylation.
872	no effect on kinase activity.
926	no effect on kinase activity.
947	constitutively autophosphorylated.
992	abolishes apc/c-mediated degradation; when associated with a-995 and a-1000.
995	abolishes apc/c-mediated degradation; when associated with a-992 and a-1000.
1000	abolishes apc/c-mediated degradation; when associated with a-992 and a-995.
1035	no effect on interaction with wwox. abolishes interaction with wwox; when associated with a-1301.
1056	abolishes interaction with nedd4 and impairs ubiquitination. promotes nuclear translocation of erbb4 intracellular domai
1056	abolishes interaction with wwp1; when associated with f-1301.
1301	abolishes interaction with nedd4 and impairs ubiquitination.
1301	no effect on interaction with wwox. abolishes interaction with wwox; when associated with a-1035. loss of interaction wi

Function

Pathways and Gene Ontology

Reactome pathways

20 pathways

ID	Pathway
R-HSA-1227986	Signaling by ERBB2
R-HSA-1236394	Signaling by ERBB4
R-HSA-1250196	SHC1 events in ERBB2 signaling
R-HSA-1250342	PI3K events in ERBB4 signaling
R-HSA-1250347	SHC1 events in ERBB4 signaling
R-HSA-1251985	Nuclear signaling by ERBB4
R-HSA-1253288	Downregulation of ERBB4 signaling
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-1963640	GRB2 events in ERBB2 signaling
R-HSA-1963642	PI3K events in ERBB2 signaling
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-6785631	ERBB2 Regulates Cell Motility
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-8847993	ERBB2 Activates PTK6 Signaling
R-HSA-8863795	Downregulation of ERBB2 signaling
R-HSA-9018519	Estrogen-dependent gene expression
R-HSA-9620244	Long-term potentiation
R-HSA-9664565	Signaling by ERBB2 KD Mutants
R-HSA-9665686	Signaling by ERBB2 TMD/JMD mutants

MSigDB gene sets: 545 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_OLFACTORY_BULB_INTERNEURON_DIFFERENTIATION, AAGCAAT_MIR137, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_REGULATION_OF_PHOSPHORYLATION, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, GOBP_SYNAPSE_ASSEMBLY, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, CMYB_01, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP

GO Biological Process (49): neural crest cell migration (GO:0001755), positive regulation of protein phosphorylation (GO:0001934), signal transduction (GO:0007165), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), epidermal growth factor receptor signaling pathway (GO:0007173), cell surface receptor signaling pathway via JAK-STAT (GO:0007259), nervous system development (GO:0007399), synapse assembly (GO:0007416), heart development (GO:0007507), lactation (GO:0007595), positive regulation of cell population proliferation (GO:0008284), negative regulation of cell population proliferation (GO:0008285), embryonic pattern specification (GO:0009880), cell migration (GO:0016477), peptidyl-tyrosine phosphorylation (GO:0018108), central nervous system morphogenesis (GO:0021551), olfactory bulb interneuron differentiation (GO:0021889), neuron differentiation (GO:0030182), regulation of cell migration (GO:0030334), ERBB4 signaling pathway (GO:0038130), ERBB2-ERBB4 signaling pathway (GO:0038135), ERBB4-ERBB4 signaling pathway (GO:0038138), positive regulation of tyrosine phosphorylation of STAT protein (GO:0042531), negative regulation of apoptotic process (GO:0043066), positive regulation of MAPK cascade (GO:0043410), mitochondrial fragmentation involved in apoptotic process (GO:0043653), cell fate commitment (GO:0045165), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of receptor signaling pathway via JAK-STAT (GO:0046427), protein autophosphorylation (GO:0046777), positive regulation of epithelial cell proliferation (GO:0050679), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), positive regulation of cardiac muscle cell proliferation (GO:0060045), mammary gland epithelial cell differentiation (GO:0060644), mammary gland alveolus development (GO:0060749), cardiac muscle tissue regeneration (GO:0061026), positive regulation of ERK1 and ERK2 cascade (GO:0070374), cellular response to epidermal growth factor stimulus (GO:0071364), establishment of planar polarity involved in nephron morphogenesis (GO:0072046), neurotransmitter receptor localization to postsynaptic specialization membrane (GO:0099645)

GO Molecular Function (14): transcription cis-regulatory region binding (GO:0000976), protein tyrosine kinase activity (GO:0004713), transmembrane receptor protein tyrosine kinase activity (GO:0004714), epidermal growth factor receptor activity (GO:0005006), epidermal growth factor receptor binding (GO:0005154), ATP binding (GO:0005524), neuregulin receptor activity (GO:0038131), protein homodimerization activity (GO:0042803), GABA receptor binding (GO:0050811), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (18): extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), plasma membrane (GO:0005886), basal plasma membrane (GO:0009925), basolateral plasma membrane (GO:0016323), neuromuscular junction (GO:0031594), presynaptic membrane (GO:0042734), signaling receptor complex (GO:0043235), postsynaptic membrane (GO:0045211), postsynaptic density membrane (GO:0098839), glutamatergic synapse (GO:0098978), GABA-ergic synapse (GO:0098982), membrane (GO:0016020), organelle (GO:0043226)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Signaling by ERBB2	6
Signaling by ERBB4	4
Signaling by Receptor Tyrosine Kinases	2
Signaling by ERBB2 in Cancer	2
Intracellular signaling by second messengers	1
PI3K/AKT Signaling in Cancer	1
MAPK1/MAPK3 signaling	1
Negative regulation of the PI3K/AKT network	1
Signaling by PTK6	1
ESR-mediated signaling	1
Post NMDA receptor activation events	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
synapse	3
protein phosphorylation	2
ERBB signaling pathway	2
cell population proliferation	2
regulation of cell population proliferation	2
intracellular membrane-bounded organelle	2
cytoplasm	2
plasma membrane region	2
synaptic membrane	2
neural crest cell development	1
mesenchymal cell migration	1
regulation of protein phosphorylation	1
positive regulation of protein modification process	1
positive regulation of phosphorylation	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
enzyme-linked receptor protein signaling pathway	1
cell surface receptor signaling pathway via STAT	1
system development	1
nervous system development	1
cell junction assembly	1
synapse organization	1
animal organ development	1
circulatory system development	1
body fluid secretion	1
mammary gland development	1
milk ejection reflex	1
positive regulation of cellular process	1
negative regulation of cellular process	1
pattern specification process	1
embryo development	1
cell motility	1
peptidyl-tyrosine modification	1
central nervous system development	1
anatomical structure morphogenesis	1
olfactory bulb development	1

Protein interactions and networks

STRING

3750 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ERBB4	NRG1	P98202	999
ERBB4	NRG2	O14511	998
ERBB4	NRG3	P56975	998
ERBB4	NRG4	Q8WWG1	998
ERBB4	EGF	P01133	997
ERBB4	HBEGF	Q99075	995
ERBB4	BTC	P35070	995
ERBB4	EREG	O14944	994
ERBB4	ERBB3	P21860	983
ERBB4	ERBB2	P04626	983
ERBB4	AREG	P15514	978
ERBB4	EGFR	P00533	977
ERBB4	DLG4	P78352	977
ERBB4	TGFA	P01135	971
ERBB4	GRB2	P29354	951

IntAct

297 interactions, top by confidence:

A	B	Type	Score
RAD51D	RAD51C	psi-mi:“MI:0914”(association)	0.860
ERBB2	ERBB4	psi-mi:“MI:0915”(physical association)	0.820
CD9	ADAM10	psi-mi:“MI:0914”(association)	0.750
ERBB4	DLG4	psi-mi:“MI:0915”(physical association)	0.740
DLG4	ERBB4	psi-mi:“MI:0915”(physical association)	0.740
ERBB4	DLG4	psi-mi:“MI:0407”(direct interaction)	0.740
VAPB	FAM83G	psi-mi:“MI:0914”(association)	0.730
ERBB4	EGFR	psi-mi:“MI:2364”(proximity)	0.650
ERBB4	DLG1	psi-mi:“MI:0915”(physical association)	0.610
ERBB4	DLG1	psi-mi:“MI:0407”(direct interaction)	0.610
ITCH	ERBB4	psi-mi:“MI:0915”(physical association)	0.590
ERBB4	LRRC7	psi-mi:“MI:0915”(physical association)	0.590
LRIG1	ERBB4	psi-mi:“MI:0915”(physical association)	0.590
ERBB3	ERBB4	psi-mi:“MI:0915”(physical association)	0.590
ERBB4	ERBB3	psi-mi:“MI:0915”(physical association)	0.590
ERBB4	DLG2	psi-mi:“MI:0407”(direct interaction)	0.590
ERBB4	DLG3	psi-mi:“MI:0407”(direct interaction)	0.590
ERBB4	LRRC7	psi-mi:“MI:0407”(direct interaction)	0.590

BioGRID (278): ERBB4 (FRET), ERBB4 (Affinity Capture-Western), GRB2 (Affinity Capture-Western), CBL (Affinity Capture-Western), ERBB4 (Reconstituted Complex), ERBB4 (Biochemical Activity), ERBB4 (Affinity Capture-Western), ERBB4 (Affinity Capture-Western), TFAP2C (Reconstituted Complex), WWOX (Reconstituted Complex), DLG3 (Two-hybrid), SNTB2 (Two-hybrid), DLG4 (Two-hybrid), YAP1 (Two-hybrid), DLG2 (Two-hybrid)

ESM2 similar proteins: A0A1L8F5J9, A0JN27, F1LTR1, F1NBL0, O15294, P35438, P35439, P56558, P61201, P61202, P61203, P61599, P61600, P63138, P79101, P81436, Q03555, Q05586, Q13888, Q15303, Q27HV0, Q2PFM2, Q2TBV5, Q4L208, Q58ED9, Q5R1P0, Q5SP67, Q5ZJ75, Q61527, Q62956, Q6IQT4, Q6IR75, Q6P1K8, Q6P632, Q7ZXR3, Q8BUV3, Q8C6G8, Q8CGY8, Q8R4D1, Q91854

Diamond homologs: A0JM20, A0M8R7, A0M8S8, A1X150, D2IYS2, G3V9H8, H2KZU7, O02466, O73798, P00519, P00520, P00521, P00529, P06213, P08069, P08581, P08922, P08923, P08941, P09208, P09760, P11362, P14616, P14617, P15127, P15208, P16056, P16092, P16591, P18460, P22607, P23049, P24062, P30530, P33497, P34925, P42684, P55144, P55146, P57097

SIGNOR signaling

46 interactions.

A	Effect	B	Mechanism
NRG1	up-regulates	ERBB4	binding
NRG2	up-regulates	ERBB4	binding
NRG3	up-regulates	ERBB4	binding
NRG4	up-regulates	ERBB4	binding
LRIG1	down-regulates	ERBB4	ubiquitination
EPGN	up-regulates	ERBB4	binding
ERBB4	up-regulates	GRB2	binding
ERBB4	up-regulates	PIK3CA	binding
ERBB4	up-regulates	PIK3CB	binding
ERBB4	up-regulates	PIK3CD	binding
ERBB4	up-regulates	PIK3CG	binding
ERBB4	up-regulates	SHC3	relocalization
ERBB4	up-regulates	STAT5A	binding
BTC	up-regulates	ERBB4	binding
ERBB4	up-regulates	CBL	binding
EREG	up-regulates	ERBB4	binding
N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-6-quinazolinyl]-2-propenamide	down-regulates	ERBB4	“chemical inhibition”
dacomitinib	down-regulates	ERBB4	“chemical inhibition”
LRIG1	down-regulates	ERBB4
LRIG3	up-regulates	ERBB4
ERBB4	up-regulates	PI3K	binding
afatinib	“down-regulates activity”	ERBB4	“chemical inhibition”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 144 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
ERBB2 Regulates Cell Motility	7	52.6×	4e-09
PI3K events in ERBB2 signaling	7	49.5×	4e-09
SHC1 events in ERBB2 signaling	8	40.1×	2e-09
GRB2 events in ERBB2 signaling	6	40.1×	2e-07
Downregulation of ERBB2 signaling	9	36.1×	1e-09
Signaling by ERBB2 TMD/JMD mutants	7	35.1×	5e-08
Negative regulation of NMDA receptor-mediated neuronal transmission	6	34.4×	6e-07
GAB1 signalosome	5	33.4×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
peptidyl-tyrosine dephosphorylation	6	40.3×	1e-06
establishment or maintenance of epithelial cell apical/basal polarity	9	39.6×	5e-10
protein localization to synapse	6	34.8×	2e-06
receptor clustering	7	33.1×	4e-07
epidermal growth factor receptor signaling pathway	12	22.5×	2e-10
regulation of postsynaptic membrane neurotransmitter receptor levels	5	18.8×	5e-04
protein dephosphorylation	10	16.8×	2e-07
cellular response to epidermal growth factor stimulus	6	14.4×	3e-04

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

ErbB4 (HER4) is one of the four members in the EGFR subfamily of receptor tyrosine kinases. Ligands include EGF, epiregulin, betacellulin and the neuregulins (Sundvall et. al.). Of these, NRG3 and NRG4 exclusively bind HER4 (Hynes et. al.). Mutations in ERBB4 have been identified in various cancer types including melanoma, lung adenocarcinoma and medulloblastoma. A therapeutic value of these aberrations still remains unknown (Arteaga et. al.).

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 10 cancer types — BLCA, BRCA, CCRCC, CHOL, COADREAD, ESCA, HCC, MEL, PRAD, STAD.

Clinical variants and AI predictions

ClinVar

777 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	8
Uncertain significance	358
Likely benign	235
Benign	117

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
2208868	NM_005235.3(ERBB4):c.1015_1034del (p.Thr339fs)	Pathogenic
2229731	NM_005235.3(ERBB4):c.1776dup (p.Cys593fs)	Pathogenic
64625	NM_005235.3(ERBB4):c.2780G>A (p.Arg927Gln)	Pathogenic
3896859	NM_005235.3(ERBB4):c.3183+2T>C	Likely pathogenic
4250421	NM_005235.3(ERBB4):c.883+1G>A	Likely pathogenic
4250422	NM_005235.3(ERBB4):c.82+1G>A	Likely pathogenic
441579	GRCh37/hg19 2q34(chr2:212384649-214064185)x1	Likely pathogenic
4618670	NM_005235.3(ERBB4):c.29G>A (p.Trp10Ter)	Likely pathogenic
520885	NM_005235.3(ERBB4):c.119_120del (p.Leu39_Ser40insTer)	Likely pathogenic
638628	NM_005235.3(ERBB4):c.785G>A (p.Cys262Tyr)	Likely pathogenic
976654	NM_005235.3(ERBB4):c.3814G>A (p.Gly1272Arg)	Likely pathogenic

SpliceAI

7984 predictions. Top by Δscore:

Variant	Effect	Δscore
2:211384059:TT:T	acceptor_gain	1.0000
2:211384061:C:CC	acceptor_gain	1.0000
2:211386847:TCATA:T	donor_loss	1.0000
2:211386848:CATAC:C	donor_loss	1.0000
2:211386849:ATAC:A	donor_loss	1.0000
2:211386850:TACCT:T	donor_loss	1.0000
2:211386851:A:T	donor_loss	1.0000
2:211386891:T:A	donor_gain	1.0000
2:211387146:TGGTT:T	acceptor_gain	1.0000
2:211387147:GGTT:G	acceptor_gain	1.0000
2:211387149:TT:T	acceptor_gain	1.0000
2:211387151:C:CC	acceptor_gain	1.0000
2:211387152:T:A	acceptor_loss	1.0000
2:211387157:A:AC	acceptor_gain	1.0000
2:211387157:A:C	acceptor_gain	1.0000
2:211387168:A:C	acceptor_gain	1.0000
2:211387943:A:AC	donor_gain	1.0000
2:211387944:C:CC	donor_gain	1.0000
2:211420435:TCTTA:T	donor_loss	1.0000
2:211420436:CTTAC:C	donor_loss	1.0000
2:211420437:TTA:T	donor_loss	1.0000
2:211420438:TA:T	donor_loss	1.0000
2:211420439:A:AC	donor_gain	1.0000
2:211420439:AC:A	donor_gain	1.0000
2:211420440:C:CC	donor_gain	1.0000
2:211420440:C:CG	donor_loss	1.0000
2:211420440:CC:C	donor_gain	1.0000
2:211420440:CCCT:C	donor_gain	1.0000
2:211420440:CCCTA:C	donor_gain	1.0000
2:211420607:TCACC:T	acceptor_gain	1.0000

AlphaMissense

8641 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:211422017:A:G	L985P	1.000
2:211422021:A:C	Y984D	1.000
2:211422022:T:A	R983S	1.000
2:211422022:T:G	R983S	1.000
2:211422023:C:G	R983T	1.000
2:211422032:T:C	D980G	1.000
2:211422038:G:T	A978D	1.000
2:211422040:C:A	M977I	1.000
2:211422040:C:G	M977I	1.000
2:211422040:C:T	M977I	1.000
2:211422041:A:G	M977T	1.000
2:211422062:A:G	L970P	1.000
2:211422070:A:C	F967L	1.000
2:211422070:A:T	F967L	1.000
2:211422071:A:G	F967S	1.000
2:211422072:A:G	F967L	1.000
2:211422079:T:A	R964S	1.000
2:211422079:T:G	R964S	1.000
2:211422080:C:A	R964I	1.000
2:211422080:C:G	R964T	1.000
2:211422081:T:C	R964G	1.000
2:211422097:C:A	M958I	1.000
2:211422097:C:G	M958I	1.000
2:211422097:C:T	M958I	1.000
2:211422098:A:G	M958T	1.000
2:211422100:C:A	W957C	1.000
2:211422100:C:G	W957C	1.000
2:211422102:A:G	W957R	1.000
2:211422102:A:T	W957R	1.000
2:211422103:A:C	C956W	1.000

dbSNP variants (sampled 300 via entrez): RS1000004244 (2:211901773 A>G), RS1000004323 (2:211437001 T>C), RS1000004987 (2:211478139 T>A), RS1000005607 (2:212284051 G>A), RS1000009048 (2:211397129 A>G), RS1000009297 (2:211839417 T>C), RS1000012594 (2:212360857 A>G), RS1000015018 (2:212479585 T>C), RS1000016063 (2:211863267 T>A,C), RS1000016135 (2:212350061 C>T), RS1000022707 (2:212073986 C>T), RS1000023567 (2:212464944 C>G), RS1000024366 (2:211507516 CA>C), RS1000025905 (2:211583784 T>C), RS1000027916 (2:211802192 G>A)

Disease associations

OMIM: gene MIM:600543 | disease phenotypes: MIM:615515, MIM:612069, MIM:181500, MIM:190350

GenCC curated gene-disease

Disease	Classification	Inheritance
amyotrophic lateral sclerosis type 19	Strong	Autosomal dominant
intellectual disability	Strong	Autosomal dominant
amyotrophic lateral sclerosis	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
amyotrophic lateral sclerosis type 19	Limited	AD

Mondo (9): amyotrophic lateral sclerosis type 19 (MONDO:0014223), amyotrophic lateral sclerosis (MONDO:0004976), frontotemporal dementia (MONDO:0017276), amyotrophic lateral sclerosis type 10 (MONDO:0012790), intellectual disability (MONDO:0001071), schizophrenia (MONDO:0005090), teratoma (MONDO:0002601), trichorhinophalangeal syndrome type I (MONDO:0008596), NK-cell enteropathy (MONDO:0016996)

Orphanet (7): Amyotrophic lateral sclerosis (Orphanet:803), Frontotemporal dementia (Orphanet:282), Frontotemporal dementia with motor neuron disease (Orphanet:275872), Trichorhinophalangeal syndrome type 1 (Orphanet:77258), NK-cell enteropathy (Orphanet:263665), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

53 total (30 of 53 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000217	Xerostomia
HP:0000708	Atypical behavior
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000726	Dementia
HP:0000739	Anxiety
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001308	Tongue fasciculations
HP:0001347	Hyperreflexia
HP:0001618	Dysphonia
HP:0001824	Weight loss
HP:0002015	Dysphagia
HP:0002094	Dyspnea
HP:0002145	Frontotemporal dementia
HP:0002180	Neurodegeneration
HP:0002307	Drooling
HP:0002313	Spastic paraparesis
HP:0002360	Sleep disturbance
HP:0002380	Fasciculations
HP:0002463	Language impairment
HP:0002505	Loss of ambulation
HP:0002747	Respiratory insufficiency due to muscle weakness
HP:0002878	Respiratory failure
HP:0003202	Skeletal muscle atrophy
HP:0003324	Generalized muscle weakness
HP:0003376	Steppage gait
HP:0003394	Muscle spasm
HP:0003470	Paralysis

GWAS associations

66 associations (top):

Study	Trait	p-value
GCST001457_1	Breast cancer	9.000000e-14
GCST001688_1	Type 1 diabetes nephropathy	2.000000e-07
GCST002097_14	Coronary artery calcification	5.000000e-06
GCST002111_3	Personality dimensions	4.000000e-06
GCST002337_101	Amyotrophic lateral sclerosis (sporadic)	1.000000e-06
GCST002445_4	Asthma (sex interaction)	9.000000e-07
GCST002575_3	Body mass index (change over time)	6.000000e-07
GCST002783_170	Body mass index	1.000000e-10
GCST002783_224	Body mass index	5.000000e-11
GCST002783_570	Body mass index	9.000000e-09
GCST003144_2	Polycystic ovary syndrome	1.000000e-12
GCST004495_30	BMI (adjusted for smoking behaviour)	2.000000e-07
GCST004495_31	BMI (adjusted for smoking behaviour)	3.000000e-11
GCST004497_126	Body mass index (joint analysis main effects and smoking interaction)	3.000000e-10
GCST004497_131	Body mass index (joint analysis main effects and smoking interaction)	8.000000e-07
GCST004499_26	BMI in non-smokers	3.000000e-07
GCST004499_27	BMI in non-smokers	1.000000e-09
GCST004574_3	Skin aging (microtopography measurement)	6.000000e-06
GCST004642_5	QT interval (ambient particulate matter interaction)	3.000000e-06
GCST004904_153	Body mass index	3.000000e-11
GCST005316_174	Intelligence (MTAG)	9.000000e-09
GCST005798_1	Sperm motility	5.000000e-09
GCST005984_26	Glomerular filtration rate	5.000000e-15
GCST006061_16	Atrial fibrillation	2.000000e-06
GCST006414_73	Atrial fibrillation	1.000000e-11
GCST006624_14	Systolic blood pressure	8.000000e-11
GCST006923_9	Loneliness	6.000000e-09
GCST006924_9	Loneliness (MTAG)	5.000000e-09
GCST006942_2	Feeling lonely	9.000000e-09
GCST006947_40	Feeling fed-up	4.000000e-10

EFO canonical traits (23, from GWAS)

EFO ID	Trait name
EFO:0004723	coronary artery calcification
EFO:0004365	personality trait
EFO:0008343	sex interaction measurement
EFO:0005937	longitudinal BMI measurement
EFO:0004340	body mass index
EFO:0004318	smoking behavior
EFO:0004682	QT interval
EFO:0008255	particulate matter air pollution measurement
EFO:0004337	intelligence
EFO:0006335	systolic blood pressure
EFO:0007865	loneliness measurement
EFO:0009588	feeling “fed-up” measurement
EFO:0006946	behavioural disinhibition measurement
EFO:0008392	triiodothyronine measurement
EFO:0004531	urate measurement
EFO:0004886	intracranial volume measurement
EFO:0010542	ureidopropionic acid measurement
EFO:0009767	glycine measurement
EFO:0009774	serine measurement
EFO:0009695	household income
EFO:0004327	electrocardiography
EFO:0007006	depressive symptom measurement
EFO:0009749	age at first sexual intercourse measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
D057180	Frontotemporal Dementia	C10.228.140.380.266.299; C10.574.950.300.299; C18.452.845.800.300.299; F03.615.400.380.299
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D013724	Teratoma	C04.557.465.910
C567429	Amyotrophic Lateral Sclerosis 10 (supp.)
C536820	Trichorhinophalangeal Syndrome, Type I (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2363049 (PROTEIN FAMILY), CHEMBL3009 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

47 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 420,907 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL4650319	MOBOCERTINIB	4	929
CHEMBL1173655	AFATINIB	4	15,144
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL180022	NERATINIB	4	9,404
CHEMBL1873475	IBRUTINIB	4	7,994
CHEMBL2105712	AFATINIB DIMALEATE	4	3,215
CHEMBL2105719	DACOMITINIB	4	750
CHEMBL2110732	DACOMITINIB ANHYDROUS	4	6,578
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3545311	BRIGATINIB	4	5,634
CHEMBL3707348	ACALABRUTINIB	4	4,504
CHEMBL3936761	ZANUBRUTINIB	4	2,484
CHEMBL4071161	TIRABRUTINIB	4	2,170
CHEMBL4085457	RITLECITINIB	4	708
CHEMBL5416410	DASATINIB	4	655
CHEMBL553	ERLOTINIB	4	108,300
CHEMBL554	LAPATINIB	4	69,326
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL939	GEFITINIB	4	117,814
CHEMBL31965	CANERTINIB	3
CHEMBL4072833	EVOBRUTINIB	3
CHEMBL428690	ALVOCIDIB	3
CHEMBL4483575	REMIBRUTINIB	3
CHEMBL483158	ALISERTIB	3
CHEMBL491473	CEDIRANIB	3
CHEMBL545315	CANERTINIB DIHYDROCHLORIDE	3
CHEMBL603469	LESTAURTINIB	3
CHEMBL587723	AEE-788	2
CHEMBL1230609	FORETINIB	2

Clinical evidence (CIViC)

Drug × variant × indication: 4 predictive associations from 4 curated evidence items; also 1 prognostic.

Variant	Therapy	Indication	Effect	Level	CIViC
ERBB4 Mutation	Lapatinib	Melanoma	Sensitivity/Response	CIViC D	EID770
ERBB4 EXPRESSION	Trastuzumab	Breast Cancer	Resistance	CIViC D	EID868
ERBB4 EXPRESSION	Lapatinib	Breast Cancer	Resistance	CIViC D	EID869
ERBB4 NUCLEAR TRANSLOCATION	Trastuzumab	Breast Cancer	Resistance	CIViC D	EID867

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3942465	ERBB4		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — Type I RTKs: ErbB (epidermal growth factor) receptor family

Most potent curated ligand interactions (16 total), top 16:

Ligand	Action	Affinity	Parameter
EGFR/ErbB-2/ErbB-4 inhibitor	Inhibition	9.3	pIC50
allitinib	Inhibition	9.1	pIC50
pirotinib	Inhibition	8.72	pIC50
compound 38 [PMID: 24915291]	Inhibition	8.48	pIC50
ibrutinib	Inhibition	8.47	pIC50
betacellulin		8.44	pIC50
acalabrutinib	Inhibition	7.8	pIC50
poziotinib	Inhibition	7.63	pIC50
AEE788	Inhibition	7.59	pIC50
WZ4002	Inhibition	7.55	pKd
compound 9 [PMID: 26006010]	Inhibition	7.19	pIC50
dacomitinib	Inhibition	7.13	pIC50
BMS-599626	Inhibition	6.72	pIC50
tucatinib	Inhibition	6.51	pIC50
neuregulin-1		6.29	pIC50
xiliertinib	Inhibition	6.15	pIC50

Binding affinities (BindingDB)

55 measured of 56 human assays (56 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-[4-(3-chloro-4- fluorophenylamino)-7-(2-(6-methyl- 6-azaspiro[2.5]octan-1- yl)ethoxy)quinazolin-6-yl]- acrylamide	IC50	0.39 nM	US-9730934: Quinazoline derivatives substituted by aniline, preparation method and use thereof
N-[4-(3-chloro-4- fluorophenylamino)-7-(2-(7-methyl- 7-azaspiro[3.5]nonan-2- yl)ethoxy)quinazolin-6-yl]- acrylamide	IC50	0.56 nM	US-9730934: Quinazoline derivatives substituted by aniline, preparation method and use thereof
N-[4-(3-chloro-4- fluorophenylamino)-7-(2- ((1R,5S,6S)-3-methyl-3- azabicyclo[3.1.0]hexan-6- ylethoxy)quinazolin-6-yl]- acrylamide	IC50	0.66 nM	US-9730934: Quinazoline derivatives substituted by aniline, preparation method and use thereof
N-[4-(3-chloro-4- fluorophenylamino)-7-(2-(3-methyl- 3-azabicyclo[3.2.1]octan-8- yl)ethoxy)quinazolin-6-yl]- acrylamide	IC50	0.8 nM	US-9730934: Quinazoline derivatives substituted by aniline, preparation method and use thereof
IBRUTINIB	IC50	0.8 nM	US-9278100: Inhibitors of bruton’s tyrosine kinase for the treatment of solid tumors
N-[4-(3-chloro-4- fluorophenylamino)-7-(8-methyl-1- oxa-8-azaspiro[4.5]decan-2- ylmethoxy)quinazolin-6-yl]- acrylamide	IC50	0.93 nM	US-9730934: Quinazoline derivatives substituted by aniline, preparation method and use thereof
N-[4-(3-chloro-4- fluorophenylamino)-7-((8-methyl-1- oxa-8-azaspiro[4.5]decan-3- yl)methoxy)quinazolin-6-yl]- acrylamide	IC50	1 nM	US-9730934: Quinazoline derivatives substituted by aniline, preparation method and use thereof
N-[4-(3-chloro-4- fluorophenylamino)-7-((7-methyl-7- azaspiro[3.5]nonan-2- yl)methoxy)quinazolin-6-yl]- acrylamide	IC50	1 nM	US-9730934: Quinazoline derivatives substituted by aniline, preparation method and use thereof
N-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexyl]prop-2-enamide	IC50	1.1 nM	US-9278100: Inhibitors of bruton’s tyrosine kinase for the treatment of solid tumors
Staurosporine	KD	1.7 nM
CHEMBL3763405	IC50	4.6 nM
CHEMBL3763627	IC50	5.4 nM
CHEMBL3765425	IC50	5.7 nM
CHEMBL3765815	IC50	6 nM
(E)-N-[4-(3-chloro-4-fluoroanilino)-7-(2-fluoroethoxy)quinazolin-6-yl]-4-piperidin-1-ylbut-2-enamide	IC50	6.44 nM	US-8623883: 4-phenylamino-quinazolin-6-yl-amides
DACOMITINIB	IC50	6.9 nM	US-8623883: 4-phenylamino-quinazolin-6-yl-amides
N-{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}-6-{2-[(2R)-pyrrolidin-2-yl]ethynyl}thieno[3,2-d]pyrimidin-4-amine	IC50	7 nM
4-(4-Fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole	KD	9.8 nM
(E)-N-[4-(3-chloro-4-fluoroanilino)-7-(2,2-difluoroethoxy)quinazolin-6-yl]-4-piperidin-1-ylbut-2-enamide	IC50	9.87 nM	US-8623883: 4-phenylamino-quinazolin-6-yl-amides
CHEMBL3763796	IC50	10 nM
CHEMBL3763757	IC50	11 nM
(E)-N-[4-(3-chloro-4-fluoroanilino)-7-(3-morpholin-4-ylpropoxy)quinazolin-6-yl]-4-piperidin-1-ylbut-2-enamide	IC50	11.3 nM	US-8623883: 4-phenylamino-quinazolin-6-yl-amides
CHEMBL3765263	IC50	12 nM
(E)-4-(azepan-1-yl)-N-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]but-2-enamide	IC50	12.1 nM	US-8623883: 4-phenylamino-quinazolin-6-yl-amides
CHEMBL3764603	IC50	15 nM
CHEMBL3764312	IC50	17 nM
(E)-N-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]-4-(4-fluoropiperidin-1-yl)but-2-enamide	IC50	18.1 nM	US-8623883: 4-phenylamino-quinazolin-6-yl-amides
TAK-285	IC50	23 nM
N-{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}-6-ethynylthieno[3,2-d]pyrimidin-4-amine	IC50	24 nM
BMS-354825	KD	27 nM
CHEMBL3763701	IC50	33 nM
(E)-N-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]-4-(3-fluoropiperidin-1-yl)but-2-enamide	IC50	45.3 nM	US-8623883: 4-phenylamino-quinazolin-6-yl-amides
5-{2-[4-({3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino)thieno[3,2-d]pyrimidin-6-yl]ethynyl}pyrazin-2-amine	IC50	47 nM
N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-3-cyanoquinolin-6-yl]-2-(dithiolan-3-yl)acetamide	IC50	50 nM	US-10246444: 1,2-dithiolane and dithiol compounds useful in treating mutant EGFR-mediated diseases and conditions
6-[(3S)-3-aminobut-1-yn-1-yl]-N-{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}thieno[3,2-d]pyrimidin-4-amine	IC50	64 nM
CHEMBL3764589	IC50	66 nM
6-[(3S)-3-aminobut-1-yn-1-yl]-N-{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}thieno[2,3-d]pyrimidin-4-amine	IC50	69 nM
N-{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}-6-ethynylthieno[2,3-d]pyrimidin-4-amine	IC50	71 nM
N-{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}-6-{2-[(2R)-pyrrolidin-2-yl]ethynyl}thieno[2,3-d]pyrimidin-4-amine	IC50	109 nM
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine	KD	150 nM
CHEMBL3765789	IC50	159 nM
PKC-412	KD	190 nM
5-{2-[4-({3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino)thieno[2,3-d]pyrimidin-6-yl]ethynyl}pyrazin-2-amine	IC50	372 nM
SYR127063	IC50	429 nM
N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-3-cyano-7-[(2S)-2,3-dihydroxypropoxy]quinolin-6-yl]dithiolane-4-carboxamide	IC50	550 nM	US-10246444: 1,2-dithiolane and dithiol compounds useful in treating mutant EGFR-mediated diseases and conditions
N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-3-cyanoquinolin-6-yl]dithiolane-4-carboxamide	IC50	550 nM	US-10246444: 1,2-dithiolane and dithiol compounds useful in treating mutant EGFR-mediated diseases and conditions
PF-06651600	IC50	606 nM
ERLOTINIB HYDROCHLORIDE	KD	1200 nM
CI-1033	KD	1700 nM
2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide	KD	1900 nM

ChEMBL bioactivities

499 potent at pChembl≥5 of 506 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.52	IC50	0.03	nM	CHEMBL4646030
10.00	IC50	0.1	nM	IBRUTINIB
9.72	IC50	0.19	nM	CHEMBL4642574
9.60	IC50	0.25	nM	IBRUTINIB
9.35	IC50	0.45	nM	CHEMBL4517633
9.30	IC50	0.5	nM	CHEMBL203644
9.22	IC50	0.6	nM	CHEMBL4211949
9.22	IC50	0.6	nM	IBRUTINIB
9.16	IC50	0.69	nM	CHEMBL2387001
9.10	IC50	0.8	nM	CHEMBL437890
9.10	IC50	0.8	nM	ALLITINIB
9.05	IC50	0.89	nM	CHEMBL2387000
9.04	Kd	0.91	nM	IBRUTINIB
9.00	IC50	1	nM	CHEMBL3959248
9.00	IC50	1	nM	CHEMBL204638
9.00	IC50	1	nM	CHEMBL203661
9.00	IC50	1	nM	AFATINIB
8.92	IC50	1.2	nM	CHEMBL2386999
8.92	IC50	1.2	nM	CHEMBL203599
8.92	IC50	1.2	nM	CHEMBL4647228
8.80	IC50	1.58	nM	ZANUBRUTINIB
8.80	IC50	1.6	nM	CHEMBL5182567
8.77	IC50	1.7	nM	CHEMBL202360
8.77	IC50	1.7	nM	CHEMBL3622673
8.74	IC50	1.8	nM	CHEMBL205059
8.74	IC50	1.8	nM	IBRUTINIB
8.70	IC50	2	nM	AEE-788
8.70	IC50	2	nM	CHEMBL3890186
8.70	IC50	2	nM	CHEMBL3896779
8.70	IC50	2	nM	CHEMBL5208454
8.62	IC50	2.4	nM	CHEMBL203645
8.62	IC50	2.4	nM	CHEMBL4075917
8.62	Kd	2.4	nM	IBRUTINIB
8.62	Kd	2.4	nM	NERATINIB
8.60	Ki	2.512	nM	CHEMBL1981725
8.57	IC50	2.7	nM	IBRUTINIB
8.52	IC50	3	nM	CHEMBL3086102
8.52	IC50	3	nM	CHEMBL3932176
8.52	IC50	3	nM	CHEMBL3970330
8.52	IC50	3	nM	CHEMBL3958482
8.52	IC50	3	nM	CHEMBL3986103
8.52	IC50	3	nM	CHEMBL3949347
8.52	IC50	3	nM	CHEMBL3977504
8.52	IC50	3	nM	CHEMBL3981551
8.52	IC50	3	nM	CHEMBL4473365
8.49	IC50	3.2	nM	CHEMBL3647967
8.49	IC50	3.2	nM	CHEMBL4068839
8.48	IC50	3.3	nM	CHEMBL3290148
8.48	IC50	3.3	nM	CHEMBL4860202
8.48	IC50	3.3	nM	MOBOCERTINIB

PubChem BioAssay actives

375 with measured affinity, of 2207 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-3-cyano-7-[(2S)-2,3-dihydroxypropoxy]quinolin-6-yl]-2-(dithiolan-4-yl)acetamide	1664190: Inhibition of HER4 (unknown origin) in presence of radiolabelled gammaATP by radioisotope filter binding assay	ic50	<0.0001	uM
N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-3-cyano-7-[(2R)-2,3-dihydroxypropoxy]quinolin-6-yl]-2-(dithiolan-4-yl)acetamide	1664190: Inhibition of HER4 (unknown origin) in presence of radiolabelled gammaATP by radioisotope filter binding assay	ic50	0.0002	uM
Ibrutinib	1615370: Inhibition of human HER4 using poly[Glu:Tyr] (4:1) as substrate preincubated for 60 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by filter binding method	ic50	0.0003	uM
N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-3-cyano-7-[(2S)-2,3-dihydroxypropoxy]quinolin-6-yl]dithiolane-4-carboxamide	1664190: Inhibition of HER4 (unknown origin) in presence of radiolabelled gammaATP by radioisotope filter binding assay	ic50	0.0004	uM
N-[4-(3-chloro-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]but-2-ynamide	260897: Inhibition of erbB4 fusion protein expressed in baculovirus by ELISA	ic50	0.0005	uM
N-[(7S)-4-amino-6-methylidene-5-(4-phenoxyphenyl)-7,8-dihydropyrimido[5,4-b]pyrrolizin-7-yl]prop-2-enamide	1375524: Inhibition of recombinant human ErbB4 using Poly(Glu, Tyr) 4:1 as substrate after 1 hr by ELISA	ic50	0.0006	uM
1-[3-(4-amino-7-cyclopentylpyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl]-3-(2-methoxy-5-methylphenyl)urea	748805: Inhibition of human EGFR extracellular domain/TIE2 intracellular domain transfected in mouse NIH/3T3 cells assessed as phosphotyrosine level preincubated for 60 mins followed by EGF stimulation by DELFIA assay	ic50	0.0007	uM
N-[4-(3-bromo-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]-5-(4-methylpiperazin-1-yl)pent-2-ynamide	260897: Inhibition of erbB4 fusion protein expressed in baculovirus by ELISA	ic50	0.0008	uM
N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]quinazolin-6-yl]prop-2-enamide	2161300: Inhibition of ErbB4 (unknown origin) using poly(Glu-Tyr) at 4:1 ratio as substrate in presence of ATP incubated for 60 mins by ELISA	ic50	0.0008	uM
1-[3-(4-amino-7-cyclopentylpyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl]-3-(2-fluoro-5-methylphenyl)urea	748805: Inhibition of human EGFR extracellular domain/TIE2 intracellular domain transfected in mouse NIH/3T3 cells assessed as phosphotyrosine level preincubated for 60 mins followed by EGF stimulation by DELFIA assay	ic50	0.0009	uM
Afatinib	1664190: Inhibition of HER4 (unknown origin) in presence of radiolabelled gammaATP by radioisotope filter binding assay	ic50	0.0010	uM
N-[4-(3-chloro-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]-5-morpholin-4-ylpent-2-ynamide	260897: Inhibition of erbB4 fusion protein expressed in baculovirus by ELISA	ic50	0.0010	uM
N-[4-(3-bromo-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]-5-morpholin-4-ylpent-2-ynamide	260897: Inhibition of erbB4 fusion protein expressed in baculovirus by ELISA	ic50	0.0010	uM
(E)-N-[4-[(1-benzylindazol-5-yl)amino]-7-(2-methoxyethoxy)quinazolin-6-yl]-4-(dimethylamino)but-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0010	uM
N-[4-(3-chloro-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]-5-(4-methylpiperazin-1-yl)pent-2-ynamide	260897: Inhibition of erbB4 fusion protein expressed in baculovirus by ELISA	ic50	0.0012	uM
N-[4-(3-chloro-4-fluoroanilino)-7-[2-(6-methyl-6-azaspiro[2.5]octan-2-yl)ethoxy]quinolin-6-yl]prop-2-enamide	1664190: Inhibition of HER4 (unknown origin) in presence of radiolabelled gammaATP by radioisotope filter binding assay	ic50	0.0012	uM
1-[3-(4-amino-7-cyclopentylpyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl]-3-(2,4-dichlorophenyl)urea	748805: Inhibition of human EGFR extracellular domain/TIE2 intracellular domain transfected in mouse NIH/3T3 cells assessed as phosphotyrosine level preincubated for 60 mins followed by EGF stimulation by DELFIA assay	ic50	0.0012	uM
Zanubrutinib	1615370: Inhibition of human HER4 using poly[Glu:Tyr] (4:1) as substrate preincubated for 60 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by filter binding method	ic50	0.0016	uM
N-[4-[(3-bromo-1H-indol-5-yl)amino]quinazolin-6-yl]prop-2-enamide	1904485: Inhibition of HER4 (unknown origin)	ic50	0.0016	uM
N-[4-(3-bromoanilino)quinazolin-6-yl]prop-2-ynamide	260897: Inhibition of erbB4 fusion protein expressed in baculovirus by ELISA	ic50	0.0017	uM
N-[4-(3-chloro-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]-5-piperidin-1-ylpent-2-ynamide	260897: Inhibition of erbB4 fusion protein expressed in baculovirus by ELISA	ic50	0.0018	uM
6-[4-[(4-ethylpiperazin-1-yl)methyl]phenyl]-N-[(1R)-1-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine	710623: Inhibition of EGFR2	ic50	0.0020	uM
(E)-N-[4-[(1-benzylindazol-5-yl)amino]-7-(2-methoxyethoxy)quinazolin-6-yl]-4-pyrrolidin-1-ylbut-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0020	uM
(E)-N-[4-(4-phenoxyanilino)pyrido[3,4-d]pyrimidin-6-yl]-4-pyrrolidin-1-ylbut-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0020	uM
N-[4-[(3-bromo-1H-indol-5-yl)amino]quinazolin-6-yl]-3-chloropropanamide	1904485: Inhibition of HER4 (unknown origin)	ic50	0.0020	uM
N-[4-(3-chloro-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]hex-2-ynamide	260897: Inhibition of erbB4 fusion protein expressed in baculovirus by ELISA	ic50	0.0024	uM
5-fluoro-2-[5-[[(1R)-2-hydroxy-1-phenylethyl]amino]-3-(3-methyl-2H-indazol-5-yl)-2-pyridinyl]phenol	1450713: Inhibition of recombinant ErbB4 (unknown origin) using poly (Glu,Tyr) 4:1 as substrate after 60 mins by ELISA	ic50	0.0024	uM
Neratinib	624815: Binding constant for ERBB4 kinase domain	kd	0.0024	uM
(E)-N-[4-[(1-benzylindazol-5-yl)amino]-7-ethoxyquinazolin-6-yl]-4-(dimethylamino)but-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0030	uM
(E)-N-[4-[(1-benzylindazol-5-yl)amino]pyrido[3,4-d]pyrimidin-6-yl]-4-(dimethylamino)but-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0030	uM
(E)-4-(dimethylamino)-N-[4-(4-phenoxyanilino)pyrido[3,4-d]pyrimidin-6-yl]but-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0030	uM
(E)-N-[4-[(1-benzylindazol-5-yl)amino]-7-(2-methoxyethoxy)quinazolin-6-yl]-4-(4-methylpiperazin-1-yl)but-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0030	uM
(E)-N-[4-[4-(benzenesulfonamido)anilino]-7-ethoxyquinazolin-6-yl]-4-pyrrolidin-1-ylbut-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0030	uM
(E)-N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]pyrido[3,4-d]pyrimidin-6-yl]-4-(dimethylamino)but-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0030	uM
N-[5-[[5-chloro-4-(2-propan-2-ylsulfonylanilino)pyrimidin-2-yl]amino]-2-[2-(dimethylamino)ethyl-methylamino]-4-methoxyphenyl]prop-2-enamide	1584367: Inhibition of recombinant N-terminal GST-tagged human ErbB4 cytoplasmic domain expressed in baculovirus expression system by Z-LYTE assay	ic50	0.0030	uM
(E)-N-[7-methoxy-4-(4-phenoxyanilino)quinazolin-6-yl]-4-piperidin-1-ylbut-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0030	uM
7-[3-methyl-4-(4-methylpiperazin-1-yl)anilino]-3-phenyl-1-[(3S)-1-prop-2-enoylpyrrolidin-3-yl]-4H-pyrimido[4,5-d]pyrimidin-2-one	1053594: Inhibition of EGFR L851Q mutant (unknown origin)	ic50	0.0030	uM
1-[(3R)-3-[4-amino-3-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one	1481346: Inhibition of recombinant human N-terminal GST-tagged ERBB4 cytoplasmic domain (708 to 993 residues) expressed in baculovirus by Z’-LYTE assay	ic50	0.0032	uM
Mobocertinib	1935456: Inhibition of mouse EGFR L858R mutant stably expressed in mouse BaF3 cells assessed as cell viability incubated for 3 days by Cell Titer-Glo assay	ic50	0.0033	uM
5-(2-methylsulfonylpyrimidin-4-yl)-6-(3-phenylmethoxyphenyl)imidazo[2,1-b][1,3]thiazole	1772926: Inhibition of ErbB4 in human T47D cells assessed as suppression of neuregulin 1-induced autophosphorylation incubated for 90 mins by sandwich ELISA	ic50	0.0033	uM
2-methyl-N-[2-[3-[[2-(prop-2-enoylamino)acetyl]amino]anilino]pyrimidin-5-yl]-5-[[3-(trifluoromethyl)benzoyl]amino]benzamide	1155503: Inhibition of HER4 (unknown origin) after 1 hr by HTRF assay	ic50	0.0033	uM
(E)-N-[4-[(1-benzylindazol-5-yl)amino]-7-ethoxyquinazolin-6-yl]-4-(4-methylpiperazin-1-yl)but-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0040	uM
(E)-N-[4-[(1-benzylindazol-5-yl)amino]-7-ethoxyquinazolin-6-yl]-4-pyrrolidin-1-ylbut-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0040	uM
(E)-N-[4-[(1-benzylindazol-5-yl)amino]-7-ethoxyquinazolin-6-yl]-4-piperidin-1-ylbut-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0040	uM
(E)-N-[4-[(1-benzylindazol-5-yl)amino]-7-ethoxyquinazolin-6-yl]-4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]but-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0040	uM
(E)-N-[4-[(1-benzylindazol-5-yl)amino]pyrido[3,4-d]pyrimidin-6-yl]-4-pyrrolidin-1-ylbut-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0040	uM
(E)-4-(dimethylamino)-N-[4-[4-(pyridin-2-ylmethyl)anilino]pyrido[3,4-d]pyrimidin-6-yl]but-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0040	uM
(E)-N-[4-[4-(pyridin-2-ylmethyl)anilino]pyrido[3,4-d]pyrimidin-6-yl]-4-pyrrolidin-1-ylbut-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0040	uM
(E)-N-[4-[(1-benzylindazol-5-yl)amino]-7-ethoxyquinazolin-6-yl]-4-[(2S,6R)-2,6-dimethylpiperazin-1-yl]but-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0040	uM
(E)-N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-7-ethoxyquinazolin-6-yl]-4-pyrrolidin-1-ylbut-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0040	uM

CTD chemical–gene interactions

56 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	increases expression, increases reaction, affects cotreatment, decreases expression, decreases reaction	4
Valproic Acid	decreases expression, increases expression	4
Aflatoxin B1	decreases expression, decreases methylation	4
Arsenic Trioxide	increases expression	3
sodium arsenite	affects acetylation, affects methylation, decreases expression	2
Arsenic	affects expression, affects methylation	2
Doxorubicin	decreases expression, affects cotreatment, affects response to substance	2
Nickel	decreases expression	2
Tobacco Smoke Pollution	decreases expression, increases methylation	2
Tretinoin	decreases expression, increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
bisphenol A	increases methylation	1
trichostatin A	decreases expression	1
pyrrolidine dithiocarbamic acid	decreases reaction, increases cleavage	1
sulindac sulfide	affects cleavage	1
ochratoxin A	decreases expression	1
4-hydroxy-2-nonenal	decreases expression	1
oxophenylarsine	increases cleavage, increases phosphorylation	1
bisindolylmaleimide I	decreases reaction, increases cleavage	1
pervanadate	decreases reaction, increases cleavage	1
27-hydroxycholesterol	decreases expression	1
batimastat	decreases reaction, increases cleavage	1
CGP 52608	affects binding, increases reaction	1
6-(methylamino)pyrido(3,4-d)pyrimidine	decreases activity	1
monomethylarsonous acid	affects methylation, affects acetylation	1
ponatinib	decreases activity	1
Irinotecan	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1

ChEMBL screening assays

591 unique, capped per target: 579 binding, 8 admet, 4 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1034137	Binding	Inhibition of EGFR E746-A750del mutant at 3 uM	Discovery of substituted 4-(pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as potent and highly selective Rho kinase (ROCK-II) inhibitors. — J Med Chem
CHEMBL1963833	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: ERBB4	PubChem BioAssay data set
CHEMBL4023735	ADMET	Inhibition of recombinant human cytoplasmic GST-tagged ERBB4 expressed in baculovirus at 1 uM by Z’-LYTE assay	Discovery of GDC-0853: A Potent, Selective, and Noncovalent Bruton’s Tyrosine Kinase Inhibitor in Early Clinical Development. — J Med Chem

Cellosaurus cell lines

13 cell lines: 9 cancer cell line, 3 induced pluripotent stem cell, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_1726	SW684	Cancer cell line	Male
CVCL_B8FH	Abcam HCT 116 ERBB4 KO	Cancer cell line	Male
CVCL_B8VD	Abcam MCF-7 ERBB4 KO	Cancer cell line	Female
CVCL_B9HQ	Abcam A-549 ERBB4 KO	Cancer cell line	Male
CVCL_D9EH	Ubigene HEK293 ERBB4 KO	Transformed cell line	Female
CVCL_E0CS	Ubigene HeLa ERBB4 KO	Cancer cell line	Female
CVCL_E4W9	KOLF2.1J ERBB4 PTC PTC/PTC	Induced pluripotent stem cell	Male
CVCL_E5GM	SP-01-CL	Cancer cell line	Male
CVCL_E5GN	SP-01-OT-CL	Cancer cell line	Male
CVCL_E7KY	KOLF2.1J ERBB4 R927Q SNV/SNV	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00542412	PHASE4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	PHASE4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	PHASE4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	PHASE4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	PHASE4	RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT00021697	PHASE3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	PHASE3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	PHASE3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	PHASE3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00136110	PHASE3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	PHASE3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00372879	PHASE3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
NCT00415519	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III
NCT00424463	PHASE3	COMPLETED	Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00868166	PHASE3	COMPLETED	Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
NCT00965497	PHASE3	COMPLETED	Escitalopram (Lexapro) for Depression MS or ALS
NCT01016522	PHASE3	TERMINATED	Safety and Tolerability of the Ketogenic Diet in Amyotrophic Lateral Sclerosis (ALS)
NCT01160263	PHASE3	COMPLETED	Study of Dopamine and Serotonin Transporters in Patients With Amyotrophic Lateral Sclerosis and Controls
NCT01281189	PHASE3	COMPLETED	Phase 3 Study of Dexpramipexole in ALS
NCT01492686	PHASE3	COMPLETED	Phase 3 Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis
NCT01583088	PHASE3	TERMINATED	Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation
NCT01622088	PHASE3	TERMINATED	Phase 3 Extension Study of Dexpramipexole in ALS
NCT02496767	PHASE3	COMPLETED	Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
NCT02623699	PHASE3	COMPLETED	An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
NCT02936635	PHASE3	COMPLETED	A Study for Patients Who Completed VITALITY-ALS (CY 4031)
NCT03127267	PHASE3	RECRUITING	Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients
NCT03280056	PHASE3	COMPLETED	Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients
NCT03491462	PHASE3	COMPLETED	Arimoclomol in Amyotropic Lateral Sclerosis
NCT03505021	PHASE3	COMPLETED	Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
NCT03548311	PHASE3	COMPLETED	Clinical Trial of Ultra-high Dose Methylcobalamin for ALS
NCT03690791	PHASE3	UNKNOWN	Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease
NCT03800524	PHASE3	UNKNOWN	Safety and Efficacy of TUDCA as add-on Treatment in Patients Affected by ALS
NCT03836716	PHASE3	TERMINATED	Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial
NCT03948178	PHASE3	TERMINATED	Effects of Oral Levosimendan on Respiratory Function in Patients With Amyotrophic Lateral Sclerosis (ALS): Open-Label Extension
NCT04165824	PHASE3	COMPLETED	Safety Study of Oral Edaravone Administered in Subjects With ALS
NCT04248465	PHASE3	TERMINATED	An Efficacy and Safety Study of Ravulizumab in ALS Participants
NCT04569084	PHASE3	TERMINATED	Efficacy and Safety Study of Oral Edaravone Administered in Subjects With ALS