Amyotrophic lateral sclerosis type 19

Summary

Amyotrophic lateral sclerosis type 19 (MONDO:0014223) is a disease caused by ERBB4 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: ERBB4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 28

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	amyotrophic lateral sclerosis type 19
Mondo ID	MONDO:0014223
OMIM	615515
DOID	DOID:0060210
UMLS	C3715155
MedGen	811607
GARD	0015980
Is cancer (heuristic)	no

Also known as: ALS19 · amyotrophic lateral sclerosis 19 · amyotrophic lateral sclerosis caused by mutation in ERBB4 · amyotrophic lateral sclerosis type 19 · ERBB4 amyotrophic lateral sclerosis

Data availability: 28 ClinVar variants · 3 GenCC gene-disease records · 3 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › spinal cord disorder › anterior horn disorder › amyotrophic lateral sclerosis › familial amyotrophic lateral sclerosis › amyotrophic lateral sclerosis type 19

Related subtypes (29): amyotrophic lateral sclerosis type 1, frontotemporal dementia and/or amyotrophic lateral sclerosis 1, spinocerebellar ataxia type 2, amyotrophic lateral sclerosis type 15, frontotemporal dementia and/or amyotrophic lateral sclerosis 7, amyotrophic lateral sclerosis type 4, amyotrophic lateral sclerosis type 21, amyotrophic lateral sclerosis type 3, amyotrophic lateral sclerosis type 6, amyotrophic lateral sclerosis type 7, amyotrophic lateral sclerosis type 8, amyotrophic lateral sclerosis type 9, amyotrophic lateral sclerosis type 10, amyotrophic lateral sclerosis type 11, amyotrophic lateral sclerosis type 12, frontotemporal dementia and/or amyotrophic lateral sclerosis 6, amyotrophic lateral sclerosis type 18, amyotrophic lateral sclerosis type 20, frontotemporal dementia and/or amyotrophic lateral sclerosis 2, amyotrophic lateral sclerosis type 22, frontotemporal dementia and/or amyotrophic lateral sclerosis 3, frontotemporal dementia and/or amyotrophic lateral sclerosis 4, juvenile amyotrophic lateral sclerosis, amyotrophic lateral sclerosis type 23, frontotemporal dementia and/or amyotrophic lateral sclerosis 8, frontotemporal dementia and/or amyotrophic lateral sclerosis 5, amyotrophic lateral sclerosis 26 with or without frontotemporal dementia, amyotrophic lateral sclerosis 27, juvenile, amyotrophic lateral sclerosis 28

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

28 retrieved; paginated sample, class counts are floors:

17 uncertain significance, 5 conflicting classifications of pathogenicity, 4 benign, 1 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
64625	NM_005235.3(ERBB4):c.2780G>A (p.Arg927Gln)	ERBB4	Pathogenic	no assertion criteria provided
3896859	NM_005235.3(ERBB4):c.3183+2T>C	ERBB4	Likely pathogenic	criteria provided, single submitter
1563977	NM_005235.3(ERBB4):c.1972A>T (p.Ile658Phe)	ERBB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2689029	NM_005235.3(ERBB4):c.625A>T (p.Thr209Ser)	ERBB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
64626	NM_005235.3(ERBB4):c.3823C>T (p.Arg1275Trp)	ERBB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
770696	NM_005235.3(ERBB4):c.1122T>G (p.His374Gln)	ERBB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
873194	NM_005235.3(ERBB4):c.3334C>T (p.Arg1112Cys)	ERBB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030895	NM_005235.3(ERBB4):c.2192C>T (p.Thr731Met)	ERBB4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1333937	NM_005235.3(ERBB4):c.2443A>G (p.Ile815Val)	ERBB4	Uncertain significance	criteria provided, single submitter
1333938	NM_005235.3(ERBB4):c.508C>T (p.Pro170Ser)	ERBB4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1414531	NM_005235.3(ERBB4):c.2674A>G (p.Ile892Val)	ERBB4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1683524	NM_005235.3(ERBB4):c.3305T>C (p.Phe1102Ser)	ERBB4	Uncertain significance	criteria provided, single submitter
1933291	NM_005235.3(ERBB4):c.891T>G (p.Phe297Leu)	ERBB4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1983403	NM_005235.3(ERBB4):c.472G>A (p.Ala158Thr)	ERBB4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2177171	NM_005235.3(ERBB4):c.3878G>A (p.Gly1293Asp)	ERBB4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2195668	NM_005235.3(ERBB4):c.1027A>T (p.Met343Leu)	ERBB4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2431554	NM_005235.3(ERBB4):c.2525G>A (p.Arg842Gln)	ERBB4	Uncertain significance	criteria provided, single submitter
2441280	NM_005235.3(ERBB4):c.1885A>G (p.Thr629Ala)	ERBB4	Uncertain significance	criteria provided, single submitter
2441281	NM_005235.3(ERBB4):c.1289+1G>C	ERBB4	Uncertain significance	criteria provided, single submitter
2500181	NM_005235.3(ERBB4):c.2487+8_2487+11del	ERBB4	Uncertain significance	criteria provided, single submitter
3391080	NM_005235.3(ERBB4):c.826G>A (p.Glu276Lys)	ERBB4	Uncertain significance	criteria provided, single submitter
3779622	NM_005235.3(ERBB4):c.329T>G (p.Leu110Arg)	ERBB4	Uncertain significance	criteria provided, single submitter
3779623	NM_005235.3(ERBB4):c.3255_3258del (p.Ser1086fs)	ERBB4	Uncertain significance	criteria provided, single submitter
4078616	NM_005235.3(ERBB4):c.3835G>A (p.Ala1279Thr)	ERBB4	Uncertain significance	criteria provided, single submitter
1178058	NM_005235.3(ERBB4):c.2202+15A>G	ERBB4	Benign	criteria provided, multiple submitters, no conflicts
1210000	NM_005235.3(ERBB4):c.1490-15T>C	ERBB4	Benign	criteria provided, multiple submitters, no conflicts
1265970	NM_005235.3(ERBB4):c.1947-18dup	ERBB4	Benign	criteria provided, multiple submitters, no conflicts
769264	NM_005235.3(ERBB4):c.884-7del	ERBB4	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ERBB4	Strong	Autosomal dominant	amyotrophic lateral sclerosis type 19	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ERBB4	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
ERBB4	Orphanet:803	Amyotrophic lateral sclerosis

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ERBB4	HGNC:3432	ENSG00000178568	Q15303	Receptor tyrosine-protein kinase erbB-4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ERBB4	Receptor tyrosine-protein kinase erbB-4	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 prolife…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ERBB4	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cranial nerve II	1
endothelial cell	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ERBB4	226	broad	marker	endothelial cell, secondary oocyte, cranial nerve II

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ERBB4	4,325

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ERBB4	Q15303	14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Downregulation of ERBB4 signaling	1	1142.0×	0.004	ERBB4
PI3K events in ERBB4 signaling	1	1038.2×	0.004	ERBB4
ERBB2 Activates PTK6 Signaling	1	815.7×	0.004	ERBB4
SHC1 events in ERBB4 signaling	1	713.8×	0.004	ERBB4
ERBB2 Regulates Cell Motility	1	713.8×	0.004	ERBB4
PI3K events in ERBB2 signaling	1	671.8×	0.004	ERBB4
GRB2 events in ERBB2 signaling	1	634.4×	0.004	ERBB4
SHC1 events in ERBB2 signaling	1	475.8×	0.004	ERBB4
Long-term potentiation	1	475.8×	0.004	ERBB4
Signaling by ERBB2 TMD/JMD mutants	1	475.8×	0.004	ERBB4
Signaling by ERBB2 KD Mutants	1	423.0×	0.004	ERBB4
Downregulation of ERBB2 signaling	1	380.7×	0.004	ERBB4
Signaling by ERBB2	1	346.1×	0.004	ERBB4
Nuclear signaling by ERBB4	1	346.1×	0.004	ERBB4
Signaling by ERBB4	1	271.9×	0.005	ERBB4
Constitutive Signaling by Aberrant PI3K in Cancer	1	126.9×	0.010	ERBB4
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	96.8×	0.012	ERBB4
Estrogen-dependent gene expression	1	75.6×	0.015	ERBB4
PIP3 activates AKT signaling	1	66.8×	0.016	ERBB4
RAF/MAP kinase cascade	1	61.1×	0.016	ERBB4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
central nervous system morphogenesis	1	8426.0×	0.002	ERBB4
establishment of planar polarity involved in nephron morphogenesis	1	8426.0×	0.002	ERBB4
cardiac muscle tissue regeneration	1	4213.0×	0.002	ERBB4
olfactory bulb interneuron differentiation	1	3370.4×	0.002	ERBB4
ERBB4 signaling pathway	1	2808.7×	0.002	ERBB4
ERBB2-ERBB4 signaling pathway	1	2808.7×	0.002	ERBB4
ERBB4-ERBB4 signaling pathway	1	2407.4×	0.002	ERBB4
mitochondrial fragmentation involved in apoptotic process	1	1404.3×	0.003	ERBB4
negative regulation of neuron migration	1	1404.3×	0.003	ERBB4
mammary gland epithelial cell differentiation	1	1203.7×	0.003	ERBB4
mammary gland alveolus development	1	991.3×	0.004	ERBB4
neurotransmitter receptor localization to postsynaptic specialization membrane	1	802.5×	0.004	ERBB4
positive regulation of protein localization to cell surface	1	766.0×	0.004	ERBB4
positive regulation of tyrosine phosphorylation of STAT protein	1	732.7×	0.004	ERBB4
positive regulation of cardiac muscle cell proliferation	1	624.1×	0.004	ERBB4
embryonic pattern specification	1	543.6×	0.005	ERBB4
positive regulation of receptor signaling pathway via JAK-STAT	1	432.1×	0.005	ERBB4
lactation	1	421.3×	0.005	ERBB4
peptidyl-tyrosine phosphorylation	1	421.3×	0.005	ERBB4
neural crest cell migration	1	337.0×	0.006	ERBB4
cellular response to epidermal growth factor stimulus	1	318.0×	0.006	ERBB4
cell fate commitment	1	295.6×	0.006	ERBB4
cell surface receptor signaling pathway via JAK-STAT	1	290.6×	0.006	ERBB4
positive regulation of protein phosphorylation	1	276.3×	0.006	ERBB4
epidermal growth factor receptor signaling pathway	1	247.8×	0.007	ERBB4
positive regulation of epithelial cell proliferation	1	244.2×	0.007	ERBB4
synapse assembly	1	230.8×	0.007	ERBB4
cell surface receptor protein tyrosine kinase signaling pathway	1	173.7×	0.009	ERBB4
regulation of cell migration	1	157.5×	0.009	ERBB4
protein autophosphorylation	1	145.3×	0.010	ERBB4

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ERBB4	MOBOCERTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ERBB4	47	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOBOCERTINIB	4	ERBB4
AFATINIB	4	ERBB4
FEDRATINIB	4	ERBB4
NERATINIB	4	ERBB4
IBRUTINIB	4	ERBB4
AFATINIB DIMALEATE	4	ERBB4
DACOMITINIB	4	ERBB4
DACOMITINIB ANHYDROUS	4	ERBB4
VANDETANIB	4	ERBB4
BOSUTINIB	4	ERBB4
BRIGATINIB	4	ERBB4
ACALABRUTINIB	4	ERBB4
ZANUBRUTINIB	4	ERBB4
TIRABRUTINIB	4	ERBB4
RITLECITINIB	4	ERBB4
DASATINIB	4	ERBB4
ERLOTINIB	4	ERBB4
LAPATINIB	4	ERBB4
MIDOSTAURIN	4	ERBB4
GEFITINIB	4	ERBB4
CANERTINIB	3	ERBB4
EVOBRUTINIB	3	ERBB4
ALVOCIDIB	3	ERBB4
REMIBRUTINIB	3	ERBB4
ALISERTIB	3	ERBB4
CEDIRANIB	3	ERBB4
CANERTINIB DIHYDROCHLORIDE	3	ERBB4
LESTAURTINIB	3	ERBB4
AEE-788	2	ERBB4
FORETINIB	2	ERBB4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ERBB4	591	Binding:579, ADMET:8, Functional:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ERBB4	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
ERBB4	591

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MOBOCERTINIB	4	ERBB4
AFATINIB	4	ERBB4
FEDRATINIB	4	ERBB4
NERATINIB	4	ERBB4
IBRUTINIB	4	ERBB4
AFATINIB DIMALEATE	4	ERBB4
DACOMITINIB	4	ERBB4
DACOMITINIB ANHYDROUS	4	ERBB4
VANDETANIB	4	ERBB4
BOSUTINIB	4	ERBB4
BRIGATINIB	4	ERBB4
ACALABRUTINIB	4	ERBB4
ZANUBRUTINIB	4	ERBB4
TIRABRUTINIB	4	ERBB4
RITLECITINIB	4	ERBB4
DASATINIB	4	ERBB4
ERLOTINIB	4	ERBB4
LAPATINIB	4	ERBB4
MIDOSTAURIN	4	ERBB4
GEFITINIB	4	ERBB4
CANERTINIB	3	ERBB4
EVOBRUTINIB	3	ERBB4
ALVOCIDIB	3	ERBB4
REMIBRUTINIB	3	ERBB4
ALISERTIB	3	ERBB4
CEDIRANIB	3	ERBB4
CANERTINIB DIHYDROCHLORIDE	3	ERBB4
LESTAURTINIB	3	ERBB4
AEE-788	2	ERBB4
FORETINIB	2	ERBB4

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ERBB4
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.