ERBB4

Chr 2

erb-b2 receptor tyrosine kinase 4

Also known as: ALS19, HER4, p180erbB4

NCBI Gene: 2066ENSG00000178568UniProt: Q15303

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. [provided by RefSeq, Jul 2008]

GeneReviewsResearchGenerating clinical summary…
MultiplemechanismLOEUF 0.27
Clinical Summary— ERBB4
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Gene-Disease Validity (ClinGen)
amyotrophic lateral sclerosis type 19 · ADLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
10 unique Pathogenic / Likely Pathogenic· 345 VUS of 761 total submissions
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Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — ERBB4
Authoritative clinical overview · Recommended first read
Open GeneReview ↗
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?
0.27LOEUF
pLI 0.999
Z-score 6.63
OE 0.16 (0.10–0.27)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?
2.01Z-score
OE missense 0.79 (0.74–0.85)
576 obs / 728.7 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?
LoF OE?0.16 (0.10–0.27)
0≤0.351.4
Missense OE?0.79 (0.74–0.85)
0≤0.61.4
Synonymous OE?1.18
0≤1.21.6
LoF obs/exp: 12 / 73.3Missense obs/exp: 576 / 728.7Syn Z: -2.23

This gene — mechanism propensity

DN
0.5673th %ile
GOF
0.74top 25%
LOF
0.50top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 70% of P/LP variants are LoF · LOEUF 0.27
GOFprediction above median
DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNThe predicted mutant protein is likely to function similarly to an engineered dominant-negative ERBB4 (DN-ErbB4), which causes defects in neuronal migration and synaptic neurotransmission.1
LOFThe severe clinical consequences in our patient demonstrate that the haploinsufficiency of ERBB4 is crucial for intellectual and cognitive function.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

  1. 1.PMID 18369103 ↗
  2. 2.PMID 23633123 ↗

ClinVar Variant Classifications

761 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3
Likely Pathogenic7
VUS345
Likely Benign239
Benign116
Conflicting12
3
Pathogenic
7
Likely Pathogenic
345
VUS
239
Likely Benign
116
Benign
12
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
1
0
0
3
Likely Pathogenic
5
2
0
0
7
VUS
11
307
23
4
345
Likely Benign
0
8
95
136
239
Benign
0
0
106
10
116
Conflicting
—12
Total18318224150722

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

22 pathogenic / likely-pathogenic (of 41) ClinVar copy-number / structural variants overlap ERBB4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

ERBB4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients