ERBB4
Chr 2ADerb-b2 receptor tyrosine kinase 4
Also known as: ALS19, HER4, p180erbB4
This gene encodes a tyrosine kinase that functions as a cell surface receptor for neuregulins and EGF family members, regulating development of the heart, central nervous system, and mammary gland through control of cell proliferation, differentiation, and migration. Mutations cause autosomal dominant amyotrophic lateral sclerosis 19. The gene is highly constrained against loss-of-function variation (pLI 0.999, LOEUF 0.265), indicating that haploinsufficiency is likely not tolerated in the general population.
Limited evidence — not for standalone diagnostic reporting
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Moderately missense-constrained (top ~2.5%)
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.
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
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
0 submitted variants in ClinVar
Protein Context — Lollipop Plot
ERBB4 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Disitamab Vedotin + Pyrotinib Versus THP in the First-line Treatment for HER2+ Advanced Breast Cancer Clinical Trial
RECRUITINGNeratinib and Everolimus, Palbociclib, or Trametinib in Treating Participants With Refractory and Advanced or Metastatic Solid Tumors With EGFR Mutation/Amplification, HER2 Mutation/Amplification, or HER3/4 Mutation or KRAS Mutation
ACTIVE NOT RECRUITINGBuilding Resilience at Schools: Emotional and Biological Assessment and Treatment of Traumatic Stress
RECRUITINGPatritumab Deruxtecan in Patients With Solid Tumor Harboring an NRG1 Fusion
RECRUITINGExternal Resources
Links to major genomics databases and tools