ERBB4

Chr 2AD

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]

Primary Disease Associations & Inheritance

Amyotrophic lateral sclerosis 19MIM #615515
AD
553
ClinVar variants
28
Pathogenic / LP
1.00
pLI score· haploinsufficient
5
Active trials
Clinical Summary— ERBB4
🧬
Gene-Disease Validity (ClinGen)
amyotrophic lateral sclerosis type 19 · ADLimited

Limited evidence — not for standalone diagnostic reporting

⚡
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.
📋
ClinVar Variants
28 Pathogenic / Likely Pathogenic· 276 VUS of 553 total submissions
💊
Clinical Trials
5 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.16 (0.10–0.27)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.79 (0.74–0.85)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.18
0≤1.21.6
LoF obs/exp: 12 / 73.3Missense obs/exp: 576 / 728.7Syn Z: -2.23

ClinVar Variant Classifications

553 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20
Likely Pathogenic8
VUS276
Likely Benign207
Benign33
Conflicting9
20
Pathogenic
8
Likely Pathogenic
276
VUS
207
Likely Benign
33
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
19
0
20
Likely Pathogenic
4
2
2
0
8
VUS
6
233
34
3
276
Likely Benign
0
7
85
115
207
Benign
0
0
24
9
33
Conflicting
—9
Total10243164127553

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

View 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.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Amyotrophic lateral sclerosis 19

MIM #615515

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — ERBB4
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Serial single-cell genomics reveals convergent subclonal evolution of resistance as early-stage breast cancer patients progress on endocrine plus CDK4/6 therapy.
Griffiths JI et al.·Nat Cancer
2021Cohort
Molecular features and clinical implications of the heterogeneity in Chinese patients with HER2-low breast cancer.
Dai LJ et al.·Nat Commun
2023Cohort
The role of the neuregulin 1-ErbB4 signaling pathway in neurological disorders.
Ding Y et al.·J Physiol Pharmacol
2024Review
Cardiac Pressure Overload Decreases ETV1 Expression in the Left Atrium, Contributing to Atrial Electrical and Structural Remodeling.
Yamaguchi N et al.·Circulation
2021Functional
Human Genetics of Hypoplastic Left Heart Syndrome.
Pfitzer C et al.·Adv Exp Med Biol
2024
Impairments of GABAergic transmission in hippocampus mediate increased susceptibility of epilepsy in the early stage of Alzheimer's disease.
Mao R et al.·Cell Commun Signal
2024
Oncogenes in melanoma: an update.
Kunz M·Eur J Cell Biol
2014Review
ERBB4 and Multiple MicroRNAs That Target ERBB4 Participate in Pregnancy-Related Cardiomyopathy.
Feyen E et al.·Circ Heart Fail
2021
ErbB4 affects Th1/Th17 cell differentiation and promotes psoriasis progression.
Tang R et al.·Cell Mol Biol (Noisy-le-grand)
2023
Neuregulin signaling pathway in smoking behavior.
Gupta R et al.·Transl Psychiatry
2017
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
HER2-positive Metastatic Breast CancerFirst-line Treatment

Disitamab Vedotin + Pyrotinib Versus THP in the First-line Treatment for HER2+ Advanced Breast Cancer Clinical Trial

RECRUITING
NCT06278870Phase PHASE3Sun Yat-Sen Memorial Hospital of Sun Yat-Sen UniversityStarted 2023-09-06
disitamab vedotinPyrotinibtrastuzumab
Advanced Malignant Solid NeoplasmEGFR Gene AmplificationEGFR Gene Mutation

Neratinib 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 RECRUITING
NCT03065387Phase PHASE1M.D. Anderson Cancer CenterStarted 2017-10-31
EverolimusNeratinibPalbociclib
Post Traumatic Stress DisorderComplex Posttraumatic Stress DisorderStress

Building Resilience at Schools: Emotional and Biological Assessment and Treatment of Traumatic Stress

RECRUITING
NCT05701111Phase NAStanford UniversityStarted 2024-02-23
Start with the Heart StudentsStart with the Heart TeachersCue Centered Therapy Counselors
Advanced Breast CancerMetastatic Breast Cancer

HCQ+ADC vs ADC in the Treatment of Advanced Breast Cancer

RECRUITING
NCT06328387Phase PHASE1, PHASE2Sun Yat-Sen Memorial Hospital of Sun Yat-Sen UniversityStarted 2024-01-29
HydroxychloroquineSacituzumab GovitecanTrastuzumab Deruxtecan
Solid Tumor, Adult

Patritumab Deruxtecan in Patients With Solid Tumor Harboring an NRG1 Fusion

RECRUITING
NCT06383884Phase PHASE2Samsung Medical CenterStarted 2024-08-13
Patritumab Deruxtecan

External Resources

Links to major genomics databases and tools