ERBB4

Chr 2

erb-b2 receptor tyrosine kinase 4

Also known as: ALS19, HER4, p180erbB4

NCBI Gene: 2066 ENSG00000178568 UniProt: Q15303

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.

ResearchSummary from RefSeq, OMIM, UniProt

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]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtAmyotrophic lateral sclerosis 19

Clinical highlights

Gene–disease validity (ClinGen)

Limited · amyotrophic lateral sclerosis type 19 · AD · ClinGen 2021

not for standalone diagnostic reporting

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

218

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.27

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in ERBB4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 70

1,455 rare PASS variants

Rare truncating (LoF)

1 in 4,000

75 rare PASS variants

Rare synonymous (reference)

1 in 86

636 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ERBB4. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 79	1 in 4,700
South Asian	~43k	1 in 50	1 in 3,300
Remaining (unassigned)	~30k	1 in 62	≈ 1 in 10,000
European (Finnish)	~27k	1 in 180	≈ 1 in 6,700
Admixed American	~22k	1 in 54	1 in 2,800
African / African American	~21k	1 in 45	1 in 1,900
East Asian	~20k	1 in 55	1 in 1,300
Ashkenazi Jewish	~13k	1 in 460	none seen
Middle Eastern	~2,884	1 in 64	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 21 of 28 coding exons well covered in gnomAD exomes; exons 8, 10, 11, 19, 22 and 2 more marginal. Genomes: all 28.? see exons ↓