EPHA4

Chr 2

EPH receptor A4

Also known as: EK8, HEK8, SEK, TYRO1

NCBI Gene: 2043 ENSG00000116106 UniProt: P54764 OMIM: 602188

EPHA4 encodes a receptor tyrosine kinase that binds ephrin ligands and regulates axonal guidance, synaptic plasticity, and nervous system development through control of cell adhesion and morphology. Mutations cause autosomal dominant amyotrophic lateral sclerosis and autosomal recessive developmental and epileptic encephalopathy with microcephaly. This gene is highly constrained against loss-of-function variation, indicating that EPHA4 function is essential for normal development.

OMIM ResearchSummary from RefSeq, UniProt

This gene belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. EPH and EPH-related receptors have been implicated in mediating developmental events, particularly in the nervous system. Receptors in the EPH subfamily typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2015]

OMIM ResearchGenerating clinical summary…

LOEUF 0.17

Clinical Summary— EPHA4

⚡

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

2 unique Pathogenic / Likely Pathogenic· 157 VUS of 301 total submissions

💊

Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.17LOEUF

pLI 1.000

Z-score 6.18

OE 0.08 (0.04–0.17)

Highly constrained

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

Missense Constraint?

2.89Z-score

OE missense 0.66 (0.61–0.72)

377 obs / 571.0 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.08 (0.04–0.17)

0≤0.351.4

Missense OE?0.66 (0.61–0.72)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 4 / 52.2Missense obs/exp: 377 / 571.0Syn Z: -0.19

ClinVar Variant Classifications

301 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic2

VUS157

Likely Benign103

Benign22

Conflicting2

Likely Pathogenic

157

VUS

103

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	1	1	0	0	2
VUS	4	146	5	2	157
Likely Benign	0	2	35	66	103
Benign	0	2	9	11	22
Conflicting	—				2
Total	5	151	49	79	286

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

View in ClinVar →

31 pathogenic / likely-pathogenic (of 37) ClinVar copy-number / structural variants overlap EPHA4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →