EPHA4

Chr 2

EPH receptor A4

Also known as: EK8, HEK8, SEK, TYRO1

NCBI Gene: 2043ENSG00000116106UniProt: P54764

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.

Summary from RefSeq, UniProt
Research Assistant →
1
Active trials
29
Pubs (1 yr)
2
P/LP submissions
—
P/LP missense
0.17
LOEUF· LoF intol.
—
Mechanism
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· 62 VUS of 100 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 OE0.08 (0.04–0.17)
0≤0.351.4
Missense OE0.66 (0.61–0.72)
0≤0.61.4
Synonymous OE1.02
0≤1.21.6
LoF obs/exp: 4 / 52.2Missense obs/exp: 377 / 571.0Syn Z: -0.19

ClinVar Variant Classifications

100 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2
VUS62
Likely Benign17
Benign4
2
Pathogenic
62
VUS
17
Likely Benign
4
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
2
0
2
Likely Pathogenic
0
0
0
0
0
VUS
1
55
4
2
62
Likely Benign
0
0
6
11
17
Benign
0
1
3
0
4
Total156151385

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

View in ClinVar →

Protein Context — Lollipop Plot

EPHA4 · protein map & ClinVar variants

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

Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
After Traumatic Brain Injury, EPHA4 Enhances Endoplasmic Reticulum Stress to Promote M1 Microglial Polarization Through the MAPK Signaling Pathway.
Tan Y et al.·Mediators Inflamm
2026Open Access
Repetitive trans-spinal magnetic stimulation improves motor function in rats with spinal cord injury and is associated with upregulation of EphA4 signaling pathway proteins.
Liu H et al.·Front Neurol
2026Open Access
Hematopoietic EphA4 deficiency alters microglial heterogeneity and improves chronic spatial memory after brain injury.
Soliman E et al.·Sci Rep
2025Open Access
Serum EphA4 is Associated with both Parenchymal Hematoma and Increased Blood-Brain Barrier Permeability after Ischemic Stroke.
Huang Y et al.·Neurocrit Care
2025
Comprehensive analysis of Ephrin ligand and receptor expression reveals exclusive domains during nephrogenesis for epha4/epha7 and efna3.
Le Bouffant R et al.·Int J Dev Biol
2025
Top 5 resultsSearch Europe PMC ↗

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