EPHA3

Chr 3

EPH receptor A3

Also known as: EK4, ETK, ETK1, HEK, HEK4, TYRO4

NCBI Gene: 2042 ENSG00000044524 UniProt: P29320 OMIM: 179611

EPHA3 encodes a receptor tyrosine kinase that binds ephrin-A ligands and regulates cell-cell adhesion, cytoskeletal organization, and cell migration, with key roles in retinotectal neuronal mapping and neuromuscular circuit development. Currently, no established Mendelian diseases have been definitively linked to EPHA3 mutations in the clinical literature. The gene is involved in nervous system development and may have roles in cardiac development through regulation of epithelial-to-mesenchymal transition.

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. This gene encodes a protein that binds ephrin-A ligands. Two alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.53

Clinical Summary— EPHA3

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

82 VUS of 106 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.53LOEUF

pLI 0.000

Z-score 4.25

OE 0.36 (0.24–0.53)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.65Z-score

OE missense 0.92 (0.86–0.99)

503 obs / 545.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.36 (0.24–0.53)

0≤0.351.4

Missense OE?0.92 (0.86–0.99)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 18 / 50.6Missense obs/exp: 503 / 545.9Syn Z: -0.94

This gene — mechanism propensity

0.76top 25%

GOF

0.76top 25%

LOF

0.2777th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

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.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

106 submitted variants in ClinVar

ClinVar

Classification Summary

VUS82

Likely Benign11

Benign6

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	82	0	0	82
Likely Benign	4	1	6	11
Benign	1	0	5	6
Total	87	1	11	99

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

View in ClinVar →

8 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap EPHA3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →