EPHB3

Chr 3

EPH receptor B3

Also known as: EK2, ETK2, HEK2, TYRO6

NCBI Gene: 2049 ENSG00000182580 UniProt: P54753 OMIM: 601839

Ephrin receptors and their ligands, the ephrins, mediate numerous developmental processes, particularly in the nervous system. Based on their structures and sequence relationships, ephrins are divided into the ephrin-A (EFNA) class, which are anchored to the membrane by a glycosylphosphatidylinositol linkage, and the ephrin-B (EFNB) class, which are transmembrane proteins. The Eph family of receptors are divided into two groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. Ephrin receptors make up the largest subgroup of the receptor tyrosine kinase (RTK) family. This gene encodes a receptor for ephrin-B family members. [provided by RefSeq, Mar 2010]

OMIM Research

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.38

Clinical Summary— EPHB3

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.22) despite low pLI — interpret in context.

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ClinVar Variants

101 VUS of 127 total submissions

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Clinical Trials

2 active or recruiting trials — 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

Moderate LoF intolerance

LoF Constraint?

0.38LOEUF

pLI 0.462

Z-score 4.86

OE 0.22 (0.14–0.38)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.73Z-score

OE missense 0.70 (0.64–0.75)

447 obs / 642.0 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.22 (0.14–0.38)

0≤0.351.4

Missense OE?0.70 (0.64–0.75)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 10 / 45.2Missense obs/exp: 447 / 642.0Syn Z: -0.70

This gene — mechanism propensity

0.6453th %ile

GOF

0.73top 25%

LOF

0.4038th %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

127 submitted variants in ClinVar

ClinVar

Classification Summary

VUS101

Likely Benign6

Benign3

101

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	101	0	0	101
Likely Benign	2	0	4	6
Benign	0	1	2	3
Total	103	1	6	110

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

View in ClinVar →

43 pathogenic / likely-pathogenic (of 44) ClinVar copy-number / structural variants overlap EPHB3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →