The EFNB3 protein functions as a cell surface ligand for Eph receptors that mediates bidirectional signaling crucial for neuronal migration, axon guidance, and forebrain development, particularly in constraining axon orientation and inducing growth cone collapse. Mutations cause autosomal dominant intellectual disability with craniofacial dysmorphism and seizures, typically presenting in early childhood. This gene shows moderate constraint against loss-of-function variants (LOEUF 0.607), consistent with its role in neurodevelopment.

OMIMResearchSummary from UniProt
MultiplemechanismLOEUF 0.61
Clinical SummaryEFNB3
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.
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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint
0.61LOEUF
pLI 0.320
Z-score 2.54
OE 0.23 (0.110.61)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
1.57Z-score
OE missense 0.69 (0.590.79)
136 obs / 198.4 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.23 (0.110.61)
00.351.4
Missense OE0.69 (0.590.79)
00.61.4
Synonymous OE1.10
01.21.6
LoF obs/exp: 3 / 12.8Missense obs/exp: 136 / 198.4Syn Z: -0.68
DN
0.6161th %ile
GOF
0.72top 25%
LOF
0.4726th %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

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

EFNB3 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

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Clinical Literature
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