ROBO4
Chr 11ADroundabout guidance receptor 4
Also known as: AOVD3, ECSM4, MRB
The ROBO4 protein functions as a receptor for Slit proteins and maintains endothelial barrier organization, playing a critical role in angiogenesis and vascular patterning. Mutations cause aortic valve disease 3, which follows autosomal dominant inheritance. The gene shows minimal constraint against loss-of-function variants (very low pLI score), suggesting the cardiovascular phenotype may involve specific functional alterations rather than simple protein loss.
Primary Disease Associations & Inheritance
Moderate evidence — consider for supplementary testing
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Mild missense constraint
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.
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
200 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 11 | 0 | 11 |
Likely Pathogenic | 2 | 1 | 3 | 0 | 6 |
VUS | 3 | 126 | 5 | 0 | 134 |
Likely Benign | 0 | 10 | 1 | 6 | 17 |
Benign | 0 | 4 | 1 | 4 | 9 |
Conflicting | — | 3 | |||
| Total | 5 | 141 | 21 | 10 | 180 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
ROBO4 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools