ROBO4

Chr 11AD

roundabout guidance receptor 4

Also known as: AOVD3, ECSM4, MRB

NCBI Gene: 54538 ENSG00000154133 UniProt: Q8WZ75 OMIM: 607528

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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Predicted to enable cell-cell adhesion mediator activity. Involved in angiogenesis and establishment of endothelial barrier. Located in extracellular exosome. Implicated in aortic valve disease 3. Biomarker of pre-eclampsia and thyroid gland carcinoma. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Aortic valve disease 3MIM #618496

Clinical highlights

Gene–disease validity (ClinGen)

Moderate · aortic valve disease 3 · AD · ClinGen 2025

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

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P/LP submissions

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P/LP missense

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LOEUF

LOF*

Mechanism· G2P

Some data sources returned errors (1)

gnomad: Error: gnomAD API error: 400

Population Genetics & Constraint

gnomAD

Constraint data not available from gnomAD.

Background carrier burden — how many people carry a rare variant somewhere in ROBO4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 32

1,424 rare PASS variants

Rare truncating (LoF)

1 in 540

198 rare PASS variants

Rare synonymous (reference)

1 in 64

529 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ROBO4. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 45	1 in 640
South Asian	~43k	1 in 28	1 in 310
Remaining (unassigned)	~30k	1 in 28	1 in 480
European (Finnish)	~27k	1 in 140	1 in 1,500
Admixed American	~22k	1 in 34	1 in 320
African / African American	~21k	1 in 28	1 in 850
East Asian	~20k	1 in 30	1 in 880
Ashkenazi Jewish	~13k	1 in 86	≈ 1 in 3,900
Middle Eastern	~2,884	1 in 32	≈ 1 in 690

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 18 coding exons well covered in gnomAD exomes and genomes.? see exons ↓