ROBO2

Chr 3AD

roundabout guidance receptor 2

Also known as: SAX3

NCBI Gene: 6092ENSG00000185008UniProt: Q9HCK4

ROBO2 encodes a transmembrane receptor for SLIT proteins that functions in axon guidance and cell migration during neuronal development. Mutations cause vesicoureteral reflux, a genitourinary condition characterized by backward flow of urine from the bladder into the ureters or kidneys, with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI ~1.0, LOEUF 0.159), indicating intolerance to protein-truncating mutations.

Summary from RefSeq, OMIM, UniProt
Research Assistant →

Primary Disease Associations & Inheritance

Vesicoureteral reflux 2MIM #610878
AD
0
Active trials
27
Pubs (1 yr)
2
P/LP submissions
—
P/LP missense
0.16
LOEUF· LoF intol.
Multiple*
Mechanism· predicted
Clinical Summary— ROBO2
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
2 unique Pathogenic / Likely Pathogenic· 357 VUS of 500 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.16LOEUF
pLI 1.000
Z-score 7.36
OE 0.08 (0.04–0.16)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
1.65Z-score
OE missense 0.83 (0.78–0.89)
660 obs / 790.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.08 (0.04–0.16)
0≤0.351.4
Missense OE0.83 (0.78–0.89)
0≤0.61.4
Synonymous OE1.11
0≤1.21.6
LoF obs/exp: 6 / 74.5Missense obs/exp: 660 / 790.5Syn Z: -1.42
DN
0.5181th %ile
GOF
0.5169th %ile
LOF
0.71top 10%

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

LOFprediction above median · LOEUF 0.16
DN1 literature citation

Literature Evidence

DNWe investigated a man with a de novo translocation, 46,X,t(Y;3)(p11;p12)dn, who exhibits multiple congenital abnormalities, including severe bilateral VUR with ureterovesical junction defects. This translocation disrupts ROBO2, which encodes a transmembrane receptor for SLIT ligand, and produces domPMID:17357069

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

500 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1
Likely Pathogenic1
VUS357
Likely Benign77
Benign44
Conflicting10
1
Pathogenic
1
Likely Pathogenic
357
VUS
77
Likely Benign
44
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
1
0
1
Likely Pathogenic
0
0
1
0
1
VUS
9
318
21
9
357
Likely Benign
1
8
23
45
77
Benign
0
5
35
4
44
Conflicting
—10
Total103318158490

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

View in ClinVar →

Protein Context — Lollipop Plot

ROBO2 · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

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Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
ROBO2 Variants Associated With Atrial Septal Defect Define a Novel Regulatory Element.
Kim SW et al.·Circ Genom Precis Med
2026
Expression Significance of Serum Circular RNA CDYL and Circular RNA ROBO2 in Patients with Acute Myocardial Infarction and the Value of Their Combined Prediction for Major Adverse Cardiovascular Events.
Wang F et al.·Int J Gen Med
2025Open AccessCohort
Overexpression of miR-25 Downregulates the Expression of ROBO2 in Idiopathic Intellectual Disability.
Ordoñez-Razo RM et al.·Int J Mol Sci
2024Open Access
Islet architecture in adult mice is actively maintained by Robo2 expression in β cells.
Waters BJ et al.·Dev Biol
2024
INF2 and ROBO2 gene mutation in an Indian family with end stage renal failure and follow-up of renal transplantation.
Shah V et al.·Nephrology (Carlton)
2024Natural history
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients