ROBO2

Chr 3AD

roundabout guidance receptor 2

ENSG00000185008 UniProt: Q9HCK4 OMIM: 602431

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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismADLOEUF 0.161 OMIM phenotype

Clinical Summary— ROBO2

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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.

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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

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.