ROBO2

Chr 3AD

roundabout guidance receptor 2

Also known as: SAX3

NCBI Gene: 6092 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

The protein encoded by this gene belongs to the ROBO family, part of the immunoglobulin superfamily of proteins that are highly conserved from fly to human. The encoded protein is a transmembrane receptor for the slit homolog 2 protein and functions in axon guidance and cell migration. Mutations in this gene are associated with vesicoureteral reflux, characterized by the backward flow of urine from the bladder into the ureters or the kidney. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

431 VUS of 695 total submissions

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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 OE?0.08 (0.04–0.16)

0≤0.351.4

Missense OE?0.83 (0.78–0.89)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 6 / 74.5Missense obs/exp: 660 / 790.5Syn Z: -1.42

This gene — mechanism propensity

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 dom1

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

References

1.PMID 17357069 ↗

ClinVar Variant Classifications

695 submitted variants in ClinVar

ClinVar

Classification Summary

VUS431

Likely Benign116

Benign115

Conflicting23

431

VUS

116

Likely Benign

115

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	12	351	51	17	431
Likely Benign	1	20	28	67	116
Benign	0	9	96	10	115
Conflicting	—				23
Total	13	380	175	94	685

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 31) ClinVar copy-number / structural variants overlap ROBO2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →