ROBO3

Chr 11AR

roundabout guidance receptor 3

Also known as: HGPPS, HGPPS1, HGPS, RBIG1, RIG1

NCBI Gene: 64221 ENSG00000154134 UniProt: Q96MS0 OMIM: 608630

The ROBO3 protein is a transmembrane receptor that guides commissural axons across the midline during neural tube development by regulating responses to multiple guidance cues including NELL2, SLIT proteins, and Netrin-1. Mutations cause horizontal gaze palsy with progressive scoliosis, an autosomal recessive disorder with congenital absence of horizontal eye movements and progressive scoliosis due to failure of corticospinal and somatosensory tracts to cross at the medulla. This gene is extremely intolerant to loss-of-function variants, reflecting its critical role in early nervous system development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene is a member of the Roundabout (ROBO) gene family that controls neurite outgrowth, growth cone guidance, and axon fasciculation. ROBO proteins are a subfamily of the immunoglobulin transmembrane receptor superfamily. SLIT proteins 1-3, a family of secreted chemorepellants, are ligands for ROBO proteins and SLIT/ROBO interactions regulate myogenesis, leukocyte migration, kidney morphogenesis, angiogenesis, and vasculogenesis in addition to neurogenesis. This gene, ROBO3, has a putative extracellular domain with five immunoglobulin (Ig)-like loops and three fibronectin (Fn) type III motifs, a transmembrane segment, and a cytoplasmic tail with three conserved signaling motifs: CC0, CC2, and CC3 (CC for conserved cytoplasmic). Unlike other ROBO family members, ROBO3 lacks motif CC1. The ROBO3 gene regulates axonal navigation at the ventral midline of the neural tube. In mouse, loss of Robo3 results in a complete failure of commissural axons to cross the midline throughout the spinal cord and the hindbrain. Mutations ROBO3 result in horizontal gaze palsy with progressive scoliosis (HGPPS); an autosomal recessive disorder characterized by congenital absence of horizontal gaze, progressive scoliosis, and failure of the corticospinal and somatosensory axon tracts to cross the midline in the medulla. [provided by RefSeq, May 2019]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.711 OMIM phenotype

Clinical Summary— ROBO3

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Gene-Disease Validity (ClinGen)

gaze palsy, familial horizontal, with progressive scoliosis 1 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

42 unique Pathogenic / Likely Pathogenic· 285 VUS of 442 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.71LOEUF

pLI 0.000

Z-score 3.48

OE 0.54 (0.41–0.71)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.61Z-score

OE missense 0.94 (0.88–1.00)

743 obs / 791.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.54 (0.41–0.71)

0≤0.351.4

Missense OE?0.94 (0.88–1.00)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 35 / 65.4Missense obs/exp: 743 / 791.1Syn Z: 1.35

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveROBO3-related familial horizontal gaze palsy with progressive scoliosisLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.76top 25%

GOF

0.73top 25%

LOF

0.3745th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

442 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic18

Likely Pathogenic24

VUS285

Likely Benign51

Benign30

Conflicting20

Pathogenic

Likely Pathogenic

285

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	18	0	0	0	18
Likely Pathogenic	7	17	0	0	24
VUS	0	261	13	11	285
Likely Benign	0	12	10	29	51
Benign	2	11	7	10	30
Conflicting	—				20
Total	27	301	30	50	428

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

View in ClinVar →

61 pathogenic / likely-pathogenic (of 65) ClinVar copy-number / structural variants overlap ROBO3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →