ROBO1

Chr 3ARAD

roundabout guidance receptor 1

Also known as: CPHD8, DUTT1, NORS, NYS8, SAX3

NCBI Gene: 6091 ENSG00000169855 UniProt: Q9Y6N7 OMIM: 602430

The protein functions as a receptor for SLIT1 and SLIT2 that mediates axonal navigation and neuronal migration during brain development, particularly guiding axons at the ventral midline of the neural tube. Mutations cause congenital nystagmus, neurooculorenal syndrome, and combined or isolated pituitary hormone deficiency with both autosomal recessive and autosomal dominant inheritance patterns reported. The gene is highly constrained against loss-of-function mutations (LOEUF 0.597), reflecting its critical role in nervous system development.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

Bilateral symmetric nervous systems have special midline structures that establish a partition between the two mirror image halves. Some axons project toward and across the midline in response to long-range chemoattractants emanating from the midline. The product of this gene is a member of the immunoglobulin gene superfamily and encodes an integral membrane protein that functions in axon guidance and neuronal precursor cell migration. This receptor is activated by SLIT-family proteins, resulting in a repulsive effect on glioma cell guidance in the developing brain. A related gene is located at an adjacent region on chromosome 3. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAR/ADLOEUF 0.603 OMIM phenotypes

Clinical Summary— ROBO1

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Gene-Disease Validity (ClinGen)

congenital heart disease · ARLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

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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

51 unique Pathogenic / Likely Pathogenic· 398 VUS of 747 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ROBO1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.60LOEUF

pLI 0.000

Z-score 4.72

OE 0.46 (0.36–0.60)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.07Z-score

OE missense 0.90 (0.85–0.95)

825 obs / 916.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.46 (0.36–0.60)

0≤0.351.4

Missense OE?0.90 (0.85–0.95)

0≤0.61.4

Synonymous OE?1.17

0≤1.21.6

LoF obs/exp: 41 / 89.1Missense obs/exp: 825 / 916.3Syn Z: -2.45

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateROBO1-related neurooculorenal syndromeLOFAR

This gene — mechanism propensity

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

0.7133th %ile

GOF

0.6638th %ile

LOF

0.4528th %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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

747 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic16

Likely Pathogenic35

VUS398

Likely Benign201

Benign45

Conflicting14

Pathogenic

Likely Pathogenic

398

VUS

201

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	15	1	0	0	16
Likely Pathogenic	33	1	1	0	35
VUS	3	377	16	2	398
Likely Benign	1	18	66	116	201
Benign	0	7	18	20	45
Conflicting	—				14
Total	52	404	101	138	709

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap ROBO1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →