ROBO3

Summary

ROBO3 (roundabout guidance receptor 3, HGNC:13433) is a protein-coding gene on chromosome 11q24.2, encoding Roundabout homolog 3 (Q96MS0). Receptor involved in axon guidance during development.

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.

Source: NCBI Gene 64221 — RefSeq curated summary.

At a glance

• Gene–disease (curated): gaze palsy, familial horizontal, with progressive scoliosis 1 (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 413 total — 15 pathogenic, 21 likely-pathogenic
• Phenotypes (HPO): 33
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_022370

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13433
Approved symbol	ROBO3
Name	roundabout guidance receptor 3
Location	11q24.2
Locus type	gene with protein product
Status	Approved
Aliases	RBIG1, FLJ21044, HGPS
Ensembl gene	ENSG00000154134
Ensembl biotype	protein_coding
OMIM	608630
Entrez	64221

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 11 retained_intron, 7 protein_coding_CDS_not_defined, 3 protein_coding

ENST00000397801, ENST00000524971, ENST00000525304, ENST00000525448, ENST00000525482, ENST00000526551, ENST00000527196, ENST00000527245, ENST00000528068, ENST00000528144, ENST00000528820, ENST00000529658, ENST00000530647, ENST00000531075, ENST00000531119, ENST00000531545, ENST00000531888, ENST00000532472, ENST00000534598, ENST00000538940, ENST00000543966

RefSeq mRNA: 8 — MANE Select: NM_022370 NM_001370356, NM_001370357, NM_001370358, NM_001370359, NM_001370361, NM_001370364, NM_001370366, NM_022370

CCDS: CCDS44755

Canonical transcript exons

ENST00000397801 — 28 exons

Exon	Start	End
ENSE00000991247	124869450	124869607
ENSE00000991248	124869948	124870068
ENSE00000991249	124870165	124870303
ENSE00000991250	124870601	124870728
ENSE00000991251	124871014	124871138
ENSE00000991252	124872381	124872552
ENSE00001014320	124868802	124869128
ENSE00001161218	124876275	124876460
ENSE00001161223	124875954	124876125
ENSE00001161230	124875564	124875685
ENSE00001161239	124875111	124875336
ENSE00001161245	124874788	124874909
ENSE00001161251	124874070	124874236
ENSE00001161257	124873697	124873862
ENSE00001161262	124873310	124873391
ENSE00001161269	124872884	124873089
ENSE00001329376	124865432	124865737
ENSE00003510366	124877161	124877184
ENSE00003515316	124879190	124879341
ENSE00003552635	124878298	124878436
ENSE00003556898	124878584	124878796
ENSE00003567511	124880418	124880608
ENSE00003569324	124877267	124877309
ENSE00003600098	124877519	124877658
ENSE00003649617	124879465	124879575
ENSE00003660019	124877937	124878131
ENSE00003660883	124879787	124879948
ENSE00003846449	124881239	124881471

Expression profiles

Bgee: expression breadth ubiquitous, 238 present calls, max score 97.32.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.6609 / max 88.0971, expressed in 1398 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
117421	3.4526	1098
117420	1.5548	900
117418	0.6857	427
117417	0.5092	310
117419	0.2331	106
117415	0.1225	59
117416	0.1030	53

Top tissues by expression

272 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	97.32	gold quality
left ovary	UBERON:0002119	96.84	gold quality
right ovary	UBERON:0002118	96.23	gold quality
omental fat pad	UBERON:0010414	93.63	gold quality
peritoneum	UBERON:0002358	93.61	gold quality
adipose tissue of abdominal region	UBERON:0007808	92.71	gold quality
ovary	UBERON:0000992	92.24	gold quality
vena cava	UBERON:0004087	92.06	gold quality
sural nerve	UBERON:0015488	91.80	gold quality
left uterine tube	UBERON:0001303	91.50	gold quality
amygdala	UBERON:0001876	91.05	gold quality
tibial nerve	UBERON:0001323	90.69	gold quality
right frontal lobe	UBERON:0002810	90.28	gold quality
tendon of biceps brachii	UBERON:0008188	90.16	silver quality
C1 segment of cervical spinal cord	UBERON:0006469	89.94	gold quality
anterior cingulate cortex	UBERON:0009835	89.81	gold quality
cingulate cortex	UBERON:0003027	89.79	gold quality
spinal cord	UBERON:0002240	89.46	gold quality
spleen	UBERON:0002106	89.25	gold quality
nucleus accumbens	UBERON:0001882	89.18	gold quality
pericardium	UBERON:0002407	89.14	gold quality
right adrenal gland	UBERON:0001233	88.74	gold quality
granulocyte	CL:0000094	88.68	gold quality
right lobe of thyroid gland	UBERON:0001119	88.48	gold quality
right adrenal gland cortex	UBERON:0035827	88.33	gold quality
muscle layer of sigmoid colon	UBERON:0035805	87.87	gold quality
putamen	UBERON:0001874	87.42	gold quality
adrenal cortex	UBERON:0001235	87.30	gold quality
right coronary artery	UBERON:0001625	87.06	gold quality
Brodmann (1909) area 9	UBERON:0013540	87.04	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.97

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): LHX2, PAX2

miRNA regulators (miRDB)

7 targeting ROBO3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6882-5P	99.35	71.13	1206
HSA-MIR-12114	98.70	63.45	730
HSA-MIR-6887-5P	98.56	68.49	1295
HSA-MIR-6795-5P	98.52	68.51	1277
HSA-MIR-3157-5P	97.41	67.61	998
HSA-MIR-383-5P	96.86	67.55	820

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 31)

• identified mutations in the ROBO3 gene in patients affected with horizontal gaze palsy with progressive scoliosis (HGPPS);ROBO3 is required for hindbrain axon midline crossing (PMID:15105459)
• mutations in the ROBO3 gene, which shares homology with roundabout genes important in axon guidance in developing Drosophila, zebrafish, and mouse. (PMID:15105459)
• The major clinical characteristics of patients with mutated ROBO3 were horizontal gaze palsy, progressive scoliosis, and brainstem malformations. (PMID:15824346)
• Here we describe and compare two human Robo3 isoforms, Robo3A and Robo3B, which differ by the insertion of 26 amino acids at the N-terminus, and these forms appear to be evolutionary conserved (PMID:16226035)
• Incidence of scoliosis in individuals harbouring heterozygous ROBO3 mutations may be greater than in the general population. (PMID:16525029)
• No evidence for association between Gilles de la Tourette Syndrome and either the ROBO3 gene. Thus, this gene is unlikely to be the susceptibility genes contributing to GTS on 11q24. (PMID:17671968)
• Four SNPs of ROBO3 showed associations with autism (PMID:18270976)
• This study found five novel homozygous ROBO3 mutations (four missense mutations and one base deletion) distributed throughout the extracellular domain of the gene in consanguineous families with horizontal gaze palsy and progressive scoliosis. (PMID:18829051)
• This is the second reported patient with synergistic convergence and the first associated with a documented pathologic genotype. (PMID:19041479)
• Slit3 inhibits Robo3-induced invasion of synovial fibroblasts in rheumatoid arthritis. (PMID:20298552)
• RIG-I or melanoma differentiation-associated gene (MDA)5 signaling through mitochondrial antiviral signaling protein MAVS is required for activation of interferon (IFN)-beta production by rotavirus-infected intestinal epithelial cells. (PMID:21187438)
• This patient had clinical and neuroimaging characteristics considered pathognomonic of horizontal gaze palsy and progressive scoliosis and yet did not have ROBO3 mutations (PMID:21510772)
• The novel ROBO3 mutation in this family may be among the most deleterious (PMID:21592015)
• Three novel ROBO3 mutations have been identified in consanguineous patients with horizontal gaze palsy and progressive scoliosis. (PMID:21850172)
• Robo3.1A may prevent the Slit responsiveness by recruiting Robo1/2 into a late endosome- and lysosome-dependent degradation pathway. (PMID:24936616)
• We report the case of a 10-month-old girl with cross-fixation and inability to abduct who was genetically proven to have horizontal gaze palsy with progressive scoliosis (recessive ROBO3 mutations). (PMID:24969490)
• human AKAP79-anchored PKC selectively phosphorylates the Robo3.1 receptor subtype on serine 1330 (PMID:25882844)
• confirmed that ROBO3 increases with clinical grade and miR-383 expression is inversely correlated to that of ROBO3 (PMID:26070964)
• In our case, we found a novel homozygous mutation p.R842* (c.2524C>T) causing a premature stop codon which is a disease-making mutation. (PMID:27267957)
• Two novel mutations in the ROBO3 gene were identified in two Jordanian families with six affected individuals. To our knowledge, this is the first molecular study of Horizontal gaze palsy and progressive scoliosis (HGPPS) in Jordan. (PMID:30985235)
• Horizontal gaze palsy and progressive scoliosis-a tale of two siblings with ROBO3 mutation. (PMID:32077773)
• HistoryA 13-year-old girl was born to consanguineous parents (PMID:32421468)
• Mutation in ROBO3 Gene in Patients with Horizontal Gaze Palsy with Progressive Scoliosis Syndrome: A Systematic Review. (PMID:32580277)
• Introducing and Reviewing a Novel Mutation of ROBO3 in Horizontal Gaze Palsy with Progressive Scoliosis from a Chinese Family. (PMID:32705527)
• High ROBO3 expression predicts poor survival in non-M3 acute myeloid leukemia. (PMID:33541130)
• Axon guidance receptor ROBO3 modulates subtype identity and prognosis via AXL-associated inflammatory network in pancreatic cancer. (PMID:35993361)
• ROBO3s: a novel ROBO3 short isoform promoting breast cancer aggressiveness. (PMID:36057630)
• A Genetic Variant of the ROBO3 Gene is Associated With Adolescent Idiopathic Scoliosis in the Chinese Population. (PMID:36149840)
• [Expression of ROBO3 and Its Effect on Cell Proliferation and Apoptosis in Pediatric Patients with Acute Myeloid Leukemia]. (PMID:36208230)
• Upregulation of ROBO3 promotes proliferation, migration and adhesion of AML cells and affects the survival of AML patients. (PMID:37084487)
• Early onset horizontal gaze palsy and progressive scoliosis due to a noncanonical splicing-site variant and a missense variant in the ROBO3 gene. (PMID:37330975)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	robo3	ENSDARG00000005645
danio_rerio	zgc:77784	ENSDARG00000042646
mus_musculus	Robo3	ENSMUSG00000032128
rattus_norvegicus	Robo3	ENSRNOG00000030016

Paralogs (36): CNTN1 (ENSG00000018236), CDON (ENSG00000064309), NEO1 (ENSG00000067141), SDK2 (ENSG00000069188), IGSF9B (ENSG00000080854), IGSF9 (ENSG00000085552), NRCAM (ENSG00000091129), MXRA5 (ENSG00000101825), IGDCC4 (ENSG00000103742), CNTN3 (ENSG00000113805), IGSF21 (ENSG00000117154), CNTN6 (ENSG00000134115), CHL1 (ENSG00000134121), PTPRQ (ENSG00000139304), CNTN4 (ENSG00000144619), BOC (ENSG00000144857), SDK1 (ENSG00000146555), HMCN2 (ENSG00000148357), NCAM1 (ENSG00000149294), CNTN5 (ENSG00000149972), IGSF10 (ENSG00000152580), ROBO4 (ENSG00000154133), NCAM2 (ENSG00000154654), VCAM1 (ENSG00000162692), NFASC (ENSG00000163531), PRTG (ENSG00000166450), ROBO1 (ENSG00000169855), DSCAM (ENSG00000171587), IGDCC3 (ENSG00000174498), VSIG10 (ENSG00000176834), DSCAML1 (ENSG00000177103), CNTN2 (ENSG00000184144), ROBO2 (ENSG00000185008), VSIG10L (ENSG00000186806), DCC (ENSG00000187323), L1CAM (ENSG00000198910)

Protein

Protein identifiers

Roundabout homolog 3 — Q96MS0 (reviewed: Q96MS0)

Alternative names: Roundabout-like protein 3

All UniProt accessions (3): Q96MS0, F5GWJ5, F5H0K7

UniProt curated annotations — full annotation on UniProt →

Function. Receptor involved in axon guidance during development. Acts as a multifunctional regulator of pathfinding that simultaneously mediates NELL2 repulsion, inhibits SLIT repulsion, and facilitates Netrin-1/NTN1 attraction. In spinal cord development plays a role in guiding commissural axons probably by preventing premature sensitivity to Slit proteins thus inhibiting Slit signaling through ROBO1/ROBO2. Binding OF NELL2 to the receptor ROBO3 promotes oligomerization of ROBO3, resulting in the repulsion of commissural axons in the midline. ROBO3 also indirectly boosts axon attraction to NTN1 without interacting with NTN1 itself.

Subunit / interactions. Monomer. Interacts (via Fibronectin type-III 1 domain) with NELL2 (via the EGF domains) with a 3:3 stoichiometry; this interaction promotes oligomerization of ROBO3 resulting in the repulsion of commissural axons in the midline.

Subcellular location. Membrane.

Disease relevance. Gaze palsy, familial horizontal, with progressive scoliosis, 1 (HGPPS1) [MIM:607313] An autosomal recessive neurologic disorder characterized by eye movement abnormalities apparent from birth, childhood-onset progressive scoliosis, distinctive brainstem malformation and defective crossing of some brainstem neuronal pathways. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the immunoglobulin superfamily. ROBO family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96MS0-1	1, Robo3.1	yes
Q96MS0-2	2

RefSeq proteins (6): NP_001357285, NP_001357286, NP_001357287, NP_001357288, NP_001357290, NP_071765* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR003961	FN3_dom	Domain
IPR007110	Ig-like_dom	Domain
IPR013098	Ig_I-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036116	FN3_sf	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR051170	Neural/epithelial_adhesion	Family

Pfam: PF00041, PF07679, PF13927

UniProt features (92 total): strand 22, glycosylation site 11, sequence variant 10, mutagenesis site 10, compositionally biased region 9, domain 8, region of interest 5, disulfide bond 5, helix 3, topological domain 2, splice variant 2, signal peptide 1, chain 1, modified residue 1, transmembrane region 1, turn 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6POK	X-RAY DIFFRACTION	1.8
6POL	X-RAY DIFFRACTION	1.8
6POG	X-RAY DIFFRACTION	2.75

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96MS0-F1	63.99	0.25

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 1263

Disulfide bonds (5): 85–143, 187–236, 279–326, 368–424, 472–521

Glycosylation sites (11): 25, 34, 41, 53, 156, 410, 459, 503, 784, 813, 820

Mutagenesis-validated functional residues (10):

Position	Phenotype
594	abolishes binding to nell2; when associated with a-602.
600	does not affect binding to nell2; when associated with a-601.
601	does not affect binding to nell2; when associated with a-600.
602	abolishes binding to nell2; when associated with a-594.
604	decreases binding to nell2.
624	decreases binding to nell2; when associated with a-626.
626	decreases binding to nell2; when associated with a-624.
630	abolishes binding to nell2.
635	does not affect binding to nell2.
639	does not affect binding to nell2.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-428542	Regulation of commissural axon pathfinding by SLIT and ROBO
R-HSA-9010553	Regulation of expression of SLITs and ROBOs
R-HSA-9010642	ROBO receptors bind AKAP5

MSigDB gene sets: 217 (showing top): YAATNRNNNYNATT_UNKNOWN, GOBP_NEURON_RECOGNITION, BENPORATH_ES_WITH_H3K27ME3, NKX25_02, GCANCTGNY_MYOD_Q6, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_AXON_GUIDANCE, HNF1_Q6, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, CHX10_01, GGGTGGRR_PAX4_03, GOBP_POSITIVE_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, EFC_Q6, GOBP_CELL_CELL_ADHESION, GOBP_TAXIS

GO Biological Process (14): neuron migration (GO:0001764), chemotaxis (GO:0006935), homophilic cell-cell adhesion (GO:0007156), axon guidance (GO:0007411), brain development (GO:0007420), axon midline choice point recognition (GO:0016199), tube development (GO:0035295), positive regulation of axonogenesis (GO:0050772), negative regulation of negative chemotaxis (GO:0050925), dendrite self-avoidance (GO:0070593), commissural neuron axon guidance (GO:0071679), positive regulation of axon guidance (GO:1902669), nervous system development (GO:0007399), cell differentiation (GO:0030154)

GO Molecular Function (2): cell-cell adhesion mediator activity (GO:0098632), protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), membrane (GO:0016020), axon (GO:0030424)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Signaling by ROBO receptors	3

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell-cell adhesion	2
axonogenesis	2
axon guidance	2
cell migration	1
generation of neurons	1
response to chemical	1
taxis	1
neuron projection guidance	1
central nervous system development	1
animal organ development	1
head development	1
axon choice point recognition	1
multicellular organism development	1
anatomical structure development	1
positive regulation of cell projection organization	1
positive regulation of neurogenesis	1
regulation of axonogenesis	1
negative chemotaxis	1
negative regulation of chemotaxis	1
regulation of negative chemotaxis	1
neuron recognition	1
positive regulation of neuron projection development	1
regulation of axon guidance	1
system development	1
cellular developmental process	1
cell adhesion mediator activity	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1
neuron projection	1

Protein interactions and networks

STRING

1357 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ROBO3	SLIT3	O75094	985
ROBO3	NELL2	Q99435	950
ROBO3	SLIT1	O75093	944
ROBO3	SLIT2	O94813	905
ROBO3	CHN1	P15882	825
ROBO3	HTATIP2	Q9BUP3	795
ROBO3	TUBA3E	Q6PEY2	769
ROBO3	TUBAL3	A6NHL2	769
ROBO3	TUBA1C	Q9BQE3	769
ROBO3	TUBA3C	P0DPH7	764
ROBO3	TUBA8	Q9NY65	764
ROBO3	NTN1	O95631	729
ROBO3	HOXA1	P49639	722
ROBO3	SALL4	Q9UJQ4	700
ROBO3	HOXB1	P14653	585

IntAct

7 interactions, top by confidence:

A	B	Type	Score
NELL2	ROBO3	psi-mi:“MI:0407”(direct interaction)	0.560
APOA1	CNMD	psi-mi:“MI:0914”(association)	0.350
ROBO3	XIAP	psi-mi:“MI:0914”(association)	0.350
ROBO3	UBE2E1	psi-mi:“MI:0914”(association)	0.350

BioGRID (18): ROBO3 (Two-hybrid), ROBO3 (Two-hybrid), LNX1 (Two-hybrid), CCDC57 (Two-hybrid), ROBO3 (Reconstituted Complex), CXCL14 (Reconstituted Complex), ROBO3 (Two-hybrid), HSF2BP (Two-hybrid), CCDC57 (Two-hybrid), XIAP (Affinity Capture-MS), BTBD1 (Affinity Capture-MS), CTPS2 (Affinity Capture-MS), UBE2E1 (Affinity Capture-MS), ROBO3 (PCA), ROBO3 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A140LHF2, A6H8M9, A7LCJ3, A8E0Y8, D3YX43, D3YZF7, O14498, O15197, O70394, O70540, P01877, P0C0K6, P0C788, P0DP72, P35590, P40223, P43121, P50895, P70289, Q00657, Q06418, Q06805, Q15109, Q28173, Q5BK54, Q5NVQ6, Q5TJE4, Q61790, Q61826, Q62151, Q62230, Q63495, Q64612, Q6UVK1, Q6UWB1, Q7Z442, Q86VR7, Q8IZF5, Q8R2Y2, Q8VHY0

Diamond homologs: A0A1Y9G8H0, A0A452E9Y6, A1KZ92, A2A8L5, A2AJ76, A4IFW2, A4IGL7, A4IIW9, A5JUY8, A7MBJ4, A8WGA3, A8WQH2, B0BNK7, B3A0P3, D2HFT7, D3YXG0, D4A1J9, D4ABX8, G5EBF1, G5EG78, H2A0M7, O15146, O35158, O55005, O89026, P05164, P07202, P09933, P0C6S8, P0C7J6, P11247, P11678, P14650, P16621, P22079, P23468, P35419, P49290, P70193, P80025

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
ROBO3	“up-regulates quantity by expression”	CFL1	“post transcriptional regulation”
SLIT2	“up-regulates activity”	ROBO3	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

413 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	21
Uncertain significance	268
Likely benign	44
Benign	28

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1704392	NM_022370.4(ROBO3):c.2770_2779+21del	Pathogenic
1804990	NM_022370.4(ROBO3):c.571del (p.Arg191fs)	Pathogenic
2173	NM_022370.4(ROBO3):c.3325dup (p.Glu1109fs)	Pathogenic
2176	NM_022370.4(ROBO3):c.1366G>T (p.Gly456Ter)	Pathogenic
2178	NM_022370.4(ROBO3):c.2315dup (p.Gln773fs)	Pathogenic
2181	NM_022370.4(ROBO3):c.2073+1G>A	Pathogenic
2182	NM_022370.4(ROBO3):c.1844_1845del (p.Thr615fs)	Pathogenic
2183	NM_022370.4(ROBO3):c.1886_1887del (p.Val629fs)	Pathogenic
2185	NM_022370.4(ROBO3):c.2317C>T (p.Gln773Ter)	Pathogenic
3391490	NM_022370.4(ROBO3):c.767-2_778del	Pathogenic
3896072	NM_022370.4(ROBO3):c.799C>T (p.Gln267Ter)	Pathogenic
419194	NM_022370.4(ROBO3):c.3467_3476del (p.Leu1156fs)	Pathogenic
4529744	NM_022370.4(ROBO3):c.873G>A (p.Trp291Ter)	Pathogenic
501316	NM_022370.4(ROBO3):c.2427G>A (p.Trp809Ter)	Pathogenic
632150	NM_022370.4(ROBO3):c.571dup (p.Arg191fs)	Pathogenic
2172	NM_022370.4(ROBO3):c.1082G>A (p.Gly361Glu)	Likely pathogenic
2174	NM_022370.4(ROBO3):c.2108G>C (p.Arg703Pro)	Likely pathogenic
2175	NM_022370.4(ROBO3):c.2113T>C (p.Ser705Pro)	Likely pathogenic
2177	NM_022370.4(ROBO3):c.955G>A (p.Glu319Lys)	Likely pathogenic
2179	NM_022370.4(ROBO3):c.14T>C (p.Leu5Pro)	Likely pathogenic
2180	NM_022370.4(ROBO3):c.196A>C (p.Ile66Leu)	Likely pathogenic
2184	NM_022370.4(ROBO3):c.733C>T (p.Arg245Trp)	Likely pathogenic
2585490	NM_022370.4(ROBO3):c.3493C>T (p.Gln1165Ter)	Likely pathogenic
2636518	NM_022370.4(ROBO3):c.2801del (p.Ala934fs)	Likely pathogenic
3064172	NM_022370.4(ROBO3):c.3937C>T (p.Gln1313Ter)	Likely pathogenic
3362580	NM_022370.4(ROBO3):c.403_404del (p.Arg135fs)	Likely pathogenic
974849	NM_022370.4(ROBO3):c.3412del (p.Arg1138fs)	Likely pathogenic
996102	NM_022370.4(ROBO3):c.2312C>T (p.Pro771Leu)	Likely pathogenic
996105	NM_022370.4(ROBO3):c.1433C>T (p.Pro478Leu)	Likely pathogenic
996106	NM_022370.4(ROBO3):c.1450T>C (p.Trp484Arg)	Likely pathogenic

SpliceAI

4356 predictions. Top by Δscore:

Variant	Effect	Δscore
11:124865736:CGGTG:C	donor_loss	1.0000
11:124865738:G:A	donor_loss	1.0000
11:124865738:G:GG	donor_gain	1.0000
11:124871012:A:AG	acceptor_gain	1.0000
11:124871013:G:GC	acceptor_gain	1.0000
11:124871013:GT:G	acceptor_gain	1.0000
11:124871013:GTC:G	acceptor_gain	1.0000
11:124871013:GTCC:G	acceptor_gain	1.0000
11:124871131:G:T	donor_gain	1.0000
11:124871135:TCAG:T	donor_loss	1.0000
11:124871136:CAGG:C	donor_loss	1.0000
11:124871137:AGGT:A	donor_loss	1.0000
11:124871138:GG:G	donor_loss	1.0000
11:124871139:GTGG:G	donor_loss	1.0000
11:124871140:T:A	donor_loss	1.0000
11:124872377:CCAGG:C	acceptor_loss	1.0000
11:124872379:A:AG	acceptor_gain	1.0000
11:124872380:G:GG	acceptor_gain	1.0000
11:124872380:G:GT	acceptor_loss	1.0000
11:124872549:GGAG:G	donor_gain	1.0000
11:124872550:G:GT	donor_gain	1.0000
11:124872550:GAG:G	donor_gain	1.0000
11:124872550:GAGGT:G	donor_loss	1.0000
11:124872551:AGGTA:A	donor_loss	1.0000
11:124872553:G:GG	donor_gain	1.0000
11:124872553:GTA:G	donor_loss	1.0000
11:124872554:T:G	donor_loss	1.0000
11:124872772:G:GT	donor_gain	1.0000
11:124872772:G:T	donor_gain	1.0000
11:124872882:A:AG	acceptor_gain	1.0000

AlphaMissense

8880 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:124868930:T:A	W97R	0.999
11:124868930:T:C	W97R	0.999
11:124868932:G:C	W97C	0.999
11:124868932:G:T	W97C	0.999
11:124870002:T:G	Y234D	0.999
11:124870228:T:C	F277S	0.999
11:124870269:T:A	W291R	0.999
11:124870269:T:C	W291R	0.999
11:124870270:G:C	W291S	0.999
11:124870271:G:C	W291C	0.999
11:124870271:G:T	W291C	0.999
11:124870665:T:G	Y324D	0.999
11:124873003:T:A	W484R	0.999
11:124873003:T:C	W484R	0.999
11:124868931:G:C	W97S	0.998
11:124869062:T:G	Y141D	0.998
11:124869070:C:G	C143W	0.998
11:124869082:C:A	N147K	0.998
11:124869082:C:G	N147K	0.998
11:124869560:T:A	W200R	0.998
11:124869560:T:C	W200R	0.998
11:124869562:G:C	W200C	0.998
11:124869562:G:T	W200C	0.998
11:124870717:T:C	L341P	0.998
11:124871118:T:A	W380R	0.998
11:124871118:T:C	W380R	0.998
11:124873804:T:A	W576R	0.998
11:124873804:T:C	W576R	0.998
11:124874165:T:C	F627S	0.998
11:124869063:A:G	Y141C	0.997

dbSNP variants (sampled 300 via entrez): RS1000121551 (11:124879145 A>G), RS1000372665 (11:124872831 C>A,G,T), RS1000566338 (11:124874834 G>A), RS1000981209 (11:124871190 C>A), RS1001085886 (11:124868267 T>G), RS1001540841 (11:124873616 T>C,G), RS1001567275 (11:124879529 G>A), RS1002054282 (11:124867283 C>G,T), RS1002136002 (11:124876282 G>A,C,T), RS1002568328 (11:124871758 G>A,C), RS1002948837 (11:124872086 C>G,T), RS1002984207 (11:124868138 C>T), RS1003028054 (11:124866184 G>A), RS1003343934 (11:124868440 C>G), RS1003632851 (11:124876508 G>A)

Disease associations

OMIM: gene MIM:608630 | disease phenotypes: MIM:607313, MIM:191100

GenCC curated gene-disease

Disease	Classification	Inheritance
gaze palsy, familial horizontal, with progressive scoliosis 1	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
gaze palsy, familial horizontal, with progressive scoliosis 1	Definitive	AR

Mondo (3): gaze palsy, familial horizontal, with progressive scoliosis 1 (MONDO:0020790), conjugate gaze palsy (MONDO:0001527), tuberous sclerosis (MONDO:0001734)

Orphanet (2): Horizontal gaze palsy with progressive scoliosis (Orphanet:2744), Tuberous sclerosis complex (Orphanet:805)

HPO phenotypes

33 total (30 of 33 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000407	Sensorineural hearing impairment
HP:0000470	Short neck
HP:0000473	Torticollis
HP:0000484	Hyperopic astigmatism
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000565	Esotropia
HP:0000634	Impaired ocular abduction
HP:0000639	Nystagmus
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001321	Cerebellar hypoplasia
HP:0001357	Plagiocephaly
HP:0002650	Scoliosis
HP:0002750	Delayed skeletal maturation
HP:0002808	Kyphosis
HP:0002944	Thoracolumbar scoliosis
HP:0003198	Myopathy
HP:0003508	Proportionate short stature
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0007650	Progressive ophthalmoplegia
HP:0007817	Horizontal supranuclear gaze palsy
HP:0008936	Axial hypotonia
HP:0009921	Duane anomaly

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006976_50	Macular thickness	1.000000e-13

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D014402	Tuberous Sclerosis	C04.445.810; C04.651.800; C04.700.700; C10.500.507.400.750; C10.562.850; C10.574.500.865; C16.131.666.507.400.750; C16.320.400.880; C16.320.700.700

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

32 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, affects cotreatment, increases abundance	2
mercuric bromide	decreases expression, affects cotreatment	2
Arsenic	affects methylation, affects cotreatment, increases abundance, increases expression	2
Benzo(a)pyrene	increases methylation, increases mutagenesis	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
GSK-J4	decreases expression	1
bufotalin	decreases expression	1
methylmercuric chloride	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Cytarabine	increases expression	1
Estradiol	affects cotreatment, increases expression	1
Etoposide	increases expression	1
Folic Acid	decreases expression	1
Ivermectin	decreases expression	1
Plant Extracts	decreases expression, affects cotreatment	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Tretinoin	decreases expression	1
Triclosan	increases expression	1
1-Methyl-4-phenylpyridinium	increases expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	increases expression	1
Copper Sulfate	increases expression	1

Clinical trials (associated diseases)

95 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00989742	PHASE4	COMPLETED	Doxycycline In Lymphangioleiomyomatosis (LAM)
NCT05044819	PHASE4	ACTIVE_NOT_RECRUITING	Assessment of Potential for Chronic Liver Injury in Participants Treated With Epidiolex (Cannabidiol) Oral Solution
NCT00789828	PHASE3	COMPLETED	Efficacy and Safety of Everolimus (RAD001) in Patients of All Ages With Subependymal Giant Cell Astrocytoma Associated With Tuberous Sclerosis Complex (TSC)(EXIST-1)
NCT00790400	PHASE3	COMPLETED	Efficacy and Safety of RAD001 in Patients Aged 18 and Over With Angiomyolipoma Associated With Either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM)
NCT02544750	PHASE3	COMPLETED	An Open-label Extension Trial of Cannabidiol (GWP42003-P, CBD) for Seizures in Tuberous Sclerosis Complex (GWPCARE6)
NCT02544763	PHASE3	COMPLETED	A Randomized Controlled Trial of Cannabidiol (GWP42003-P, CBD) for Seizures in Tuberous Sclerosis Complex (GWPCARE6)
NCT02634931	PHASE3	COMPLETED	Long-term Trial of Topical Sirolimus to Angiofibroma in Patient With Tuberous Sclerosis Complex
NCT02635789	PHASE3	COMPLETED	Phase III Trial of Topical Formulation of Sirolimus to Skin Lesions in Patients With Tuberous Sclerosis Complex (TSC)
NCT02962414	PHASE3	ACTIVE_NOT_RECRUITING	Roll-over Study to Collect and Assess Long-term Safety of Everolimus in Patients With TSC and Refractory Seizures Who Have Completed the EXIST-3 Study [CRAD001M2304] and Who Are Benefitting From Continued Treatment
NCT05323734	PHASE3	COMPLETED	Adjunctive GNX Treatment Compared With Placebo in Children and Adults With TSC-related Epilepsy
NCT05495425	PHASE3	COMPLETED	Clinical Study of NPC-12Y Gel in Patients With Skin Lesions Associated With TSC
NCT05534672	PHASE3	RECRUITING	Placebo Controlled Study to Assess the Efficacy and Safety of Rapamycin in Drug Resistant Epilepsy Associated With Tuberous Sclerosis Complex
NCT05604170	PHASE3	TERMINATED	Open-label Study of Adjunctive GNX Treatment in Children and Adults With TSC-related Epilepsy
NCT07403266	PHASE3	RECRUITING	Treatment With Full-spectrum Cannabis Extract of Refractory Epilepsy Associated With Tuberous Sclerosis Complex (TSC)
NCT00126672	PHASE2	COMPLETED	RAPAMYCIN FOR KIDNEY ANGIOMYOLIPOMAS
NCT00457808	PHASE2	COMPLETED	Rapamycin Therapy for Patients With Tuberous Sclerosis Complex and Sporadic LAM
NCT00490789	PHASE2	UNKNOWN	Trial of Efficacy and Safety of Sirolimus in Tuberous Sclerosis and LAM
NCT01289912	PHASE2	COMPLETED	Trial of RAD001 and Neurocognition in Tuberous Sclerosis Complex (TSC)
NCT01526356	PHASE2	COMPLETED	Topical Rapamycin to Erase Angiofibromas in TSC
NCT01929642	PHASE2	COMPLETED	Rapalogues for Autism Phenotype in TSC: A Feasibility Study
NCT01954693	PHASE2	UNKNOWN	A Study of Everolimus in the Treatment of Neurocognitive Problems in Tuberous Sclerosis
NCT02104011	PHASE2	COMPLETED	Treatment of Renal Angiomyolipomas in Tuberous Sclerosis by Beta-blockers
NCT02201212	PHASE2	COMPLETED	Everolimus for Cancer With TSC1 or TSC2 Mutation
NCT02451696	PHASE2	COMPLETED	A Pilot Study To Evaluate The Effects of Everolimus on Brain mTOR Activity and Cortical Hyperexcitability in TSC and FCD
NCT02849457	PHASE2	COMPLETED	Preventing Epilepsy Using Vigabatrin In Infants With Tuberous Sclerosis Complex
NCT03356769	PHASE2	UNKNOWN	Aspirin as an add-on Treatment of Refractory Epilepsy in Tuberous Sclerosis Complex
NCT03363763	PHASE2	TERMINATED	Topical Sirolimus Ointment for Cutaneous Angiofibromas in Subjects With Tuberous Sclerosis Complex
NCT04285346	PHASE2	COMPLETED	Adjunctive Ganaxolone Treatment (Part A) in TSC Followed by Long-term Treatment (Part B)
NCT05059327	PHASE2	COMPLETED	Basimglurant (NOE-101) in Children, Adolescents, and Young Adults With TSC
NCT05103358	PHASE2	ACTIVE_NOT_RECRUITING	Phase 2 Basket Trial of Nab-sirolimus in Patients With Malignant Solid Tumors With Pathogenic Alterations in TSC1/TSC2 Genes (PRECISION 1)
NCT05104983	PHASE2	RECRUITING	Stopping TSC Onset and Progression 2B: Sirolimus TSC Epilepsy Prevention Study
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT01031901	PHASE1	COMPLETED	Topical Rapamycin Therapy to Alleviate Cutaneous Manifestations of Tuberous Sclerosis Complex (TSC) and Neurofibromatosis I (NF1)
NCT06965881	PHASE1	TERMINATED	Study to Evaluate the Pharmacokinetics and Safety Effects Following Coadministration of Carbamazepine or Itraconazole With Radiprodil in Healthy Adults
NCT06975605	PHASE1	COMPLETED	Phase 1, Open-label, Drug-drug Interaction Study to Assess Effect Between Radiprodil and the Co-administered Drugs.
NCT07369505	PHASE1	RECRUITING	Sapu003 in Advanced mTOR-sensitive Solid Tumors
NCT01730209	PHASE2/PHASE3	UNKNOWN	Efficacy of RAD001/Everolimus in Autism and NeuroPsychological Deficits in Children With Tuberous Sclerosis Complex
NCT03826628	PHASE2/PHASE3	COMPLETED	Dose-Ranging Efficacy and Safety Study of Topical Rapamycin Cream for Facial Angiofibroma Associated With Tuberous Sclerosis Complex
NCT04987463	PHASE2/PHASE3	UNKNOWN	Efficacy and Safety of Rapamycin Versus Vigabatrin in the Prevention of Tuberous Sclerosis Complex Symptoms in Infants
NCT00411619	PHASE1/PHASE2	COMPLETED	Everolimus (RAD001) Therapy of Giant Cell Astrocytoma in Patients With Tuberous Sclerosis Complex