ROBO2

Summary

ROBO2 (roundabout guidance receptor 2, HGNC:10250) is a protein-coding gene on chromosome 3p12.3, encoding Roundabout homolog 2 (Q9HCK4). Receptor for SLIT2, and probably SLIT1, which are thought to act as molecular guidance cue in cellular migration, including axonal navigation at the ventral midline of the neural tube and projection of axons to different regions during neuronal development.

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.

Source: NCBI Gene 6092 — RefSeq curated summary.

At a glance

• Gene–disease (curated): vesicoureteral reflux 2 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 31
• Clinical variants (ClinVar): 681 total
• Phenotypes (HPO): 3
• Cancer driver (intOGen): activating (oncogene-like) across 11 cancer types
• MANE Select transcript: NM_001395656

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10250
Approved symbol	ROBO2
Name	roundabout guidance receptor 2
Location	3p12.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1568
Ensembl gene	ENSG00000185008
Ensembl biotype	protein_coding
OMIM	602431
Entrez	6092

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 13 protein_coding, 3 nonsense_mediated_decay, 2 retained_intron

ENST00000332191, ENST00000461745, ENST00000469233, ENST00000470802, ENST00000471893, ENST00000473767, ENST00000475334, ENST00000487694, ENST00000490534, ENST00000490991, ENST00000602589, ENST00000696574, ENST00000696593, ENST00000696629, ENST00000696630, ENST00000696631, ENST00000705983, ENST00000705984

RefSeq mRNA: 24 — MANE Select: NM_001395656 NM_001128929, NM_001290039, NM_001290040, NM_001290065, NM_001378190, NM_001378191, NM_001378192, NM_001378193, NM_001378194, NM_001378195, NM_001378196, NM_001378197, NM_001378198, NM_001378199, NM_001378200, NM_001378201, NM_001378202, NM_001378203, NM_001394212, NM_001394213, NM_001394214, NM_001395656, NM_001395657, NM_002942

CCDS: CCDS43109, CCDS54609, CCDS93314, CCDS93315, CCDS93316, CCDS93317, CCDS93318, CCDS93319, CCDS93320, CCDS93321

Canonical transcript exons

ENST00000696593 — 28 exons

Exon	Start	End
ENSE00001290947	77550818	77550989
ENSE00001292171	77562651	77562732
ENSE00001297167	77098014	77098340
ENSE00001298880	77546338	77546462
ENSE00001307960	77563167	77563329
ENSE00001311581	77557944	77558149
ENSE00001318599	77477414	77477571
ENSE00001851138	77642671	77642943
ENSE00001878695	77646054	77649964
ENSE00002229820	77493244	77493382
ENSE00002233784	77522775	77522902
ENSE00002388919	77481099	77481219
ENSE00003321718	77527403	77527414
ENSE00003492785	77577490	77577614
ENSE00003518907	77622227	77622432
ENSE00003522913	77602210	77602491
ENSE00003531028	77579947	77580118
ENSE00003541438	77564954	77565120
ENSE00003552076	77617513	77617773
ENSE00003587095	77588751	77588933
ENSE00003618104	77595142	77595184
ENSE00003627374	77574499	77574730
ENSE00003639672	77568313	77568434
ENSE00003650165	77596623	77596750
ENSE00003667147	77634870	77635043
ENSE00003690297	77644704	77644904
ENSE00003789626	77607798	77607954
ENSE00003967745	77040099	77040846

Expression profiles

Bgee: expression breadth ubiquitous, 192 present calls, max score 98.99.

FANTOM5 (CAGE): breadth broad, TPM avg 6.8564 / max 627.1530, expressed in 563 samples.

FANTOM5 promoters (16 alternative TSS)

Promoter ID	TPM avg	Samples expressed
37372	3.1915	453
37369	1.4746	339
37353	0.7559	151
37354	0.3304	103
37352	0.2166	83
37368	0.1530	77
37347	0.1478	71
37370	0.1375	65
37373	0.0985	34
37367	0.0738	37

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	98.99	gold quality
cortical plate	UBERON:0005343	98.87	gold quality
ventricular zone	UBERON:0003053	97.12	gold quality
buccal mucosa cell	CL:0002336	95.14	gold quality
prefrontal cortex	UBERON:0000451	87.59	gold quality
islet of Langerhans	UBERON:0000006	87.19	gold quality
cartilage tissue	UBERON:0002418	87.09	gold quality
Brodmann (1909) area 46	UBERON:0006483	84.84	gold quality
pons	UBERON:0000988	84.00	gold quality
frontal cortex	UBERON:0001870	82.42	gold quality
neocortex	UBERON:0001950	82.00	gold quality
endothelial cell	CL:0000115	81.36	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.34	gold quality
tibia	UBERON:0000979	81.34	gold quality
superior frontal gyrus	UBERON:0002661	80.08	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	80.04	gold quality
cerebral cortex	UBERON:0000956	79.86	gold quality
Brodmann (1909) area 9	UBERON:0013540	79.63	gold quality
substantia nigra pars compacta	UBERON:0001965	79.38	gold quality
entorhinal cortex	UBERON:0002728	79.38	gold quality
anterior cingulate cortex	UBERON:0009835	79.29	gold quality
caudate nucleus	UBERON:0001873	79.18	gold quality
right lung	UBERON:0002167	78.92	gold quality
Brodmann (1909) area 23	UBERON:0013554	78.04	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.41	gold quality
postcentral gyrus	UBERON:0002581	77.24	gold quality
putamen	UBERON:0001874	76.95	gold quality
middle temporal gyrus	UBERON:0002771	76.74	gold quality
substantia nigra pars reticulata	UBERON:0001966	76.67	gold quality
cerebellar vermis	UBERON:0004720	76.57	gold quality

Single-cell (SCXA)

Detected in 15 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	8976.77
E-HCAD-25	yes	8561.95
E-HCAD-30	yes	8278.39
E-ANND-2	yes	3232.72
E-GEOD-75140	yes	1181.58
E-MTAB-10662	yes	248.30
E-CURD-119	yes	26.07
E-HCAD-10	yes	16.05
E-MTAB-5061	yes	15.07
E-HCAD-5	yes	14.33
E-ENAD-27	yes	11.46
E-GEOD-83139	yes	10.15
E-ANND-3	yes	7.36
E-MTAB-6058	no	1061.14
E-MTAB-10290	no	191.03

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DLX1, ROBO1

miRNA regulators (miRDB)

293 targeting ROBO2, 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-3163	100.00	77.23	8605
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-25-3P	99.98	74.60	1817

Literature-anchored findings (GeneRIF, showing 26)

• two differentially expressed isoforms were isolated and identified. Exons 1 and 2 of human ROBO2a lie in an inherently unstable DNA segment at human chromosome 3p12.3. (PMID:16829019)
• Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux. (PMID:17357069)
• a relatively high frequency of ROBO2 variants (5.1%) was found in familial vesicoureteral reflux (PMID:18235093)
• mRNA expression of ROBO2 in lymphocytes was significantly reduced in the autistic group (PMID:18270976)
• gene variants in ROBO2 are rare causes of VUR in humans. Our results provide further evidence for the genetic heterogeneity of this disorder (PMID:19350278)
• data suggests the importance of abrogation of SLIT2-ROBO1 and SLIT2-ROBO2 interactions in the initiation and progression of CACX and also for early diagnosis and prognosis of the disease (PMID:22719878)
• Results not completely rule out that some ROBO2 variants may be the sole cause of vesicoureteric reflux, but it is clear from the overall frequency that most of them cannot be. (PMID:23536131)
• The finding that a polymorphism associated with the ROBO2 gene, which is involved in neurodevelopment, confers risk for the common emotionally reactive, impulsive aspects of conduct disorder, independent of concurrent risk for psychopathy. (PMID:23982283)
• Frameshift mutations of ROBO1 and ROBO2 genes and alteration of ROBO2 expression in gastric and colorectal cancers suggest that both genes might play roles in the pathogenesis of both cancers. (PMID:24247621)
• Down-regulation of ROBO2 expression is associated with prostate cancers. (PMID:24272677)
• Common variation near ROBO2 is associated with expressive vocabulary in infancy. (PMID:25226531)
• Mutations of the SLIT2-ROBO2 pathway genes SLIT2 and SRGAP1 confer risk for congenital anomalies of the kidney and urinary tract (PMID:26026792)
• Overexpression of ROBO2 induces its tumor suppressive effects in Breast cancer (PMID:26542734)
• ROBO2 somatic mutation is associated with myelodysplastic syndrome progression. Overexpression of ROBO2 produces anti-proliferative and pro-apoptotic effects in leukemia cells. This effect was lost in ROBO mutants and ROBO-SLIT2 signaling is impaired. (PMID:26608094)
• human placental multipotent mesenchymal stromal cell express Slit2 and both Robo1 and Robo4 are present in human umbilical vein endothelial cells. (PMID:26745454)
• ROBO2 variants were not found to be associated with nonsyndromic vesicoureteral reflux with or without renal hypoplasia/dysplasia, providing further evidence for genetic heterogeneity (PMID:27002985)
• ROBO2 and RASSF2A gene methylations may be related to gastric tumorigenesis, and ROBO2 gene methylation is associated with sporadic gastric cancer. (PMID:27461616)
• determined the crystal structure of the tandem Ig4-5 domains (D4-5) of human Robo2 and found that a hydrophobic surface on D4 mediates close homotypic contacts with a reciprocal D4 (PMID:29017837)
• results suggest that Robo2 functions as a receptor for NELL1/2, particularly under circumstances where Robo2 undergoes proteolytic digestion (PMID:30700556)
• The gene ROBO2 was decreased in patients with COPD and this decrease was significantly negatively correlated with the disease stages of COPD (PMID:31571851)
• Investigation of DNA variants specific to ROBO2 Isoform ‘a’ in Irish vesicoureteric reflux patients reveals marked CpG island variation. (PMID:32041992)
• ROBO2 hampers malignant biological behavior and predicts a better prognosis in pancreatic adenocarcinoma. (PMID:34148491)
• An ancient founder mutation located between ROBO1 and ROBO2 is responsible for increased microtia risk in Amerindigenous populations. (PMID:35584116)
• Conformational Change of the Hairpin-like-structured Robo2 Ectodomain Allows NELL1/2 Binding. (PMID:35940226)
• SALL4 advances the proliferation and tumor cell stemness of colon cancer cells through the transcription and regulation of ROBO2. (PMID:37660281)
• Overexpression of miR-25 Downregulates the Expression of ROBO2 in Idiopathic Intellectual Disability. (PMID:38612763)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	robo2	ENSDARG00000014891
mus_musculus	Robo2	ENSMUSG00000052516
rattus_norvegicus	Robo2	ENSRNOG00000029598

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), ROBO3 (ENSG00000154134), NCAM2 (ENSG00000154654), VCAM1 (ENSG00000162692), NFASC (ENSG00000163531), PRTG (ENSG00000166450), ROBO1 (ENSG00000169855), DSCAM (ENSG00000171587), IGDCC3 (ENSG00000174498), VSIG10 (ENSG00000176834), DSCAML1 (ENSG00000177103), CNTN2 (ENSG00000184144), VSIG10L (ENSG00000186806), DCC (ENSG00000187323), L1CAM (ENSG00000198910)

Protein

Protein identifiers

Roundabout homolog 2 — Q9HCK4 (reviewed: Q9HCK4)

All UniProt accessions (15): Q9HCK4, A0A8Q3SIP4, A0A8Q3SIT0, A0A8Q3SIU0, A0A8Q3SIW8, A0A8Q3WLE3, A0A994J5N3, A0A994J7I9, F8W703, F8WBR3, H7C4J7, H7C4U9, H7C4V8, H7C4W9, R4GMM8

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for SLIT2, and probably SLIT1, which are thought to act as molecular guidance cue in cellular migration, including axonal navigation at the ventral midline of the neural tube and projection of axons to different regions during neuronal development.

Subunit / interactions. Interacts with SLIT2.

Subcellular location. Membrane.

Disease relevance. Vesicoureteral reflux 2 (VUR2) [MIM:610878] A disease belonging to the group of congenital anomalies of the kidney and urinary tract. It is characterized by the reflux of urine from the bladder into the ureters and sometimes into the kidneys, and is a risk factor for urinary tract infections. Primary disease results from a developmental defect of the ureterovesical junction. In combination with intrarenal reflux, the resulting inflammatory reaction may result in renal injury or scarring, also called reflux nephropathy. Extensive renal scarring impairs renal function and may predispose patients to hypertension, proteinuria, renal insufficiency and end-stage renal disease. The disease is caused by variants affecting the gene represented in this entry. A chromosomal aberration involving ROBO2 is a cause of multiple congenital abnormalities, including severe bilateral VUR with ureterovesical junction defects. Translocation t(Y;3)(p11;p12) with PCDH11Y. This translocation disrupts ROBO2 and produces dominant-negative ROBO2 proteins that abrogate SLIT-ROBO signaling in vitro.

Similarity. Belongs to the immunoglobulin superfamily. ROBO family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9HCK4-1	1	yes
Q9HCK4-2	2
Q9HCK4-3	3

RefSeq proteins (24): NP_001122401, NP_001276968, NP_001276969, NP_001276994, NP_001365119, NP_001365120, NP_001365121, NP_001365122, NP_001365123, NP_001365124, NP_001365125, NP_001365126, NP_001365127, NP_001365128, NP_001365129, NP_001365130, NP_001365131, NP_001365132, NP_001381141, NP_001381142, NP_001381143, NP_001382585, NP_001382586, NP_002933 (=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
IPR013106	Ig_V-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 (100 total): strand 52, domain 8, glycosylation site 6, compositionally biased region 5, disulfide bond 5, helix 5, region of interest 4, turn 3, topological domain 2, modified residue 2, splice variant 2, sequence variant 2, signal peptide 1, chain 1, transmembrane region 1, sequence conflict 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
5NOI	X-RAY DIFFRACTION	2.4
6I9S	X-RAY DIFFRACTION	2.48
6IAA	X-RAY DIFFRACTION	3.6
1UEM	SOLUTION NMR
1UJT	SOLUTION NMR
2EDJ	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HCK4-F1	67.78	0.43

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 (2): 1154, 1156

Disulfide bonds (5): 52–110, 154–203, 246–293, 335–391, 439–488

Glycosylation sites (6): 123, 426, 752, 782, 789, 845

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-376176	Signaling by ROBO receptors
R-HSA-428542	Regulation of commissural axon pathfinding by SLIT and ROBO
R-HSA-8985801	Regulation of cortical dendrite branching
R-HSA-9010553	Regulation of expression of SLITs and ROBOs
R-HSA-9010642	ROBO receptors bind AKAP5
R-HSA-9830674	Formation of the ureteric bud
R-HSA-1266738	Developmental Biology
R-HSA-422475	Axon guidance
R-HSA-9675108	Nervous system development
R-HSA-9830369	Kidney development

MSigDB gene sets: 345 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_DN, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_FOREBRAIN_NEURON_DEVELOPMENT, LI_CISPLATIN_RESISTANCE_DN, GOBP_OLFACTORY_BULB_INTERNEURON_DIFFERENTIATION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEURON_RECOGNITION, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, GOBP_OUTFLOW_TRACT_SEPTUM_MORPHOGENESIS, GOBP_VENTRICULAR_SEPTUM_MORPHOGENESIS, GOBP_METANEPHROS_DEVELOPMENT, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS, GOBP_SYNAPSE_ASSEMBLY, GOBP_ENDOCARDIAL_CUSHION_DEVELOPMENT, GOBP_RETINAL_GANGLION_CELL_AXON_GUIDANCE

GO Biological Process (28): metanephros development (GO:0001656), ureteric bud development (GO:0001657), heart induction (GO:0003129), outflow tract septum morphogenesis (GO:0003148), aortic valve morphogenesis (GO:0003180), pulmonary valve morphogenesis (GO:0003184), endocardial cushion formation (GO:0003272), chemotaxis (GO:0006935), homophilic cell-cell adhesion (GO:0007156), axon guidance (GO:0007411), central nervous system development (GO:0007417), brain development (GO:0007420), axon midline choice point recognition (GO:0016199), olfactory bulb interneuron development (GO:0021891), retinal ganglion cell axon guidance (GO:0031290), cellular response to hormone stimulus (GO:0032870), aorta development (GO:0035904), positive regulation of Notch signaling pathway (GO:0045747), positive regulation of axonogenesis (GO:0050772), negative regulation of negative chemotaxis (GO:0050925), negative regulation of synapse assembly (GO:0051964), ventricular septum morphogenesis (GO:0060412), apoptotic process involved in luteolysis (GO:0061364), cell-cell adhesion (GO:0098609), cell adhesion (GO:0007155), nervous system development (GO:0007399), cell differentiation (GO:0030154), tube development (GO:0035295)

GO Molecular Function (3): axon guidance receptor activity (GO:0008046), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (5): plasma membrane (GO:0005886), cell surface (GO:0009986), axolemma (GO:0030673), extracellular exosome (GO:0070062), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Signaling by ROBO receptors	4
Developmental Biology	2
Axon guidance	1
Kidney development	1
Nervous system development	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
heart valve morphogenesis	2
axonogenesis	2
axon guidance	2
cellular anatomical structure	2
kidney development	1
mesonephric tubule development	1
organ induction	1
heart field specification	1
regulation of heart morphogenesis	1
outflow tract morphogenesis	1
cardiac septum morphogenesis	1
aortic valve development	1
pulmonary valve development	1
endocardial cushion morphogenesis	1
anatomical structure formation involved in morphogenesis	1
response to chemical	1
taxis	1
cell-cell adhesion	1
neuron projection guidance	1
nervous system development	1
system development	1
central nervous system development	1
animal organ development	1
head development	1
axon choice point recognition	1
forebrain neuron development	1
olfactory bulb interneuron differentiation	1
response to hormone	1
cellular response to chemical stimulus	1
cellular response to endogenous stimulus	1
artery development	1
Notch signaling pathway	1
regulation of Notch signaling pathway	1
positive regulation of signal transduction	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

Protein interactions and networks

STRING

2080 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ROBO2	SLIT3	O75094	999
ROBO2	SLIT2	O94813	999
ROBO2	SLIT1	O75093	998
ROBO2	NTN1	O95631	858
ROBO2	SOX17	Q9H6I2	764
ROBO2	GDNF	P39905	713
ROBO2	SEMA3F	Q13275	665
ROBO2	NELL2	Q99435	659
ROBO2	SRGAP1	Q7Z6B7	653
ROBO2	SRGAP3	O43295	648
ROBO2	SRGAP2	O75044	640
ROBO2	NTNG1	Q9Y2I2	603
ROBO2	DCC	P43146	598
ROBO2	NTNG2	Q96CW9	596
ROBO2	FOXP2	O15409	565

IntAct

48 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
TMEM237	ROBO2	psi-mi:“MI:0915”(physical association)	0.560
GPR152	ROBO2	psi-mi:“MI:0915”(physical association)	0.560
METTL3	WTAP	psi-mi:“MI:0914”(association)	0.530
	ROBO2	psi-mi:“MI:0407”(direct interaction)	0.440
ROBO2	Dlg4	psi-mi:“MI:0407”(direct interaction)	0.440
ROBO2	ROBO2	psi-mi:“MI:0915”(physical association)	0.400
ROBO1	ROBO2	psi-mi:“MI:0915”(physical association)	0.400
ROBO2	BNIP3L	psi-mi:“MI:0915”(physical association)	0.370
ROBO2	HLA-DPB1	psi-mi:“MI:0915”(physical association)	0.370
CENPU	ROBO2	psi-mi:“MI:0915”(physical association)	0.370
ROBO2	NR1H2	psi-mi:“MI:0915”(physical association)	0.370
ROBO2	NR4A1	psi-mi:“MI:0915”(physical association)	0.370
ROBO2	RDH11	psi-mi:“MI:0915”(physical association)	0.370
RPS6KA5	ROBO2	psi-mi:“MI:0915”(physical association)	0.370
KCNRG	ROBO2	psi-mi:“MI:0915”(physical association)	0.370
PARD6B	PARD3	psi-mi:“MI:0914”(association)	0.350
Tmem109	ASXL2	psi-mi:“MI:0914”(association)	0.350
Cep72	TBC1D31	psi-mi:“MI:0914”(association)	0.350
KIF2A	GNS	psi-mi:“MI:0914”(association)	0.350
VAPA		psi-mi:“MI:0914”(association)	0.350
TMEM248	TAF1	psi-mi:“MI:0914”(association)	0.350
KIF1C	HSPA8	psi-mi:“MI:0914”(association)	0.350
FADD	NUP42	psi-mi:“MI:0914”(association)	0.350
MYC	PDZD2	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
CACNA1C	SYT5	psi-mi:“MI:0914”(association)	0.350

BioGRID (53): ROBO2 (Affinity Capture-MS), ROBO2 (Affinity Capture-MS), ROBO2 (Affinity Capture-MS), ROBO2 (Affinity Capture-MS), ROBO2 (Affinity Capture-MS), ROBO2 (Affinity Capture-MS), ROBO2 (Affinity Capture-MS), ROBO2 (Affinity Capture-MS), ROBO2 (Affinity Capture-MS), ROBO2 (Affinity Capture-MS), ROBO2 (Two-hybrid), ROBO2 (Two-hybrid), ROBO2 (Two-hybrid), ROBO2 (Proximity Label-MS), ROBO2 (Proximity Label-MS)

ESM2 similar proteins: A4IGL7, D3ZB51, E9PZ19, O75882, O94779, O95970, P00533, P02469, P07942, P13590, P15209, P24503, P24786, P33150, P39038, P55245, P55283, P68500, P97300, P97527, P97546, Q01279, Q01973, Q03351, Q16288, Q16620, Q1EGL2, Q3B7N0, Q3UQ28, Q5IFJ9, Q5IS37, Q5IS82, Q5R945, Q63604, Q6IS24, Q6VNS1, Q7TPD3, Q7TT15, Q8K4Y5, Q8N475

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
ROBO2	“up-regulates quantity by expression”	CFL1	“post transcriptional regulation”
SLIT2	“up-regulates activity”	ROBO2	binding

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 11 cancer types — CHRCC, CLLSLL, COAD, COADREAD, EGC, ESCA, HCC, MEL, MLYM, PRAD, UCS.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	424
Likely benign	93
Benign	115

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

9618 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:77098142:T:A	W64R	0.999
3:77098142:T:C	W64R	0.999
3:77098144:G:C	W64C	0.999
3:77098144:G:T	W64C	0.999
3:77477524:T:A	W167R	0.999
3:77477524:T:C	W167R	0.999
3:77477526:G:C	W167C	0.999
3:77477526:G:T	W167C	0.999
3:77481115:T:C	L188P	0.999
3:77493307:T:C	F244S	0.999
3:77493348:T:A	W258R	0.999
3:77493348:T:C	W258R	0.999
3:77493349:G:C	W258S	0.999
3:77493350:G:C	W258C	0.999
3:77493350:G:T	W258C	0.999
3:77522801:T:C	L278P	0.999
3:77522891:T:C	L308P	0.999
3:77550885:T:C	L376P	0.999
3:77558063:T:A	W451R	0.999
3:77558063:T:C	W451R	0.999
3:77563271:T:A	W542R	0.999
3:77563271:T:C	W542R	0.999
3:77565049:T:C	F593S	0.999
3:77568429:T:A	W656R	0.999
3:77568429:T:C	W656R	0.999
3:77574545:G:C	R673P	0.999
3:77574579:G:C	W684C	0.999
3:77574579:G:T	W684C	0.999
3:77577564:T:A	W760R	0.999
3:77577564:T:C	W760R	0.999

dbSNP variants (sampled 300 via entrez): RS1000001121 (3:76448943 A>C,G), RS1000003093 (3:76234726 T>C), RS1000004726 (3:76558579 A>C), RS1000007204 (3:77437187 G>A,T), RS1000009292 (3:77214532 G>A,C), RS1000009503 (3:76808278 T>C), RS1000009721 (3:77180789 A>G,T), RS1000015070 (3:76475351 G>T), RS1000015154 (3:76119766 A>G), RS1000016801 (3:76040157 A>C), RS1000017672 (3:76039152 A>C,G), RS1000017675 (3:77221833 T>C), RS1000018902 (3:76399102 T>C), RS1000019792 (3:76924737 A>G), RS1000020709 (3:76759486 A>T)

Disease associations

OMIM: gene MIM:602431 | disease phenotypes: MIM:610878, MIM:610805

GenCC curated gene-disease

Disease	Classification	Inheritance
vesicoureteral reflux 2	Strong	Autosomal dominant
familial vesicoureteral reflux	Supportive	Autosomal dominant

Mondo (3): vesicoureteral reflux 2 (MONDO:0012573), congenital anomaly of kidney and urinary tract (MONDO:0019719), familial vesicoureteral reflux (MONDO:0017329)

Orphanet (2): Familial vesicoureteral reflux (Orphanet:289365), Renal or urinary tract malformation (Orphanet:93545)

HPO phenotypes

3 total (3 of 3 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000076	Vesicoureteral reflux
HP:0000089	Renal hypoplasia

GWAS associations

31 associations (top):

Study	Trait	p-value
GCST000271_5	Brain imaging in schizophrenia (dorsolateral prefrontal cortex interaction)	4.000000e-06
GCST001821_5	Metabolite levels (5-HIAA/ MHPG Ratio)	7.000000e-06
GCST002136_3	Periodontitis (PAL4Q3)	3.000000e-06
GCST002611_1	Expressive vocabulary in infants	1.000000e-08
GCST003262_536	Post bronchodilator FEV1	2.000000e-06
GCST003264_1034	Post bronchodilator FEV1/FVC ratio	3.000000e-06
GCST003264_184	Post bronchodilator FEV1/FVC ratio	3.000000e-06
GCST005830_87	Hand grip strength	1.000000e-08
GCST006087_18	Familial lung adenocarcinoma	3.000000e-06
GCST007317_10	Response to ketamine in bipolar disorder or major depression (dissociation effects)	8.000000e-06
GCST007317_2	Response to ketamine in bipolar disorder or major depression (dissociation effects)	2.000000e-06
GCST007317_4	Response to ketamine in bipolar disorder or major depression (dissociation effects)	5.000000e-06
GCST007565_56	Morning person	2.000000e-19
GCST007565_67	Morning person	3.000000e-16
GCST007576_357	Chronotype	2.000000e-19
GCST007576_380	Chronotype	6.000000e-06
GCST008017_7	Bitter taste perception (6-n-propylthiouracil) in obesity with metabolic syndrome	7.000000e-06
GCST008162_30	Hip circumference	4.000000e-06
GCST009379_256	Type 2 diabetes	1.000000e-08
GCST009391_2041	Metabolite levels	5.000000e-06
GCST010698_78	Subcortical volume (min-P)	2.000000e-12
GCST010699_33	Brain morphology (min-P)	6.000000e-09
GCST010701_131	Cortical surface area (MOSTest)	2.000000e-10
GCST010702_128	Subcortical volume (MOSTest)	9.000000e-16
GCST010703_212	Brain morphology (MOSTest)	2.000000e-11
GCST010818_14	Gut microbiota alpha diversity (PD_whole_tree index)	8.000000e-06
GCST010819_2	Gut microbiota alpha diversity (Chao1 index)	4.000000e-06
GCST010989_225	Body size at age 10	7.000000e-09
GCST011354_54	Bell’s palsy	2.000000e-06
GCST011741_27	LDL cholesterol levels in HIV infection	1.000000e-05

EFO canonical traits (15, from GWAS)

EFO ID	Trait name
EFO:0005132	5-HIAA measurement
EFO:0005133	MHPG measurement
EFO:0006316	infant expressive language ability
EFO:0004314	forced expiratory volume
EFO:0004713	FEV/FVC ratio
EFO:0006941	grip strength measurement
EFO:0006953	family history of lung cancer
EFO:0009748	response to ketamine
EFO:0009750	dissociation measurement
EFO:0008328	chronotype measurement
EFO:0004346	neuroimaging measurement
EFO:0007874	gut microbiome measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0009902	handedness

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C566906	Cakut (supp.)
C567053	Vesicoureteral Reflux 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects cotreatment, increases expression	7
aristolochic acid I	decreases expression	2
bisphenol A	affects methylation, increases expression	2
entinostat	decreases expression, affects cotreatment	2
belinostat	decreases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tretinoin	decreases expression, increases expression	2
Aflatoxin B1	decreases expression, increases methylation	2
bisphenol F	affects methylation, increases methylation, affects cotreatment	1
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
trichostatin A	decreases expression	1
sodium arsenite	decreases expression	1
benzo(e)pyrene	affects methylation	1
aflatoxin B2	decreases methylation	1
aluminum sulfate	decreases 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, increases expression	1
dorsomorphin	decreases expression, increases expression, affects cotreatment	1
bisphenol S	increases methylation	1
Sunitinib	decreases expression	1
Fulvestrant	affects methylation, decreases methylation, affects cotreatment	1
Panobinostat	affects cotreatment, decreases expression	1
Acetaminophen	increases expression	1
Citrinin	decreases expression	1
Hydralazine	affects cotreatment, increases expression	1
Methapyrilene	affects methylation	1

Cellosaurus cell lines

1 cell lines: 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B5NG	PGPC17_11	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04115345	PHASE1	COMPLETED	A Study of a Renal Autologous Cell Therapy (REACT) in Patients With Chronic Kidney Disease (CKD) From Congenital Anomalies of the Kidney and Urinary Tract (CAKUT).
NCT05694169	PHASE1	TERMINATED	A Study of Participants With Chronic Kidney Disease Previously Treated With REACT
NCT04537364	Not specified	COMPLETED	Prediction of Renal Parenchymal Damage of CAKUT
NCT06921733	Not specified	RECRUITING	Ultrasound Localization Microscopy in Patient With Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)