ROBO4

Summary

ROBO4 (roundabout guidance receptor 4, HGNC:17985) is a protein-coding gene on chromosome 11q24.2, encoding Roundabout homolog 4 (Q8WZ75). Receptor for Slit proteins, at least for SLIT2, and seems to be involved in angiogenesis and vascular patterning. In precision oncology, ROBO4 EXPRESSION confers sensitivity to Angiogenesis Inhibitor in Cancer (CIViC Level B).

Predicted to enable cell-cell adhesion mediator activity. Involved in establishment of endothelial barrier. Located in extracellular exosome. Implicated in aortic valve disease 3. Biomarker of pre-eclampsia and thyroid gland carcinoma.

Source: NCBI Gene 54538 — RefSeq curated summary.

At a glance

• Gene–disease (curated): aortic valve disease 3 (Strong, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 310 total — 15 likely-pathogenic
• Phenotypes (HPO): 15
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• MANE Select transcript: NM_019055

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17985
Approved symbol	ROBO4
Name	roundabout guidance receptor 4
Location	11q24.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20798, MRB, ECSM4
Ensembl gene	ENSG00000154133
Ensembl biotype	protein_coding
OMIM	607528
Entrez	54538

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 12 protein_coding, 5 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000306534, ENST00000525182, ENST00000526899, ENST00000527279, ENST00000529941, ENST00000532216, ENST00000532300, ENST00000533054, ENST00000533337, ENST00000534407, ENST00000877817, ENST00000877818, ENST00000877819, ENST00000877820, ENST00000877821, ENST00000877822, ENST00000877823, ENST00000877824, ENST00000877825, ENST00000954783

RefSeq mRNA: 2 — MANE Select: NM_019055 NM_001301088, NM_019055

CCDS: CCDS73409, CCDS8455

Canonical transcript exons

ENST00000306534 — 18 exons

Exon	Start	End
ENSE00002164693	124897726	124897865
ENSE00002444802	124886464	124886822
ENSE00002521861	124883691	124884913
ENSE00003480419	124887358	124887499
ENSE00003492374	124895081	124895193
ENSE00003518316	124893860	124894045
ENSE00003541351	124885041	124885247
ENSE00003554141	124896198	124896318
ENSE00003572513	124891666	124891802
ENSE00003615582	124886977	124887213
ENSE00003621342	124896513	124896670
ENSE00003645080	124893688	124893730
ENSE00003650136	124895785	124895912
ENSE00003650493	124891299	124891562
ENSE00003664568	124894201	124894369
ENSE00003665566	124895457	124895685
ENSE00003668502	124887733	124887840
ENSE00003674807	124896932	124897261

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 95.53.

FANTOM5 (CAGE): breadth broad, TPM avg 13.0434 / max 446.5369, expressed in 586 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
122967	12.0325	540
122966	0.4969	155
122968	0.3723	106
122965	0.1086	60
206486	0.0330	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower lobe of lung	UBERON:0008949	95.53	gold quality
apex of heart	UBERON:0002098	94.92	gold quality
omental fat pad	UBERON:0010414	94.44	gold quality
adipose tissue of abdominal region	UBERON:0007808	94.40	gold quality
peritoneum	UBERON:0002358	94.38	gold quality
upper lobe of lung	UBERON:0008948	94.11	gold quality
upper lobe of left lung	UBERON:0008952	94.06	gold quality
spleen	UBERON:0002106	93.91	gold quality
sural nerve	UBERON:0015488	93.70	gold quality
subcutaneous adipose tissue	UBERON:0002190	93.47	gold quality
adipose tissue	UBERON:0001013	93.35	gold quality
right lung	UBERON:0002167	93.14	gold quality
visceral pleura	UBERON:0002401	92.71	gold quality
endothelial cell	CL:0000115	92.67	gold quality
connective tissue	UBERON:0002384	92.61	gold quality
tendon of biceps brachii	UBERON:0008188	92.32	gold quality
parietal pleura	UBERON:0002400	91.77	gold quality
pleura	UBERON:0000977	91.45	gold quality
right lobe of thyroid gland	UBERON:0001119	89.35	gold quality
heart left ventricle	UBERON:0002084	89.05	gold quality
cardiac ventricle	UBERON:0002082	89.04	gold quality
superficial temporal artery	UBERON:0001614	88.63	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.59	gold quality
metanephros cortex	UBERON:0010533	88.14	gold quality
mammary duct	UBERON:0001765	88.01	gold quality
lung	UBERON:0002048	87.83	gold quality
left lobe of thyroid gland	UBERON:0001120	87.71	gold quality
thyroid gland	UBERON:0002046	87.51	gold quality
mucosa of stomach	UBERON:0001199	87.18	gold quality
mammary gland	UBERON:0001911	87.15	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-9801	yes	757.69
E-MTAB-6678	yes	418.60
E-HCAD-10	yes	32.11
E-ANND-3	yes	12.31
E-MTAB-5061	yes	6.01
E-MTAB-8205	no	75.38
E-CURD-112	no	3.07

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GABPA, SOX17, SP1

miRNA regulators (miRDB)

20 targeting ROBO4, 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-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-377-5P	99.70	65.28	712
HSA-MIR-6086	99.70	65.38	699
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-942-5P	99.41	68.40	1977
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-5693	99.24	66.67	1106
HSA-MIR-4710	98.61	65.96	1048
HSA-MIR-5581-3P	98.55	70.31	1161
HSA-MIR-4726-3P	98.49	63.89	1385
HSA-MIR-640	98.44	66.93	644
HSA-MIR-4768-3P	98.16	66.02	2330
HSA-MIR-6880-5P	98.08	65.59	1282
HSA-MIR-1972	97.67	67.38	1172
HSA-MIR-152-5P	96.42	66.59	960

Literature-anchored findings (GeneRIF, showing 40)

• roundabout gene family extends beyond neuronal tissue and that roundabout/slit interactions are likely to have a role in angiogenesis (PMID:11944987)
• We therefore hypothesize that expression of MRB is involved in regulating the migration of endothelial cells during tumor angiogenesis. (PMID:15894287)
• Expression of Robo1 is mainly in tumor cells, whereas Robo4 is primarily in endothelial cells of tumor vessels. Therefore, the Robo proteins provide potential target structures for the anti-tumorigenic and anti-angiogenic therapy of colorectal carcinoma. (PMID:16685377)
• 3-kb upstream promoter of human Robo4 contains information for cell type-specific expression in the intact endothelium. (PMID:17495228)
• ROBO4 mRNA decreases during pulmonary fibrosis and hypertension (PMID:17496152)
• No evidence for association between Gilles de la Tourette Syndrome and either the ROBO4 gene. Thus, this gene is unlikely to be the susceptibility genes contributing to GTS on 11q24. (PMID:17671968)
• One SNP of ROBO3 showed association with autism (PMID:18270976)
• role of the GABP-binding motif in mediating Robo4 expression in the intact endothelium (PMID:18519813)
• Robo1 is essential for Robo4-mediated filopodia induction (PMID:18948384)
• The knockdown of robo4 abrogated the chemotactic response of endothelial cells to serum but enhanced a chemokinetic response to Slit2, while robo1 knockdown cells do not display chemotactic response to serum or VEGF. (PMID:18980679)
• Investigated Robo4 in fibrovascular membranes (FVMs) from patients with proliferative diabetic retinopathy and in 2 cell lines. The level of Robo4 mRNA was high in FVMs. Found Robo4 may play a role in the formation of FVMs. (PMID:19495426)
• data reveal that a Slit2-Robo4-paxillin-GIT1 network inhibits the cellular protrusive activity underlying neovascularization and vascular leak, and identify a new therapeutic target for ameliorating diseases involving the vascular system (PMID:19855388)
• Activating with the soluble ligand Slit an endothelium-specific, Robo4-dependent signaling pathway that strengthens the vascular barrier, diminishing deleterious aspects of the host’s response to the pathogen-induced cytokine storm. (PMID:20375003)
• REVIEW: Robo4-dependent Slit signaling stabilizes the vasculature during pathologic angiogenesis and cytokine storm (PMID:21423011)
• Protein expression of Slit2/3 and Robo1/4 was also identified in OVCAR-3 and SKOV-3 cells. (PMID:21465248)
• targeting Slit2/Robo4 signaling may protect the integrity of the lymphatic barrier and limit the dissemination of HIV in the host. (PMID:22241990)
• Here I will discuss the regulation mechanism of Robo4 gene expression by transcription factors and epigenetic control. [Review] (PMID:23023422)
• SiRNA knockdown of Robo4 in pulmonary microvascular endothelial cells prevented Slit2 inhibition of Andes virus induced permeability demonstrating that Robo4 receptors determine pulmonary microvascular endothelial cells responsiveness to Slit2 (PMID:23702092)
• SLIT3-ROBO4 activation promotes vascular network formation in human engineered tissue and angiogenesis in vivo. (PMID:24090675)
• Slit2-Robo4 is a key regulator of endothelial inflammation, and its dysregulation during endotoxemia is a novel mechanism for LPS-induced vascular pathogenesis. (PMID:24272999)
• Endothelial cell-specific DNA methylation pattern of the Robo4 proximal promoter is determined during cell differentiation and contributes to regulation of EC-specific Robo4 gene expression. (PMID:24855053)
• Plasma Robo4 levels are increased, transiently, following cardiac surgery requiring CPB (PMID:25360813)
• This study demonistrated that roundabout 4 regulates blood-tumor barrier permeability through the modulation of ZO-1, Occludin, and Claudin-5 expression. (PMID:25470344)
• BM Robo4 expression can serve as a new biomarker to predict clinical outcomes in AML patients and Robo4 may serve as a potential therapeutic target in patients with higher Robo4 expression. (PMID:25794001)
• Robo4 suppressed glioma-induced endothelial cell proliferation, migration and tube formation in vitro by inhibiting VEGR2-mediated activation of PI3K/AKT and FAK signaling pathways. (PMID:25833462)
• Overexpression of Roundabout4 is associated with glioma. (PMID:25859844)
• Increased or decreased expression of Robo4 by stimulation or knockdown of HIF-1alpha suggesting that Robo4 is positively regulated by HIF-1alpha under normoxic and hypoxic conditions in microvascular endothelial cells in vitro. (PMID:26066603)
• results indicate that AP-1 complexes regulate Robo4 gene expression in endothelial cells (PMID:26459591)
• These results suggest that Slit2/Robo1 binding exerts an effect on cell migration, which is negatively regulated by Robo4, and Robo1 may function by interacting with CdGAP in HUVECs. (PMID:26713366)
• Low expression level of ROBO4 is associated with evasive resistance and disease progression in cancer. (PMID:26956051)
• there was a increase in Robo4 expression under hyperglycemic conditions, while there was a decrease under hypoxic and combined hypoxic and hyperglycemic conditions, suggesting Robo4 might play different roles in various stages of diabetic retinopathy (PMID:27041242)
• Results show that hyperglycemia-induced upregulation of Robo4 in retinal endothelial cells is directly mediated by transcription factor SP1 which increases the transcription of Robo4 via an additional binding site in Robo4 promoter. SP1/Robo4 can regulate the migration, monolayer permeability and angiogenesis of retinal endothelial cells under hyperglycemic conditions. (PMID:28341181)
• GM-CSF and IL-1beta. Taken together, we demonstrated novel Robo4 functions in inflammation, i.e., it promotes IL-6 production by endothelial cells and immune cells via crosstalk. (PMID:29137978)
• In human brain endothelial cells that were damaged by hypoxia plus IL-1beta, treatment with recombinant ANXA2 (rA2) rescued the expression of junctional proteins and decreased trans-endothelial permeability. The protective effects were mediated in part by interactions with F-actin and VE-cadherin, and the ability of rA2 to modulate signaling via Robo4 -paxillin- ARF6. (PMID:29786451)
• Nuclear Localization of Robo is Associated with Better Survival in Bladder Cancer. (PMID:30019121)
• Targeted sequencing of ROBO4 showed enrichment for rare variants in BAV/AscAA probands compared with controls. (PMID:30455415)
• Robo 4 is a tumor endothelial marker expressed in the vascular network of various tumor entities. (PMID:30662335)
• VEGF and Robo4 were co-expressed in FVMs from proliferative diabetic retinopathy (PDR) patients. In the early stages, VEGF was upregulated and contributed to retinopahy development, whereas, in the late stage, VEGF and Robo4 worked together to aggravate disease progression. However, miR-15a could downregulate VEGF and Robo4 to ameliorate Diabetic retinopathy development. (PMID:30980286)
• Regulatory mechanisms of Robo4 and their effects on angiogenesis. (PMID:31160487)
• PRC2 Components Maintain DNA Hypermethylation of the Upstream Promoter and Regulate Robo4 Expression in Endothelial Cells. (PMID:32238717)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Robo4	ENSMUSG00000032125
rattus_norvegicus	Robo4	ENSRNOG00000049289

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), ROBO3 (ENSG00000154134), 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 4 — Q8WZ75 (reviewed: Q8WZ75)

Alternative names: Magic roundabout

All UniProt accessions (2): Q8WZ75, B4DYV8

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for Slit proteins, at least for SLIT2, and seems to be involved in angiogenesis and vascular patterning. May mediate the inhibition of primary endothelial cell migration by Slit proteins. Involved in the maintenance of endothelial barrier organization and function.

Subunit / interactions. Interacts with SLIT2 and ENAH.

Tissue specificity. Specifically expressed in endothelial cells. Expressed in endothelial and intimal cells of the ascending aorta.

Disease relevance. Aortic valve disease 3 (AOVD3) [MIM:618496] A common defect in the aortic valve in which two rather than three leaflets are present. It is often associated with aortic valve calcification, stenosis and insufficiency. In extreme cases, the blood flow may be so restricted that the left ventricle fails to grow, resulting in hypoplastic left heart syndrome. AOVD3 features are bicuspid aortic valve, aortic valve stenosis, and ascending aortic aneurysm. Some patients have atrial septal defects. AOVD3 inheritance is autosomal dominant with incomplete penetrance. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity. Belongs to the immunoglobulin superfamily. ROBO family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8WZ75-1	1	yes
Q8WZ75-2	2
Q8WZ75-3	3

RefSeq proteins (2): NP_001288017, NP_061928* (*=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

Pfam: PF00041, PF07679, PF13927

UniProt features (44 total): sequence variant 12, sequence conflict 6, glycosylation site 5, domain 4, splice variant 4, region of interest 4, compositionally biased region 3, modified residue 2, disulfide bond 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WZ75-F1	57.67	0.23

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): 805, 938

Disulfide bonds (2): 53–114, 158–207

Glycosylation sites (5): 246, 360, 389, 396, 680

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 160 (showing top): GOBP_ENDOTHELIAL_CELL_DEVELOPMENT, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEURON_RECOGNITION, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOCC_CELL_SURFACE, GOBP_NEUROGENESIS, AAAYRNCTG_UNKNOWN, CAGCTG_AP4_Q5, GOBP_CELL_CELL_ADHESION, VART_KSHV_INFECTION_ANGIOGENIC_MARKERS_UP, GROSS_HYPOXIA_VIA_ELK3_UP, GOBP_BLOOD_VESSEL_MORPHOGENESIS, GOBP_ENDOTHELIUM_DEVELOPMENT, RYTTCCTG_ETS2_B, LEF1_Q6

GO Biological Process (9): angiogenesis (GO:0001525), homophilic cell-cell adhesion (GO:0007156), axon guidance (GO:0007411), regulation of cell migration (GO:0030334), blood vessel endothelial cell migration (GO:0043534), negative regulation of blood vessel endothelial cell migration (GO:0043537), establishment of endothelial barrier (GO:0061028), dendrite self-avoidance (GO:0070593), cell differentiation (GO:0030154)

GO Molecular Function (3): signaling receptor activity (GO:0038023), cell-cell adhesion mediator activity (GO:0098632), protein binding (GO:0005515)

GO Cellular Component (5): plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), membrane (GO:0016020), axon (GO:0030424), extracellular exosome (GO:0070062)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell-cell adhesion	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
axonogenesis	1
neuron projection guidance	1
cell migration	1
regulation of cell motility	1
endothelial cell migration	1
negative regulation of endothelial cell migration	1
blood vessel endothelial cell migration	1
regulation of blood vessel endothelial cell migration	1
endothelial cell development	1
neuron recognition	1
cellular developmental process	1
molecular transducer activity	1
cell adhesion mediator activity	1
binding	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
cellular anatomical structure	1
neuron projection	1
extracellular vesicle	1

Protein interactions and networks

STRING

1386 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ROBO4	SLIT3	O75094	998
ROBO4	SLIT2	O94813	996
ROBO4	SLIT1	O75093	979
ROBO4	UNC5B	Q8IZJ1	908
ROBO4	PXN	P49023	860
ROBO4	GIT1	Q9Y2X7	683
ROBO4	FN1	P02751	609
ROBO4	ROBO1	Q9Y6N7	589
ROBO4	ARHGAP39	Q9C0H5	577
ROBO4	NTN4	Q9HB63	553
ROBO4	VASN	Q6EMK4	515
ROBO4	CDH5	P33151	512
ROBO4	SEMA3E	O15041	503
ROBO4	CD93	Q9NPY3	488
ROBO4	PLXND1	Q9Y4D7	469

IntAct

11 interactions, top by confidence:

A	B	Type	Score
ROBO4	CEP19	psi-mi:“MI:0915”(physical association)	0.560
ROBO4	FLT1	psi-mi:“MI:0403”(colocalization)	0.430
TARM1	ROBO4	psi-mi:“MI:0915”(physical association)	0.400
ROBO1	ROBO4	psi-mi:“MI:0915”(physical association)	0.400
WAS	ROBO4	psi-mi:“MI:0915”(physical association)	0.370
WASL	ROBO4	psi-mi:“MI:0915”(physical association)	0.370
ROBO4	WIPF1	psi-mi:“MI:0915”(physical association)	0.370
FLT1	MTCL2	psi-mi:“MI:0914”(association)	0.350
CEP19	ROBO4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (10): ROBO4 (Affinity Capture-MS), SLIT2 (Affinity Capture-Western), CEP19 (Two-hybrid), ROBO4 (Proximity Label-MS), ROBO4 (Affinity Capture-MS), ROBO4 (Affinity Capture-MS), ROBO4 (Proximity Label-MS), RXRA (Reconstituted Complex), PPARG (Reconstituted Complex), THRB (Reconstituted Complex)

ESM2 similar proteins: A2APT9, A5PJC7, B0BN44, O94989, O95153, P14753, P19235, P25118, P36941, P40238, Q01114, Q07303, Q13671, Q2KL21, Q3U4N7, Q3UYR4, Q400G9, Q49LS3, Q5F267, Q5FWH6, Q5GH66, Q5JXC2, Q5R866, Q6UX68, Q6ZVH7, Q7TNF8, Q7Z3H0, Q80VJ8, Q80W87, Q8BG26, Q8BX43, Q8C310, Q8CII8, Q8MII8, Q8N386, Q8NBR0, Q8TE82, Q8WZ75, Q921Q7, Q93038

Diamond homologs: A0A087WV53, A1KZ92, A2AJ76, A4IFW2, A4IGL7, A6NDA9, B0BNK7, B0V2N1, D2HFT7, D3YXG0, D4A1J9, D4ABX8, F1NWE3, G5EG78, O15146, O73775, O75325, O94898, P07722, P15364, P20916, P20917, P23468, P43146, P48960, P53813, P70193, P70211, Q03142, Q08761, Q08879, Q13332, Q13449, Q1ENI8, Q1RMS4, Q1WIM1, Q21038, Q24372, Q26474, Q2Q421

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SLIT2	up-regulates	ROBO4	binding

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	15
Uncertain significance	215
Likely benign	26
Benign	24

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
1184826	NM_019055.6(ROBO4):c.2389G>T (p.Glu797Ter)	Likely pathogenic
1184827	NM_019055.6(ROBO4):c.703G>A (p.Val235Met)	Likely pathogenic
1333606	NM_019055.6(ROBO4):c.1146C>G (p.Tyr382Ter)	Likely pathogenic
1677958	NM_019055.6(ROBO4):c.679+1G>T	Likely pathogenic
2441673	NM_019055.6(ROBO4):c.980_981del (p.Ser327fs)	Likely pathogenic
3393140	NM_019055.6(ROBO4):c.1042_1048dup	Likely pathogenic
3780562	NM_019055.6(ROBO4):c.2041del (p.Leu681fs)	Likely pathogenic
560395	NM_019055.6(ROBO4):c.283G>A (p.Ala95Thr)	Likely pathogenic
560397	NM_019055.6(ROBO4):c.1233T>A (p.His411Gln)	Likely pathogenic
560399	NM_019055.6(ROBO4):c.740T>C (p.Val247Ala)	Likely pathogenic
560400	NM_019055.6(ROBO4):c.839A>C (p.Tyr280Ser)	Likely pathogenic
560401	NM_019055.6(ROBO4):c.1864G>C (p.Asp622His)	Likely pathogenic
560402	NM_019055.6(ROBO4):c.2245_2246delinsCT (p.Ala749Leu)	Likely pathogenic
560404	NM_019055.6(ROBO4):c.2056+1G>T	Likely pathogenic
560405	NM_019055.6(ROBO4):c.1601_1614del (p.Gly534fs)	Likely pathogenic

SpliceAI

3194 predictions. Top by Δscore:

Variant	Effect	Δscore
11:124887356:A:AC	donor_gain	1.0000
11:124887357:C:CC	donor_gain	1.0000
11:124887841:C:CC	acceptor_gain	1.0000
11:124895780:CTCA:C	donor_loss	1.0000
11:124895781:TCAC:T	donor_loss	1.0000
11:124895782:CACCT:C	donor_loss	1.0000
11:124895783:A:AC	donor_gain	1.0000
11:124895784:C:CC	donor_gain	1.0000
11:124895787:T:A	donor_gain	1.0000
11:124895908:GGGCT:G	acceptor_gain	1.0000
11:124895909:GGCT:G	acceptor_gain	1.0000
11:124895911:CT:C	acceptor_gain	1.0000
11:124895912:TC:T	acceptor_loss	1.0000
11:124895913:C:CC	acceptor_gain	1.0000
11:124896196:AC:A	donor_gain	1.0000
11:124896197:CC:C	donor_gain	1.0000
11:124896228:C:CA	donor_gain	1.0000
11:124896232:ATGT:A	donor_gain	1.0000
11:124885223:C:T	acceptor_gain	0.9900
11:124887057:C:CT	acceptor_gain	0.9900
11:124887352:TCTTA:T	donor_loss	0.9900
11:124887353:CTTAC:C	donor_loss	0.9900
11:124887354:TTA:T	donor_loss	0.9900
11:124887355:TAC:T	donor_loss	0.9900
11:124887356:ACTGG:A	donor_loss	0.9900
11:124887357:C:CG	donor_loss	0.9900
11:124887357:CTG:C	donor_gain	0.9900
11:124887357:CTGG:C	donor_gain	0.9900
11:124887357:CTGGG:C	donor_gain	0.9900
11:124887497:CTC:C	acceptor_gain	0.9900

AlphaMissense

6446 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:124897137:C:A	W65C	0.997
11:124897137:C:G	W65C	0.997
11:124897139:A:G	W65R	0.996
11:124897139:A:T	W65R	0.996
11:124896558:C:A	W171C	0.995
11:124896558:C:G	W171C	0.995
11:124895790:A:G	W268R	0.993
11:124895790:A:T	W268R	0.993
11:124895531:A:G	F321S	0.992
11:124896560:A:G	W171R	0.992
11:124896560:A:T	W171R	0.992
11:124893929:A:G	W479R	0.991
11:124893929:A:T	W479R	0.991
11:124895131:A:G	W367R	0.990
11:124895131:A:T	W367R	0.990
11:124896264:A:C	Y205D	0.989
11:124895788:C:A	W268C	0.988
11:124895788:C:G	W268C	0.988
11:124896991:C:T	C114Y	0.988
11:124897138:C:G	W65S	0.988
11:124895488:G:C	S335R	0.987
11:124895488:G:T	S335R	0.987
11:124895490:T:G	S335R	0.987
11:124896244:G:C	N211K	0.987
11:124896244:G:T	N211K	0.987
11:124896655:A:C	F139C	0.987
11:124896978:G:C	N118K	0.987
11:124896978:G:T	N118K	0.987
11:124896991:C:G	C114S	0.987
11:124896992:A:T	C114S	0.987

dbSNP variants (sampled 300 via entrez): RS1000168368 (11:124887593 T>C), RS1000250530 (11:124892151 C>G,T), RS1000516169 (11:124889911 C>A,T), RS1000641027 (11:124886083 C>T), RS1001075718 (11:124883762 G>A), RS1001203707 (11:124899346 T>C), RS1001242725 (11:124884429 T>C,G), RS1001255978 (11:124890995 T>C), RS1001287417 (11:124891240 T>C,G), RS1001765625 (11:124896380 A>C,G,T), RS1002078077 (11:124894487 T>C,G), RS1002266987 (11:124889191 T>C), RS1002322237 (11:124898279 A>C), RS1002373610 (11:124895343 C>T), RS1002524568 (11:124887157 G>A)

Disease associations

OMIM: gene MIM:607528 | disease phenotypes: MIM:607086, MIM:618496, MIM:142340

GenCC curated gene-disease

Disease	Classification	Inheritance
aortic valve disease 3	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
aortic valve disease 3	Moderate	AD

Mondo (4): thoracic aortic aneurysm (MONDO:0005396), familial thoracic aortic aneurysm and aortic dissection (MONDO:0019625), aortic valve disease 3 (MONDO:0032783), congenital diaphragmatic hernia (MONDO:0005711)

Orphanet (2): Familial thoracic aortic aneurysm and aortic dissection (Orphanet:91387), Congenital diaphragmatic hernia (Orphanet:2140)

HPO phenotypes

15 total (15 of 15 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000822	Hypertension
HP:0001631	Atrial septal defect
HP:0001647	Bicuspid aortic valve
HP:0001650	Aortic valve stenosis
HP:0001659	Aortic regurgitation
HP:0001680	Coarctation of aorta
HP:0002616	Aortic root aneurysm
HP:0004380	Aortic valve calcification
HP:0004383	Hypoplastic left ventricle
HP:0004933	Ascending aortic dissection
HP:0004962	Thoracic aorta calcification
HP:0005113	Aortic arch aneurysm
HP:0011103	Abnormal left ventricular outflow tract morphology
HP:0030148	Heart murmur

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002861_2	Breast cancer (survival)	1.000000e-09
GCST009936_18	Venous thromboembolism	9.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0000714	survival time

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D017545	Aortic Aneurysm, Thoracic	C14.907.055.239.125; C14.907.109.139.125
D065630	Hernias, Diaphragmatic, Congenital	C16.131.433; C23.300.707.960.500.116

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
ROBO4 EXPRESSION	Angiogenesis Inhibitor	Cancer	Sensitivity/Response	CIViC B	EID1166

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression, increases mutagenesis	3
Formaldehyde	decreases expression, increases expression	3
sodium arsenite	increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
bisphenol F	affects cotreatment, decreases methylation	1
sotorasib	affects cotreatment, decreases expression	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
terbufos	increases methylation	1
arsenite	affects binding, decreases reaction	1
cobaltous chloride	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
CD 437	decreases expression	1
3-(4’-hydroxy-3’-adamantylbiphenyl-4-yl)acrylic acid	decreases expression	1
abrine	increases expression	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
2,6-dichloro-(1,4)benzoquinone	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acetaminophen	decreases expression	1
Arsenic	affects methylation	1
Fonofos	increases methylation	1
Estradiol	affects cotreatment, increases expression	1
Malathion	decreases expression	1
Parathion	increases methylation	1
Triclosan	decreases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	decreases methylation	1
Okadaic Acid	increases expression	1
Copper Sulfate	increases expression	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_A5QJ	WMUi020-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00339053	PHASE4	UNKNOWN	Immunonutrition and Thoracoabdominal Aorta Aneurysm Repair
NCT02291718	PHASE4	COMPLETED	Thoracoabdominal Arortic CTA Study
NCT05213676	PHASE4	RECRUITING	De-implementing Inhaled Nitric Oxide for Congenital Diaphragmatic Hernia
NCT07247240	PHASE4	NOT_YET_RECRUITING	Efficacy of Inhaled Nitric Oxide in Congenital Diaphragmatic Hernia
NCT00257946	PHASE3	TERMINATED	Type of Material in Repair of Congenital Diaphragmatic Hernia
NCT03861182	PHASE3	TERMINATED	Contribution of PRF in CDH in Children With Prothetic Patch Closure
NCT06946576	PHASE3	NOT_YET_RECRUITING	Safety and Efficacy of Fetoscopic Endoluminal Tracheal Occlusion in Congenital Diaphragmatic Hernia
NCT07187206	PHASE3	RECRUITING	Safety and Efficacy of FETO in CDH Phase III
NCT00373438	PHASE2	UNKNOWN	Fetoscopic Tracheal Balloon Occlusion in Left Diaphragmatic Hernia
NCT00966823	PHASE2	TERMINATED	Fetal Tracheal Balloon Study in Diaphragmatic Hernia
NCT01302977	PHASE2	UNKNOWN	Fetal Tracheal Occlusion in Severe Diaphragmatic Hernia: a Randomized Trial
NCT01731509	PHASE2	UNKNOWN	Early FETO for Severe Congenital Diaphragmatic Hernia
NCT02875860	PHASE2	COMPLETED	‘TOTAL’ (Tracheal Occlusion To Accelerate Lung Growth) Trial
NCT02951130	PHASE2	COMPLETED	Milrinone in Congenital Diaphragmatic Hernia
NCT05201144	PHASE2	RECRUITING	A Trial of Phosphodiesterase-5 Inhibitor in Neonatal Congenital Diaphragmatic Hernia (TOP-CDH)
NCT01033214	PHASE1	UNKNOWN	ENTRUST - TAArget® Thoracic Stent Graft Clinical Trial
NCT03998631	PHASE1	UNKNOWN	Comparison of Carbon Dioxide and Saline Flush to Saline Flush in TEVAR and TAVI Procedures to Reduce Cerebral Ischemia
NCT03526588	PHASE1	TERMINATED	Umbilical Cord Blood Mononuclear Cells for Hypoxic Neurologic Injury in Infants With Congenital Diaphragmatic Hernia (CDH)
NCT00604799	PHASE2/PHASE3	COMPLETED	VALOR: The Talent Thoracic Stent Graft System Clinical Study
NCT07483177	PHASE1/PHASE2	NOT_YET_RECRUITING	HEART: Pilot Randomized Controlled Trial
NCT00111176	Not specified	COMPLETED	STARZ-TX2 Clinical Study: Study of Thoracic Aortic Aneurysm Repair With the Zenith TX2 Endovascular Graft
NCT00413231	Not specified	COMPLETED	Valor II: The Valiant Thoracic Stent Graft System Clinical Study
NCT00435942	Not specified	COMPLETED	Phase II Study of the Safety and Efficacy of the Relay Thoracic Stent-Graft
NCT00549315	Not specified	UNKNOWN	Clinical Study of Thoracic Aortic Aneurysm Exclusion
NCT00583817	Not specified	ENROLLING_BY_INVITATION	Endovascular Treatment of Thoracic Aortic Disease
NCT00597870	Not specified	COMPLETED	Physician-Sponsored IDE for the Talent Endoluminal Stent Graft System for the Treatment of Thoracic Lesions
NCT00805948	Not specified	TERMINATED	Post-Approval Clinical Study of the Talent Thoracic Stent Graft to Treat Thoracic Aortic Aneurysms (THRIVE)
NCT01082172	Not specified	COMPLETED	South American Thoracic Stent-Graft Study
NCT01327742	Not specified	APPROVED_FOR_MARKETING	Phase II Clinical Study of the Safety and Efficacy of the Relay Thoracic Stent-Graft
NCT01390181	Not specified	TERMINATED	The Effect of Losartan in Bicuspid Aortic Valve Patients
NCT01480206	Not specified	COMPLETED	Overlay of 3D Scans on Live Fluoroscopy for Endovascular Procedures in the Hybrid OR
NCT01839695	Not specified	COMPLETED	Safety and Efficacy of Valiant Mona LSA Stent Graft System
NCT02010892	Not specified	UNKNOWN	Effective Treatments for Thoracic Aortic Aneurysms (ETTAA Study): A Prospective Cohort Study
NCT02164201	Not specified	COMPLETED	Post Market Surveillance Study Evaluating BioFoam Surgical Matrix in Cardiovascular Surgery
NCT02256163	Not specified	COMPLETED	Identification of Genes and Pathogenesis Involved in Familial Thoracic Aortic Aneurysm
NCT02365454	Not specified	COMPLETED	NEXUS™ Aortic Arch Stent Graft System First In Man Study
NCT02735720	Not specified	TERMINATED	The CardiOvascular Remodeling Following Endovascular Aortic Repair (CORE) Study
NCT03142074	Not specified	RECRUITING	Biomechanical and Microstructural Properties of Ascending Aortic Aneurysms
NCT03440697	Not specified	ACTIVE_NOT_RECRUITING	Pathogenetic Basis of Aortopathy and Aortic Valve Disease
NCT03824626	Not specified	UNKNOWN	Biomechanical Reappraisal of Planning for Thoracic Endovascular Aortic Repair