UNC5B

Summary

UNC5B (unc-5 netrin receptor B, HGNC:12568) is a protein-coding gene on chromosome 10q22.1, encoding Netrin receptor UNC5B (Q8IZJ1). Receptor for netrin required for axon guidance.

This gene encodes a member of the netrin family of receptors. This particular protein mediates the repulsive effect of netrin-1 and is a vascular netrin receptor. This encoded protein is also in a group of proteins called dependence receptors (DpRs) which are involved in pro- and anti-apoptotic processes. Many DpRs are involved in embryogenesis and in cancer progression. Two alternatively spliced transcript variants have been described for this gene.

Source: NCBI Gene 219699 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 224 total
• MANE Select transcript: NM_170744

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12568
Approved symbol	UNC5B
Name	unc-5 netrin receptor B
Location	10q22.1
Locus type	gene with protein product
Status	Approved
Aliases	UNC5H2, p53RDL1
Ensembl gene	ENSG00000107731
Ensembl biotype	protein_coding
OMIM	607870
Entrez	219699

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000335350, ENST00000373192, ENST00000935473, ENST00000935474, ENST00000935475, ENST00000935476, ENST00000935477

RefSeq mRNA: 2 — MANE Select: NM_170744 NM_001244889, NM_170744

CCDS: CCDS58083, CCDS7309

Canonical transcript exons

ENST00000335350 — 17 exons

Exon	Start	End
ENSE00000708470	71292467	71292554
ENSE00000708471	71293405	71293573
ENSE00000708472	71293700	71293933
ENSE00000708473	71295811	71295960
ENSE00000708474	71296578	71296742
ENSE00000834345	71297909	71298090
ENSE00000987070	71299112	71302864
ENSE00001027371	71285326	71285429
ENSE00001027372	71284720	71284863
ENSE00001101245	71290915	71291109
ENSE00001101416	71288568	71288732
ENSE00001143393	71287598	71287765
ENSE00001143400	71286689	71286869
ENSE00001143429	71279821	71280045
ENSE00001249545	71291432	71291821
ENSE00001340805	71288958	71288990
ENSE00001391022	71212570	71213064

Expression profiles

Bgee: expression breadth ubiquitous, 266 present calls, max score 97.98.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.9916 / max 303.2654, expressed in 1411 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
105412	13.4313	1396
105413	0.2844	155
105414	0.2759	139

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
inferior vagus X ganglion	UBERON:0005363	97.98	gold quality
mucosa of paranasal sinus	UBERON:0005030	97.47	silver quality
subthalamic nucleus	UBERON:0001906	96.46	gold quality
tibia	UBERON:0000979	95.69	gold quality
substantia nigra pars reticulata	UBERON:0001966	95.26	gold quality
ventral tegmental area	UBERON:0002691	95.24	gold quality
lateral globus pallidus	UBERON:0002476	95.19	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.17	gold quality
pons	UBERON:0000988	94.82	gold quality
buccal mucosa cell	CL:0002336	94.74	gold quality
dorsal plus ventral thalamus	UBERON:0001897	94.74	gold quality
superior vestibular nucleus	UBERON:0007227	94.71	gold quality
seminal vesicle	UBERON:0000998	93.91	gold quality
medulla oblongata	UBERON:0001896	93.49	gold quality
substantia nigra pars compacta	UBERON:0001965	93.40	gold quality
pharyngeal mucosa	UBERON:0000355	92.43	gold quality
lower lobe of lung	UBERON:0008949	91.82	gold quality
penis	UBERON:0000989	90.57	gold quality
pancreatic ductal cell	CL:0002079	90.02	silver quality
gingival epithelium	UBERON:0001949	89.62	gold quality
gingiva	UBERON:0001828	89.49	gold quality
saphenous vein	UBERON:0007318	89.12	gold quality
nipple	UBERON:0002030	89.11	gold quality
periodontal ligament	UBERON:0008266	88.78	gold quality
paraflocculus	UBERON:0005351	88.21	gold quality
pylorus	UBERON:0001166	88.05	gold quality
cerebellar vermis	UBERON:0004720	87.98	silver quality
right hemisphere of cerebellum	UBERON:0014890	87.78	gold quality
spinal cord	UBERON:0002240	87.47	gold quality
cerebellum	UBERON:0002037	87.30	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-8271	yes	569.65
E-ANND-3	yes	17.45
E-CURD-112	yes	16.02
E-MTAB-5061	yes	13.52
E-GEOD-81608	yes	8.48
E-GEOD-83139	yes	7.76
E-GEOD-81547	yes	6.15

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP53

miRNA regulators (miRDB)

163 targeting UNC5B, 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-8485	100.00	77.57	4731
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-4728-5P	99.85	69.39	4718

Literature-anchored findings (GeneRIF, showing 40)

• Modulation of G(ialpha(2)) signaling by the axonal guidance of this protein (PMID:12359238)
• may represent tumor suppressor that inhibit tumor extension outside the region of netrin-1 availability by inducing apoptosis (PMID:12655055)
• PIKE-L acts as a downstream survival effector for netrin-1 through UNC5B in the nervous system (PMID:18469807)
• Knockdown of Netrin-4 expression in EC increased their ability to form tubular structures; Netrin-4 bound only to neogenin but not to Unc5B or Unc5C receptors (PMID:18719102)
• In this study, we show that Unc5B, a member of the netrin receptor family, interacts with neogenin as a coreceptor for RGMa. (PMID:19273616)
• Netrin-1 can promote the potential of proliferation and invasion of extravillous trophoblasts in vitro through its receptors neogenin and UNC5B. (PMID:19570425)
• Stronger expression of UNC5B and UNC5C receptors in synovial fibroblasts might contribute to the disordered phenotype of rheumatoid arthritis and osteoarthritis. (PMID:19822088)
• UNC5B receptor is localized to villous and extravillous cytotrophoblasts proximal to anchoring areas during the first trimester. (PMID:19826074)
• Down-regulation of UNC5b gene expression is related to angiogenesis of hepatocellular carcinoma. (PMID:20092749)
• The recruitment of PP2A to UNC5H2/B allows the activation of DAPk via a PP2A-mediated dephosphorylation and that this mechanism is involved in angiogenesis regulation. (PMID:21172653)
• Robo4 specifically binds to UNC5B, a vascular Netrin receptor, revealing unexpected interactions between two endothelial guidance receptors. (PMID:21238923)
• The mRNA expression analysis using tissue samples revealed that UNC5B mRNA was down-expressed in about 20% of CRC patients, and the patients with low-UNC5B-expression tumors showed a significantly higher recurrence rate after curative surgery. (PMID:21922135)
• Hypoxia-inducible factor 1 controls the expression of the uncoordinated-5-B receptor, but not of netrin-1, in first trimester human placenta (PMID:22252496)
• Low UNC5B expression was an independent risk factor for postoperative recurrence in patients with different stages and grades bladder cancer. (PMID:23055195)
• Reducing Unc5b levels in Sip1 knockout slices and brains rescues cell migration in cortical interneurons. (PMID:23312517)
• UNC5B was downregulated in kidney carcinoma. (PMID:23526078)
• UNC5B protein expressed in macrophages in hypoxic regions of atherosclerotic regions in human. (PMID:23599441)
• Higher netrin-1 and lower UNC5B expression in all prostate carcinoma cell lines indicated that netrin-1 and UNC5B could be used to predict metastasis. (PMID:23666553)
• Data indicate that dysregulation of expression of netrin-1 NTN1 in smooth muscle cell (SMC) and its chemorepulsive receptor UNC5B in macrophages are involved in the development of atherosclerosis and unstable plaques. (PMID:24122613)
• UNC5B expression is decreased in bladder cancer cells compared to normal bladder cell lines. (PMID:24528886)
• unc5b expression is greater in adipose tissue of obese versus lean subjects. (PMID:24584118)
• Our results suggest that UNC5B overexpression inhibits the proliferation and migration of bladder cancer cells by inducing cell cycle arrest at G2/M phase. (PMID:27846823)
• Negative regulation of Naa10 towards NTN1 and its receptor UNC5B were also detected upon treatment of all-trans retinoid acid, which was often used to induce morphological differentiation. (PMID:27910960)
• These findings point to a new important function of UNC5B and provide a potential basis for hASCs-mediated bone regeneration. (PMID:29158083)
• LncRNA TNRC6C-AS1 regulates UNC5B in thyroid cancer to influence cell proliferation, migration, and invasion as a competing endogenous RNA of miR-129-5p. (PMID:29893424)
• UNC5B-AS1 plays an important role in tumourigenesis and metastasis of PTC and may be a potential therapeutic target for PTC. (PMID:30805847)
• Netrin-1 and its receptor Unc5b may have essential roles in periodontal inflammation (PMID:31769036)
• Netrin-1 works with UNC5B to regulate angiogenesis in diabetic kidney disease. (PMID:31884526)
• silencing of UNC5B, an NTN4 receptor, abrogated the NTN4-induced cellular activities of SEPCs in vitro and blood-flow recovery and neovascularization in vivo in ischemic muscle by reducing EPC homing and incorporation. (PMID:31914695)
• LncRNA UNC5B-AS1 promotes malignant progression of prostate cancer by competitive binding to caspase-9. (PMID:32196578)
• Netrin-1 promotes naive pluripotency through Neo1 and Unc5b co-regulation of Wnt and MAPK signaling. (PMID:32231305)
• UNC5B mediates G2/M phase arrest of bladder cancer cells by binding to CDC14A and P53. (PMID:32372016)
• Polyomavirus Small T Antigen Induces Apoptosis in Mammalian Cells through the UNC5B Pathway in a PP2A-Dependent Manner. (PMID:32404521)
• UNC-5 netrin receptor B regulates adipogenesis of human adipose-derived stem cells through JNK pathway. (PMID:32762046)
• The intracellular domain of UNC5B facilities proliferation and metastasis of bladder cancer cells. (PMID:33345442)
• Long non-coding RNA PITPNA-AS1 regulates UNC5B expression in papillary thyroid cancer via sponging miR-129-5p. (PMID:33706585)
• UNC5B Promotes Vascular Endothelial Cell Senescence via the ROS-Mediated P53 Pathway. (PMID:34239689)
• A ligand-insensitive UNC5B splicing isoform regulates angiogenesis by promoting apoptosis. (PMID:34381052)
• Delta40p53 isoform up-regulates netrin-1/UNC5B expression and potentiates netrin-1 pro-oncogenic activity. (PMID:34470826)
• Netrin-1 induces the anti-apoptotic and pro-survival effects of B-ALL cells through the Unc5b-MAPK axis. (PMID:35974411)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	unc5b	ENSDARG00000033327
mus_musculus	Unc5b	ENSMUSG00000020099
rattus_norvegicus	Unc5b	ENSRNOG00000000567
drosophila_melanogaster	unc-5	FBGN0034013
caenorhabditis_elegans		WBGENE00006745

Paralogs (4): UNC5A (ENSG00000113763), UNC5CL (ENSG00000124602), UNC5D (ENSG00000156687), UNC5C (ENSG00000182168)

Protein

Protein identifiers

Netrin receptor UNC5B — Q8IZJ1 (reviewed: Q8IZJ1)

Alternative names: Protein unc-5 homolog 2, Protein unc-5 homolog B, p53-regulated receptor for death and life protein 1

All UniProt accessions (1): Q8IZJ1

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for netrin required for axon guidance. Mediates axon repulsion of neuronal growth cones in the developing nervous system upon ligand binding. Axon repulsion in growth cones may be caused by its association with DCC that may trigger signaling for repulsion. Functions as a netrin receptor that negatively regulates vascular branching during angiogenesis. Mediates retraction of tip cell filopodia on endothelial growth cones in response to netrin. It also acts as a dependence receptor required for apoptosis induction when not associated with netrin ligand. Mediates apoptosis by activating DAPK1. In the absence of NTN1, activates DAPK1 by reducing its autoinhibitory phosphorylation at Ser-308 thereby increasing its catalytic activity.

Subunit / interactions. Interacts with the cytoplasmic part of DCC. Interacts with GNAI2 via its cytoplasmic part. Interacts (via death domain) with DAPK1 (via death domain). Interacts (via extracellular domain) with FLRT3 (via extracellular domain); the interaction is direct. Interacts (via extracellular domain) with FLRT2 and FLRT3 (via extracellular domain), but has higher affinity for FLRT3. Identified in a complex with FLRT3 and ADGRL3; does not interact with ADGRL3 by itself.

Subcellular location. Cell membrane. Membrane raft.

Tissue specificity. Highly expressed in brain. Also expressed at lower level in developing lung, cartilage, kidney and hematopoietic and immune tissues.

Post-translational modifications. Phosphorylated on cytoplasmic tyrosine residues. Proteolytically cleaved by caspases during apoptosis. The cleavage does not take place when the receptor is associated with netrin ligand. Its cleavage by caspases is required to induce apoptosis. Palmitoylation is required for pro-apoptotic activity, but not for location at lipid rafts.

Induction. By p53/TP53.

Miscellaneous. Down-regulated in multiple cancers including colorectal, breast, ovary, uterus, stomach, lung, or kidney cancers.

Similarity. Belongs to the unc-5 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8IZJ1-1	1	yes
Q8IZJ1-2	2

RefSeq proteins (2): NP_001231818, NP_734465* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000488	Death_dom	Domain
IPR000884	TSP1_rpt	Repeat
IPR000906	ZU5_dom	Domain
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR013098	Ig_I-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR033772	UPA	Domain
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR036383	TSP1_rpt_sf	Homologous_superfamily
IPR037936	UNC5A-D	Family
IPR042156	Death_UNC5B	Domain
IPR057755	UNC5A-D-like_N	Domain

Pfam: PF00090, PF00531, PF00791, PF07679, PF17217, PF25609

UniProt features (33 total): disulfide bond 9, domain 6, region of interest 2, glycosylation site 2, topological domain 2, sequence variant 2, sequence conflict 2, signal peptide 1, chain 1, site 1, modified residue 1, lipid moiety-binding region 1, splice variant 1, transmembrane region 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IZJ1-F1	77.60	0.52

Functional residue map

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

Catalytic / active sites (1): 412–413 (cleavage; by caspase-3)

Post-translational modifications (2): 581, 403

Disulfide bonds (9): 69–130, 81–128, 174–225, 258–295, 262–299, 273–285, 314–348, 318–353, 326–338

Glycosylation sites (2): 222, 347

Mutagenesis-validated functional residues (1):

Position	Phenotype
412	abolishes cleavage by caspase-3 and subsequent induction of apoptosis.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-373752	Netrin-1 signaling
R-HSA-418886	Netrin mediated repulsion signals
R-HSA-418889	Caspase activation via Dependence Receptors in the absence of ligand

MSigDB gene sets: 199 (showing top): GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, BENPORATH_ES_WITH_H3K27ME3, PEREZ_TP63_TARGETS, PID_NETRIN_PATHWAY, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GOBP_NEUROGENESIS, LHX3_01, CLASPER_LYMPHATIC_VESSELS_DURING_METASTASIS_UP, GOBP_NEGATIVE_REGULATION_OF_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, NKX62_Q2, GOBP_APOPTOTIC_SIGNALING_PATHWAY, MARTINEZ_RB1_TARGETS_DN, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM3

GO Biological Process (8): angiogenesis (GO:0001525), apoptotic process (GO:0006915), anterior/posterior axon guidance (GO:0033564), negative regulation of neuron apoptotic process (GO:0043524), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), negative regulation of extrinsic apoptotic signaling pathway in absence of ligand (GO:2001240), signal transduction (GO:0007165), netrin-activated signaling pathway (GO:0038007)

GO Molecular Function (2): netrin receptor activity (GO:0005042), protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), membrane raft (GO:0045121), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Axon guidance	1
Netrin-1 signaling	1
Caspase activation via extrinsic apoptotic signalling pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
axon guidance	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
positive regulation of intracellular signal transduction	1
extrinsic apoptotic signaling pathway in absence of ligand	1
negative regulation of signal transduction in absence of ligand	1
negative regulation of extrinsic apoptotic signaling pathway	1
regulation of extrinsic apoptotic signaling pathway in absence of ligand	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell surface receptor signaling pathway	1
transmembrane signaling receptor activity	1
netrin-activated signaling pathway	1
binding	1
membrane	1
cell periphery	1
membrane microdomain	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1252 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UNC5B	NTN1	O95631	999
UNC5B	NEO1	Q92859	990
UNC5B	NTN4	Q9HB63	937
UNC5B	FLRT3	Q9NZU0	923
UNC5B	ROBO4	Q8WZ75	908
UNC5B	DCC	P43146	816
UNC5B	DSCAM	O60469	797
UNC5B	NTN3	O00634	729
UNC5B	DAPK1	P53355	728
UNC5B	ALOX12	P18054	717
UNC5B	RND1	Q92730	691
UNC5B	FLRT2	O43155	685
UNC5B	SLIT3	O75094	657
UNC5B	RGMA	Q96B86	649
UNC5B	FYN	P06241	634

IntAct

52 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
IGF1R	PIK3R2	psi-mi:“MI:2364”(proximity)	0.590
Agap2	UNC5B	psi-mi:“MI:0915”(physical association)	0.580
UNC5B	Agap2	psi-mi:“MI:0915”(physical association)	0.580
INSR	PIK3R2	psi-mi:“MI:2364”(proximity)	0.570
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
UNC5B	NEO1	psi-mi:“MI:0915”(physical association)	0.400
UNC5B	NTN1	psi-mi:“MI:0915”(physical association)	0.400
Dcc	UNC5B	psi-mi:“MI:0915”(physical association)	0.400
UNC5B	KCNA4	psi-mi:“MI:0915”(physical association)	0.400
M		psi-mi:“MI:0914”(association)	0.350
RNF149	CCDC85C	psi-mi:“MI:0914”(association)	0.350
LRRIQ1	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350
MFSD14A	FAM171A2	psi-mi:“MI:0914”(association)	0.350
SLC37A1	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC37A2	WWP2	psi-mi:“MI:0914”(association)	0.350
SLC4A1	UPK3BL1	psi-mi:“MI:0914”(association)	0.350
TMEM17	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
TMEM216	SNAP23	psi-mi:“MI:2364”(proximity)	0.270
BET1	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
CANX	ESYT2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (119): PPP2R1B (Affinity Capture-Western), PPP2R1B (Two-hybrid), DAPK1 (Two-hybrid), UNC5B (Affinity Capture-Western), UNC5B (Affinity Capture-Western), KIAA1524 (Affinity Capture-Western), UNC5B (Affinity Capture-MS), UNC5B (Affinity Capture-Western), UNC5B (Proximity Label-MS), UNC5B (Proximity Label-MS), UNC5B (Affinity Capture-MS), UNC5B (Proximity Label-MS), UNC5B (Proximity Label-MS), UNC5B (Proximity Label-MS), UNC5B (Proximity Label-MS)

ESM2 similar proteins: A0A8M9PFP2, A1X150, A2A863, A4IH88, B0S5G3, B2RXS4, F1LW30, F1R520, G5ED46, L7VG99, O08721, O08722, O08747, O60486, O73878, O94985, O95185, P10493, P14543, P16144, P35590, P54761, P55292, Q06806, Q0VCN6, Q14393, Q5FWR8, Q5R9Q9, Q61592, Q63772, Q64632, Q6DDG2, Q6Q0N0, Q6UXZ4, Q6ZN44, Q761X5, Q7T2Z5, Q8IZJ1, Q8K1S2, Q8K1S3

Diamond homologs: A0A0G2K2P5, A0A8P0N4K0, C5IAW9, F1LW30, O08721, O08722, O08747, O62683, O95049, O95185, O97758, P39447, P57105, Q07157, Q0P5E6, Q13424, Q28626, Q32LE7, Q3T0C9, Q5EBL8, Q5ZIK2, Q61234, Q6NXB2, Q6QA76, Q6R653, Q6UXZ4, Q6ZN44, Q761X5, Q7KRY7, Q7T2Z5, Q80VW5, Q86UL8, Q8IV45, Q8IZJ1, Q8JGT4, Q8K1S2, Q8K1S3, Q8K1S4, Q95168, Q9CZG9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
UNC5B	“down-regulates activity”	DCC	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 56 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
EPH-ephrin mediated repulsion of cells	6	32.1×	8e-06
EPH-Ephrin signaling	6	24.2×	2e-05
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	5	11.8×	1e-03
PIP3 activates AKT signaling	5	8.1×	4e-03
RAF/MAP kinase cascade	5	7.5×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
ephrin receptor signaling pathway	6	43.9×	2e-06
protein autophosphorylation	6	18.6×	1e-04
cell surface receptor protein tyrosine kinase signaling pathway	5	18.5×	6e-04
axon guidance	7	13.5×	1e-04
positive regulation of MAPK cascade	6	10.3×	2e-03
positive regulation of cell migration	7	9.2×	7e-04
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	5	8.3×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	181
Likely benign	14
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

3056 predictions. Top by Δscore:

Variant	Effect	Δscore
10:71280024:G:GT	donor_gain	1.0000
10:71280025:A:T	donor_gain	1.0000
10:71284715:CCCA:C	acceptor_loss	1.0000
10:71284716:CCAG:C	acceptor_loss	1.0000
10:71284718:A:AG	acceptor_gain	1.0000
10:71284718:A:T	acceptor_loss	1.0000
10:71284719:G:A	acceptor_loss	1.0000
10:71284719:G:GG	acceptor_gain	1.0000
10:71284860:GCCT:G	donor_gain	1.0000
10:71284864:G:GG	donor_gain	1.0000
10:71286684:T:A	acceptor_gain	1.0000
10:71286687:A:AG	acceptor_gain	1.0000
10:71286687:A:AT	acceptor_loss	1.0000
10:71286687:AG:A	acceptor_gain	1.0000
10:71286687:AGGT:A	acceptor_gain	1.0000
10:71286687:AGGTG:A	acceptor_gain	1.0000
10:71286688:G:A	acceptor_loss	1.0000
10:71286688:G:GG	acceptor_gain	1.0000
10:71286688:GG:G	acceptor_gain	1.0000
10:71286688:GGT:G	acceptor_gain	1.0000
10:71286688:GGTG:G	acceptor_gain	1.0000
10:71286688:GGTGG:G	acceptor_gain	1.0000
10:71286865:CTACG:C	donor_loss	1.0000
10:71286870:G:GG	donor_gain	1.0000
10:71287594:GCAGT:G	acceptor_loss	1.0000
10:71287595:CA:C	acceptor_loss	1.0000
10:71287596:A:AC	acceptor_loss	1.0000
10:71287596:A:AG	acceptor_gain	1.0000
10:71287596:AGT:A	acceptor_gain	1.0000
10:71287597:G:GT	acceptor_gain	1.0000

AlphaMissense

6133 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:71279946:T:A	C69S	1.000
10:71279946:T:C	C69R	1.000
10:71279947:G:C	C69S	1.000
10:71279948:C:G	C69W	1.000
10:71279977:T:C	F79S	1.000
10:71279982:T:A	C81S	1.000
10:71279983:G:C	C81S	1.000
10:71279996:G:C	W85C	1.000
10:71279996:G:T	W85C	1.000
10:71284797:T:C	C128R	1.000
10:71284799:C:G	C128W	1.000
10:71284803:T:C	C130R	1.000
10:71284805:C:G	C130W	1.000
10:71284810:C:A	A132D	1.000
10:71284814:G:C	W133C	1.000
10:71284814:G:T	W133C	1.000
10:71284852:T:A	V146D	1.000
10:71284861:C:A	A149D	1.000
10:71285329:T:C	L151P	1.000
10:71285397:T:A	C174S	1.000
10:71285397:T:C	C174R	1.000
10:71285398:G:C	C174S	1.000
10:71285399:C:G	C174W	1.000
10:71286695:T:A	W187R	1.000
10:71286695:T:C	W187R	1.000
10:71286697:G:C	W187C	1.000
10:71286697:G:T	W187C	1.000
10:71286765:T:C	L210P	1.000
10:71286803:T:G	Y223D	1.000
10:71286809:T:A	C225S	1.000

dbSNP variants (sampled 300 via entrez): RS1000005101 (10:71238025 C>T), RS1000010630 (10:71242906 G>A), RS1000088212 (10:71247891 C>G), RS1000088230 (10:71284399 A>C), RS1000157602 (10:71264422 A>C,T), RS1000169863 (10:71229013 C>T), RS1000207843 (10:71220686 TGTATGGTAA>T), RS1000228014 (10:71232448 G>C), RS1000240217 (10:71237852 T>C), RS1000250788 (10:71294938 C>G,T), RS1000256910 (10:71221512 A>G), RS1000288112 (10:71221318 C>T), RS1000288597 (10:71232215 C>T), RS1000403155 (10:71263837 G>C), RS1000411739 (10:71226664 C>T)

Disease associations

OMIM: gene MIM:607870 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): autism spectrum disorder (MONDO:0005258)

Orphanet (1): NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST000246_19	Attention deficit hyperactivity disorder	4.000000e-06
GCST001670_3	Vitiligo	2.000000e-08
GCST002875_50	Diisocyanate-induced asthma	7.000000e-06
GCST007576_186	Chronotype	2.000000e-08
GCST007576_436	Chronotype	1.000000e-07
GCST010546_20	Problematic alcohol use	4.000000e-08
GCST90013538_4	Coronary artery aneurysm in Kawasaki disease	4.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006995	response to diisocyanate
EFO:0008328	chronotype measurement
EFO:0009458	alcohol use disorder measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	5
sodium arsenite	decreases expression, increases expression	4
bisphenol A	decreases expression, decreases methylation, increases expression	3
Acetaminophen	decreases expression, affects cotreatment, increases expression	3
Cyclosporine	increases expression	3
methylmercuric chloride	increases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression, increases expression	2
Benzo(a)pyrene	increases methylation, affects methylation	2
Estradiol	decreases expression, increases expression, affects cotreatment	2
Phenobarbital	affects expression, increases expression	2
Aflatoxin B1	affects methylation, decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
propionaldehyde	increases expression	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	decreases expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
zinc chloride	increases expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	affects methylation	1
ferrous chloride	decreases expression	1
aflatoxin B2	increases methylation	1
cupric chloride	decreases expression	1
hydroquinone	increases expression	1
pentanal	increases expression	1
cordycepin	affects expression	1
phenethyl isothiocyanate	increases expression	1
perfluoro-n-nonanoic acid	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	PHASE3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD
NCT06229210	PHASE3	RECRUITING	Safety and Tolerability Trial of Lumateperone in Pediatric Patients With Schizophrenia, Bipolar Disorder or Autism Spectrum Disorder