UVRAG

Summary

UVRAG (UV radiation resistance associated, HGNC:12640) is a protein-coding gene on chromosome 11q13.5, encoding UV radiation resistance-associated gene protein (Q9P2Y5). Versatile protein that is involved in regulation of different cellular pathways implicated in membrane trafficking.

This gene complements the ultraviolet sensitivity of xeroderma pigmentosum group C cells and encodes a protein with a C2 domain. The protein activates the Beclin1-PI(3)KC3 complex, promoting autophagy and suppressing the proliferation and tumorigenicity of human colon cancer cells. Chromosomal aberrations involving this gene are associated with left-right axis malformation and mutations in this gene have been associated with colon cancer.

Source: NCBI Gene 7405 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 125 total
• Druggable target: yes
• MANE Select transcript: NM_003369

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12640
Approved symbol	UVRAG
Name	UV radiation resistance associated
Location	11q13.5
Locus type	gene with protein product
Status	Approved
Aliases	VPS38
Ensembl gene	ENSG00000198382
Ensembl biotype	protein_coding
OMIM	602493
Entrez	7405

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 8 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000356136, ENST00000525183, ENST00000525872, ENST00000528264, ENST00000528420, ENST00000530501, ENST00000531818, ENST00000532130, ENST00000533454, ENST00000876952, ENST00000969466

RefSeq mRNA: 5 — MANE Select: NM_003369 NM_001386671, NM_001386672, NM_001386673, NM_001386674, NM_003369

CCDS: CCDS8241

Canonical transcript exons

ENST00000356136 — 15 exons

Exon	Start	End
ENSE00000927643	76065710	76065788
ENSE00000927644	76115924	76116015
ENSE00001039954	75888829	75888903
ENSE00001039968	75911954	75912039
ENSE00001153107	75815210	75815524
ENSE00001228370	76140711	76144232
ENSE00003479735	76004005	76004089
ENSE00003507207	75879879	75880040
ENSE00003540595	75851883	75852000
ENSE00003569079	75861746	75861780
ENSE00003616626	76008807	76008867
ENSE00003647343	76007534	76007621
ENSE00003658476	76016815	76016980
ENSE00003693028	75983387	75983513
ENSE00003784097	75961444	75961549

Expression profiles

Bgee: expression breadth ubiquitous, 279 present calls, max score 95.62.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.1525 / max 699.8821, expressed in 1812 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
115933	21.1525	1812

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	95.62	gold quality
corpus callosum	UBERON:0002336	92.74	gold quality
calcaneal tendon	UBERON:0003701	91.70	gold quality
subcutaneous adipose tissue	UBERON:0002190	91.00	gold quality
adipose tissue	UBERON:0001013	90.51	gold quality
connective tissue	UBERON:0002384	90.13	gold quality
colonic epithelium	UBERON:0000397	90.00	gold quality
adipose tissue of abdominal region	UBERON:0007808	89.77	gold quality
omental fat pad	UBERON:0010414	89.63	gold quality
peritoneum	UBERON:0002358	89.62	gold quality
monocyte	CL:0000576	88.96	gold quality
parietal pleura	UBERON:0002400	88.83	gold quality
leukocyte	CL:0000738	88.80	gold quality
mononuclear cell	CL:0000842	88.74	gold quality
lymph node	UBERON:0000029	88.46	gold quality
tonsil	UBERON:0002372	88.22	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.14	gold quality
tendon	UBERON:0000043	87.68	gold quality
sural nerve	UBERON:0015488	87.61	gold quality
paraflocculus	UBERON:0005351	87.60	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.59	gold quality
pleura	UBERON:0000977	87.53	gold quality
granulocyte	CL:0000094	87.44	gold quality
tibia	UBERON:0000979	87.43	gold quality
popliteal artery	UBERON:0002250	87.37	gold quality
tibial artery	UBERON:0007610	87.36	gold quality
cortical plate	UBERON:0005343	86.85	gold quality
middle frontal gyrus	UBERON:0002702	86.81	gold quality
bone marrow cell	CL:0002092	86.56	gold quality
frontal pole	UBERON:0002795	86.53	silver quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	5.92
E-MTAB-11011	no	583.88
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYCN

miRNA regulators (miRDB)

111 targeting UVRAG, 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-190A-3P	100.00	80.35	5520
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-8076	99.78	68.52	1170
HSA-MIR-1299	99.77	71.24	2389

Literature-anchored findings (GeneRIF, showing 34)

• UVRAG: a new player in autophagy and tumor cell growth. (PMID:17106237)
• Frameshift mutations in the polyadenine tract in UVRAG gene are present in gastric carcinomas. (PMID:18495205)
• Data suggest that a Beclin1-binding autophagic tumour suppressor, UVRAG, interacts with the class C Vps complex, a key component of the endosomal fusion machinery. (PMID:18552835)
• Bcl-xL and UVRAG cause a monomer-dimer switch in Beclin1 (PMID:18641390)
• These results suggest that mammalian cells have at least two distinct class III PI3-kinase complexes, and that beclin 1 interacts distinctly with mammalian Atg14 and UVRAG in two of these complexes. (PMID:18843052)
• There is an association of UVRAG polymorphisms with susceptibility to non-segmental vitiligo in a Korean sample. (PMID:20163458)
• A specific sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 regulates both receptor degradation and cytokinesis, whereas ATG14L, a PI3K-III subunit involved in autophagy, is not required. (PMID:20643123)
• Data indicate that mechanisms other than autophagy contribute to the tumorigenicity of microsatellite unstable colon carcinomas with monoallelic UVRAG mutation. (PMID:20724836)
• UVRAG has an essential role in the intrinsic mitochondrial pathway of apoptosis by regulating the localization of Bax. (PMID:21597469)
• UVRAG has cytoprotective functions in the cytosol that control the localization of Bax in tumor cells exposed to apoptotic stimuli (PMID:21606679)
• analysis of how the Beclin1 coiled-coil domain interface regulates homodimer and heterodimer formation with Atg14L and UVRAG (PMID:22314358)
• in Escherichia coli-containing phagosomes of mouse macrophages, Slamf1 interacts with the class III PI3K Vps34 in a complex with Beclin-1 and UVRAG (PMID:22493499)
• UVRAG promotes DNA double-strand-break repair by directly binding and activating DNA-PK in nonhomologous end joining. Disruption of UVRAG increases genetic instability and sensitivity of cells to irradiation. (PMID:22542840)
• Akt1 may inhibit autophagy by decreasing UVRAG expression, which also sensitizes cancer cells to UV irradiation. (PMID:23200933)
• UVRAG is required for virus entry through combinatorial interaction with the class C-Vps complex and SNAREs. (PMID:24550300)
• The reports that Grb2, when in excess, interacts with ultraviolet radiation resistance-associated gene protein (UVRAG) under excess conditions of AICD-Grb2 or Grb2. (PMID:24882360)
• Beclin 1 and UVRAG confer protection against radiation-induced DNA DNA double strand breaks and may maintain centrosome stability in established tumor cells. (PMID:24956373)
• Dephosphorylation of UVRAG facilitates the lysosomal degradation of epidermal growth factor receptor (EGFR), reduces EGFR signaling, and suppresses cancer cell proliferation and tumor growth. (PMID:25533187)
• HCV, by differentially inducing the expression of Rubicon and UVRAG, temporally regulated the autophagic flux to enhance its replication. (PMID:25807108)
• tubulation requires mTOR activity, and we identified two direct mTOR phosphorylation sites on UVRAG (S550 and S571) that activate VPS34. (PMID:26139536)
• UVRAG frameshift is expressed as a truncated protein in colorectal cancer with microsatellite instability and promotes tumorigenesis. UVRAG(FS) expression renders cells more sensitive to standard chemotherapy regimen due to a DNA repair defect. (PMID:26234763)
• Under-expression of UVRAG is associated with colorectal cancer. (PMID:26717041)
• UVRAG is a regulator of CRL4(DDB2)-mediated nucleotide excision repair and its expression levels may influence melanoma predisposition. (PMID:27203177)
• UVRAG plays an essential role in protecting cells from UV-induced DNA damage by activating the nucleotide excision repair pathway (PMID:27439570)
• miR-216b enhances the efficacy of vemurafenib and reverses drug resistance by targeting Beclin-1, UVRAG and ATG5 in melanoma. (PMID:28982601)
• Our findings suggest that up-regulation of UVRAG by HDAC1 inhibition potentiates DNA-damage-mediated cell death in colorectal cancer cells (PMID:29277783)
• our study showed that the expression of miR-125b-5p is downregulated in peripheral blood mononuclear cells of systemic lupus erythematosus patients, accompanied by increased UVRAG expression and autophagy activation (PMID:29710477)
• To induce the redistribution of Beclin 1 among its self-associated form or Atg14L/UVRAG-containing complexes enhances both autophagy and endolysosomal trafficking. (PMID:29866835)
• results establish UVRAG as an important effector for melanocytes’ response to alpha-MSH signaling as a direct target of MITF and reveal the molecular basis underlying the association between oncogenic BRAF and compromised UV protection in melanoma. (PMID:30061422)
• miR183 inhibits starvationinduced autophagy and apoptosis by targeting UVRAG in human gastric cancer cells. (PMID:30221685)
• UVRAG is ubiquitinated by SMURF1 at lysine residues 517 and 559, which decreases the association of UVRAG with RUBCN and promotes autophagosome maturation. (PMID:30686098)
• GORASP2/GRASP55 collaborates with the PtdIns3K UVRAG complex to facilitate autophagosome-lysosome fusion. (PMID:30894053)
• TNF-alpha-dependent neuronal necroptosis regulated in Alzheimer’s disease by coordination of RIPK1-p62 complex with autophagic UVRAG. (PMID:34646380)
• UVRAG: orchestrating the initiation of reticulophagy. (PMID:38054642)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	uvrag	ENSDARG00000023815
mus_musculus	Uvrag	ENSMUSG00000035354
rattus_norvegicus	Uvrag	ENSRNOG00000016206
drosophila_melanogaster	Uvrag	FBGN0032499
caenorhabditis_elegans	T23G11.7	WBGENE00011972
caenorhabditis_elegans		WBGENE00021319

Protein

Protein identifiers

UV radiation resistance-associated gene protein — Q9P2Y5 (reviewed: Q9P2Y5)

Alternative names: p63

All UniProt accessions (4): E9PK00, E9PR71, Q9P2Y5, H0YDD1

UniProt curated annotations — full annotation on UniProt →

Function. Versatile protein that is involved in regulation of different cellular pathways implicated in membrane trafficking. Involved in regulation of the COPI-dependent retrograde transport from Golgi and the endoplasmic reticulum by associating with the NRZ complex; the function is dependent on its binding to phosphatidylinositol 3-phosphate (PtdIns(3)P). During autophagy acts as a regulatory subunit of the alternative PI3K complex II (PI3KC3-C2) that mediates formation of phosphatidylinositol 3-phosphate and is believed to be involved in maturation of autophagosomes and endocytosis. Activates lipid kinase activity of PIK3C3. Involved in the regulation of degradative endocytic trafficking and cytokinesis, and in regulation of ATG9A transport from the Golgi to the autophagosome; the functions seems to implicate its association with PI3KC3-C2. Involved in maturation of autophagosomes and degradative endocytic trafficking independently of BECN1 but depending on its association with a class C Vps complex (possibly the HOPS complex); the association is also proposed to promote autophagosome recruitment and activation of Rab7 and endosome-endosome fusion events. Enhances class C Vps complex (possibly HOPS complex) association with a SNARE complex and promotes fusogenic SNARE complex formation during late endocytic membrane fusion. In case of negative-strand RNA virus infection is required for efficient virus entry, promotes endocytic transport of virions and is implicated in a VAMP8-specific fusogenic SNARE complex assembly. Involved in maintaining chromosomal stability. Promotes DNA double-strand break (DSB) repair by association with DNA-dependent protein kinase complex DNA-PK and activating it in non-homologous end joining (NHEJ). Required for centrosome stability and proper chromosome segregation.

Subunit / interactions. Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex II (PI3KC3-C2) in which the core composed of the catalytic subunit PIK3C3, the regulatory subunit PIK3R4 and BECN1 is associated with UVRAG; in the complex interacts directly with BECN1. PI3KC3-C2 can associate with further regulatory subunits such as RUBCN and probably SH3GLB1/Bif-1. Interacts with SH3GLB1; UVRAG bridges the interaction to BECN1 indicative for an association with the PI3K complex PI3KC3-C2. Interacts with RINT1. Associates with the NRZ complex under basal conditions and dissociates from it under autophagy conditions to associate with the PI3K complex; these complex associations seem to be mutually exclusive. Interacts with VPS16; VPS11; VPS18; VPS33 (VPS33A or VPS33B) and VPS39; indicative for an association with a class C Vps tethering complex (possibly the HOPS complex). Interacts with RAB7A; RAB7A competes with UVRAG for RUBCN binding. Interacts with STX7, VTI1B, STX8. Interacts with PRKDC, XRCC6 and XRCC5; indicative for an association with the DNA-dependent protein kinase complex DNA-PK. Interacts with CEP63. Directly interacts with FEZ1 and SCOC; the interaction with SCOC is reduced by amino acid starvation, but the complex is stabilized in the presence of FEZ1. Interacts with BECN1P1/BECN2. Interacts with SLAMF1. Interacts with RUBCNL/PACER; promoting targeting of UVRAG to autophagosome. Interacts with WNK1.

Subcellular location. Late endosome. Lysosome. Cytoplasmic vesicle. Autophagosome. Early endosome. Endoplasmic reticulum. Midbody. Chromosome. Centromere.

Tissue specificity. Highly expressed in brain, lung, kidney and liver.

Post-translational modifications. Phosphorylated at Ser-498 by MTOR under basal conditions; increases the interaction with RUBCN implicated in inhibitory effect of RUBCN on PI3KC3 and decreases interaction with RAB7,A and VPS16 and VPS39 (indicative for a class C Vps complex, possibly the HOPS complex).

Disease relevance. A chromosomal aberration involving UVRAG has been observed in a patient with heterotaxy (left-right axis malformation). Inversion Inv(11)(q13.5;q25).

Isoforms (2)

UniProt ID	Names	Canonical?
Q9P2Y5-1	1	yes
Q9P2Y5-2	2

RefSeq proteins (5): NP_001373600, NP_001373601, NP_001373602, NP_001373603, NP_003360* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR018791	UV_resistance/autophagy_Atg14	Family
IPR035892	C2_domain_sf	Homologous_superfamily

Pfam: PF00168, PF10186

Enzyme classification (BRENDA):

• EC 2.7.1.137 — phosphatidylinositol 3-kinase (BRENDA: 29 organisms, 131 substrates, 146 inhibitors, 16 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.03–44	7
PHOSPHATIDYLINOSITOL	0.034–64	3
PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE	0.004–15	2
PHOSPHATIDYLINOSITOL 4-PHOSPHATE	0.009–10	2
1,2-DIOCTANOYLPHOSPHATIDYLINOSITOL 4,5-DIPHOSPHA	0.05	1
PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE	0.011	1

UniProt features (25 total): modified residue 10, region of interest 5, compositionally biased region 4, chain 1, domain 1, splice variant 1, sequence variant 1, mutagenesis site 1, coiled-coil region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9ZPD	ELECTRON MICROSCOPY	3.38
9ZPC	ELECTRON MICROSCOPY	3.83
7BL1	ELECTRON MICROSCOPY	9.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P2Y5-F1	69.04	0.33

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 (10): 493, 498, 508, 518, 522, 549, 550, 571, 582, 689

Mutagenesis-validated functional residues (1):

Position	Phenotype
498	abolishes phosphorylation by mtor, decreases interaction with rubcn, increases interaction with vps16 and vps39, promote

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1632852	Macroautophagy
R-HSA-9679504	Translation of Replicase and Assembly of the Replication Transcription Complex
R-HSA-9694676	Translation of Replicase and Assembly of the Replication Transcription Complex
R-HSA-9754560	SARS-CoV-2 modulates autophagy

MSigDB gene sets: 306 (showing top): GOBP_REGULATION_OF_AUTOPHAGY, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GOBP_REGULATION_OF_PHOSPHORYLATION, GOCC_VACUOLAR_MEMBRANE, GOBP_VESICLE_ORGANIZATION, GEORGES_CELL_CYCLE_MIR192_TARGETS, GOBP_MEMBRANE_FUSION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_DISASSEMBLY, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, chr11q13

GO Biological Process (21): DNA repair (GO:0006281), retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum (GO:0006890), autophagy (GO:0006914), spindle organization (GO:0007051), chromosome segregation (GO:0007059), centrosome cycle (GO:0007098), regulation of autophagy (GO:0010506), regulation of cytokinesis (GO:0032465), receptor catabolic process (GO:0032801), SNARE complex assembly (GO:0035493), phosphatidylinositol-3-phosphate biosynthetic process (GO:0036092), symbiont entry into host cell (GO:0046718), maintenance of Golgi location (GO:0051684), regulation of protein serine/threonine kinase activity (GO:0071900), multivesicular body sorting pathway (GO:0071985), autophagosome maturation (GO:0097352), double-strand break repair via classical nonhomologous end joining (GO:0097680), positive regulation of autophagosome maturation (GO:1901098), DNA damage response (GO:0006974), vesicle-mediated transport (GO:0016192), protein-containing complex organization (GO:0043933)

GO Molecular Function (3): SNARE binding (GO:0000149), SH3 domain binding (GO:0017124), protein binding (GO:0005515)

GO Cellular Component (19): lytic vacuole (GO:0000323), autophagosome membrane (GO:0000421), chromosome, centromeric region (GO:0000775), cytoplasm (GO:0005737), lysosome (GO:0005764), endosome (GO:0005768), early endosome (GO:0005769), late endosome (GO:0005770), endoplasmic reticulum (GO:0005783), centrosome (GO:0005813), midbody (GO:0030496), endoplasmic reticulum-Golgi intermediate compartment membrane (GO:0033116), phosphatidylinositol 3-kinase complex, class III (GO:0035032), phagocytic vesicle (GO:0045335), chromosome (GO:0005694), autophagosome (GO:0005776), cytoplasmic vesicle (GO:0031410), protein-containing complex (GO:0032991), DNA-dependent protein kinase complex (GO:0070418)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Autophagy	1
SARS-CoV-1 Infection	1
Early SARS-CoV-2 Infection Events	1
SARS-CoV-2-host interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell cycle process	3
vacuole	2
cellular anatomical structure	2
endomembrane system	2
endosome	2
cytoplasm	2
DNA metabolic process	1
DNA damage response	1
Golgi vesicle transport	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
microtubule cytoskeleton organization	1
microtubule organizing center organization	1
autophagy	1
regulation of catabolic process	1
cytokinesis	1
regulation of cell cycle process	1
regulation of cell division	1
macromolecule catabolic process	1
receptor metabolic process	1
vesicle fusion	1
protein-containing complex assembly	1
phosphatidylinositol phosphate biosynthetic process	1
viral life cycle	1
symbiont entry into host	1
Golgi localization	1
maintenance of organelle location	1
protein serine/threonine kinase activity	1
regulation of protein kinase activity	1
vesicle-mediated transport	1
macroautophagy	1
protein-containing complex disassembly	1
double-strand break repair via nonhomologous end joining	1
positive regulation of organelle organization	1
positive regulation of macroautophagy	1
positive regulation of protein-containing complex disassembly	1
autophagosome maturation	1
regulation of autophagosome maturation	1
cellular response to stress	1

Protein interactions and networks

STRING

1590 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UVRAG	ATG14	Q6ZNE5	999
UVRAG	PIK3C3	Q8NEB9	999
UVRAG	BECN1	Q14457	999
UVRAG	PIK3R4	Q99570	999
UVRAG	RUBCN	Q92622	998
UVRAG	AMBRA1	Q9C0C7	997
UVRAG	SH3GLB1	Q9Y371	996
UVRAG	BCL2	P10415	974
UVRAG	VPS16	Q9H269	938
UVRAG	NRBF2	Q96F24	910
UVRAG	ATG7	O95352	891
UVRAG	ATG5	Q9H1Y0	845
UVRAG	ATG12	O94817	841
UVRAG	ATG13	O75143	812
UVRAG	ATG3	Q9NT62	806

IntAct

158 interactions, top by confidence:

A	B	Type	Score
BECN1	ATG14	psi-mi:“MI:0914”(association)	0.980
UVRAG	BECN1	psi-mi:“MI:0915”(physical association)	0.970
BECN1	PIK3C3	psi-mi:“MI:0915”(physical association)	0.970
UVRAG	BECN1	psi-mi:“MI:0914”(association)	0.970
BECN1	UVRAG	psi-mi:“MI:0407”(direct interaction)	0.970
BECN1	UVRAG	psi-mi:“MI:0915”(physical association)	0.970
PIK3C3	BECN1	psi-mi:“MI:0914”(association)	0.970
BECN1	PIK3C3	psi-mi:“MI:0914”(association)	0.970
BECN1	UVRAG	psi-mi:“MI:0914”(association)	0.970
BECN1	BCL2	psi-mi:“MI:0914”(association)	0.950
UVRAG	PIK3C3	psi-mi:“MI:0914”(association)	0.940
UVRAG	PIK3C3	psi-mi:“MI:0915”(physical association)	0.940
RUBCN	BECN1	psi-mi:“MI:0914”(association)	0.920

BioGRID (189): UVRAG (Reconstituted Complex), UVRAG (Affinity Capture-Western), BECN1 (Affinity Capture-Western), PIK3C3 (Affinity Capture-Western), UVRAG (Affinity Capture-Western), UVRAG (Affinity Capture-Western), BECN1 (Affinity Capture-Western), UVRAG (Reconstituted Complex), UVRAG (Affinity Capture-MS), UVRAG (Affinity Capture-Western), USP18 (Affinity Capture-Western), UVRAG (Affinity Capture-MS), UVRAG (Affinity Capture-MS), UVRAG (Affinity Capture-MS), UVRAG (Affinity Capture-MS)

ESM2 similar proteins: A7UA95, A9ZLX4, B0V207, B5KFD7, D4ACE5, E7F221, E7FCN8, F6U5F9, O00750, O08764, O54828, P49805, P56720, Q00IB7, Q059U7, Q05AA6, Q0QWG9, Q13322, Q1JPG0, Q2I0E5, Q3B7M3, Q3UMR0, Q5F479, Q5JV73, Q60416, Q62130, Q62925, Q6NVC9, Q6NXD8, Q7L4E1, Q80TI1, Q8BK03, Q8BYR5, Q8C0V9, Q8C6B2, Q8IY22, Q8K245, Q8N5H7, Q92574, Q9BXL6

Diamond homologs: Q8K245, Q8S9J3, Q9P2Y5, Q9VK07

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
UVRAG	“up-regulates activity”	BECN1	binding
UVRAG	“up-regulates activity”	PIK3C3	binding
UVRAG	“up-regulates activity”	RINT1	binding
ZRANB1	“up-regulates activity”	UVRAG	deubiquitination
SMURF1	“down-regulates activity”	UVRAG	ubiquitination
MTOR	“up-regulates activity”	UVRAG	phosphorylation
UVRAG	“form complex”	“Vps34 Complex II”	binding
TFE3	“up-regulates quantity by expression”	UVRAG	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 73 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
Activation of BAD and translocation to mitochondria	8	101.5×	1e-12
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	78.4×	1e-10
RNA Polymerase III Chain Elongation	7	74.0×	2e-10
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	67.2×	5e-09
Activation of BH3-only proteins	8	66.2×	3e-11
RNA Polymerase III Transcription Termination	7	57.9×	7e-10
RNA Polymerase III Transcription Initiation From Type 2 Promoter	8	56.4×	9e-11
RNA Polymerase III Transcription Initiation From Type 1 Promoter	8	54.4×	9e-11

GO biological processes:

GO term	Partners	Fold	FDR
cellular response to glucose starvation	8	39.1×	3e-08
protein targeting	5	26.6×	2e-04
autophagosome maturation	5	25.4×	3e-04
regulation of macroautophagy	5	21.4×	5e-04
phosphatidylinositol 3-kinase/protein kinase B signal transduction	7	21.4×	2e-05
autophagy	8	12.8×	5e-05
intracellular protein localization	7	10.6×	5e-04
defense response to virus	7	7.0×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	97
Likely benign	5
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

5273 predictions. Top by Δscore:

Variant	Effect	Δscore
11:75851870:T:TA	acceptor_gain	1.0000
11:75851874:A:AG	acceptor_gain	1.0000
11:75851875:T:G	acceptor_gain	1.0000
11:75851881:A:AG	acceptor_gain	1.0000
11:75851881:AGC:A	acceptor_gain	1.0000
11:75851881:AGCG:A	acceptor_gain	1.0000
11:75851882:G:GT	acceptor_gain	1.0000
11:75851882:GC:G	acceptor_gain	1.0000
11:75851882:GCG:G	acceptor_gain	1.0000
11:75851882:GCGG:G	acceptor_gain	1.0000
11:75851882:GCGGC:G	acceptor_gain	1.0000
11:75851978:T:TA	donor_gain	1.0000
11:75851979:A:AA	donor_gain	1.0000
11:75852000:GGTA:G	donor_loss	1.0000
11:75852001:GTAA:G	donor_loss	1.0000
11:75852002:T:A	donor_loss	1.0000
11:75861742:CCAG:C	acceptor_loss	1.0000
11:75861743:CA:C	acceptor_loss	1.0000
11:75861744:A:AG	acceptor_gain	1.0000
11:75861744:A:AT	acceptor_loss	1.0000
11:75861745:G:GA	acceptor_gain	1.0000
11:75861745:G:T	acceptor_loss	1.0000
11:75861745:GA:G	acceptor_gain	1.0000
11:75861781:G:A	donor_loss	1.0000
11:75861781:G:GG	donor_gain	1.0000
11:75861782:TAA:T	donor_loss	1.0000
11:75879871:A:AG	acceptor_gain	1.0000
11:75879871:AT:A	acceptor_gain	1.0000
11:75879872:T:G	acceptor_gain	1.0000
11:75879876:CAG:C	acceptor_loss	1.0000

AlphaMissense

4565 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:75851899:T:C	L45P	1.000
11:75851914:C:A	A50D	1.000
11:75861757:A:C	S83R	1.000
11:75861759:T:A	S83R	1.000
11:75861759:T:G	S83R	1.000
11:75879883:C:A	P92H	1.000
11:75879888:T:A	W94R	1.000
11:75879888:T:C	W94R	1.000
11:75879890:G:C	W94C	1.000
11:75879890:G:T	W94C	1.000
11:75888866:T:C	L157P	1.000
11:75961446:T:C	L199P	1.000
11:76007596:T:C	L325P	1.000
11:76008844:T:C	L346S	1.000
11:76016842:C:A	A363D	1.000
11:76016845:T:C	L364P	1.000
11:76016847:G:C	G365R	1.000
11:76016848:G:A	G365D	1.000
11:76016863:T:C	L370P	1.000
11:76016943:G:C	D397H	1.000
11:76016944:A:C	D397A	1.000
11:76065711:T:C	F410L	1.000
11:76065713:T:A	F410L	1.000
11:76065713:T:G	F410L	1.000
11:76065718:T:A	L412Q	1.000
11:76065718:T:C	L412P	1.000
11:76065757:G:A	G425D	1.000
11:76065760:T:A	V426D	1.000
11:76065766:T:C	L428P	1.000
11:76065769:T:C	L429P	1.000

dbSNP variants (sampled 300 via entrez): RS1000006987 (11:76113410 C>G), RS1000007562 (11:75843915 C>A,T), RS1000009478 (11:75964793 G>A,C), RS1000011579 (11:75897079 G>C), RS1000027651 (11:76142661 A>G), RS1000032389 (11:76055564 C>T), RS1000035169 (11:75920634 G>A,C), RS1000056833 (11:76056308 T>C), RS1000061735 (11:75951340 T>C), RS1000064325 (11:76061739 A>C), RS1000066141 (11:75882579 A>G), RS1000067664 (11:75903515 C>T), RS1000071150 (11:76029822 T>A), RS1000085686 (11:76079800 A>G), RS1000096253 (11:76050387 A>G)

Disease associations

OMIM: gene MIM:602493 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): prostate cancer (MONDO:0008315)

Orphanet (1): Familial prostate cancer (Orphanet:1331)

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST004615_73	Hemoglobin concentration	4.000000e-10
GCST006611_152	HDL cholesterol	2.000000e-13
GCST008916_84	Asthma	8.000000e-29
GCST010083_177	Hemoglobin levels	3.000000e-09
GCST011176_2	Stroke	5.000000e-07
GCST90002397_534	Mean spheric corpuscular volume	5.000000e-11
GCST90010718_3	Thumb osteoarthritis severity (hand Klsum)	3.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004509	hemoglobin measurement
EFO:0004612	high density lipoprotein cholesterol measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4296018 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
Arsenic	affects methylation, affects cotreatment, increases abundance, increases expression	2
Benzo(a)pyrene	decreases expression	2
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
bisphenol A	decreases methylation	1
arsenite	affects binding, decreases reaction	1
cobaltous chloride	increases expression	1
butyraldehyde	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
sodium chromate(VI)	decreases expression	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
CPG-oligonucleotide	increases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
Imatinib Mesylate	increases expression	1
Zoledronic Acid	increases expression	1
Arsenic Trioxide	decreases reaction, increases expression, affects reaction	1
Leflunomide	increases expression	1
Alitretinoin	decreases expression	1
Acetylcysteine	decreases reaction, increases expression	1
Asbestos	affects expression	1
Carbon Disulfide	increases expression	1
Diazinon	increases methylation	1
Diethylstilbestrol	increases expression	1
Doxorubicin	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118759	Binding	Binding affinity to UVRAG in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8AC	Abcam Raji UVRAG KO	Cancer cell line	Male
CVCL_C0B7	Abcam THP-1 UVRAG KO	Cancer cell line	Male
CVCL_C7CV	Abcam PC-3 UVRAG KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer