RNF7

Summary

RNF7 (ring finger protein 7, HGNC:10070) is a protein-coding gene on chromosome 3q23, encoding RING-box protein 2 (Q9UBF6). Catalytic component of multiple cullin-5-RING E3 ubiquitin-protein ligase complexes (ECS complexes), which mediate the ubiquitination and subsequent proteasomal degradation of target proteins.

The protein encoded by this gene is a highly conserved ring finger protein. It is an essential subunit of SKP1-cullin/CDC53-F box protein ubiquitin ligases, which are a part of the protein degradation machinery important for cell cycle progression and signal transduction. This protein interacts with, and is a substrate of, casein kinase II (CSNK2A1/CKII). The phosphorylation of this protein by CSNK2A1 has been shown to promote the degradation of IkappaBalpha (CHUK/IKK-alpha/IKBKA) and p27Kip1(CDKN1B). Alternatively spliced transcript variants encoding distinct isoforms have been reported.

Source: NCBI Gene 9616 — RefSeq curated summary.

At a glance

• Gene–disease (curated): retinitis pigmentosa 47 (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 519 total — 25 pathogenic, 20 likely-pathogenic
• Phenotypes (HPO): 1
• MANE Select transcript: NM_014245

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10070
Approved symbol	RNF7
Name	ring finger protein 7
Location	3q23
Locus type	gene with protein product
Status	Approved
Aliases	SAG, ROC2, CKBBP1, RBX2
Ensembl gene	ENSG00000114125
Ensembl biotype	protein_coding
OMIM	603863
Entrez	9616

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 3 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000273480, ENST00000393000, ENST00000477012, ENST00000477393, ENST00000480908, ENST00000486377, ENST00000498828

RefSeq mRNA: 3 — MANE Select: NM_014245 NM_001201370, NM_014245, NM_183237

CCDS: CCDS3118, CCDS43158, CCDS56283

Canonical transcript exons

ENST00000273480 — 3 exons

Exon	Start	End
ENSE00000817618	141738298	141738516
ENSE00001205713	141745159	141747560
ENSE00003611782	141743509	141743556

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 97.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 79.3339 / max 250.4997, expressed in 1826 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
38932	70.2969	1826
38931	3.4622	1620
38930	2.9335	1522
38929	2.6414	1469

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left adrenal gland	UBERON:0001234	97.56	gold quality
left adrenal gland cortex	UBERON:0035825	97.53	gold quality
right adrenal gland	UBERON:0001233	97.52	gold quality
right adrenal gland cortex	UBERON:0035827	97.43	gold quality
right testis	UBERON:0004534	97.41	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.40	gold quality
left testis	UBERON:0004533	97.37	gold quality
adenohypophysis	UBERON:0002196	97.28	gold quality
adrenal cortex	UBERON:0001235	97.26	gold quality
body of pancreas	UBERON:0001150	97.18	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.18	gold quality
adrenal tissue	UBERON:0018303	97.16	gold quality
ascending aorta	UBERON:0001496	97.07	gold quality
popliteal artery	UBERON:0002250	97.07	gold quality
tibial artery	UBERON:0007610	97.07	gold quality
thoracic aorta	UBERON:0001515	97.05	gold quality
aorta	UBERON:0000947	97.04	gold quality
gastrocnemius	UBERON:0001388	97.03	gold quality
adrenal gland	UBERON:0002369	97.03	gold quality
right coronary artery	UBERON:0001625	96.94	gold quality
muscle of leg	UBERON:0001383	96.92	gold quality
pituitary gland	UBERON:0000007	96.87	gold quality
lower esophagus mucosa	UBERON:0035834	96.86	gold quality
mucosa of transverse colon	UBERON:0004991	96.85	gold quality
transverse colon	UBERON:0001157	96.84	gold quality
left coronary artery	UBERON:0001626	96.84	gold quality
descending thoracic aorta	UBERON:0002345	96.83	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.82	gold quality
islet of Langerhans	UBERON:0000006	96.79	gold quality
apex of heart	UBERON:0002098	96.78	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.39
E-CURD-122	yes	4.44
E-GEOD-70580	no	275.35
E-ENAD-20	no	237.97
E-HCAD-31	no	2.46

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HIF1A, NR4A1

miRNA regulators (miRDB)

52 targeting RNF7, 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-3646	100.00	73.56	5283
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-548AG	99.77	69.25	1492
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-548AI	99.69	69.24	1494
HSA-MIR-548BA	99.69	69.14	1514
HSA-MIR-570-5P	99.69	69.24	1494
HSA-MIR-3158-5P	99.65	67.51	1763

Literature-anchored findings (GeneRIF, showing 23)

• SAG possesses a potent peroxidase property to decompose hydrogen peroxide in the presence of dithiothreitol (PMID:11999705)
• results show that the Ring-H2 finger motif of CKBBP1 is necessary for efficient binding to CKIIbeta, as well as for optimal cell proliferation (PMID:12470599)
• sensitive to apoptosis gene protein inhibits peroxynitrite-induced DNA damage. (PMID:12565832)
• results indicate that protein kinase CKII may control IkappaBalpha and p27Kip1 degradation and thereby G1/S phase transition through the phosphorylation of threonine 10 within CKBBP1 protein (PMID:12748192)
• These studies suggested that CK2 might regulate SAG-SCF E3 ligase activity through modulating SAG’s stability, rather than its enzymatic activity directly. (PMID:16874460)
• Endogenous levels of pro-caspase 3 were decreased by overexpression of SAG protein. (PMID:17217622)
• Promotes hypoxia-inducible factor 1 alpha subunit (HIF-1 alpha) ubiquitination and degradation. (PMID:17828303)
• Sensitive to apoptosis gene may play an important role in regulating the apoptosis induced by heat shock presumably through maintaining the cellular redox status. (PMID:18454945)
• The findings showed that SAG E3 ubiquitin ligase plays an essential role in cancer cell proliferation and tumor growth (PMID:20103673)
• SAG plays an important role in regulating ionizing radiation-induced apoptosis (PMID:20933570)
• Data suggest that the sensitive-to-apoptosis gene may be a candidate gene for good prognosis in rectal cancer, independent of therapeutic response of different individuals. (PMID:22171132)
• Single nucleotide polymorphism rs16851720 was associated with liver fibrosis progression. (PMID:22841784)
• Sag is a Kras-cooperating oncogene that promotes lung tumorigenesis (PMID:24430184)
• NEDD4-1 overexpression sensitizes cancer cells to etoposide-induced apoptosis by reducing SAG levels through targeted degradation. SAG is added to a growing list of NEDD4-1 substrates and mediates its biological function. (PMID:25216516)
• These findings indicate that Rbx1 and Rbx2 can both activate Cul5-Vif E3 ligase in vitro, but they may undergo a more delicate selection mechanism in vivo. (PMID:25912140)
• MAF1, RNF7 and SETD3 are identified as PCNA-associated proteins in human cells and given this interaction with PCNA, Maf1, RNF7, and SetD3 are potentially involved in DNA replication, DNA repair, or associated processes. (PMID:26030842)
• SAG/RBX2 E3 ligase complexes with UBCH10 and UBE2S ubiquitin-conjugating enzymes to ubiquitylate beta-TrCP1 via K11-linkage for degradation. (PMID:27910872)
• We demonstrated that RNF7 knockdown induced growth suppression of prostate cancer cells and inactivated ERK1/2 pathway, which suggested RNF7 might be a potential novel therapeutic target for CRPC. (PMID:28252001)
• RNF7 gene variant is associated with the risk of developing liver fibrosis and cirrhosis in an Eastern European population. (PMID:28338112)
• This is the first report on a diagnostic test for simultaneous genotyping of IFNL3, ABCB11, and RNF7 in Chronic hepatitis C (CHC) patients. Reliable and inexpensive, the assay should provide useful information for the clinical management of CHC, like identification of patients at risk of rapid disease progression or with high chances of response to classic therapy. (PMID:28860020)
• Results identified RNF7 to interact with CARMA2 regulating its NF-kappaB-activating capacity. Mechanistically, RNF7 influences CARMA2 signaling by regulating the ubiquitination state of MALT1 and the NF-kappaB-regulatory molecule NEMO. (PMID:29194363)
• RNF7 inhibits apoptosis and sunitinib sensitivity and promotes glycolysis in renal cell carcinoma via the SOCS1/JAK/STAT3 feedback loop. (PMID:35562668)
• RNF7 Facilitated the Tumorigenesis of Pancreatic Cancer by Activating PI3K/Akt Signaling Pathway. (PMID:36644576)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	rnf7	ENSDARG00000055524
mus_musculus	Rnf7l	ENSMUSG00000048185
mus_musculus	Rnf7	ENSMUSG00000051234
rattus_norvegicus	Rnf7	ENSRNOG00000011663
drosophila_melanogaster	Roc2	FBGN0044020
caenorhabditis_elegans	rbx-2	WBGENE00019993

Paralogs (2): RBX1 (ENSG00000100387), ANAPC11 (ENSG00000141552)

Protein

Protein identifiers

RING-box protein 2 — Q9UBF6 (reviewed: Q9UBF6)

Alternative names: CKII beta-binding protein 1, RING finger protein 7, Regulator of cullins 2, Sensitive to apoptosis gene protein

All UniProt accessions (2): F8WEU8, Q9UBF6

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic component of multiple cullin-5-RING E3 ubiquitin-protein ligase complexes (ECS complexes), which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. It is thereby involved in various biological processes, such as cell cycle progression, signal transduction and transcription. The functional specificity of the E3 ubiquitin-protein ligase ECS complexes depend on the variable SOCS box-containing substrate recognition component. Within ECS complexes, RNF7/RBX2 recruits the E2 ubiquitination enzyme to the complex via its RING-type and brings it into close proximity to the substrate. Catalytic subunit of various SOCS-containing ECS complexes, such as the ECS(SOCS7) complex, that regulate reelin signaling by mediating ubiquitination and degradation of DAB1. The ECS(SOCS2) complex mediates the ubiquitination and subsequent proteasomal degradation of phosphorylated EPOR and GHR. Promotes ubiquitination and degradation of NF1, thereby regulating Ras protein signal transduction. As part of the ECS(ASB9) complex, catalyzes ubiquitination and degradation of CKB. The ECS(SPSB3) complex catalyzes ubiquitination of nuclear CGAS. As part of the ECS(RAB40C) complex, mediates ANKRD28 ubiquitination and degradation, thereby inhibiting protein phosphatase 6 (PP6) complex activity and focal adhesion assembly during cell migration. The ECS(ASB7) complex acts a negative regulator of H3K9me3 histone mark by mediating ubiquitination and degradation of SUV39H1. As part of some ECS complex, catalyzes ‘Lys-11’-linked ubiquitination and degradation of BTRC. ECS complexes and ARIH2 collaborate in tandem to mediate ubiquitination of target proteins; ARIH2 mediating addition of the first ubiquitin on CRLs targets. Specifically catalyzes the neddylation of CUL5 via its interaction with UBE2F. Does not catalyze neddylation of other cullins (CUL1, CUL2, CUL3, CUL4A or CUL4B). May play a role in protecting cells from apoptosis induced by redox agents. Inactive. (Microbial infection) Following infection by HIV-1 virus, catalytic component of a cullin-5-RING E3 ubiquitin-protein ligase complex (ECS complex) hijacked by the HIV-1 Vif protein, which catalyzes ubiquitination and degradation of APOBEC3F and APOBEC3G.

Subunit / interactions. Catalytic component of multiple cullin-5-RING E3 ubiquitin-protein ligase complexes (ECS complexes, also named CRL5 complexes) composed of CUL5, Elongin BC (ELOB and ELOC), RNF7/RBX2 and a variable SOCS box domain-containing protein as substrate-specific recognition component. Also interacts (with lower preference) with CUL1, CUL2, CUL3, CUL4A and CUL4B; additional evidence is however required to confirm this result in vivo. Interacts with UBE2F. Interacts with CSNK2B, the interaction is not affected by phosphorylation by CK2. May also interact with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5. (Microbial infection) Following infection by HIV-1 virus, component of a cullin-5-RING E3 ubiquitin-protein ligase complex (ECS complex) hijacked by the HIV-1 Vif protein.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Expressed in heart, liver, skeletal muscle and pancreas. At very low levels expressed in brain, placenta and lung.

Post-translational modifications. Phosphorylation at Thr-10 by CK2 promotes its degradation by the proteasome.

Domain organisation. The RING-type zinc finger domain is essential for ubiquitin ligase activity. It coordinates an additional third zinc ion.

Induction. By 1,10-phenanthroline.

Pathway. Protein modification; protein ubiquitination. Protein modification; protein neddylation.

Similarity. Belongs to the RING-box family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9UBF6-1	1	yes
Q9UBF6-2	2, SAG-v
Q9UBF6-3	3
Q9UBF6-4	4

RefSeq proteins (3): NP_001188299, NP_055060, NP_899060 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR024766	Znf_RING_H2	Domain
IPR051031	RING-box_E3_Ubiquitin_Ligase	Family

Pfam: PF12678

UniProt features (34 total): binding site 12, strand 7, splice variant 3, modified residue 2, mutagenesis site 2, helix 2, initiator methionine 1, chain 1, zinc finger region 1, sequence conflict 1, turn 1, region of interest 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
9T7V	ELECTRON MICROSCOPY	2.95
9SDX	ELECTRON MICROSCOPY	2.97
9SDY	ELECTRON MICROSCOPY	3.06
7ONI	ELECTRON MICROSCOPY	3.4
9EG1	ELECTRON MICROSCOPY	3.52
9OMA	ELECTRON MICROSCOPY	4.14
2ECL	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBF6-F1	83.02	0.59

Functional residue map

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

Ligand- & substrate-binding residues (12): 82; 85; 87; 88; 99; 102; 50; 53; 61; 64; 73; 80

Post-translational modifications (2): 2, 10

Mutagenesis-validated functional residues (2):

Position	Phenotype
10	abolished phosphorylation by ck2, leading to increased protein stability. does not affect its subcellular location of e3
10	mimics phosphorylation; leading to decreased protein stability.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-8951664	Neddylation
R-HSA-9705462	Inactivation of CSF3 (G-CSF) signaling
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 387 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, ATF_B, GOBP_G_PROTEIN_COUPLED_RECEPTOR_INTERNALIZATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, RORA1_01, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS, GOBP_FOCAL_ADHESION_ASSEMBLY, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_PHOTOTRANSDUCTION, GOBP_PROTEIN_NEDDYLATION

GO Biological Process (27): ubiquitin-dependent protein catabolic process (GO:0006511), protein ubiquitination (GO:0016567), positive regulation of cell migration (GO:0030335), endoplasmic reticulum unfolded protein response (GO:0030968), reelin-mediated signaling pathway (GO:0038026), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), post-translational protein modification (GO:0043687), protein neddylation (GO:0045116), response to redox state (GO:0051775), negative regulation of focal adhesion assembly (GO:0051895), protein K11-linked ubiquitination (GO:0070979), negative regulation of focal adhesion disassembly (GO:0120184), regulation of neuron migration (GO:2001222), epithelial to mesenchymal transition (GO:0001837), proteasomal protein catabolic process (GO:0010498), layer formation in cerebral cortex (GO:0021819), SCF-dependent proteasomal ubiquitin-dependent protein catabolic process (GO:0031146), intracellular signal transduction (GO:0035556), erythropoietin-mediated signaling pathway (GO:0038162), innate immune response (GO:0045087), phosphocreatine biosynthetic process (GO:0046314), defense response to virus (GO:0051607), positive regulation of focal adhesion assembly (GO:0051894), growth hormone receptor signaling pathway (GO:0060396), growth hormone receptor signaling pathway via JAK-STAT (GO:0060397), negative regulation of growth hormone receptor signaling pathway (GO:0060400), cGAS/STING signaling pathway (GO:0140896)

GO Molecular Function (9): copper ion binding (GO:0005507), zinc ion binding (GO:0008270), NEDD8 transferase activity (GO:0019788), ubiquitin protein ligase activity (GO:0061630), NEDD8 ligase activity (GO:0061663), cullin family protein binding (GO:0097602), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), Cul5-RING ubiquitin ligase complex (GO:0031466)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Post-translational protein modification	1
Signaling by CSF3 (G-CSF)	1
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein modification by small protein conjugation	2
regulation of cell migration	2
negative regulation of cell-substrate junction organization	2
intracellular anatomical structure	2
transition metal ion binding	2
ubiquitin-like protein ligase activity	2
protein ubiquitination	1
modification-dependent protein catabolic process	1
cell migration	1
positive regulation of cell motility	1
cellular response to unfolded protein	1
response to endoplasmic reticulum stress	1
intracellular signal transduction	1
cell surface receptor signaling pathway	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
protein modification process	1
response to stimulus	1
negative regulation of cell-matrix adhesion	1
focal adhesion assembly	1
regulation of focal adhesion assembly	1
negative regulation of cell junction assembly	1
protein polyubiquitination	1
focal adhesion disassembly	1
regulation of focal adhesion disassembly	1
neuron migration	1
mesenchymal cell differentiation	1
protein catabolic process	1
cerebral cortex radial glia-guided migration	1
anatomical structure formation involved in morphogenesis	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
signal transduction	1
cytokine-mediated signaling pathway	1
cellular response to erythropoietin	1
immune response	1
defense response to symbiont	1
ubiquitin-like protein transferase activity	1
ubiquitin-protein transferase activity	1
NEDD8 transferase activity	1

Protein interactions and networks

STRING

2086 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNF7	CUL5	Q93034	999
RNF7	ELOB	Q15370	997
RNF7	ELOC	Q15369	997
RNF7	CUL2	Q13617	996
RNF7	CUL1	Q13616	995
RNF7	CUL4A	Q13619	995
RNF7	CBFB	Q13951	989
RNF7	SKP1	P34991	983
RNF7	UBE2F	Q969M7	978
RNF7	CUL3	Q13618	966
RNF7	NEDD8	Q15843	956
RNF7	CUL7	Q14999	954
RNF7	CISH	Q9NSE2	952
RNF7	CUL4B	Q13620	937
RNF7	DDB1	Q16531	880

IntAct

61 interactions, top by confidence:

A	B	Type	Score
CUL5	RNF7	psi-mi:“MI:0915”(physical association)	0.900
RNF7	CUL5	psi-mi:“MI:0915”(physical association)	0.900
SPSB2	ELOC	psi-mi:“MI:0914”(association)	0.670
SPSB4	ELOC	psi-mi:“MI:0914”(association)	0.670
RNF7	ASB6	psi-mi:“MI:0915”(physical association)	0.670
RNF7	ASB1	psi-mi:“MI:0915”(physical association)	0.670
RNF7	ASB7	psi-mi:“MI:0915”(physical association)	0.670
RAB40C	ELOC	psi-mi:“MI:0914”(association)	0.640
RAB40C	ELOC	psi-mi:“MI:0407”(direct interaction)	0.640
RNF7	IKBKG	psi-mi:“MI:0915”(physical association)	0.580
vif	RNF7	psi-mi:“MI:0915”(physical association)	0.560
SOCS3	ELOC	psi-mi:“MI:0914”(association)	0.530
CUL3	ZSWIM8	psi-mi:“MI:0914”(association)	0.530
RNF7	SOCS7	psi-mi:“MI:0914”(association)	0.530
SPSB2	ARHGEF10	psi-mi:“MI:0914”(association)	0.530
PCNA	RNF7	psi-mi:“MI:0915”(physical association)	0.510
vif	UBL4A	psi-mi:“MI:0914”(association)	0.500
vif	HDAC3	psi-mi:“MI:0914”(association)	0.500
vif	DNAJB2	psi-mi:“MI:0914”(association)	0.460
SPTAN1	RNF7	psi-mi:“MI:0915”(physical association)	0.400
RNF7	ASB2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (306): NEDD4 (Affinity Capture-Western), RNF7 (Affinity Capture-Western), CUL5 (Affinity Capture-Western), RNF7 (Biochemical Activity), UBE2D1 (Reconstituted Complex), RNF7 (Two-hybrid), CUL1 (Biochemical Activity), CUL2 (Biochemical Activity), CUL3 (Biochemical Activity), CUL4A (Biochemical Activity), CUL4B (Biochemical Activity), CUL5 (Biochemical Activity), UBE2F (Reconstituted Complex), CUL5 (Reconstituted Complex), CBFB (Reconstituted Complex)

ESM2 similar proteins: A0A7U2QYM2, A8MRC7, B4G0F3, B8BKI7, B9SQI7, C6JS30, E0CTF3, F1MF74, F4JJJ3, O13959, O14023, O48538, O81210, P32481, P33095, P36872, P90916, Q02908, Q08273, Q0VCW8, Q1ZXC6, Q23457, Q2HXK9, Q2HXL0, Q2R483, Q4KLJ8, Q54K33, Q54XD8, Q5ZAJ0, Q61Y48, Q6H8D6, Q6J2K5, Q6PH52, Q8BVF2, Q8L828, Q8N4F7, Q940X7, Q948T9, Q948U0, Q94981

Diamond homologs: O13959, P62877, P62878, Q08273, Q20052, Q23457, Q3ZCF6, Q54K33, Q54L48, Q5R8A2, Q5UQ40, Q7X843, Q8BGI1, Q8QG64, Q940X7, Q9CPX9, Q9M2B0, Q9M9L0, Q9NHX0, Q9NYG5, Q9UBF6, Q9W5E1, Q9WTZ1, Q9Y225, O74757, P0C041, Q08CG8, Q12157, Q9LF64, O22755, Q8W571, Q9LZJ6, Q9LZV8, Q9SG96, Q9SRQ8, Q9UT86, Q9ZT49, Q9FL07, Q7S834, Q8L649

SIGNOR signaling

15 interactions.

A	Effect	B	Mechanism
CSNK2A1	up-regulates	RNF7	phosphorylation
CSNK2B	“up-regulates activity”	RNF7	phosphorylation
Ub:E2	“up-regulates activity”	RNF7	ubiquitination
RNF7	“down-regulates activity”	CDC34	polyubiquitination
CUL1	“up-regulates activity”	RNF7	binding
RNF7	down-regulates	ROS
RNF7	“down-regulates activity”	PMAIP1	ubiquitination
RNF7	“down-regulates activity”	CDKN1B	ubiquitination
RNF7	“down-regulates activity”	CASP3	ubiquitination
RNF7	“down-regulates activity”	DEPTOR	ubiquitination
RNF7	“down-regulates activity”	HIF1A	ubiquitination
RNF7	“down-regulates activity”	NFKBIA	ubiquitination
RNF7	“down-regulates activity”	JUN	ubiquitination
RNF7	“down-regulates activity”	NF1	ubiquitination
RNF7	“form complex”	“Elongin E3-Cul-5”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 42 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
Inactivation of CSF3 (G-CSF) signaling	5	66.5×	7e-07
Neddylation	15	21.5×	6e-15
Class I MHC mediated antigen processing & presentation	10	21.2×	2e-09
Antigen processing: Ubiquitination & Proteasome degradation	16	18.0×	6e-15
Adaptive Immune System	10	9.0×	4e-06

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of protein ubiquitination	5	28.8×	4e-05
ubiquitin-dependent protein catabolic process	11	22.1×	1e-10
protein ubiquitination	19	21.3×	4e-19
proteasome-mediated ubiquitin-dependent protein catabolic process	14	19.7×	4e-13
protein polyubiquitination	6	18.7×	4e-05
intracellular signal transduction	11	11.3×	1e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	25
Likely pathogenic	20
Uncertain significance	246
Likely benign	134
Benign	50

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
102422	NM_000541.5(SAG):c.523C>T (p.Arg175Ter)	Pathogenic
1066818	NC_000002.11:g.(?234224701)(234224801_?)dup	Pathogenic
1069163	NC_000002.11:g.(?234217836)(234217930_?)del	Pathogenic
12951	NM_000541.5(SAG):c.926del (p.Asn309fs)	Pathogenic
1356012	NM_000541.5(SAG):c.858dup (p.Leu288fs)	Pathogenic
1389528	NM_000541.5(SAG):c.695_704del (p.Asn232fs)	Pathogenic
1440983	NM_000541.5(SAG):c.619del (p.Leu207fs)	Pathogenic
1449236	NM_000541.5(SAG):c.178_181del (p.Lys60fs)	Pathogenic
1452228	NM_000541.5(SAG):c.74C>A (p.Ser25Ter)	Pathogenic
1460172	NC_000002.11:g.(?234237727)(234247303_?)del	Pathogenic
1901641	NM_000541.5(SAG):c.807delA (p.Glu270fs)	Pathogenic
1940817	NM_000541.5(SAG):c.341dup (p.Leu115fs)	Pathogenic
2423272	NC_000002.11:g.(?234224701)(234224801_?)del	Pathogenic
2851019	NM_000541.5(SAG):c.544C>T (p.Gln182Ter)	Pathogenic
41895	NM_000541.5(SAG):c.577C>T (p.Arg193Ter)	Pathogenic
41897	NM_000541.5(SAG):c.874C>T (p.Arg292Ter)	Pathogenic
41898	NM_000541.5(SAG):c.916G>T (p.Glu306Ter)	Pathogenic
4531166	SAG, 1-BP DEL, 636T	Pathogenic
4531167	S133L	Pathogenic
4699726	NM_000541.5(SAG):c.376-2A>G	Pathogenic
801912	NM_000541.5(SAG):c.571C>T (p.Gln191Ter)	Pathogenic
831716	NC_000002.12:g.(?233316075)(233316135_?)del	Pathogenic
862338	NM_000541.5(SAG):c.440G>T (p.Cys147Phe)	Pathogenic
984410	NM_000541.5(SAG):c.648+1G>C	Pathogenic
989451	NM_000541.5(SAG):c.649-1G>C	Pathogenic
1066985	NM_000541.5(SAG):c.1047-2A>G	Likely pathogenic
1067757	NM_000541.5(SAG):c.76-2A>C	Likely pathogenic
1479039	NM_000541.5(SAG):c.649-1G>A	Likely pathogenic
1490119	NM_000541.5(SAG):c.435+1G>A	Likely pathogenic
1511520	NM_000541.5(SAG):c.72_75+15del	Likely pathogenic

SpliceAI

2631 predictions. Top by Δscore:

Variant	Effect	Δscore
2:233309141:A:G	acceptor_gain	1.0000
2:233318746:CTTAG:C	acceptor_loss	1.0000
2:233318748:TAG:T	acceptor_loss	1.0000
2:233318749:A:AC	acceptor_loss	1.0000
2:233318749:A:AG	acceptor_gain	1.0000
2:233318749:AGAT:A	acceptor_gain	1.0000
2:233318750:G:A	acceptor_loss	1.0000
2:233318750:G:GG	acceptor_gain	1.0000
2:233318750:GAT:G	acceptor_gain	1.0000
2:233318750:GATG:G	acceptor_gain	1.0000
2:233320628:A:AG	acceptor_gain	1.0000
2:233320629:G:GG	acceptor_gain	1.0000
2:233320629:GT:G	acceptor_gain	1.0000
2:233320629:GTGT:G	acceptor_gain	1.0000
2:233320795:G:T	donor_gain	1.0000
2:233321349:G:GT	donor_gain	1.0000
2:233322944:A:AG	acceptor_gain	1.0000
2:233322945:G:GG	acceptor_gain	1.0000
2:233327119:A:AG	acceptor_gain	1.0000
2:233327120:G:GA	acceptor_gain	1.0000
2:233327120:GTCCT:G	acceptor_gain	1.0000
2:233327195:G:GT	donor_gain	1.0000
2:233327195:GAA:G	donor_gain	1.0000
2:233327198:G:GG	donor_gain	1.0000
2:233327202:GA:G	donor_gain	1.0000
2:233327204:G:GG	donor_gain	1.0000
2:233328611:GAG:G	donor_gain	1.0000
2:233328611:GAGG:G	donor_loss	1.0000
2:233328612:AG:A	donor_loss	1.0000
2:233328613:GGTAA:G	donor_loss	1.0000

AlphaMissense

760 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:141738430:T:C	F30S	1.000
3:141738444:T:A	W35R	1.000
3:141738444:T:C	W35R	1.000
3:141738457:C:A	A39D	1.000
3:141738462:T:A	W41R	1.000
3:141738462:T:C	W41R	1.000
3:141738464:G:C	W41C	1.000
3:141738464:G:T	W41C	1.000
3:141738468:T:A	W43R	1.000
3:141738468:T:C	W43R	1.000
3:141738470:G:C	W43C	1.000
3:141738470:G:T	W43C	1.000
3:141738489:T:A	C50S	1.000
3:141738489:T:C	C50R	1.000
3:141738490:G:A	C50Y	1.000
3:141738490:G:C	C50S	1.000
3:141738490:G:T	C50F	1.000
3:141738491:C:G	C50W	1.000
3:141738493:C:A	A51D	1.000
3:141738496:T:A	I52N	1.000
3:141738496:T:C	I52T	1.000
3:141738496:T:G	I52S	1.000
3:141738498:T:A	C53S	1.000
3:141738498:T:C	C53R	1.000
3:141738499:G:A	C53Y	1.000
3:141738499:G:C	C53S	1.000
3:141738499:G:T	C53F	1.000
3:141738500:C:G	C53W	1.000
3:141738502:G:C	R54T	1.000
3:141738502:G:T	R54M	1.000

dbSNP variants (sampled 300 via entrez): RS1000074885 (3:141737484 G>A,C), RS1000438092 (3:141747395 T>C), RS1000771382 (3:141736563 T>C), RS1000820038 (3:141738169 T>A,C,G), RS1001200573 (3:141747951 T>C), RS1001997419 (3:141743506 T>C), RS1003816413 (3:141746250 T>G), RS1003885953 (3:141743065 CTT>C), RS1004410191 (3:141737661 G>T), RS1004542756 (3:141746832 C>G), RS1004699214 (3:141740629 A>G), RS1004740635 (3:141741080 C>G,T), RS1005548661 (3:141747936 G>A,T), RS1005625175 (3:141744447 A>G), RS1005734101 (3:141742075 A>G)

Disease associations

OMIM: gene MIM:603863 | disease phenotypes: MIM:258100, MIM:613758, MIM:620228, MIM:268000, MIM:613411

GenCC curated gene-disease

Disease	Classification	Inheritance
Oguchi disease-1	Definitive	Autosomal recessive
retinitis pigmentosa 47	Definitive	Autosomal dominant
retinitis pigmentosa 96	Strong	Autosomal dominant
retinal disorder	Moderate	Autosomal recessive
Oguchi disease	Supportive	Autosomal recessive
retinitis pigmentosa	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
retinitis pigmentosa 47	Definitive	AR

Mondo (9): Oguchi disease (MONDO:0019152), Oguchi disease-1 (MONDO:0009775), retinitis pigmentosa 47 (MONDO:0013407), inherited retinal dystrophy (MONDO:0019118), retinitis pigmentosa 96 (MONDO:0859367), retinitis pigmentosa (MONDO:0019200), Oguchi disease-2 (MONDO:0013259), retinal disorder (MONDO:0005283), cone dystrophy (MONDO:0000455)

Orphanet (4): Oguchi disease (Orphanet:75382), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Retinitis pigmentosa (Orphanet:791), Progressive cone dystrophy (Orphanet:1871)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000556	Retinal dystrophy

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST000769_8	Calcium levels	9.000000e-06
GCST001438_2	Crohn’s disease	1.000000e-12
GCST001623_1	Hepatitis C induced liver fibrosis	9.000000e-09
GCST003225_12	Pelvic organ prolapse (moderate/severe)	7.000000e-06
GCST008058_303	Estimated glomerular filtration rate	3.000000e-11
GCST90026415_14	Mild obesity-related type 2 diabetes	4.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004838	calcium measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D000077765	Cone Dystrophy	C11.270.151; C11.768.216
D012164	Retinal Diseases	C11.768
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
C537743	Oguchi disease (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, decreases expression, increases abundance	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Arsenic	affects methylation, decreases expression, increases abundance	2
triphenyl phosphate	affects expression	1
arsenite	affects binding, increases reaction	1
cobaltous chloride	increases expression	1
CGP 52608	affects binding, increases reaction	1
4,5,6,7-tetrabromo-2-azabenzimidazole	decreases phosphorylation	1
abrine	increases expression	1
Resveratrol	increases expression, affects cotreatment	1
Acetaminophen	decreases expression	1
Dieldrin	decreases response to substance	1
Doxorubicin	increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ivermectin	decreases expression	1
Lead	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Ozone	affects expression, increases abundance	1
Plant Extracts	increases expression, affects cotreatment	1
Smoke	decreases expression	1
Tretinoin	decreases expression	1
Valproic Acid	decreases expression	1
1-Methyl-4-phenylpyridinium	decreases reaction, increases abundance, increases activity, decreases response to substance	1
Cyclosporine	increases expression	1
Reactive Oxygen Species	decreases reaction, increases abundance	1
Cadmium Chloride	increases expression	1
Lactic Acid	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01955135	PHASE4	COMPLETED	Anesthesia for Retinopathy of Prematurity
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT01373476	PHASE2	COMPLETED	Multicentre, Randomized, Controlled Trial of Qideng Mingmu Capsule in The Treatment of Diabetic Retinopathy
NCT01793090	PHASE2	COMPLETED	EPI-743 in Cobalamin C Defect: Effects on Visual and Neurological Impairment
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa
NCT05392179	PHASE2	COMPLETED	A Study in Subjects With Retinitis Pigmentosa
NCT06627179	PHASE2	RECRUITING	Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
NCT06628947	PHASE2	RECRUITING	A Phase II Study of Intravitreal KIO-301 in Patients With Late-stage Retinitis Pigmentosa
NCT06912633	PHASE2	RECRUITING	Safety of a Single, Intravitreal Injection of 6.0M jCell (Famzeretcel) in Retinitis Pigmentosa (RP)
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy