RNF2

Summary

RNF2 (ring finger protein 2, HGNC:10061) is a protein-coding gene on chromosome 1q25.3, encoding E3 ubiquitin-protein ligase RING2 (Q99496). E3 ubiquitin-protein ligase that mediates monoubiquitination of ‘Lys-119’ of histone H2A (H2AK119Ub), thereby playing a central role in histone code and gene regulation. In precision oncology, BAP1 Mutation confers sensitivity to Olaparib in Malignant Mesothelioma (CIViC Level B); 8 further curated variant–drug associations are listed below. It is haploinsufficient (ClinGen: sufficient evidence).

Polycomb group (PcG) of proteins form the multiprotein complexes that are important for the transcription repression of various genes involved in development and cell proliferation. The protein encoded by this gene is one of the PcG proteins. It has been shown to interact with, and suppress the activity of, transcription factor CP2 (TFCP2/CP2). Studies of the mouse counterpart suggested the involvement of this gene in the specification of anterior-posterior axis, as well as in cell proliferation in early development. This protein was also found to interact with huntingtin interacting protein 2 (HIP2), an ubiquitin-conjugating enzyme, and possess ubiquitin ligase activity.

Source: NCBI Gene 6045 — RefSeq curated summary.

At a glance

• Gene–disease (curated): BAP1-related tumor predisposition syndrome (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 9
• Clinical variants (ClinVar): 3,683 total — 313 pathogenic, 97 likely-pathogenic (top 1% of genes corpus-wide)
• Regional missense constraint (gnomAD): 3 of 7 regions constrained (≈26% of expected missense variation)
• GTEx eGene: eQTL in 17 tissues, sQTL in 1 (q < 0.05)
• Phenotypes (HPO): 181
• Precision-oncology evidence (CIViC): 9 curated variant–drug associations
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 14 cancer types (inferred from mutation patterns)
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.32 (highly constrained)
• Transcription factor: yes — 17 downstream targets (CollecTRI)
• MANE Select transcript: NM_007212
• Interaction hub: 2,006 STRING partners (top 7% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10061
Approved symbol	RNF2
Name	ring finger protein 2
Location	1q25.3
Locus type	gene with protein product
Status	Approved
Aliases	BAP-1, BAP1, DING, HIPI3, RING1B, RING2
Ensembl gene	ENSG00000121481
Ensembl biotype	protein_coding
OMIM	608985
Entrez	6045

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 18 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

MANE Select: ENST00000367510

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 2, TSL 5: 1

ENST00000367510, ENST00000367509, ENST00000453650, ENST00000498201, ENST00000715230, ENST00000910311, ENST00000910312, ENST00000910313, ENST00000910314, ENST00000910315, ENST00000925207, ENST00000925208, ENST00000925209, ENST00000925210, ENST00000942958, ENST00000942959, ENST00000986916, ENST00001091422, ENST00001091423, ENST00001128037, ENST00001144695

RefSeq mRNA: 1 — MANE Select: NM_007212 NM_007212

CCDS: CCDS1365

Canonical transcript exons

ENST00000367510 — 7 exons

Exon	Start	End
ENSE00000822928	185091579	185091739
ENSE00000822929	185093061	185093276
ENSE00000822931	185099791	185099962
ENSE00001030494	185100200	185102603
ENSE00003685196	185087552	185087640
ENSE00003784417	185098072	185098344
ENSE00004026246	185045558	185045649

Expression profiles

Bgee: expression breadth ubiquitous, 178 present calls, max score 95.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.3616 / max 344.8437, expressed in 1815 samples.

Highest expression (Bgee): primordial germ cell in gonad, cortical plate, ganglionic eminence, ventricular zone, islet of Langerhans.

Genetic regulation across tissues (GTEx eQTL / sQTL)

RNF2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 17 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

18 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Artery Tibial	eqtl	1.6e-07	-0.20	1:185203616:C:T
Cells Cultured fibroblasts	eqtl	5.4e-07	-0.12	1:185085555:A:G
Skin Sun Exposed Lower leg	eqtl	3.5e-04	-0.13	1:185119565:T:C
Colon Transverse	eqtl	4.3e-04	-0.16	1:185112891:T:G
Testis	eqtl	5.3e-04	-0.10	1:185127495:A:G
Skin Not Sun Exposed Suprapubic	eqtl	1.3e-03	-0.12	1:185091886:G:A
Adipose Subcutaneous	eqtl	1.7e-03	+0.11	1:185164892:A:C
Artery Aorta	eqtl	2.1e-03	-0.19	1:185208759:T:A
Brain Hippocampus	eqtl	3.7e-03	-0.27	1:184626212:C:T
Breast Mammary Tissue	eqtl	3.8e-03	+0.12	1:184959033:T:C
Muscle Skeletal	eqtl	4.7e-03	-0.13	1:185085555:A:G
Brain Cerebellum	eqtl	5.6e-03	-0.22	1:184895310:C:T
Thyroid	eqtl	6.4e-03	-0.12	1:185119565:T:C
Brain Frontal Cortex BA9	eqtl	8.4e-03	+0.27	1:185171530:A:G
Esophagus Mucosa	eqtl	1.1e-02	+0.13	1:185164892:A:C
Cells EBV-transformed lymphocytes	sqtl	2.1e-02	+0.46	1:184614524:C:T
Whole Blood	eqtl	3.3e-02	+0.14	1:184991666:G:A
Esophagus Gastroesophageal Junction	eqtl	3.5e-02	+0.19	1:184567477:T:G

FANTOM5 promoters

9 alternative TSS:

Promoter ID	TPM avg	Samples expressed
7238	17.0221	1777
7236	6.6053	1737
7237	2.2253	1287
7235	1.6465	1115
7239	1.2580	642
7234	0.9622	686
7233	0.8695	593
7240	0.5574	257
201846	0.2152	87

Top tissues by expression

showing 100 of 267 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	95.43	gold quality
cortical plate	UBERON:0005343	93.40	gold quality
ganglionic eminence	UBERON:0004023	92.71	gold quality
ventricular zone	UBERON:0003053	89.92	gold quality
islet of Langerhans	UBERON:0000006	88.17	gold quality
stromal cell of endometrium	CL:0002255	87.16	gold quality
adrenal tissue	UBERON:0018303	87.16	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.45	gold quality
monocyte	CL:0000576	86.15	gold quality
leukocyte	CL:0000738	85.50	gold quality
mononuclear cell	CL:0000842	85.40	gold quality
calcaneal tendon	UBERON:0003701	84.37	gold quality
colonic epithelium	UBERON:0000397	83.70	gold quality
buccal mucosa cell	CL:0002336	83.38	silver quality
embryo	UBERON:0000922	83.32	gold quality
hindlimb stylopod muscle	UBERON:0004252	81.96	gold quality
pancreas	UBERON:0001264	81.61	gold quality
rectum	UBERON:0001052	81.43	gold quality
tendon	UBERON:0000043	81.35	gold quality
gall bladder	UBERON:0002110	80.57	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	80.04	gold quality
omental fat pad	UBERON:0010414	79.99	gold quality
peritoneum	UBERON:0002358	79.95	gold quality
prefrontal cortex	UBERON:0000451	79.63	gold quality
adipose tissue of abdominal region	UBERON:0007808	79.50	gold quality
bone marrow cell	CL:0002092	79.48	gold quality
granulocyte	CL:0000094	79.47	gold quality
left adrenal gland	UBERON:0001234	79.22	gold quality
ectocervix	UBERON:0012249	79.22	gold quality
right testis	UBERON:0004534	79.19	gold quality
testis	UBERON:0000473	78.94	gold quality
lymph node	UBERON:0000029	78.93	gold quality
right adrenal gland	UBERON:0001233	78.92	gold quality
tonsil	UBERON:0002372	78.86	gold quality
blood	UBERON:0000178	78.85	gold quality
right adrenal gland cortex	UBERON:0035827	78.79	gold quality
choroid plexus epithelium	UBERON:0003911	78.77	silver quality
body of pancreas	UBERON:0001150	78.65	gold quality
left testis	UBERON:0004533	78.62	gold quality
muscle of leg	UBERON:0001383	78.55	gold quality
gastrocnemius	UBERON:0001388	78.48	gold quality
left adrenal gland cortex	UBERON:0035825	78.45	gold quality
adrenal gland	UBERON:0002369	78.39	gold quality
smooth muscle tissue	UBERON:0001135	78.26	gold quality
body of uterus	UBERON:0009853	78.19	gold quality
endocervix	UBERON:0000458	78.14	gold quality
vermiform appendix	UBERON:0001154	77.71	gold quality
esophagus mucosa	UBERON:0002469	77.65	gold quality
adrenal cortex	UBERON:0001235	77.51	gold quality
minor salivary gland	UBERON:0001830	77.29	gold quality
bone marrow	UBERON:0002371	77.18	gold quality
descending thoracic aorta	UBERON:0002345	77.04	gold quality
connective tissue	UBERON:0002384	77.04	gold quality
adipose tissue	UBERON:0001013	77.03	gold quality
oocyte	CL:0000023	76.84	silver quality
left ovary	UBERON:0002119	76.82	gold quality
subcutaneous adipose tissue	UBERON:0002190	76.79	gold quality
right ovary	UBERON:0002118	76.71	gold quality
tendon of biceps brachii	UBERON:0008188	76.69	silver quality
lower esophagus mucosa	UBERON:0035834	76.69	gold quality
Brodmann (1909) area 9	UBERON:0013540	76.68	gold quality
left coronary artery	UBERON:0001626	76.58	gold quality
esophagus	UBERON:0001043	76.43	gold quality
tibial artery	UBERON:0007610	76.38	gold quality
popliteal artery	UBERON:0002250	76.35	gold quality
vagina	UBERON:0000996	76.24	gold quality
right atrium auricular region	UBERON:0006631	76.16	gold quality
aorta	UBERON:0000947	76.11	gold quality
left uterine tube	UBERON:0001303	76.06	gold quality
upper lobe of left lung	UBERON:0008952	76.05	gold quality
thoracic aorta	UBERON:0001515	75.96	gold quality
mouth mucosa	UBERON:0003729	75.96	gold quality
saliva-secreting gland	UBERON:0001044	75.95	gold quality
ascending aorta	UBERON:0001496	75.90	gold quality
muscle layer of sigmoid colon	UBERON:0035805	75.88	gold quality
cartilage tissue	UBERON:0002418	75.85	silver quality
dorsolateral prefrontal cortex	UBERON:0009834	75.85	gold quality
right lung	UBERON:0002167	75.83	gold quality
primary visual cortex	UBERON:0002436	75.83	gold quality
coronary artery	UBERON:0001621	75.78	gold quality
caecum	UBERON:0001153	75.73	gold quality
corpus callosum	UBERON:0002336	75.69	gold quality
skin of abdomen	UBERON:0001416	75.61	gold quality
Brodmann (1909) area 23	UBERON:0013554	75.61	silver quality
left lobe of thyroid gland	UBERON:0001120	75.55	gold quality
skin of leg	UBERON:0001511	75.51	gold quality
endometrium	UBERON:0001295	75.49	gold quality
stomach	UBERON:0000945	75.48	gold quality
neocortex	UBERON:0001950	75.33	gold quality
upper lobe of lung	UBERON:0008948	75.33	gold quality
right coronary artery	UBERON:0001625	75.29	gold quality
thyroid gland	UBERON:0002046	75.28	gold quality
heart	UBERON:0000948	75.26	gold quality
heart left ventricle	UBERON:0002084	75.24	gold quality
ovary	UBERON:0000992	75.23	gold quality
medial globus pallidus	UBERON:0002477	75.18	silver quality
mucosa of transverse colon	UBERON:0004991	75.14	gold quality
cortex of kidney	UBERON:0001225	75.13	gold quality
body of stomach	UBERON:0001161	74.99	gold quality
cardiac ventricle	UBERON:0002082	74.96	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.98

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 159 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Hippocampus	tissue	124.1	low
Postcentral gyrus	tissue	91.5
Frontal cortex	tissue	82.6
Cerebral cortex	tissue	72.4	low
Motor cortex	tissue	72.4
Putamen	tissue	70.6
Bone marrow	tissue	69.8	medium
Nucleus accumbens	tissue	69.1
Caudate putamen	tissue	68.6
Somatosensory cortex	tissue	67.9
Basal ganglia	tissue	66.0	low
Skin 1	tissue	65.6	medium
Prefrontal cortex	tissue	64.2
Hippocampal formation	tissue	63.0
Entorhinal cortex	tissue	63.0
Occipital cortex	tissue	62.0
Insular cortex	tissue	61.2
Temporal cortex	tissue	60.9
Testis	tissue	59.6	medium
Retrosplenial and cingulate cortex	tissue	58.4
Hippocampal formation	tissue	58.0
Cerebral cortex	tissue	57.5	not detected
Motor cortex	tissue	57.5
Retrosplenial cortex	tissue	56.4
Prefrontal cortex	tissue	55.0
Occipital cortex	tissue	54.3
Somatosensory cortex	tissue	53.1
Putamen	tissue	52.6
Thalamus	tissue	52.5
Entorhinal cortex	tissue	52.4
Hypothalamus	tissue	52.2
Midbrain	tissue	52.0
Spinal cord	tissue	51.9
Pons	tissue	51.7
Retrosplenial and cingulate cortex	tissue	51.3
Septum	tissue	50.6
Amygdala	tissue	50.0
Corpus callosum	tissue	49.7
Retrosplenial cortex	tissue	49.4
Ventral forebrain	tissue	49.2
Thalamus	tissue	48.6
Insular cortex	tissue	48.3
Superior colliculi	tissue	47.3
Periaqueductal gray	tissue	46.5
Substantia nigra	tissue	46.4
Pons	tissue	46.4
Locus coeruleus	tissue	45.0
Skeletal muscle	tissue	44.8	low
Medulla oblongata	tissue	44.4
Temporal cortex	tissue	44.1
Midbrain	tissue	44.0
Superior colliculi	tissue	43.4
Amygdala	tissue	43.1
Ventral forebrain	tissue	42.4
Septum	tissue	41.4
Basal ganglia	tissue	41.1	medium
Tongue	tissue	40.8
Cerebellum	tissue	39.7	low
Vagina	tissue	39.4	low
Olfactory bulb	tissue	39.3

Brain sub-regions (HPA Brain Atlas): detected in 381; highest nTPM — Hippocampus, CA1 (120.4), Hippocampus, CA3 (118.1), Posterior cingulate cortex (113.9), Hippocampus, CA2 (113.1), Dentate gyrus (109.4).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

17 targets:

Target	Regulation
BAP1
CASP1
CBX2
COX7C
CP
CXCL8
DLD
FEZF2	Repression
HBA1
HOXB9
MEIS1	Repression
MEIS2	Repression
PC
PRKN
SCNN1A
STRA8
UBC

Upstream regulators (CollecTRI, top): E2F1

miRNA regulators (miRDB)

Targeting RNF2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 185 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-3143	99.93	71.96	3104

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.321, missense Z 2.97 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000367510 splits into 7 regions with different missense tolerance; 3 are missense-constrained (≈26% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
1:185,087,554–185,091,699	43 / 82.7	0.52	no
1:185,091,700–185,093,119	4 / 39.9	0.10	yes (p 1.3e-08)
1:185,093,120–185,093,236	33 / 46.8	0.71	no
1:185,093,237–185,098,078	2 / 18.6	0.11	yes (p 1.2e-04)
1:185,098,079–185,098,318	94 / 99.2	0.95	no
1:185,098,319–185,099,884	16 / 47.7	0.34	yes (p 4.4e-06)
1:185,099,885–185,100,298	59 / 69.1	0.85	no
ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• The human PcG protein dinG interacts with CP2, a mammalian member of the grainyhead-like family of transcription factors, in vitro and in vivo. The functional consequence of this interaction is repression of CP2-dependent transcription. (PMID:11865070)
• The E3 ubiquitin ligase RNF2 might have a dual function: facilitating the ubiquitination of its target substrates and recruiting the substrates to the proteasome. (PMID:15773819)
• Altered mRNA expression is associated with therapy failure and death in patients with multiple types of cancer. (PMID:15931389)
• Bmi-1-Ring1B complex stabilizes the interaction of the ubiquitin ligase complex. (PMID:16714294)
• Ring1B and Bmi1 are degraded by an exogenous E3, independent of their RING domain. The RING domains of both proteins mediate their association and subsequent stabilization. (PMID:17157253)
• caspases-3 and caspase-9 play novel roles in transcription by regulating polycomb protein function through direct cleaving of Ring1B. (PMID:17379327)
• With prohibitin, regulates the activity of E2F1 transcription factor via dual pathways. (PMID:17873902)
• Results show that a phosphorylated form of Mel-18 targets the Ring1B histone H2A ubiquitin ligase to chromatin. (PMID:17936708)
• Data show that the presence of flexible regions could allow C-terminal region of RING1B to bind a variety of different factors, ultimately recruiting RING1B and its associated PcG proteins to different genomic loci. (PMID:18616292)
• a novel mechanism by which RNF2 and PHB2 modulate the CP2-mediated transcriptional pathway. (PMID:18629613)
• Studies in mammalian cells have found a multiplicity of protein complexes containing Ring1A and Ring1B, suggesting an expanded regulatory role for Ring1A, Ring1B proteins in the epigenetic regulation of gene expression. (PMID:19412891)
• Ring1B plays an important role in the induction of T helper (Th)2 cell-driven allergic airway inflammation through the control of Bim-dependent apoptosis of effector T helper (Th)2 cells in vivo. (PMID:20237291)
• polycomb protein Ring1B regulation by self-ubiquitination or by E6-AP may have implications to the pathogenesis of Angelman syndrome (PMID:20351251)
• Polycomb Group protein targeting to different chromatin locations relies, in part, on binding partners of the C-terminal domain of RING1B that are diverse in sequence and structure. (PMID:20696397)
• identification of genes regulated by ring finger protein 2 (PMID:21347701)
• Crystallography of a complex of the Bmi1/Ring1b RING-RING heterodimer & UbcH5c shows that UbcH5c interacts with Ring1b only. Bmi1/Ring1b interacts with nucleosomal DNA & an acidic patch on histone H4 to achieve specific monoubiquitination of H2A. (PMID:21772249)
• the reduction of LPS-mediated IL-8 promoter activation was not related to de novo X-DING-CD4 protein synthesis, but depended on function of the exogenous X-DING-CD4 protein. (PMID:22031506)
• These data provide evidence that the X-DING-CD4 gene contributes to early cellular protection from HIV infection in some individuals and this protection depends solely on the unique genetic regulation of the host. (PMID:22042911)
• The organism reacts to HIV-infection by an overexpression of DING proteins. (PMID:22427948)
• knockdown of RNF2 significantly inhibits both cell proliferation and colony formation and induces apoptosis in cancer cells (PMID:23318437)
• Results indicate that RNF2 is an E3 ligase for p53 degradation in selective cells, implicating RNF2 as a therapeutic target to restore tumor suppression through p53 in certain tumor cells. (PMID:23319651)
• Ring2 may effect the DNA repair through other pathways but not through the expressions of NER protein. (PMID:23712474)
• BMI-1 and RING1B expression was enhanced with the development of embryos in early pregnancy. (PMID:23727134)
• Expressed the isolated N-terminal region of Ring1B, N-Ring1B, comprising the first 221 residues of the 334-residue-long Ring1B and found that the N-Ring1B is a well-folded, monomeric fragment, with native-like structure which unfolds irreversibly. (PMID:24284202)
• The acidic patch functions within the nucleosome as nucleosomes containing a mutated acidic patch exhibit defective H2A/H2AXub by RNF168 and RING1B/BMI1 in vitro (PMID:24603765)
• Bmi1 and possibly RNF2 may be attractive biomarkers of gemcitabine resistance in the context of RRM1 expression. (PMID:24614341)
• we identify p63 as a target of Ring1B to regulate Fak expression in breast cancer epithelial cells (PMID:24742605)
• Data indicate that RING finger protein 2 (RNF2) knockdown can increase the sensitivity of U87 cells to X ray radiation. (PMID:24796740)
• Authors describe a critical role for the polycomb group protein Ring1b in nonhomologous end-joining (NHEJ)-mediated end-to-end chromosome fusions. (PMID:24813883)
• Ring1B and the SNAG-associated chromatin modifier EZH2 formed distinct protein complexes with Snail and that EZH2 was required for Snail-Ring1A/B recruitment to the target promoter. (PMID:24903147)
• combinatorial silencing along with Ezh2 depleted epigenetically modified H2- and H3-histones and inhibited pancreatic cancer cell growth in vitro and in vivo (xenograft model) (PMID:25431952)
• BAP1 deficiency causes increased expression of FoxK2 target genes in a Ring1B-Bmi1-dependent manner (PMID:25451922)
• O-GlcNAc modifies and regulates an essential epigenetic tool, RING1B, which may contribute to human embryonic stem cells pluripotency maintenance and differentiation. (PMID:26100231)
• The enzymatic activity of BMI1 and RING1B were evaluated and compared. (PMID:26151332)
• Our findings support the notion that epigenetic regulators, such as RNF2, directly and functionally control powerful gene networks that are vital in multiple cancer processes. (PMID:26450788)
• overexpression of RNF2, as examined by immunohistochemical analysis, might serve as a novel prognostic biomarker and potential therapeutic target for urothelial carcinoma of the bladder patients. (PMID:26869491)
• Study detected RNF2 expression to be overexpressed in esophageal carcinoma cell lines and was associated with the poor prognosis of esophageal carcinoma patients. Data also reflect its important role in the growth of esophageal carcinoma cells by shRNA silencing of RNF2 expression. (PMID:26936624)
• Our findings identify RING1B as a trait of the cell-of-origin in Ewing sarcoma (PMID:27317769)
• These data suggest that RNF2 is an important upstream negative regulator of SIK1 and that restoration of SIK1 levels induced by loss of RNF2 inhibited HCC cell growth and promoted apoptosis, which may represent a promising therapeutic strategy for HCC treatment. (PMID:27911266)
• Study found that prostate cancer (PCa) tissues have high RNF2 expression which is positively correlated with tumor grade indicating that RNF2 may have oncogenic function in PCa. (PMID:28029659)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rnf2	ENSDARG00000010381
mus_musculus	Rnf2	ENSMUSG00000026484
rattus_norvegicus	Rnf2	ENSRNOG00000002454
drosophila_melanogaster	Psc	FBGN0005624
drosophila_melanogaster	Su(z)2	FBGN0265623

Paralogs (7): PCGF1 (ENSG00000115289), PCGF6 (ENSG00000156374), BMI1 (ENSG00000168283), PCGF5 (ENSG00000180628), PCGF3 (ENSG00000185619), RING1 (ENSG00000204227), PCGF2 (ENSG00000277258)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1101759) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 17 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased monocyte cell number	1
decreased bone marrow cell number	1
abnormal mesoderm development	1
failure to gastrulate	1
embryonic growth arrest	1
abnormal B cell differentiation	1
abnormal bone marrow cell morphology/development	1
decreased erythrocyte cell number	1
abnormal embryonic epiblast morphology	1
cervical vertebral transformation	1
thoracic vertebral transformation	1
decreased B cell number	1
thrombocytosis	1
abnormal common myeloid progenitor cell morphology	1
abnormal sternum ossification	1
abnormal neuron differentiation	1
embryonic lethality during organogenesis, complete penetrance	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pan paniscus	A1YFY1	100.0%	Diamond
Pan troglodytes	A2T6X5	100.0%	Diamond
Macaca mulatta	Q8WMN5	100.0%	Diamond
Pongo abelii	Q5R9J5	99.7%	Diamond
Gorilla gorilla gorilla	A1YER5	98.7%	Diamond
Xenopus laevis	Q66J69	97.4%	Diamond
Canis lupus familiaris	Q5TJF3	95.2%	Diamond
Sus scrofa	O77666	89.4%	Diamond
Arabidopsis thaliana	Q94AY3	67.1%	Diamond
Caenorhabditis elegans	H2KYH3	50.0%	Diamond
Schizosaccharomyces pombe 972h-	O94264	41.6%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
SWT1	protein-coding	54823
TRMT1L	protein-coding	81627
LINC01633	ncRNA	101929069
NIBAN1	protein-coding	116496
IVNS1ABP	protein-coding	10625
CBSLR	ncRNA	124904470

Protein

Protein identifiers

E3 ubiquitin-protein ligase RING2 — Q99496 (reviewed: Q99496)

Alternative names: Huntingtin-interacting protein 2-interacting protein 3, Protein DinG, RING finger protein 1B, RING finger protein 2, RING finger protein BAP-1, RING-type E3 ubiquitin transferase RING2

All UniProt accessions (2): Q99496, X6RFN3

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that mediates monoubiquitination of ‘Lys-119’ of histone H2A (H2AK119Ub), thereby playing a central role in histone code and gene regulation. H2AK119Ub gives a specific tag for epigenetic transcriptional repression and participates in X chromosome inactivation of female mammals. May be involved in the initiation of both imprinted and random X inactivation. Essential component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones, rendering chromatin heritably changed in its expressibility. E3 ubiquitin-protein ligase activity is enhanced by BMI1/PCGF4. Acts as the main E3 ubiquitin ligase on histone H2A of the PRC1 complex, while RING1 may rather act as a modulator of RNF2/RING2 activity. Association with the chromosomal DNA is cell-cycle dependent. In resting B- and T-lymphocytes, interaction with AURKB leads to block its activity, thereby maintaining transcription in resting lymphocytes. Also acts as a negative regulator of autophagy by mediating ubiquitination of AMBRA1, leading to its subsequent degradation.

Subunit / interactions. Component of chromatin-associated Polycomb (PcG) complexes. Component of a number of PRC1-like complexes; these complexes contain either the polycomb group ring finger protein PCGF1, or PCGF2, or PCGF3, or PCGF4, or PCGF5, or PCGF6. Part of a complex that contains RNF2, UB2D3 and BMI1; within that complex RNF2 and BMI1 form a tight heterodimer, where UB2D3 interacts only with RNF2. The complex composed of RNF2, UB2D3 and BMI1 binds nucleosomes, and has activity only with nucleosomal histone H2A. Part of a complex that contains PCGF5, RNF2 and UBE2D3. Part of a complex that contains AUTS2, PCGF5, RNF2, CSNK2B and RYBP. Interacts with RYBP, PCGF2, CBX4, CBX6, CBX7 and CBX8. Interacts with RNF1/RING1, BMI1 and PHC2. Interaction with RYBP and CBX7 is mutually exclusive; both compete for the same binding site on RNF2. Component of repressive BCOR complex containing a Polycomb group subcomplex at least composed of RYBP, PCGF1, BCOR and RING1. Interacts with CBX2 and PHC1. Interacts with CHTOP. Interacts with AURKB. Part of the E2F6.com-1 complex in G0 phase composed of E2F6, MGA, MAX, TFDP1, CBX3, BAT8, EUHMTASE1, RNF1/RING1, RNF2/RING2, MBLR, L3MBTL2 and YAF2. Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1/HCF1, WDR5 and RBBP5, as well as the facultative components BACC1, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MGA, MYST1/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10. Interacts with RYBP, HIP2 and TFCP2. Interacts with NUPR1. Interacts with SAMD7 in a PHC2-dependent manner.

Subcellular location. Nucleus. Cytoplasm. Chromosome.

Post-translational modifications. Monoubiquitinated, by auto-ubiquitination. Polyubiquitinated in the presence of UBE2D3 (in vitro).

Disease relevance. Luo-Schoch-Yamamoto syndrome (LUSYAM) [MIM:619460] An autosomal dominant disorder characterized by intrauterine growth retardation, severe intellectual disability, behavioral problems, early-onset seizures, feeding difficulties, and dysmorphic features. White matter abnormalities and delayed myelination are observed on brain imaging. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. The hPRC-H complex purification reported probably presents a mixture of different PRC1-like complexes.

Isoforms (2)

UniProt ID	Names	Canonical?
Q99496-1	1	yes
Q99496-2	2

RefSeq proteins (1): NP_009143* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site
IPR032443	RAWUL	Domain
IPR037937	RING2_RAWUL_dom	Domain
IPR043540	RING1/RING2	Family

Pfam: PF13923, PF16207

Enzyme classification (BRENDA)

• EC 2.3.2.27 — RING-type E3 ubiquitin transferase (BRENDA: 28 organisms, 138 substrates, 10 inhibitors, 1 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
[UBE2W]-S-UBIQUITINYL-L-CYSTEINE	0.3014	1

UniProt features (63 total): mutagenesis site 15, helix 15, strand 11, turn 5, modified residue 4, cross-link 3, region of interest 3, sequence variant 2, initiator methionine 1, chain 1, splice variant 1, zinc finger region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

28 structures by resolution:

PDB	Title	Method	Resolution (Å)
3GS2	Ring1B C-terminal domain/Cbx7 Cbox Complex	X-RAY DIFFRACTION	1.7
3IXS	Ring1B C-terminal domain/RYBP C-terminal domain Complex	X-RAY DIFFRACTION	1.7
6WI7	RING1B-BMI1 fusion in closed conformation	X-RAY DIFFRACTION	1.7
3H8H	Structure of the C-terminal domain of human RNF2/RING1B;	X-RAY DIFFRACTION	2
4S3O	PCGF5-RING1B-UbcH5c complex	X-RAY DIFFRACTION	2
2H0D	Structure of a Bmi-1-Ring1B Polycomb group ubiquitin ligase complex	X-RAY DIFFRACTION	2.5
3RPG	Bmi1/Ring1b-UbcH5c complex structure	X-RAY DIFFRACTION	2.65
28OE	Human PRC1.4 in complex with native UBCH5C bound to a H3Kc27me3 mononucleosome	ELECTRON MICROSCOPY	2.74
9DBY	ncPRC1RYBP bound to singly modified H2AK119Ub nucleosome	ELECTRON MICROSCOPY	2.8
9V9Q	Cryo-EM structure of the cPRC1-UbcH5c E3-E2 complex bound to the H2BK120ub-modified …	ELECTRON MICROSCOPY	2.8
8PP7	human RYBP-PRC1 bound to mononucleosome	ELECTRON MICROSCOPY	2.91
9DGG	ncPRC1RYBP bound to unmodified nucleosome	ELECTRON MICROSCOPY	2.98
9V6S	Cryo-EM structure of a single cPRC1 complex engaged on one face of an endogenous 147-bp …	ELECTRON MICROSCOPY	3
8GRM	Cryo-EM structure of PRC1 bound to H2AK119-UbcH5b-Ub nucleosome	ELECTRON MICROSCOPY	3.05
6WI8	Inhibitor compound-induced confrontational change in Ring1b-Bmi1 domain structure	X-RAY DIFFRACTION	3.09
9DDE	ncPRC1RYBP bound to H2AK119Ub/H1.4 chromatosome	ELECTRON MICROSCOPY	3.2
9V9R	Cryo-EM structure of the ncPRC1.1-UbcH5c E3-E2 complex bound to the H2BK120ub-modified …	ELECTRON MICROSCOPY	3.2
9V9Y	Cryo-EM structure of the ncPRC1.4 complex containing one RNF2-BMI1 and one RYBP bound to …	ELECTRON MICROSCOPY	3.2
4R8P	Crystal structure of the Ring1B/Bmi1/UbcH5c PRC1 ubiquitylation module bound to the …	X-RAY DIFFRACTION	3.28
9V9X	Cryo-EM structure of the ncPRC1.4 complex containing one RNF2-BMI1 bound to the …	ELECTRON MICROSCOPY	3.3
9V9P	Cryo-EM structure of the cPRC1-di-nucleosome (CBX7) complex	ELECTRON MICROSCOPY	3.4
9V9U	Cryo-EM structure of the ncPRC1.4 complex containing two RNF2-BMI1 bound to the …	ELECTRON MICROSCOPY	3.7
9V9V	Cryo-EM structure of the ncPRC1.4 complex containing one RNF2-BMI1 and one RYBP bound to …	ELECTRON MICROSCOPY	3.8
9V6X	Cryo-EM structure of the cPRC1 complex bound to an endogenous 184-bp mono-nucleosome	ELECTRON MICROSCOPY	4
9V9H	Cryo-EM structure of the cPRC1-di-nucleosome (tight) complex	ELECTRON MICROSCOPY	4.5
9V6Q	Cryo-EM structure of two cPRC1 complexes bound to opposite faces of an endogenous 147-bp …	ELECTRON MICROSCOPY	4.6
9V8L	Cryo-EM structure of the cPRC1-di-nucleosome (loose) complex	ELECTRON MICROSCOPY	6.6
7ND1	First-in-class small molecule inhibitors of Polycomb Repressive Complex 1 (PRC1) RING …	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99496-F1	78.27	0.44

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Metabolic proteins, Predicted intracellular proteins, Disease related genes, Potential drug targets, Human disease related genes, Congenital malformations, Congenital malformations of the nervous system

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm; nuclear bodies

Antibody reliability (HPA): IH uncertain · IF enhanced

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 (7)

Type	Positions
Phosphoserine	168, 41, 143
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in ubiquitin)	112
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in sumo2)	249, 323
N-acetylserine	2

Mutagenesis-validated functional residues (15)

Position	Phenotype
41	no effect on ubiquitin ligase activity on histone h2a.
51	strong decrease in hip2-binding; when associated with s-54.
54	strong decrease in hip2-binding; when associated with w-51.
56	loss of ubiquitin ligase activity on histone h2a.
69	loss of hip2-binding and loss of ubiquitin ligase activity on histone h2a.
70	loss of ubiquitin ligase activity on histone h2a.
81	decreases ubiquitin ligase activity on histone h2a.
93	mildly decreases ubiquitin ligase activity on histone h2a.
97–98	loss of ubiquitin ligase activity on histone h2a.
97	strongly decreases ubiquitin ligase activity on histone h2a.
98	nearly abolishes ubiquitin ligase activity on histone h2a.
168	decreases ubiquitin ligase activity on histone h2a.
247	reduced interaction with cbx7.
258	reduced interaction with cbx7.
262	reduced interaction with cbx7.

Function

Pathways and Gene Ontology

Reactome pathways

7 curated (TAS) of 25; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

25 pathways:

ID	Pathway	Evidence
R-HSA-2559580	Oxidative Stress Induced Senescence	curated
R-HSA-8939243	RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	curated
R-HSA-3108214	SUMOylation of DNA damage response and repair proteins	curated
R-HSA-4570464	SUMOylation of RNA binding proteins	curated
R-HSA-4551638	SUMOylation of chromatin organization proteins	curated
R-HSA-3899300	SUMOylation of transcription cofactors	curated
R-HSA-8953750	Transcriptional Regulation by E2F6	curated
R-HSA-2559583	Cellular Senescence	—
R-HSA-8953897	Cellular responses to stimuli	—
R-HSA-2262752	Cellular responses to stress	—
R-HSA-9976102	Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	electronic
R-HSA-74160	Gene expression (Transcription)	—
R-HSA-212436	Generic Transcription Pathway	—
R-HSA-9006925	Intracellular signaling by second messengers	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-1257604	PIP3 activates AKT signaling	—
R-HSA-6807070	PTEN Regulation	—
R-HSA-597592	Post-translational protein modification	—
R-HSA-73857	RNA Polymerase II Transcription	—
R-HSA-8943724	Regulation of PTEN gene transcription	electronic
R-HSA-3108232	SUMO E3 ligases SUMOylate target proteins	—
R-HSA-2990846	SUMOylation	—
R-HSA-4655427	SUMOylation of DNA methylation proteins	electronic
R-HSA-162582	Signal Transduction	—
R-HSA-8878171	Transcriptional regulation by RUNX1	—

MSigDB gene sets: 837 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, BENPORATH_ES_WITH_H3K27ME3, GOBP_AXIS_SPECIFICATION, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_MYELOID_CELL_DEVELOPMENT, GOBP_INFLAMMATORY_RESPONSE, CMYB_01, GOBP_ERYTHROCYTE_HOMEOSTASIS, MAZ_Q6, GOBP_GROWTH, GOBP_PROTEIN_TARGETING, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, BROWNE_HCMV_INFECTION_16HR_UP

GO Biological Process (9): negative regulation of transcription by RNA polymerase II (GO:0000122), chromatin remodeling (GO:0006338), DNA-templated transcription (GO:0006351), germ cell development (GO:0007281), protein ubiquitination (GO:0016567), heterochromatin formation (GO:0031507), epigenetic regulation of gene expression (GO:0040029), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (9): chromatin binding (GO:0003682), zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), RING-like zinc finger domain binding (GO:0071535), histone H2AK119 ubiquitin ligase activity (GO:0140862), ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (14): ubiquitin ligase complex (GO:0000151), chromatin (GO:0000785), euchromatin (GO:0000791), sex chromatin (GO:0001739), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), nuclear body (GO:0016604), PcG protein complex (GO:0031519), PRC1 complex (GO:0035102), MLL1 complex (GO:0071339), ribonucleoprotein complex (GO:1990904), heterochromatin (GO:0000792), chromosome (GO:0005694)

Reactome top-level categories

14 top-level categories:

Category	Pathways
SUMO E3 ligases SUMOylate target proteins	5
Cellular Senescence	1
Transcriptional regulation by RUNX1	1
PTEN Regulation	1
Generic Transcription Pathway	1
Differentiation of T cells	1
Intracellular signaling by second messengers	1
RNA Polymerase II Transcription	1
Cellular responses to stimuli	1
Cellular responses to stress	1
Post-translational protein modification	1
SUMOylation	1
Metabolism of proteins	1
PIP3 activates AKT signaling	1

GO top-level categories

47 GO namespaces:

Category	Terms
cellular anatomical structure	3
DNA-templated transcription	2
regulation of DNA-templated transcription	2
binding	2
chromatin	2
intracellular membraneless organelle	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
chromatin organization	1
gene expression	1
RNA biosynthetic process	1
developmental process involved in reproduction	1
gamete generation	1
cellular process involved in reproduction in multicellular organism	1
cell development	1
protein modification by small protein conjugation	1
cellular component assembly	1
heterochromatin boundary formation	1
negative regulation of gene expression, epigenetic	1
heterochromatin organization	1
chromatin remodeling	1
regulation of gene expression	1
negative regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
protein domain specific binding	1
histone H2A ubiquitin ligase activity	1
ubiquitin-like protein transferase activity	1
catalytic activity	1
cation binding	1
intracellular protein-containing complex	1
transferase complex	1
chromosome	1
heterochromatin	1
sex chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
nucleoplasm	1
nuclear protein-containing complex	1
nuclear ubiquitin ligase complex	1
PcG protein complex	1
MLL1/2 complex	1
protein-containing complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 13 of 32 annotations. The rest are phylogenetic / computational / electronic (IEA).

13 experimentally-supported GO terms:

GO term	NS	Evidence
chromatin remodeling	BP	direct assay
epigenetic regulation of gene expression	BP	mutant phenotype
negative regulation of transcription by RNA polymerase II	BP	mutant phenotype
MLL1 complex	CC	direct assay
PRC1 complex	CC	direct assay
PcG protein complex	CC	direct assay
nuclear body	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
ubiquitin ligase complex	CC	direct assay
RING-like zinc finger domain binding	MF	physical interaction
chromatin binding	MF	direct assay
zinc ion binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 2,006 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNF2	BMI1	P35226	925
RNF2	EED	O75530	901
RNF2	PCGF6	Q9BYE7	896
RNF2	SUZ12	Q15022	894
RNF2	PHC1	P78364	888
RNF2	EZH2	Q15910	885
RNF2	H2AC20	Q16777	873
RNF2	H2AC19	P20670	873
RNF2	PHC2	Q8IXK0	831
RNF2	CBX2	Q14781	819
RNF2	R4GMX3	R4GMX3	810
RNF2	PCGF1	Q9BSM1	781
RNF2	RYBP	Q8N488	775
RNF2	RING1	Q06587	760
RNF2	YAF2	Q8IY57	727

IntAct

Human interaction partners of RNF2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 53 partners by confidence:

Partner	Interaction type	MIscore	Records
RYBP	physical association	0.970	13
BMI1	physical association	0.960	10
CBX7	direct interaction	0.960	10
PCGF2	physical association	0.950	9
PCGF1	physical association	0.950	6
CBX8	direct interaction	0.920	4
PCGF5	association	0.890	4
PCGF6	physical association	0.880	1
CBX6	direct interaction	0.860	3
RING1	physical association	0.850	3
CSNK2A1	physical association	0.800	1
CSNK2B	physical association	0.800	1
AUTS2	physical association	0.740	1
E2F6	association	0.730	1
PCGF3	physical association	0.720	5
USP7	physical association	0.690	3
UBE2D3	physical association	0.670	6
UBE2E2	physical association	0.670	6
UBE2E3	physical association	0.670	6
UBE2D1	physical association	0.670	4
UBE2D2	physical association	0.670	4
UBE2D4	physical association	0.670	4
CBX4	association	0.660	4
USP11	association	0.590	4
ATXN1	physical association	0.560	6
YAF2	physical association	0.560	6
PSEN2	physical association	0.560	3
UBE2K	physical association	0.560	3
ABCB1	physical association	0.510	2
H2AC11	physical association	0.500	4

BioGRID (1,347 interactions; top human partners by supporting records in a sample of 600 records): BMI1 (Co-purification; 4 records), HIST2H2AC (Biochemical Activity; 2 records), UBE2D3 (Reconstituted Complex; 2 records), AARS2 (Affinity Capture-MS), ABCB6 (Affinity Capture-MS), ABCD3 (Affinity Capture-MS), ABCE1 (Affinity Capture-MS), ABCF1 (Affinity Capture-MS), ABCF3 (Affinity Capture-MS), ACACA (Affinity Capture-MS), ACIN1 (Affinity Capture-MS), ACOT8 (Affinity Capture-MS), ACTG1 (Affinity Capture-MS), ADAM9 (Affinity Capture-MS), ADAMTS6 (Affinity Capture-MS)

SIGNOR signaling

7 signaling interactions:

A	Effect	B	Mechanism
BCOR	“up-regulates activity”	RNF2	binding
KDM2B	“up-regulates activity”	RNF2	binding
UBAP2L	“up-regulates activity”	RNF2	binding
RNF2	“form complex”	“Polycomb repressive complex 1”	binding
Ub:E2	“up-regulates activity”	RNF2	ubiquitination
RNF2	“down-regulates quantity by destabilization”	AMBRA1	ubiquitination
RNF2	“form complex”	“Noncanonical PRC1”	binding

Protein complexes (CORUM) (31)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

31 complexes by size:

Complex	Subunits	Members
CEN complex	37	SUPT16H, BMI1, CENPC, CENPU, FBL, RNF2, COBLL1, CUL4A, DDB1, HSPA5, NUP93, KIF23, ZFP91, CENPI, CENPK, RACGAP1, SSRP1, ZC3H13, CENPH, CENPM, HSPA8, VIRMA, CBX3, CENPB, SMARCA5, SRRT, CBX8, CENPA, CENPO, PLPPR3, RSF1, WDR11, WTAP, CENPL, DHX38, RING1, SHCBP1
★ MLL1-WDR5 complex	27	INO80C, KANSL1, MGAM, RUVBL1, TAF1, TAF6, ASH2L, CHD8, PRPF31, RNF2, SENP3, TEX10, WDR5, PELP1, HSPA4, KAT8, MCRS1, RBBP5, TAF4, HCFC1, KMT2A, LAS1L, PHF20, TAF7, TAF9, BACC1, E2F6
Polycomb repressive complex 1 (PRC1, hPRC-H, YY1)	13	BMI1, CBX4, CBX8, HSPA1A, PHC3, RNF2, SMARCA5, YY1, CBX2, PHC1, PHC2, RING1, SCMH1
★ PRC1.6a complex	13	RYBP, TFDP1, HDAC1, MAX, MGA, PCGF6, WDR5, CBX3, E2F6, HDAC2, L3MBTL2, RING1, RNF2
★ PRC1.6b complex	13	CBX3, HDAC1, L3MBTL2, MGA, PCGF6, RING1, WDR5, E2F6, HDAC2, MAX, RNF2, TFDP1, YAF2
Polycomb repressive complex 1 (PRC1, hPRC-H)	12	BMI1, CBX2, CBX4, HSPA1A, RING1, RNF2, SCMH1, SMARCA5, CBX8, PHC1, PHC2, PHC3
E2F-6 complex	12	E2F6, EHMT2, GJB3, L3MBTL2, TFDP1, EHMT1, MAX, MGA, PCGF6, RING1, RNF2, YAF2
PRC1.2c complex	11	SCML1, CBX4, PHC2, PHC3, RING1, SCMH1, CBX2, CBX8, PCGF2, PHC1, RNF2
PRC1.4c complex	11	CBX8, PHC1, RING1, RNF2, CBX2, CBX6, PHC2, PHC3, SCMH1, BMI1, CBX4
MOF complex	10	WDR5, KMT2A, KMT2D, RBBP5, RNF2, TAF1, TAF6, TAF9, KAT8, SETD1A
PRC1.3a complex	10	RING1, CSNK2A1, FBRSL1, RNF2, RYBP, AUTS2, CSNK2A2, CSNK2B, FBRS, PCGF3
PRC1.3b complex	10	AUTS2, FBRS, FBRSL1, RING1, CSNK2A1, CSNK2A2, CSNK2B, PCGF3, RNF2, YAF2
PRC1.5a complex	10	AUTS2, CSNK2A1, FBRS, PCGF5, RNF2, CSNK2A2, CSNK2B, FBRSL1, RING1, RYBP
PRC1.5c	10	CSNK2B, FBRS, FBRSL1, RNF2, YAF2, AUTS2, CSNK2A1, CSNK2A2, PCGF5, RING1
PRC1.1c complex	9	BCOR, KDM2B, PCGF1, RNF2, RYBP, SKP1, USP7, BCORL1, RING1
PRC1.1d complex	9	SKP1, YAF2, BCOR, BCORL1, PCGF1, RING1, USP7, KDM2B, RNF2
BCOR complex	8	RNF2, RYBP, SKP1, BCOR, HSPA8, KDM2B, PCGF1, RING1
hPRC1L complex	4	BMI1, PHC2, RING1, RNF2
PRC1.1a complex	4	PCGF1, RING1, RNF2, RYBP
PRC1.1b complex	4	RING1, RNF2, YAF2, PCGF1
PRC1.2a complex	4	PCGF2, RING1, RNF2, RYBP
PRC1.2b complex	4	PCGF2, RING1, RNF2, YAF2
PRC1.4a complex	4	BMI1, RING1, RNF2, RYBP
PRC1.4b complex	4	BMI1, RING1, RNF2, YAF2
PCGF5–RING1B–UBE2D3 complex	3	BMI1, RNF2, UBE2D3
PCGF1-RING1B complex	2	PCGF1, RNF2
PCGF2-RING1B complex	2	PCGF2, RNF2
PCGF3-RING1B complex	2	RNF2, PCGF3
PCGF4-RING1B complex	2	BMI1, RNF2
PCGF5-RING1B complex	2	PCGF5, RNF2
PCGF6-RING1B complex	2	PCGF6, RNF2

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 53 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
SUMOylation of DNA methylation proteins	6	93.7×	1e-09
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	12	83.9×	1e-18
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	8	68.5×	2e-11
Transcriptional Regulation by E2F6	8	54.5×	1e-10
SUMOylation of transcription cofactors	7	39.5×	1e-08
SUMOylation of RNA binding proteins	7	38.7×	1e-08
PTEN Regulation	6	31.9×	5e-07
Transcriptional regulation by RUNX1	9	30.6×	5e-10

GO biological processes:

GO term	Partners	Fold	FDR
protein K11-linked ubiquitination	6	46.1×	3e-07
negative regulation of proteasomal ubiquitin-dependent protein catabolic process	5	39.3×	8e-06
protein monoubiquitination	5	33.7×	1e-05
protein K48-linked ubiquitination	9	29.7×	2e-09
protein K63-linked ubiquitination	5	26.2×	4e-05
protein polyubiquitination	11	24.9×	2e-10
ubiquitin-dependent protein catabolic process	8	11.7×	1e-05
chromatin remodeling	6	8.6×	2e-03

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

BAP1 is a deubiquitylase thought to be a key regulator of many cancer-associated pathways. Germline alterations in BAP1 have been characterized as predisposing variants to familial melanocytic skin tumors. These alterations also have been linked to the development of mesothelioma, uveal melanoma, cutaneous melanoma and others. Clinically, the role of BAP1 is still being investigated. However, the development of intradermal tumors known as melanocytic BAP1-associated intradermal tumors (MBAITs) are enough for a patient to be subject to more intense surveillance to catch other malignancies as early as possible.

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 14 cancer types — BRCA, CCRCC, CESC, CHOL, ESCA, HCC, PANCREAS, PLMESO, PRCC, RCC, SACA, SKCM…(+2 more).

intOGen’s role is a computational inference from cohort mutation patterns and may diverge from the gene’s curated/literature role; read it alongside the evidence above.

Genetic variants

Variant evidence for RNF2: 3,683 ClinVar records (410 pathogenic / likely pathogenic); 5 CIViC cancer variants; 9 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

3,683 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	313
Likely pathogenic	97
Uncertain significance	1414
Likely benign	1001
Benign	59

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 410 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
221278	NM_004656.4(BAP1):c.1717del (p.Leu573fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	14
30302	NM_004656.4(BAP1):c.2050C>T (p.Gln684Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	7
434478	NM_004656.4(BAP1):c.1358_1359del (p.Lys453fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	7
580226	NM_004656.4(BAP1):c.178C>T (p.Arg60Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	7
422219	NM_004656.4(BAP1):c.1777C>T (p.Gln593Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	6
449856	NM_004656.4(BAP1):c.1203dup (p.Glu402Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	6
490777	NM_004656.4(BAP1):c.1174C>T (p.Gln392Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
628182	NM_004656.4(BAP1):c.1882_1885del (p.Ser628fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
656678	NM_004656.4(BAP1):c.1938T>A (p.Tyr646Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
822865	NM_004656.4(BAP1):c.898_899del (p.Arg300fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
1450488	NM_004656.4(BAP1):c.605G>A (p.Trp202Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
485270	NM_004656.4(BAP1):c.1695dup (p.Glu566Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
584646	NM_004656.4(BAP1):c.1321C>T (p.Gln441Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
584647	NM_004656.4(BAP1):c.1203T>G (p.Tyr401Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
826235	NM_004656.4(BAP1):c.619del (p.Arg207fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	4

Per-variant reference — Sugi Variant

Explore RNF2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 33 predictions of 1,946):

Position(s)	Effect	Δscore	Sites
1:185087550–185087551	acceptor_loss	1.0000	6
1:185093059–185093060	acceptor_loss	1.0000	2
1:185093277–185093278	donor_loss	1.0000	6
1:185098065	acceptor_gain	1.0000
1:185098345–185098346	donor_loss	1.0000	4
1:185099789	acceptor_loss	1.0000
1:185099963–185099964	donor_loss	1.0000	4
3:52402422–52402423	acceptor_loss	1.0000	3
3:52402426	acceptor_gain	1.0000
3:52402600–52402601	donor_loss	1.0000	5

AlphaMissense

1,355 missense substitutions predicted likely pathogenic (of 2,241 scored), across 272 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M50	9	0.986	1.000
M62	9	0.974	0.999
M57	9	0.937	0.999
H69	8	1.000	1.000
D103	8	1.000	1.000
F71	8	0.999	1.000
N84	8	0.999	1.000
D107	8	0.999	1.000
H258	8	0.999	1.000
D56	8	0.997	1.000
F106	8	0.992	1.000
F230	8	0.992	1.000
D257	8	0.988	0.998
H46	8	0.974	0.997
N105	8	0.968	0.999
S143	8	0.949	0.999
S82	8	0.947	0.997
H233	8	0.941	0.998
D34	8	0.910	0.991
S47	8	0.901	0.998

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

5 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Chromophobe (TCGA)	unfavorable	3.41e-05
Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA)	unfavorable	0.000275
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	0.000367
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	0.00077
Kidney Renal Papillary Cell Carcinoma (TCGA)	unfavorable	0.00091

Disease associations

OMIM: gene MIM:608985 | disease phenotypes: MIM:614327, MIM:619762, MIM:619460, MIM:606661, MIM:155720, MIM:254500

GenCC curated gene-disease

4 curated gene-disease records:

Disease	Classification	Inheritance	Records
BAP1-related tumor predisposition syndrome	Definitive	Autosomal dominant	6
Kury-Isidor syndrome	Strong	Autosomal dominant	2
renal cell carcinoma	Strong	Autosomal dominant
Luo-Schoch-Yamamoto syndrome	Strong	Autosomal dominant	2

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
BAP1-related tumor predisposition syndrome	Definitive	AD

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (7 panels, 0 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

7 panels:

Panel	Rating
Early onset or syndromic epilepsy	amber
Fetal anomalies	amber
Hypotonic infant	amber
Intellectual disability	amber
Leukodystrophy, childhood onset	amber
Paediatric disorders	amber
Unexplained death in infancy and sudden unexplained death in childhood	amber

Mondo (10): BAP1-related tumor predisposition syndrome (MONDO:0013692), neurodevelopmental disorder (MONDO:0700092), Kury-Isidor syndrome (MONDO:0859230), hereditary neoplastic syndrome (MONDO:0015356), Luo-Schoch-Yamamoto syndrome (MONDO:0859171), melanoma, uveal, susceptibility to, 2 (MONDO:0011696), astrocytoma (excluding glioblastoma) (MONDO:0019781), uveal melanoma (MONDO:0006486), plasma cell myeloma (MONDO:0009693), renal cell carcinoma (MONDO:0005086)

Orphanet (5): BAP1-related tumor predisposition syndrome (Orphanet:289539), Inherited cancer-predisposing syndrome (Orphanet:140162), Uveal melanoma (Orphanet:39044), Multiple myeloma (Orphanet:29073), AL amyloidosis (Orphanet:85443)

HPO phenotypes

showing 60 of 181 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000020	Urinary incontinence
HP:0000044	Hypogonadotropic hypogonadism
HP:0000126	Hydronephrosis
HP:0000141	Amenorrhea
HP:0000154	Wide mouth
HP:0000160	Narrow mouth
HP:0000207	Triangular mouth
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000248	Brachycephaly
HP:0000280	Coarse facial features
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000343	Long philtrum
HP:0000360	Tinnitus
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000403	Recurrent otitis media
HP:0000445	Wide nose
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000488	Retinopathy
HP:0000490	Deeply set eye
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis
HP:0000520	Proptosis
HP:0000527	Long eyelashes
HP:0000577	Exotropia
HP:0000602	Ophthalmoplegia
HP:0000618	Blindness
HP:0000687	Widely spaced teeth
HP:0000712	Emotional lability
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0000765	Abnormal thorax morphology
HP:0000802	Impotence
HP:0000870	Increased circulating prolactin concentration
HP:0000958	Dry skin
HP:0000960	Sacral dimple
HP:0000998	Hypertrichosis
HP:0001067	Neurofibroma
HP:0001085	Papilledema
HP:0001156	Brachydactyly
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001262	Excessive daytime somnolence
HP:0001263	Global developmental delay
HP:0001269	Hemiparesis
HP:0001270	Motor delay
HP:0001279	Syncope
HP:0001288	Gait disturbance
HP:0001317	Abnormal cerebellum morphology
HP:0001342	Cerebral hemorrhage
HP:0001347	Hyperreflexia
HP:0001385	Hip dysplasia

GWAS associations

9 associations:

Study	Trait	p-value
GCST004264_3	Clopidogrel active metabolite levels	7e-13
GCST004521_274	Autism spectrum disorder or schizophrenia	3e-12
GCST002149_14	Schizophrenia	1e-8
GCST004902_20	Parkinson’s disease	3e-8
GCST004521_77	Autism spectrum disorder or schizophrenia	4e-8
GCST004264_27	Clopidogrel active metabolite levels	2e-7
GCST001241_15	Bipolar disorder	2e-6
GCST001762_275	Obesity-related traits	2e-6
GCST004862_201	Itch intensity from mosquito bite adjusted by bite size	2e-6

EFO canonical traits (from GWAS)

4 canonical traits:

EFO ID	Trait name
EFO:0005119	antioxidant measurement
EFO:0007966	clopidogrel metabolite measurement
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement

MeSH disease descriptors

5 disease descriptors:

Descriptor	Name	Tree numbers
D001254	Astrocytoma	C04.557.465.625.600.380.080; C04.557.470.670.380.080; C04.557.580.625.600.380.080
D002292	Carcinoma, Renal Cell	C04.557.470.200.025.390; C04.588.945.947.535.160; C12.050.351.937.820.535.160; C12.050.351.968.419.473.160; C12.200.758.820.750.160; C12.200.777.419.473.160; C12.900.820.535.160; C12.950.419.473.160; C12.950.983.535.160
D009101	Multiple Myeloma	C04.557.595.500; C14.907.454.460; C15.378.147.780.650; C15.378.463.515.460; C20.683.515.845; C20.683.780.650
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066032 (PROTEIN-PROTEIN INTERACTION)

Clinical evidence (CIViC)

Drug × variant × indication, from 10 curated evidence items; also 4 prognostic, 1 functional. CIViC evidence level: A (validated) → B (clinical) → C (case study) → D (preclinical) → E (inferential).

9 predictive associations by evidence level:

Variant	Therapy	Indication	Effect	Level	CIViC
BAP1 Mutation	Olaparib	Malignant Mesothelioma	Sensitivity/Response	CIViC B	EID11740 +1
BRCA1 Loss-of-function OR BAP1 Loss-of-function	Rucaparib	Malignant Mesothelioma	Sensitivity/Response	CIViC B	EID11739
BAP1 Mutation	Sunitinib + Everolimus	Clear Cell Renal Cell Carcinoma	Resistance	CIViC B	EID5339
BAP1 ALTERNATIVE TRANSCRIPT (ATI)	Apitolisib + Olaparib	Malignant Mesothelioma	Sensitivity/Response	CIViC D	EID5929
BAP1 Loss	Olaparib	Renal Carcinoma	Sensitivity/Response	CIViC D	EID5930
BAP1 Loss	EPZ011989	Malignant Pleural Mesothelioma	Sensitivity/Response	CIViC D	EID8329
BAP1 Mutation	CDK4/6 Inhibition	Malignant Pleural Mesothelioma	Sensitivity/Response	CIViC D	EID12008
BAP1 Mutation	Trichostatin A + Vorinostat + Panobinostat + Valproic Acid	Uveal Melanoma	Sensitivity/Response	CIViC D	EID1234
BAP1 Loss	Mocetinostat + Vorinostat	Malignant Mesothelioma	Sensitivity/Response	CIViC E	EID1235

CIViC column: a representative evidence item (EID); +N = additional CIViC items supporting the same association.

CIViC curated variants (5)

Named clinical variants curated in CIViC for this gene (the catalogue beneath the predictive evidence above):

EXPRESSION, Mutation (protein altering variant,loss of function variant), ALTERNATIVE TRANSCRIPT (ATI), Loss, Loss-of-function.

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases response to substance, decreases methylation	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol A	decreases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
jinfukang	decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
Bortezomib	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases methylation, increases abundance	1
Caffeine	decreases phosphorylation	1
Calcitriol	increases expression	1
Diethylstilbestrol	increases expression	1
Doxorubicin	decreases expression	1
Fonofos	decreases methylation	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Gold	decreases expression	1
Ivermectin	decreases expression	1
Nitrogen Dioxide	decreases methylation, increases abundance	1
Parathion	decreases methylation	1
Phenobarbital	affects expression	1
Valproic Acid	decreases methylation	1
Cyclosporine	increases expression	1
Lactic Acid	decreases expression	1

ChEMBL screening assays

16 unique, capped per target: 16 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5548040	Binding	PROTAC activity at CRBN/RING1B in human K562 cells assessed as degradation of RING1B protein expression incubated for 24 hrs by Western blotting analysis	Discovery and Characterization of a Novel Cereblon-Recruiting PRC1 Bridged PROTAC Degrader. — *J Med Chem*

Cellosaurus cell lines

16 cell lines: 11 cancer cell line, 5 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A5W5	SEES3-1V human RNF2, clone1	Embryonic stem cell	Male
CVCL_A5W6	SEES3-1V human RNF2, clone2	Embryonic stem cell	Male
CVCL_A5W7	SEES3-1V human RNF2, clone3	Embryonic stem cell	Male
CVCL_B2DY	Abcam HeLa RNF2 KO	Cancer cell line	Female
CVCL_B8NV	Abcam HCT 116 RNF2 KO	Cancer cell line	Male
CVCL_B9B7	Abcam MCF-7 RNF2 KO	Cancer cell line	Female
CVCL_B9R6	Abcam A-549 RNF2 KO	Cancer cell line	Male
CVCL_DX52	HAP1 RING1 (-) RNF2 (-) 1	Cancer cell line	Male
CVCL_E1NP	HAP1 RING1 (-) RNF2 (-) 2	Cancer cell line	Male
CVCL_TJ30	HAP1 RNF2 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 541 trials:

NCT	Phase	Status	Title
NCT00414765	Phase 4	COMPLETED	Aldesleukin in Participants With Metastatic Renal Cell Carcinoma or Metastatic Melanoma
NCT00777504	Phase 4	UNKNOWN	Study to the Optimal Duration of Therapy With Oral Angiogenesis Inhibitors
NCT00930345	Phase 4	TERMINATED	Biological, Pathological and Imagery Markers in the First-line Treatment of Metastatic Clear-cell Renal Cell Carcinoma
NCT01206764	Phase 4	COMPLETED	A Trial of Everolimis in Patients With Advanced Renal Cell Carcinoma.
NCT01266837	Phase 4	COMPLETED	Open Label, Single Arm Trial to Characterize Patients With Metastatic RCC Treated With Everolimus After Failure of the First VEGF-targeted Therapy (MARC-2)
NCT02056587	Phase 4	COMPLETED	Everolimus in Patients With Metastatic Renal Cell Carcinoma Following Progression on Prior Bevacizumab Treatment
NCT02338570	Phase 4	TERMINATED	Outcome-related Factors in Patients With Metastatic Renal Cell Carcinoma Treated With Everolimus (ORCHIDEE)
NCT02596035	Phase 4	COMPLETED	An Investigational Immuno-therapy Safety Trial of Nivolumab in Patients With Advanced or Metastatic Renal Cell Carcinoma
NCT02982954	Phase 4	COMPLETED	A Study to Evaluate the Safety of Nivolumab and Ipilimumab in Subjects With Previously Untreated Advanced or Metastatic Renal Cell Cancer
NCT05949424	Phase 4	UNKNOWN	OPTI - DOSE: Optimal Dosing of Oral Anticancer Drugs in Older Adults
NCT07028125	Phase 4	RECRUITING	Digital Monitoring of Self-reported Symptoms by Patients Treated With Cabozantinib Plus Nivolumab for Advanced Clear-cell Renal Carcinoma
NCT07405086	Phase 4	RECRUITING	Morning Versus Afternoon Administration of Immunotherapy for the Treatment of Advanced or Metastatic Solid Tumors, The Knight SHIFT Study
NCT04586348	Phase 4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	Phase 4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00033904	Phase 3	COMPLETED	Survival Study Of Oncophage® vs. Observation In Patients With Kidney Cancer
NCT00126178	Phase 3	TERMINATED	Clinical Trial Studying a Personalized Cancer Vaccine in Patients With Non-metastatic Kidney Cancer
NCT00291369	Phase 3	COMPLETED	Cytokines in Patients With Metastatic Renal Cell Carcinoma of Intermediate Prognosis
NCT00410124	Phase 3	COMPLETED	RAD001 Plus Best Supportive Care (BSC) Versus BSC Plus Placebo in Patients With Metastatic Carcinoma of the Kidney Which Has Progressed After Treatment With Sorafenib and/or Sunitinib
NCT00474786	Phase 3	COMPLETED	Temsirolimus Versus Sorafenib As Second-Line Therapy In Patients With Advanced RCC Who Have Failed First-Line Sunitinib
NCT00478114	Phase 3	COMPLETED	Efficacy and Safety of Sorafenib in Advanced Renal Cell Carcinoma (RCC)
NCT00606632	Phase 3	COMPLETED	Pre-surgical Detection of Clear Cell Renal Cell Carcinoma (ccRCC) Using Radiolabeled G250-Antibody
NCT00606866	Phase 3	COMPLETED	MRI Study of BAY 43-9006 in Metastatic Renal Cell Carcinoma
NCT00631371	Phase 3	COMPLETED	Study Comparing Bevacizumab + Temsirolimus vs. Bevacizumab + Interferon-Alfa In Advanced Renal Cell Carcinoma Subjects
NCT00732914	Phase 3	COMPLETED	Sequential Study to Treat Renal Cell Carcinoma
NCT00869011	Phase 3	UNKNOWN	Exercise for Patients With Renal Cell Cancer Receiving Sunitinib
NCT00930033	Phase 3	COMPLETED	Clinical Trial to Assess the Importance of Nephrectomy
NCT01030783	Phase 3	COMPLETED	A Study to Compare Tivozanib (AV-951) to Sorafenib in Subjects With Advanced Renal Cell Carcinoma
NCT01076010	Phase 3	COMPLETED	An Extension Treatment Protocol for Subjects Who Have Participated in a Study of Tivozanib Versus Sorafenib in Kidney Carcinoma (Protocol AV-951-09-301).
NCT01198158	Phase 3	TERMINATED	Everolimus With or Without Bevacizumab in Treating Patients With Advanced Kidney Cancer That Progressed After First-Line Therapy
NCT01223027	Phase 3	COMPLETED	Study of Dovitinib Versus Sorafenib in Patients With Metastatic Renal Cell Carcinoma
NCT01224288	Phase 3	ACTIVE_NOT_RECRUITING	Dynamic Contrast Enhancement Computed Tomography for Evaluating Tumor Perfusion in Patients With Metastatic Renal Cell Carcinoma Receiving Targeted Therapies: Renal Cell Carcinoma (RCC) Scramble
NCT01235962	Phase 3	COMPLETED	A Study to Evaluate Pazopanib as an Adjuvant Treatment for Localized Renal Cell Carcinoma (RCC)
NCT01265810	Phase 3	COMPLETED	Caphosol in Oral Mucositis Due to Targeted Therapy
NCT01265901	Phase 3	COMPLETED	IMA901 in Patients Receiving Sunitinib for Advanced/Metastatic Renal Cell Carcinoma
NCT01481870	Phase 3	UNKNOWN	Comparison of Sequential Therapies With Sunitinib and Sorafenib in Advanced Renal Cell Carcinoma
NCT01582672	Phase 3	TERMINATED	Phase 3 Trial of Autologous Dendritic Cell Immunotherapy Plus Standard Treatment of Advanced Renal Cell Carcinoma
NCT01613846	Phase 3	COMPLETED	Phase III Sequential Open-label Study to Evaluate the Efficacy and Safety of Sorafenib Followed by Pazopanib Versus Pazopanib Followed by Sorafenib in the Treatment of Advanced / Metastatic Renal Cell Carcinoma (SWITCH-II)
NCT01762592	Phase 3	WITHDRAWN	REDECT 2: REnal Masses: Pivotal Trial to DEteCT Clear Cell Renal Cell Carcinoma With PET/CT
NCT01865747	Phase 3	COMPLETED	A Study of Cabozantinib (XL184) vs Everolimus in Subjects With Metastatic Renal Cell Carcinoma
NCT02231749	Phase 3	COMPLETED	Nivolumab Combined With Ipilimumab Versus Sunitinib in Previously Untreated Advanced or Metastatic Renal Cell Carcinoma (CheckMate 214)
NCT02420821	Phase 3	COMPLETED	A Study of Atezolizumab in Combination With Bevacizumab Versus Sunitinib in Participants With Untreated Advanced Renal Cell Carcinoma (RCC)
NCT02811861	Phase 3	ACTIVE_NOT_RECRUITING	Lenvatinib/Everolimus or Lenvatinib/Pembrolizumab Versus Sunitinib Alone as Treatment of Advanced Renal Cell Carcinoma
NCT02853331	Phase 3	COMPLETED	Study to Evaluate the Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Axitinib Versus Sunitinib Monotherapy in Participants With Renal Cell Carcinoma (MK-3475-426/KEYNOTE-426)
NCT03024996	Phase 3	TERMINATED	A Study of Atezolizumab as Adjuvant Therapy in Participants With Renal Cell Carcinoma (RCC) at High Risk of Developing Metastasis Following Nephrectomy
NCT03055013	Phase 3	ACTIVE_NOT_RECRUITING	Nivolumab in Treating Patients With Localized Kidney Cancer Undergoing Nephrectomy
NCT03141177	Phase 3	COMPLETED	A Study of Nivolumab Combined With Cabozantinib Compared to Sunitinib in Previously Untreated Advanced or Metastatic Renal Cell Carcinoma
NCT03142334	Phase 3	COMPLETED	Safety and Efficacy Study of Pembrolizumab (MK-3475) as Monotherapy in the Adjuvant Treatment of Renal Cell Carcinoma Post Nephrectomy (MK-3475-564/KEYNOTE-564)
NCT03260894	Phase 3	COMPLETED	Pembrolizumab (MK-3475) Plus Epacadostat vs Standard of Care in mRCC (KEYNOTE-679/ECHO-302)
NCT03288532	Phase 3	RECRUITING	Renal Adjuvant MultiPle Arm Randomised Trial
NCT03408652	Phase 3	TERMINATED	Efficacy and Safety of Systemic Treatments of Bone Metastases From Kidney Cancer in Patients Treated With Targeted Therapies
NCT03592472	Phase 3	RECRUITING	A Study of Pazopanib With or Without Abexinostat in Patients With Locally Advanced or Metastatic Renal Cell Carcinoma (RENAVIV)
NCT03693573	Phase 3	WITHDRAWN	A Study of Atezolizumab in Combination With Bevacizumab in Untreated Locally Advanced or Metastatic Clear Cell or Non-Clear Cell Renal Cell Carcinoma
NCT03729245	Phase 3	TERMINATED	A Study of Bempegaldesleukin (NKTR-214: BEMPEG) in Combination With Nivolumab Compared With the Investigator’s Choice of a Tyrosine Kinase Inhibitor (TKI) Therapy (Either Sunitinib or Cabozantinib Monotherapy) for Advanced Metastatic Renal Cell Carcinoma (RCC)
NCT03873402	Phase 3	ACTIVE_NOT_RECRUITING	A Study of Nivolumab Combined With Ipilimumab Versus Nivolumab Alone in Participants With Advanced Kidney Cancer
NCT03937219	Phase 3	ACTIVE_NOT_RECRUITING	Study of Cabozantinib in Combination With Nivolumab and Ipilimumab in Patients With Previously Untreated Advanced or Metastatic Renal Cell Carcinoma
NCT04510597	Phase 3	RECRUITING	Comparing the Outcome of Immunotherapy-Based Drug Combination Therapy With or Without Surgery to Remove the Kidney in Metastatic Kidney Cancer, the PROBE Trial
NCT04588246	Phase 3	TERMINATED	Comparing Whole Brain Radiotherapy Using a Technique That Avoids the Hippocampus to Stereotactic Radiosurgery in Patients With Cancer That Has Spread to the Brain and Come Back in Other Areas of the Brain After Earlier Stereotactic Radiosurgery
NCT04764487	Phase 3	UNKNOWN	A Web-mediated Follow-up With the Web-application KidneyPRO Versus Standard Follow-up for Patients With Advanced Renal Cell Carcinoma Treated With Axitinib/Pembrolizumab in First Line
NCT04987203	Phase 3	COMPLETED	Study to Compare Tivozanib in Combination With Nivolumab to Tivozanib Monotherapy in Subjects With Renal Cell Carcinoma
NCT05078047	Phase 3	ACTIVE_NOT_RECRUITING	Study Comparing the Standard Administration of IO Versus the Same IO Administered Each 3 Months in Patients in Response After 6 Months of Standard IO