RBL2

Summary

RBL2 (RB transcriptional corepressor like 2, HGNC:9894) is a protein-coding gene on chromosome 16q12.2, encoding Retinoblastoma-like protein 2 (Q08999). Key regulator of entry into cell division.

Enables promoter-specific chromatin binding activity. Involved in regulation of lipid kinase activity. Acts upstream of or within negative regulation of gene expression. Located in chromosome; cytosol; and nuclear lumen.

Source: NCBI Gene 5934 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Brunet-Wagner neurodevelopmental syndrome (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 15
• Clinical variants (ClinVar): 198 total — 5 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 25
• MANE Select transcript: NM_005611

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9894
Approved symbol	RBL2
Name	RB transcriptional corepressor like 2
Location	16q12.2
Locus type	gene with protein product
Status	Approved
Aliases	Rb2, p130
Ensembl gene	ENSG00000103479
Ensembl biotype	protein_coding
OMIM	180203
Entrez	5934

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 19 protein_coding, 5 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000262133, ENST00000379935, ENST00000544405, ENST00000561512, ENST00000562837, ENST00000562850, ENST00000564605, ENST00000567964, ENST00000680543, ENST00000894786, ENST00000894787, ENST00000894788, ENST00000894789, ENST00000894790, ENST00000894791, ENST00000894792, ENST00000894793, ENST00000894794, ENST00000937511, ENST00000949706, ENST00000949707, ENST00000949708, ENST00000949709, ENST00000949710, ENST00000949711

RefSeq mRNA: 5 — MANE Select: NM_005611 NM_001323608, NM_001323609, NM_001323610, NM_001323611, NM_005611

CCDS: CCDS10748

Canonical transcript exons

ENST00000262133 — 22 exons

Exon	Start	End
ENSE00001307883	53434471	53434796
ENSE00001825589	53490130	53491648
ENSE00003468455	53442658	53442858
ENSE00003478371	53459451	53459617
ENSE00003482757	53479154	53479225
ENSE00003487915	53454656	53454842
ENSE00003508883	53465438	53465602
ENSE00003511762	53481671	53481835
ENSE00003524909	53461741	53461850
ENSE00003527109	53462552	53462655
ENSE00003537531	53439016	53439146
ENSE00003568219	53451703	53451831
ENSE00003593374	53467058	53467169
ENSE00003598367	53480567	53480769
ENSE00003618269	53447042	53447106
ENSE00003623341	53470383	53470663
ENSE00003630968	53453705	53453769
ENSE00003637652	53464226	53464363
ENSE00003640595	53470746	53470922
ENSE00003641284	53469916	53470185
ENSE00003643337	53479886	53479991
ENSE00003687820	53453452	53453612

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 97.98.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.7934 / max 635.3004, expressed in 1811 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154082	27.0478	1809
154086	1.1565	94
154084	1.1500	340
154089	0.6970	75
154083	0.5495	234
154088	0.4845	73
154091	0.4149	70
154090	0.1164	38
154085	0.0867	34
154087	0.0849	39

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
germinal epithelium of ovary	UBERON:0001304	97.98	gold quality
superficial temporal artery	UBERON:0001614	97.93	gold quality
epithelium of nasopharynx	UBERON:0001951	97.57	gold quality
nasopharynx	UBERON:0001728	97.55	gold quality
calcaneal tendon	UBERON:0003701	97.52	gold quality
lymph node	UBERON:0000029	97.32	gold quality
cardia of stomach	UBERON:0001162	97.24	gold quality
tonsil	UBERON:0002372	97.15	gold quality
body of pancreas	UBERON:0001150	97.14	gold quality
pylorus	UBERON:0001166	97.11	gold quality
mucosa of paranasal sinus	UBERON:0005030	97.09	gold quality
amniotic fluid	UBERON:0000173	97.03	gold quality
right lung	UBERON:0002167	97.02	gold quality
fundus of stomach	UBERON:0001160	96.97	gold quality
colonic epithelium	UBERON:0000397	96.89	gold quality
lower lobe of lung	UBERON:0008949	96.84	gold quality
vermiform appendix	UBERON:0001154	96.68	gold quality
gall bladder	UBERON:0002110	96.60	gold quality
urethra	UBERON:0000057	96.58	gold quality
caecum	UBERON:0001153	96.55	gold quality
bone marrow cell	CL:0002092	96.44	gold quality
tibia	UBERON:0000979	96.41	gold quality
trabecular bone tissue	UBERON:0002483	96.37	gold quality
endometrium	UBERON:0001295	96.36	gold quality
skin of hip	UBERON:0001554	96.30	gold quality
seminal vesicle	UBERON:0000998	96.28	gold quality
right uterine tube	UBERON:0001302	96.25	gold quality
renal medulla	UBERON:0000362	96.21	gold quality
thymus	UBERON:0002370	96.21	gold quality
synovial joint	UBERON:0002217	96.18	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	13.75
E-GEOD-150728	no	852.89

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

6 targets.

Target	Regulation
BRCA1	Repression
DHFR	Repression
DNMT3B	Repression
E2F4	Unknown
MYOD1	Repression
RAD51	Repression

Upstream regulators (CollecTRI, top): CTCF, CTCFL, DIDO1, DNMT3B, E2F3, EGR1, ESR1, EZH2, FOXO1, FOXO3, FOXO4, ID2, MBD2, NAB2, NR1I2, SP1, TFAP2A, TFAP2B, TFDP1, TP53, TP63, TP73, TWIST1, TWIST2, ZEB1

miRNA regulators (miRDB)

146 targeting RBL2, 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-3163	100.00	77.23	8605
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192

Literature-anchored findings (GeneRIF, showing 40)

• may have a role in the mechanisms of proliferation and differentiation during human placental development (PMID:11642725)
• regulation of expression of p130, p107 and E2F-4 in human cells (PMID:12006580)
• p130 and its truncated form might substitute Rb in mediating p53-induced cell cycle arrest in Rb(-/-) Saos2 cells (PMID:12386819)
• p130 turnover is regulated by Cdk-dependent G1 phosphorylation leading to ubiquitin-dependent proteolysis (PMID:12435635)
• Expression of this gene predicts outcome in squamous cell carcinoma of the esophagus. (PMID:12474056)
• report shows hypophosphorylation of the retinoblastoma family proteins induced by H2O2 was because of the activity of protein phosphatase 2A (PMID:12621062)
• reduced p130 expression may contribute to the aggressive character of anplastic carcinoma; and p130 may specify the growth characteristics of microcarcinoma (PMID:12637156)
• We investigated occupancy of ER-alpha promoter by pRb2/p130-E2F4/5-HDAC1-SUV39 H1-p300 and pRb2/p130-E2F4/5-HDAC1-SUV39H1-DNMT1 complexes, and provided a link between pRb2/p130 and chromatin-modifying enzymes in the regulation of ER-alpha transcription (PMID:12789259)
• Analysis of gene expression level profiles showed that parental cell line undergoes apoptosis through an E2F1/p73-dependent pathway while its drug resistant variant evades it. (PMID:12789260)
• ATRA mediates growth inhibition by stabilizing Rb2/p130 via a mechanism that involves induction of PP2A, an enzyme that can potentially dephosphorylate Rb2/p130, thereby protecting it from degradation by the proteasome. (PMID:12915404)
• T Ag recruits a phosphatase activity in a DNA J domain-dependent manner to reduce the phosphorylation of p130 (PMID:12968030)
• The interaction between HIV-1 tat and Rb2 may be a possible mechanism in the pathogenesis of AIDS-related lymphoma. (PMID:13679860)
• Rb2/P130 target genes in non-small-cell lung neoplasms are identified by microarray analysis. (PMID:14534545)
• Reduced transcription of the RB2/p130 gene is associated with lung cancer (PMID:14587097)
• Induction of p130 and p107 play an important role in the inhibition of growth of C33A cells by MIS. (PMID:14671316)
• pRb2/p130 has a role as a tumour suppressor protein in hepatocellular carcinoma (PMID:15059924)
• pRb2/p130 overexpression is able to arrest cell growth in ovarian carcinoma cells, suggesting the putative role of pRb2/p130 as a tumor suppressor in this malignancy. (PMID:15131049)
• VEGF together with pRb2/p130 may have a role in hepatocellular carcinoma in a p27((KIP1))-independent manner (PMID:15161709)
• Disruption of E2F4 through small interfering RNA prevented p130/E2F4 complex formation and sensitized prostate cancer cells to IR-induced apoptosis. (PMID:15231644)
• the PP2A catalytic subunit (PP2A/C) specifically interacts with both p130 and p107 in quiescent cells as well as cells progressing throughout the cell cycle (PMID:15467457)
• Rb2/ p130 expression can additionally be an indicator of a better prognosis in patients with gliomas (PMID:15696973)
• p130/p107/p105Rb has a role in transcriptional repression in DNA-damage-induced cell-cycle exit at G2 (PMID:15827088)
• developmental expression of RB, p130 and p107 in mouse and human retina (PMID:15939381)
• RBP2 resembles other chromatin-associated transcriptional regulators and RBP2 binding to activate transcription and promote differentiation. (PMID:15949438)
• p130 is a trancriptional regulator of the cell cycle genes. (PMID:16135806)
• Involved in progression and regulation of telomerase (PMID:16364039)
• These results demonstrate a mechanistic role for p130 and compensatory roles for p107 and RB in the long-term senescence-like growth arrest response of breast cancer cells to DNA damage. (PMID:16537896)
• ER-beta and pRb2/p130 proteins co-immunoprecipitate in both nucleus and cytoplasm of MCF-7 breast cancer cells. The interaction of pRb2/130 with ER-beta may have a functional significance in regulating ER-beta activity. (PMID:16760287)
• All-trans-retinoic acid (ATRA) has been shown to arrest the growth of ovarian carcinoma cells in G0/G1 and to significantly elevate levels of Rb2/p130 protein. (review) (PMID:16936753)
• supportive role in the genesis of retinoblastoma has recently been proposed for the RB1-related gene RB2/p130. (review) (PMID:16936755)
• Mutated RBL2 is associated with Burkitt lymphoma (PMID:17485552)
• Evolutionarily conserved multisubunit protein complex that contains p130 and E2F4 mediates the repression of cell cycle-dependent genes in quiescence. (PMID:17531812)
• no mutation of p53 and RB2/p130 genes was identified in any of the blood samples from Malaysian nasopharyngeal carcinoma (PMID:17694957)
• There was a strong correlation between the expression of p130 in Stage 1 & 3, but not Stage 2, tumors. High levels of p130 were detected in the cytoplasm rather than the nucleus, suggesting an aberrant subcellular localization of this tumor suppressor. (PMID:17905135)
• Differentiating human adipose-derived human stem cells (hASC), do not undergo clonal expansion and p130 expression gradually diminishes across differentiation. However, p107 expression is transiently increased during hASC differentiation. (PMID:18086563)
• Collectively, these data support the notion that p130 controls the homeostasis of the differentiated keratinocytes and is therefore targeted by E7 for degradation to establish conditions permissive for viral DNA amplification. (PMID:18321970)
• P130 may be required to prevent the onset of terminal growth arrest in unstimulated prostate cancer cells lacking a functional Rb allele. (PMID:18418057)
• It is possible that a hyperphosphorylated form of Rb2/p130 may contribute to the resistance of ovarian carcinoma cells to ATRA mediated growth suppression (PMID:18446820)
• pRb2/p130 has a role in reducing survival in human soft tissue sarcomas (PMID:18676747)
• Loss of heterozygosity within RBL2/p130 gene is associated with retinoblastoma. (PMID:19252413)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	rbl2	ENSDARG00000045636
mus_musculus	Rbl2	ENSMUSG00000031666
rattus_norvegicus	Rbl2	ENSRNOG00000012153
drosophila_melanogaster	Rbf	FBGN0015799
drosophila_melanogaster	Rbf2	FBGN0038390
caenorhabditis_elegans	lin-35	WBGENE00003020

Paralogs (2): RBL1 (ENSG00000080839), RB1 (ENSG00000139687)

Protein

Protein identifiers

Retinoblastoma-like protein 2 — Q08999 (reviewed: Q08999)

Alternative names: 130 kDa retinoblastoma-associated protein, Retinoblastoma-related protein 2, pRb2

All UniProt accessions (3): Q08999, F5H837, J3KSF7

UniProt curated annotations — full annotation on UniProt →

Function. Key regulator of entry into cell division. Directly involved in heterochromatin formation by maintaining overall chromatin structure and, in particular, that of constitutive heterochromatin by stabilizing histone methylation. Recruits and targets histone methyltransferases KMT5B and KMT5C, leading to epigenetic transcriptional repression. Controls histone H4 ‘Lys-20’ trimethylation. Probably acts as a transcription repressor by recruiting chromatin-modifying enzymes to promoters. Potent inhibitor of E2F-mediated trans-activation, associates preferentially with E2F5. Binds to cyclins A and E. Binds to and may be involved in the transforming capacity of the adenovirus E1A protein. May act as a tumor suppressor.

Subunit / interactions. Interacts with AATF. Interacts with KMT5B, KMT5C and USP4. Component of the DREAM complex (also named LINC complex) at least composed of E2F4, E2F5, LIN9, LIN37, LIN52, LIN54, MYBL1, MYBL2, RBL1, RBL2, RBBP4, TFDP1 and TFDP2. The complex exists in quiescent cells where it represses cell cycle-dependent genes. It dissociates in S phase when LIN9, LIN37, LIN52 and LIN54 form a subcomplex that binds to MYBL2. Interacts with RINT1. Interacts with PML (isoform PML-1, isoform PML-2, isoform PML-3, isoform PML-4 and isoform PML-5). Interacts with RBBP9. Interacts with CD53. (Microbial infection) Interacts with JC virus small t antigen.

Subcellular location. Nucleus.

Post-translational modifications. During G0 and early G1 phase of the cell cycle, phosphorylated on Ser-639 and on 5 sites within the domain B. Phosphorylation on Ser-672 in G1 leads to its ubiquitin-dependent proteolysis.

Disease relevance. Brunet-Wagner neurodevelopmental syndrome (BRUWAG) [MIM:619690] An autosomal recessive disorder characterized by severe developmental delay, intellectual disability, poor or absent speech, infantile hypotonia, inability to walk, behavioral abnormalities, and dysmorphic features. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the retinoblastoma protein (RB) family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q08999-1	1	yes
Q08999-2	2

RefSeq proteins (5): NP_001310537, NP_001310538, NP_001310539, NP_001310540, NP_005602* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002719	RB_B	Domain
IPR002720	RB_A	Domain
IPR013763	Cyclin-like_dom	Domain
IPR015030	RB_C	Domain
IPR024599	RB_N	Domain
IPR028309	RB_fam	Family
IPR036915	Cyclin-like_sf	Homologous_superfamily

Pfam: PF01857, PF01858, PF11934

UniProt features (46 total): modified residue 21, region of interest 8, compositionally biased region 6, sequence conflict 4, sequence variant 3, splice variant 2, chain 1, glycosylation site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
5C1D	X-RAY DIFFRACTION	2.05
4XI9	X-RAY DIFFRACTION	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q08999-F1	69.12	0.31

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 (21): 413, 417, 639, 642, 662, 672, 688, 948, 952, 966, 971, 972, 973, 974, 981, 982, 986, 1035, 1068, 1080 …

Glycosylation sites (1): 420

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-1362277	Transcription of E2F targets under negative control by DREAM complex
R-HSA-1362300	Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1
R-HSA-1538133	G0 and Early G1
R-HSA-6804114	TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest
R-HSA-69202	Cyclin E associated events during G1/S transition
R-HSA-69205	G1/S-Specific Transcription
R-HSA-69231	Cyclin D associated events in G1
R-HSA-69656	Cyclin A:Cdk2-associated events at S phase entry
R-HSA-9617828	FOXO-mediated transcription of cell cycle genes

MSigDB gene sets: 334 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, REACTOME_G1_S_SPECIFIC_TRANSCRIPTION, CCAWYNNGAAR_UNKNOWN, GOBP_REGULATION_OF_PHOSPHORYLATION, CHUNG_BLISTER_CYTOTOXICITY_DN, GOBP_CELL_CYCLE_PHASE_TRANSITION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, MORF_RAD21, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, FOXO4_01, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE_PROCESS

GO Biological Process (7): chromatin organization (GO:0006325), regulation of transcription by RNA polymerase II (GO:0006357), negative regulation of gene expression (GO:0010629), cell differentiation (GO:0030154), regulation of lipid kinase activity (GO:0043550), negative regulation of G1/S transition of mitotic cell cycle (GO:2000134), regulation of cell cycle (GO:0051726)

GO Molecular Function (4): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), promoter-specific chromatin binding (GO:1990841), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (8): chromatin (GO:0000785), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), chromosome (GO:0005694), nucleolus (GO:0005730), cytosol (GO:0005829), extracellular exosome (GO:0070062), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
G0 and Early G1	2
G1/S Transition	2
Mitotic G1 phase and G1/S transition	1
TP53 Regulates Transcription of Cell Cycle Genes	1
G1 Phase	1
S Phase	1
FOXO-mediated transcription	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
nuclear lumen	2
intracellular membraneless organelle	2
cellular component organization	1
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
cellular developmental process	1
lipid kinase activity	1
regulation of kinase activity	1
G1/S transition of mitotic cell cycle	1
negative regulation of mitotic cell cycle phase transition	1
negative regulation of cell cycle G1/S phase transition	1
regulation of G1/S transition of mitotic cell cycle	1
cell cycle	1
regulation of cellular process	1
transcription cis-regulatory region binding	1
chromatin binding	1
nucleic acid binding	1
binding	1
chromosome	1
protein-containing complex	1
cytoplasm	1
extracellular vesicle	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1940 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RBL2	E2F4	Q16254	997
RBL2	E2F5	Q15329	992
RBL2	PPP1R3A	Q16821	981
RBL2	HDAC1	Q13547	952
RBL2	LIN9	Q5TKA1	897
RBL2	RHAG	Q02094	874
RBL2	CDK2	P24941	872
RBL2	LIN37	Q96GY3	867
RBL2	LIN54	Q6MZP7	862
RBL2	LIN52	Q52LA3	828
RBL2	DNMT1	P26358	820
RBL2	RBBP4	P31149	802
RBL2	DGCR8	Q8WYQ5	796
RBL2	CDKN1A	P38936	788
RBL2	LATS2	Q9NRM7	776

IntAct

115 interactions, top by confidence:

A	B	Type	Score
CCND2	CDK4	psi-mi:“MI:0914”(association)	0.960
CDK2	CCNE2	psi-mi:“MI:0914”(association)	0.940
CDKN1A	CCNE2	psi-mi:“MI:0914”(association)	0.890
CDK2	CCNB2	psi-mi:“MI:0914”(association)	0.860
E7	RBL1	psi-mi:“MI:0914”(association)	0.820
RBBP4	CDK2AP1	psi-mi:“MI:0914”(association)	0.790
LIN37	RBL2	psi-mi:“MI:0914”(association)	0.770
RBL2	LIN37	psi-mi:“MI:0915”(physical association)	0.770
CDKN1A	CDK14	psi-mi:“MI:0914”(association)	0.770
RBL2	E2F4	psi-mi:“MI:0915”(physical association)	0.750
E2F4	RBL2	psi-mi:“MI:0915”(physical association)	0.750
LIN37	MYBL2	psi-mi:“MI:0914”(association)	0.730
LIN9	RBL2	psi-mi:“MI:0914”(association)	0.700
LIN9	RBL2	psi-mi:“MI:0915”(physical association)	0.700
RBL2	LIN9	psi-mi:“MI:0914”(association)	0.700
RBL2	E7	psi-mi:“MI:0915”(physical association)	0.660
CCND3	CDK1	psi-mi:“MI:0914”(association)	0.640
CCNA2	GMNN	psi-mi:“MI:0914”(association)	0.640
LIN37	MYBL1	psi-mi:“MI:0914”(association)	0.640

BioGRID (199): RBL2 (Affinity Capture-Western), PML (Affinity Capture-Western), E2F4 (Affinity Capture-Western), RBL2 (Affinity Capture-Western), PML (Co-localization), RBL2 (Affinity Capture-MS), RBL2 (Reconstituted Complex), RBL2 (Affinity Capture-MS), RBL2 (Affinity Capture-MS), RBL2 (Affinity Capture-MS), RBL2 (Affinity Capture-MS), RBL2 (Affinity Capture-MS), RBL2 (Two-hybrid), RBL2 (Affinity Capture-MS), CDK2 (Affinity Capture-Western)

ESM2 similar proteins: A1A5P5, A2YNY4, A2YXJ7, A7P514, A8KBY2, A9SVH7, A9UL13, A9UL14, B1ABR6, B1ABS0, B9GLX8, B9SVG9, D3ZYB7, D4A770, F1R3W0, O55081, O82677, P06400, P13405, P33568, P97358, Q08999, Q09263, Q24472, Q2ABE5, Q2R374, Q3LXA7, Q3UAW9, Q4JF75, Q4V8D6, Q620W3, Q64700, Q66IW8, Q66WV0, Q69ZR2, Q84QM3, Q8GSL4, Q8H0J6, Q8H252, Q8R0Z2

Diamond homologs: D3ZS28, O55081, P28749, Q08999, Q54FX2, Q64700, Q64701

SIGNOR signaling

27 interactions.

A	Effect	B	Mechanism
CDK2	down-regulates	RBL2	phosphorylation
CDK2	unknown	RBL2	phosphorylation
CDK6	unknown	RBL2	phosphorylation
PPP2CA	up-regulates	RBL2	dephosphorylation
FOXO3	“up-regulates quantity”	RBL2	“transcriptional regulation”
FOXO	“up-regulates quantity”	RBL2	“transcriptional regulation”
TWIST2	“down-regulates quantity by repression”	RBL2	“transcriptional regulation”
TWIST1	“down-regulates quantity by repression”	RBL2	“transcriptional regulation”
RBL2	“up-regulates activity”	RAD50	binding
SCF-SKP2	“down-regulates quantity by destabilization”	RBL2	polyubiquitination
RBL2	“down-regulates quantity”	MYOD1	“transcriptional regulation”
RBL2	down-regulates	Cell_cycle_progress
RBL2	up-regulates	Cell_cycle_block

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 81 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
Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1	12	107.7×	8e-21
Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)	11	104.2×	4e-19
G0 and Early G1	14	91.8×	7e-23
Polo-like kinase mediated events	8	75.8×	2e-12
Transcription of E2F targets under negative control by DREAM complex	9	73.0×	8e-14
TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest	6	63.9×	6e-09
Cyclin E associated events during G1/S transition	14	59.7×	5e-20
TP53 Regulates Transcription of Cell Cycle Genes	7	56.8×	6e-10

GO biological processes:

GO term	Partners	Fold	FDR
G1/S transition of mitotic cell cycle	15	42.4×	4e-18
positive regulation of fibroblast proliferation	7	29.1×	1e-06
G2/M transition of mitotic cell cycle	5	22.0×	3e-04
regulation of mitotic cell cycle	5	16.9×	7e-04
Ras protein signal transduction	5	14.5×	1e-03
protein import into nucleus	6	12.2×	7e-04
regulation of cell cycle	10	10.5×	7e-06
cell division	14	9.1×	1e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	5
Uncertain significance	142
Likely benign	6
Benign	3

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
1332912	NC_000016.9:g.(53498276_53499349)_(53504835_53513065)del	Pathogenic
1332913	NM_005611.4(RBL2):c.926dup (p.Leu310fs)	Pathogenic
1332914	NM_005611.4(RBL2):c.573-1358_766+5del	Pathogenic
1333650	NM_005611.4(RBL2):c.1596_1597del (p.Leu533fs)	Pathogenic
2683915	NM_005611.4(RBL2):c.574C>T (p.Arg192Ter)	Pathogenic
1332911	NM_005611.4(RBL2):c.556C>T (p.Arg186Ter)	Likely pathogenic
1339436	NM_005611.4(RBL2):c.901dup (p.Tyr301fs)	Likely pathogenic
3065286	NM_005611.4(RBL2):c.1472_1473del (p.His491fs)	Likely pathogenic
3341363	NM_005611.4(RBL2):c.3139C>T (p.Arg1047Ter)	Likely pathogenic
3391286	NM_005611.4(RBL2):c.2284_2285insGACG (p.Val762fs)	Likely pathogenic

SpliceAI

3757 predictions. Top by Δscore:

Variant	Effect	Δscore
16:53434784:C:G	donor_gain	1.0000
16:53434794:G:GT	donor_gain	1.0000
16:53439079:G:GG	donor_gain	1.0000
16:53439101:GAAAC:G	donor_gain	1.0000
16:53442650:A:AG	acceptor_gain	1.0000
16:53442654:C:G	acceptor_gain	1.0000
16:53442656:A:AG	acceptor_gain	1.0000
16:53442657:G:GG	acceptor_gain	1.0000
16:53442657:GCTTA:G	acceptor_gain	1.0000
16:53442678:A:G	acceptor_gain	1.0000
16:53442846:G:GT	donor_gain	1.0000
16:53442855:AGCGG:A	donor_loss	1.0000
16:53442856:GCG:G	donor_gain	1.0000
16:53442857:CGGT:C	donor_loss	1.0000
16:53442859:G:A	donor_loss	1.0000
16:53442859:G:GG	donor_gain	1.0000
16:53451828:AAAG:A	donor_loss	1.0000
16:53451829:AAGG:A	donor_loss	1.0000
16:53451832:GTAG:G	donor_loss	1.0000
16:53451833:T:A	donor_loss	1.0000
16:53453613:GTTT:G	donor_gain	1.0000
16:53453703:A:AG	acceptor_gain	1.0000
16:53453704:G:GG	acceptor_gain	1.0000
16:53453766:GTTT:G	donor_gain	1.0000
16:53453770:G:GG	donor_gain	1.0000
16:53454654:A:AG	acceptor_gain	1.0000
16:53454655:G:GG	acceptor_gain	1.0000
16:53454655:GT:G	acceptor_gain	1.0000
16:53454655:GTA:G	acceptor_gain	1.0000
16:53454655:GTAA:G	acceptor_gain	1.0000

AlphaMissense

7540 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:53465534:T:A	W599R	1.000
16:53465534:T:C	W599R	1.000
16:53439031:T:A	W86R	0.999
16:53439031:T:C	W86R	0.999
16:53442689:T:A	W135R	0.999
16:53442689:T:C	W135R	0.999
16:53451748:T:C	L228P	0.999
16:53465496:T:C	L586P	0.999
16:53470138:C:A	A733D	0.999
16:53470144:T:A	V735D	0.999
16:53470174:T:A	I745N	0.999
16:53470174:T:C	I745T	0.999
16:53470174:T:G	I745S	0.999
16:53470407:T:C	I757T	0.999
16:53470771:T:C	L851P	0.999
16:53470780:T:C	L854P	0.999
16:53470824:T:A	W869R	0.999
16:53470824:T:C	W869R	0.999
16:53470899:T:C	C894R	0.999
16:53470900:G:A	C894Y	0.999
16:53470901:T:G	C894W	0.999
16:53479893:G:C	R928T	0.999
16:53479894:A:C	R928S	0.999
16:53479894:A:T	R928S	0.999
16:53479899:T:A	V930D	0.999
16:53480699:T:A	L1005H	0.999
16:53480699:T:C	L1005P	0.999
16:53480708:T:C	F1008S	0.999
16:53480710:T:G	Y1009D	0.999
16:53480747:C:A	A1021D	0.999

dbSNP variants (sampled 300 via entrez): RS1000021796 (16:53448722 G>A,C), RS1000072973 (16:53461761 C>T), RS1000142816 (16:53487356 A>G), RS1000209359 (16:53462134 T>G), RS1000284167 (16:53455265 G>A,T), RS1000298570 (16:53467472 C>T), RS1000354136 (16:53481439 T>G), RS1000382484 (16:53433253 G>C), RS1000391254 (16:53449031 T>A), RS1000498240 (16:53443097 CTTATT>C), RS1000531629 (16:53443215 C>A,T), RS1000555775 (16:53468025 A>C,G), RS1000662901 (16:53479363 A>C), RS1000710046 (16:53486287 T>A), RS1000770098 (16:53433026 C>T)

Disease associations

OMIM: gene MIM:180203 | disease phenotypes: MIM:619690

GenCC curated gene-disease

Disease	Classification	Inheritance
Brunet-Wagner neurodevelopmental syndrome	Strong	Autosomal recessive
complex neurodevelopmental disorder	Limited	Autosomal recessive

Mondo (2): Brunet-Wagner neurodevelopmental syndrome (MONDO:0859217), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (0):

HPO phenotypes

25 total (25 of 25 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000294	Low anterior hairline
HP:0000311	Round face
HP:0000316	Hypertelorism
HP:0000431	Wide nasal bridge
HP:0000486	Strabismus
HP:0000629	Periorbital fullness
HP:0000648	Optic atrophy
HP:0000666	Horizontal nystagmus
HP:0000733	Motor stereotypy
HP:0001272	Cerebellar atrophy
HP:0001319	Neonatal hypotonia
HP:0002059	Cerebral atrophy
HP:0003623	Neonatal onset
HP:0004330	Increased skull ossification
HP:0007979	Gaze-evoked horizontal nystagmus
HP:0011344	Severe global developmental delay
HP:0012471	Thick vermilion border
HP:0025336	Delayed ability to sit
HP:0031936	Delayed ability to walk
HP:0032794	Myoclonic seizure
HP:0033128	Delayed ability to crawl
HP:0033725	Thin corpus callosum
HP:0045074	Thin eyebrow
HP:0100716	Self-injurious behavior

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST005316_205	Intelligence (MTAG)	6.000000e-14
GCST005316_206	Intelligence (MTAG)	4.000000e-14
GCST006269_303	General cognitive ability	3.000000e-12
GCST006269_755	General cognitive ability	4.000000e-09
GCST008157_61	Body fat mass	5.000000e-06
GCST008163_390	Height	2.000000e-06
GCST009391_2000	Metabolite levels	8.000000e-06
GCST012227_383	Hip circumference adjusted for BMI	2.000000e-10
GCST012227_384	Hip circumference adjusted for BMI	6.000000e-18
GCST012227_385	Hip circumference adjusted for BMI	1.000000e-08
GCST90000025_91	Appendicular lean mass	9.000000e-52
GCST90013406_173	Liver enzyme levels (alkaline phosphatase)	4.000000e-15
GCST90020025_209	Waist-to-hip ratio adjusted for BMI	2.000000e-14
GCST90020027_22	Waist-hip index	1.000000e-13
GCST90020028_1498	Hip circumference adjusted for BMI	5.000000e-09

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0010542	ureidopropionic acid measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0004980	appendicular lean mass
EFO:0004533	alkaline phosphatase measurement
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
palbociclib	affects reaction, increases expression, affects binding, decreases reaction, increases phosphorylation (+2 more)	4
Doxorubicin	increases phosphorylation, decreases response to substance, affects binding, increases reaction, increases expression (+2 more)	3
Estradiol	affects binding, increases reaction, decreases expression, affects cotreatment, increases expression	3
Hydrogen Peroxide	decreases phosphorylation, decreases reaction, decreases expression, increases expression	3
Tretinoin	decreases ubiquitination, increases expression, affects response to substance, affects binding, increases reaction	3
sodium arsenite	affects cotreatment, increases abundance, decreases expression	2
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, decreases expression	2
Okadaic Acid	decreases phosphorylation, decreases reaction, decreases expression	2
Sirolimus	decreases reaction, increases phosphorylation, affects binding, affects cotreatment	2
aristolochic acid I	decreases expression	1
ON123300	decreases phosphorylation	1
UF010 compound	increases activity	1
FR900359	affects phosphorylation	1
moringin	decreases expression, affects cotreatment	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects folding, decreases reaction, affects binding	1
riddelliine	decreases expression, increases metabolic processing	1
arsenite	decreases reaction, affects binding	1
cobaltous chloride	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	decreases expression	1
4-hydroxy-2-nonenal	decreases expression	1
aflatoxin B2	decreases methylation	1
calmidazolium	decreases phosphorylation	1
avobenzone	increases expression	1
calyculin A	decreases phosphorylation, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
FTI 277	decreases phosphorylation, affects cotreatment	1

Cellosaurus cell lines

7 cell lines: 7 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C7DI	Abcam A-549 RBL2 KO	Cancer cell line	Male
CVCL_C7E8	Abcam HCT 116 RBL2 KO	Cancer cell line	Male
CVCL_C7EN	Abcam THP-1 RBL2 KO	Cancer cell line	Male
CVCL_D7Z9	Ubigene A-549 RBL2 KO	Cancer cell line	Male
CVCL_E2IJ	HAP1 RBL2 (-) 1	Cancer cell line	Male
CVCL_E2IK	HAP1 RBL2 (-) 2	Cancer cell line	Male
CVCL_E2IL	HAP1 RBL2 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder