RB1CC1

Summary

RB1CC1 (RB1 inducible coiled-coil 1, HGNC:15574) is a protein-coding gene on chromosome 8q11.23, encoding RB1-inducible coiled-coil protein 1 (Q8TDY2). Involved in autophagy. It is a selective cancer dependency (DepMap: 12.3% of cell lines).

The protein encoded by this gene interacts with signaling pathways to coordinately regulate cell growth, cell proliferation, apoptosis, autophagy, and cell migration. This tumor suppressor also enhances retinoblastoma 1 gene expression in cancer cells. Alternative splicing results in multiple transcript variants encoding distinct isoforms.

Source: NCBI Gene 9821 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 238 total — 2 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 3
• Cancer dependency (DepMap): dependent in 12.3% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_014781

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15574
Approved symbol	RB1CC1
Name	RB1 inducible coiled-coil 1
Location	8q11.23
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0203, Cc1, DRAGOU14, FIP200, ATG17, PPP1R131
Ensembl gene	ENSG00000023287
Ensembl biotype	protein_coding
OMIM	606837
Entrez	9821

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 9 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000025008, ENST00000435644, ENST00000517963, ENST00000518211, ENST00000518468, ENST00000518710, ENST00000519912, ENST00000521611, ENST00000522957, ENST00000523594, ENST00000935608, ENST00000935609, ENST00000959507

RefSeq mRNA: 2 — MANE Select: NM_014781 NM_001083617, NM_014781

CCDS: CCDS34892, CCDS47856

Canonical transcript exons

ENST00000025008 — 24 exons

Exon	Start	End
ENSE00000693781	52683549	52683719
ENSE00000693782	52676369	52676571
ENSE00000693784	52668021	52668191
ENSE00000693785	52661535	52661719
ENSE00000693786	52661095	52661281
ENSE00000693787	52660926	52661007
ENSE00000693788	52660596	52660657
ENSE00000693798	52645702	52645867
ENSE00001086970	52642704	52642812
ENSE00001151070	52622458	52623859
ENSE00001192241	52673845	52674274
ENSE00001503955	52656008	52657908
ENSE00002101111	52714075	52714435
ENSE00003472702	52634921	52634968
ENSE00003472825	52642351	52642591
ENSE00003493374	52630470	52630528
ENSE00003568709	52636015	52636069
ENSE00003578563	52658873	52658976
ENSE00003601459	52624717	52624787
ENSE00003607260	52628032	52628168
ENSE00003609199	52657998	52658124
ENSE00003623658	52683887	52684013
ENSE00003639250	52686853	52686967
ENSE00003668943	52685399	52685520

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 98.10.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.6261 / max 442.2705, expressed in 1802 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
93062	26.0141	1802
93060	0.3721	167
93061	0.1541	64
93054	0.0780	23
93063	0.0078	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	98.10	gold quality
bronchial epithelial cell	CL:0002328	97.72	gold quality
caput epididymis	UBERON:0004358	97.60	gold quality
postcentral gyrus	UBERON:0002581	97.47	gold quality
corpus epididymis	UBERON:0004359	97.44	gold quality
biceps brachii	UBERON:0001507	97.29	gold quality
cauda epididymis	UBERON:0004360	97.25	gold quality
jejunal mucosa	UBERON:0000399	97.24	gold quality
parietal lobe	UBERON:0001872	97.05	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.94	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.89	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.68	gold quality
orbitofrontal cortex	UBERON:0004167	96.62	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.54	gold quality
trabecular bone tissue	UBERON:0002483	96.51	gold quality
superior frontal gyrus	UBERON:0002661	96.22	gold quality
jejunum	UBERON:0002115	96.20	gold quality
superior vestibular nucleus	UBERON:0007227	96.12	gold quality
entorhinal cortex	UBERON:0002728	95.90	gold quality
cartilage tissue	UBERON:0002418	95.85	gold quality
heart right ventricle	UBERON:0002080	95.84	gold quality
calcaneal tendon	UBERON:0003701	95.75	gold quality
pons	UBERON:0000988	95.69	gold quality
amniotic fluid	UBERON:0000173	95.65	gold quality
substantia nigra pars compacta	UBERON:0001965	95.57	gold quality
Brodmann (1909) area 46	UBERON:0006483	95.49	gold quality
cortical plate	UBERON:0005343	95.39	gold quality
oral cavity	UBERON:0000167	95.36	gold quality
trigeminal ganglion	UBERON:0001675	95.32	gold quality
superficial temporal artery	UBERON:0001614	95.31	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.47

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
CDKN2A	Unknown
RB1	Activation

Upstream regulators (CollecTRI, top): ATF2, E2F1, SP1, TP53

miRNA regulators (miRDB)

190 targeting RB1CC1, 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-340-5P	100.00	72.50	4437
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4795-3P	100.00	74.62	4024
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-6833-3P	100.00	70.63	3197
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4789-5P	99.98	70.76	2721

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 12.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• RB1CC1 is frequently mutated in breast cancer and shows characteristics of a classical tumor-suppressor gene. (PMID:12068296)
• RB1CC1 gene preferentially expressed and contributed to the maturation of human embryonic musculoskeletal cells, and may regulate the proliferative activity and maturation of tumor cells derived from these tissues. (PMID:12163359)
• RB1CC1 induces the expression of RB1, especially of underphosphorylated forms, then suppresses cell cycle progression in human neoplastic cells (PMID:14533007)
• expression and promoter activities of RB1CC1 in developing murine and human tissues; RB1CC1 expression is controlled more stringently by modification at intron 1 in humans than in mice (PMID:15375585)
• Rb1cc1 expression is a prerequisite for the induction of RB1 and myosin heavy chain. Rb1cc1 plays a crucial role in muscular differentiation and function. (PMID:15968549)
• FIP200 regulates of cell size by interaction with the TSC1-TSC2 complex. (PMID:16043512)
• FIP200 increases p21 protein levels via stabilization of its upstream regulator p53 and decreases cyclin D1 protein. Both effects are critical for FIP200-induced G1 arrest and may contribute to the antitumor activities of FIP200 in breast cancer. (PMID:16061648)
• RB1CC1 insufficiency causes neuronal atrophy through mTOR signaling alteration and involved in the pathology of Alzheimer’s diseases. (PMID:17706618)
• RB1CC1 and PACE4 genes might be the DNA targets of sodium arsenite treatment in human lymphoblastoid cells. (PMID:17707572)
• Cellular functions of FIP200 and its interacting proteins, and the emerging roles of FIP200 in embryogenesis and cancer development. Review. (PMID:18036779)
• provide the first evidence for the existence of a close-spatially controlled-mode of regulation of FIP200 and PIASy nucleocytoplasmic functions (PMID:18285457)
• These results suggest that FIP200 is a novel mammalian autophagy factor that functions together with ULKs. (PMID:18443221)
• The ULK-Atg13-FIP200 complexes are direct targets of mTOR and important regulators of autophagy in response to mTOR signaling. (PMID:19225151)
• ATG13 and ULK1 are phosphorylated by the mTOR pathway in a nutrient starvation-regulated manner, indicating that the ULK1.ATG13.FIP200 complex acts as a node for integrating incoming autophagy signals into autophagosome biogenesis. (PMID:19258318)
• Nuclear RB1CC1 directly activates the RB1 promoter to enhance RB1 expression associated with breast cancer. (PMID:19437535)
• Nuclear RB1CC1 directly activates the RB1 promoter to enhance RB1 expression in cancer cells. (PMID:19437535)
• Studies elucidated the inhibitory mechanism in which mTORC1 phosphorylates the autophagy regulatory complex containing unc-51-like kinase 1 (ULK1), the mammalian Atg13 protein, and focal adhesion kinase interacting protein of 200 kD (FIP200). (PMID:19690328)
• the 3’-untranslated region of RB1-inducible coiled-coil 1 gene is mutated in colon tumors (PMID:19888451)
• present study indicates that RB1CC1 together with hSNF5 and/or p53 enhances the RB1 pathway through transcriptional activation of RB1, p16 and p21 (PMID:20614030)
• RB1CC1, RB1 and p53 have prognostic roles in breast cancer in Japanese patients (PMID:21203526)
• downregulation of FIP200 protein in glioblastoma tumor cells, astrocytes, and brain microvessel endothelial cells promotes apoptosis, most likely due to the removal of a direct interaction of FIP200 with Pyk2 that inhibits Pyk2 activation (PMID:21602932)
• RB1CC1 activates the expression of p16 (also called INK4a/CDKN2a) through the activation of its promoter. RB1CC1 essentially requires binding with hSNF5 to activate the p16 promoter. (PMID:21637919)
• Nuclear expression of RB1CC1 predicts a better clinical outcome and is useful in the follow-up of salivary gland cancers. (PMID:21717524)
• p53 regulates autophagy through a direct molecular interaction with RB1CC1/FIP200, a protein that is essential for the very apical step of autophagy initiation. (PMID:21775823)
• RB1CC1 thus appears to play a unique role as a modulator of TGF-beta signaling by restricting substrate specificity of Arkadia. (PMID:21795712)
• RB1CC1 protein suppresses type II collagen synthesis in chondrocytes and causes dwarfism (PMID:22049074)
• analysis of preparation of the monoclonal antibody for RB1CC1 (PMID:22396748)
• The APC-independent beta-catenin degradation by FIP200 suggests a role for FIP200 in tumor suppression in the presence of APC dysfunction. (PMID:22751121)
• Interaction between FIP200 and ATG16L1 distinguishes ULK1 complex-dependent and -independent autophagy. (PMID:23262492)
• Liver-specific deficiency of FIP200 leads to chronic liver injury associated with fibrosis and inflammation. (PMID:23960084)
• miR-133b targeted and downregulated RB1CC1 in prostate cancer cells. (PMID:24610824)
• RB1CC1 knockdown in PC3 cells enhances clonal growth in vitro and tumor growth in vivo. (PMID:24732589)
• RB1CC1 has been implicated in cell cycle progression, cell growth, cell proliferation, cell survival, cell spreading/migration and neurodegeneration. (PMID:26151896)
• MiR-20a and miR-20b negatively regulate autophagy by targeting RB1CC1/FIP200 in breast cancer cells (PMID:26829385)
• miR-224-3p regulates autophagy in hrHPV-induced cervical cancer cells through targeting FIP200 expression. (PMID:27615604)
• This is the first report demonstrating that polymorphisms in the autophagy-related FIP200 gene may predict hypertension in patients with mCRC treated with FOLFIRI and bevacizumab. (PMID:28347919)
• Data suggest that, in patients with diabetic kidney disease, urinary excretion of mRNAs for MAP1LC3A, WIPI2, and RB1CC1 is down-regulated as compared to healthy control subjects; these transcripts may serve as urinary autophagy biomarkers. (MAP1LC3A = microtubule associated protein 1 light chain 3; WIPI2 = WD repeat domain phosphoinositide-interacting protein 2; RB1CC1 = RB1 inducible coiled-coil 1) (PMID:28760651)
• RB1CC1 was shown to target ZBTB38 to initiate autophagy in spinal cord injury. (PMID:30075197)
• These findings suggested that PHF8 played an oncogenic role in facilitating FIP200-dependent autophagic degradation of E-cadherin, EMT and metastasis in hepatocellular carcinoma (HCC). PHF8 might be a promising target for prevention, treatment and prognostic prediction of HCC. (PMID:30180906)
• the recruitment of the FIP200 CTR slows the phase separation of ubiquitinated proteins by p62 in a reconstituted system. Our data provide the molecular basis for a crosstalk between cargo condensation and autophagosome formation. (PMID:30853400)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rb1cc1	ENSDARG00000076559
mus_musculus	Rb1cc1	ENSMUSG00000025907
rattus_norvegicus	Rb1cc1	ENSRNOG00000006833
drosophila_melanogaster	Atg17	FBGN0037363
caenorhabditis_elegans		WBGENE00020334

Protein

Protein identifiers

RB1-inducible coiled-coil protein 1 — Q8TDY2 (reviewed: Q8TDY2)

Alternative names: FAK family kinase-interacting protein of 200 kDa

All UniProt accessions (7): E5RH44, E5RH63, E5RHX0, E5RJC1, Q8TDY2, H0YC28, H0YC30

UniProt curated annotations — full annotation on UniProt →

Function. Involved in autophagy. Regulates early events but also late events of autophagosome formation through direct interaction with Atg16L1. Required for the formation of the autophagosome-like double-membrane structure that surrounds the Salmonella-containing vacuole (SCV) during S.typhimurium infection and subsequent xenophagy. Involved in repair of DNA damage caused by ionizing radiation, which subsequently improves cell survival by decreasing apoptosis. Inhibits PTK2/FAK1 and PTK2B/PYK2 kinase activity, affecting their downstream signaling pathways. Plays a role as a modulator of TGF-beta-signaling by restricting substrate specificity of RNF111. Functions as a DNA-binding transcription factor. Is a potent regulator of the RB1 pathway through induction of RB1 expression. Plays a crucial role in muscular differentiation. Plays an indispensable role in fetal hematopoiesis and in the regulation of neuronal homeostasis.

Subunit / interactions. Part of a complex consisting of ATG13/KIAA0652, ULK1 and RB1CC1. This complex associates with ATG101. Interacts with PTK2/FAK1 and PTK2B/PYK2. Interacts with GABARAP and GABARAPL1. Interacts with ATG16L1; the interaction is required for ULK1 complex-dependent autophagy. Interacts with RNF111, SKI and SMAD7. Interacts with COP1 in the cytoplasm of proliferating cells in response to UV stimulation. Interacts with TP53. Interacts with C9orf72. Interacts with WDR45B. Interacts with ATG13; this interaction is increased in the absence of TMEM39A. Interacts with WIPI2. Interacts with TAX1BP1. Interacts (via phosphorylated FFAT motif) with MOSPD2, VAPA and VAPB.

Subcellular location. Nucleus. Cytoplasm. Cytosol. Preautophagosomal structure. Lysosome.

Tissue specificity. Expression levels correlated closely with those of RB1 in cancer cell lines as well as in various normal human tissues. Abundantly expressed in human musculoskeletal and cultured osteosarcoma cells.

Post-translational modifications. Phosphorylation at Ser-734 of the FFAT motif activates interaction with MOSPD2, VAPA and VAPB.

Domain organisation. The FFAT motif is involved in the interaction with MOSPD2, VAPA and VAPB and its phosphorylation regulates these interactions.

Miscellaneous. Probably involved in the tumorigenesis of breast cancer. RB1CC1 is frequently mutated in breast cancer and shows characteristics of a classical tumor suppressor gene.

Similarity. Belongs to the ATG17 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8TDY2-1	1	yes
Q8TDY2-2	2

RefSeq proteins (2): NP_001077086, NP_055596* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019460	Atg11_C	Domain
IPR040040	ATG11	Family

Pfam: PF10377

UniProt features (49 total): modified residue 19, strand 9, sequence variant 6, helix 5, coiled-coil region 2, short sequence motif 2, chain 1, region of interest 1, splice variant 1, sequence conflict 1, turn 1, compositionally biased region 1

Structure

Experimental structures (PDB)

18 structures.

PDB	Method	Resolution (Å)
7D0E	X-RAY DIFFRACTION	1.4
9D34	X-RAY DIFFRACTION	1.42
8YFL	X-RAY DIFFRACTION	1.5
8YFM	X-RAY DIFFRACTION	1.5
6DCE	X-RAY DIFFRACTION	1.56
9J54	X-RAY DIFFRACTION	1.61
7CZG	X-RAY DIFFRACTION	1.8
7CZM	X-RAY DIFFRACTION	2
8YFK	X-RAY DIFFRACTION	2
7EA2	X-RAY DIFFRACTION	2.14
8YFN	X-RAY DIFFRACTION	2.3
8W6B	X-RAY DIFFRACTION	2.39
7EAA	X-RAY DIFFRACTION	2.6
6GMA	X-RAY DIFFRACTION	3.2
8SOI	ELECTRON MICROSCOPY	4.2
8SRM	ELECTRON MICROSCOPY	4.46
8SQZ	ELECTRON MICROSCOPY	5.85
9C82	ELECTRON MICROSCOPY	6.84

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TDY2-F1	73.10	0.22

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 (19): 238, 243, 253, 257, 261, 266, 624, 647, 650, 652, 653, 734, 1091, 1222, 1370, 1484, 222, 229, 237

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1632852	Macroautophagy

MSigDB gene sets: 384 (showing top): AP1_01, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_AUTOPHAGY, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_VACUOLE_ORGANIZATION, DACOSTA_UV_RESPONSE_VIA_ERCC3_XPCS_DN, GOBP_LIPOPROTEIN_METABOLIC_PROCESS, GOCC_VACUOLAR_MEMBRANE, MORF_BRCA1, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, TGACCTY_ERR1_Q2, MORF_RAD51L3, GOBP_MACROAUTOPHAGY

GO Biological Process (20): autophagosome assembly (GO:0000045), autophagy of mitochondrion (GO:0000422), pexophagy (GO:0000425), liver development (GO:0001889), autophagy (GO:0006914), heart development (GO:0007507), negative regulation of cell population proliferation (GO:0008285), positive regulation of autophagy (GO:0010508), ribophagy (GO:0034517), piecemeal microautophagy of the nucleus (GO:0034727), innate immune response (GO:0045087), positive regulation of cell size (GO:0045793), positive regulation of JNK cascade (GO:0046330), defense response to virus (GO:0051607), reticulophagy (GO:0061709), glycophagy (GO:0061723), extrinsic apoptotic signaling pathway (GO:0097191), negative regulation of extrinsic apoptotic signaling pathway (GO:2001237), apoptotic process (GO:0006915), negative regulation of apoptotic process (GO:0043066)

GO Molecular Function (4): protein kinase binding (GO:0019901), protein-membrane adaptor activity (GO:0043495), molecular adaptor activity (GO:0060090), protein binding (GO:0005515)

GO Cellular Component (12): phagophore assembly site (GO:0000407), autophagosome membrane (GO:0000421), lysosome (GO:0005764), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), nuclear membrane (GO:0031965), phagophore assembly site membrane (GO:0034045), Atg1/ULK1 kinase complex (GO:1990316), nucleus (GO:0005634), cytoplasm (GO:0005737), vacuole (GO:0005773), organelle membrane (GO:0031090)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Autophagy	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
macroautophagy	4
cytoplasm	4
cellular anatomical structure	3
autophagy	2
apoptotic signaling pathway	2
binding	2
organelle membrane	2
membrane	2
intracellular membrane-bounded organelle	2
Atg12 activating enzyme activity	1
protein-phosphatidylethanolamide deconjugating activity	1
Atg12 conjugating enzyme activity	1
Atg12 ligase activity	1
organelle assembly	1
Atg1/ULK1 kinase complex assembly	1
autophagosome organization	1
autophagy of peroxisome	1
gland development	1
hepaticobiliary system development	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
animal organ development	1
circulatory system development	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
positive regulation of catabolic process	1
regulation of autophagy	1
microautophagy	1
nucleophagy	1
nucleus disassembly	1
immune response	1
defense response to symbiont	1
regulation of cell size	1
JNK cascade	1
positive regulation of MAPK cascade	1
regulation of JNK cascade	1
defense response	1
response to virus	1

Protein interactions and networks

STRING

2320 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RB1CC1	ULK1	O75385	999
RB1CC1	ATG13	O75143	998
RB1CC1	ATG101	Q9BSB4	998
RB1CC1	ULK2	Q8IYT8	997
RB1CC1	PTK2	Q05397	993
RB1CC1	CALCOCO2	Q13137	989
RB1CC1	ATG16L1	Q676U5	989
RB1CC1	CCPG1	Q9ULG6	989
RB1CC1	ATG12	O94817	979
RB1CC1	TP53	P04637	969
RB1CC1	PTK2B	Q14289	969
RB1CC1	ATG10	Q9H0Y0	949
RB1CC1	ATG3	Q9NT62	934
RB1CC1	GABARAP	O95166	928
RB1CC1	GABARAPL2	P60520	928

IntAct

147 interactions, top by confidence:

A	B	Type	Score
ATG101	ATG13	psi-mi:“MI:0914”(association)	0.950
ATG13	ULK1	psi-mi:“MI:0914”(association)	0.940
ULK1	ATG13	psi-mi:“MI:0914”(association)	0.940
ULK1	RB1CC1	psi-mi:“MI:0915”(physical association)	0.910
RB1CC1	ATG101	psi-mi:“MI:0915”(physical association)	0.860
ATG13	RB1CC1	psi-mi:“MI:0915”(physical association)	0.820
RB1CC1	ATG13	psi-mi:“MI:0914”(association)	0.820
RB1CC1	ATG16L1	psi-mi:“MI:0915”(physical association)	0.800
ATG16L1	RB1CC1	psi-mi:“MI:0914”(association)	0.800
MAP1LC3C	ATG13	psi-mi:“MI:0914”(association)	0.750
BRK1	HSBP1	psi-mi:“MI:0914”(association)	0.740
MAP1LC3B	ATG13	psi-mi:“MI:0914”(association)	0.730
VAPB	FAM83G	psi-mi:“MI:0914”(association)	0.730
RB1CC1	C9orf72	psi-mi:“MI:0915”(physical association)	0.710
RB1CC1	C9orf72	psi-mi:“MI:2364”(proximity)	0.710

BioGRID (564): RB1CC1 (Affinity Capture-Western), ATG101 (Affinity Capture-MS), RB1CC1 (Affinity Capture-Western), RB1CC1 (Affinity Capture-Western), RB1CC1 (Affinity Capture-MS), RB1CC1 (Affinity Capture-MS), BAP1 (Two-hybrid), BLID (Two-hybrid), EPSTI1 (Two-hybrid), ERRFI1 (Two-hybrid), GLCE (Two-hybrid), GREB1 (Two-hybrid), IL13RA2 (Two-hybrid), IL24 (Two-hybrid), ITIH5 (Two-hybrid)

ESM2 similar proteins: A0A2R8Q3S9, A2VCV0, A9ULX8, E1BN97, F1NVK6, F6UF99, P28236, P79169, P79368, Q06220, Q09108, Q0P557, Q0VA42, Q1LZF8, Q28132, Q29030, Q2T9I9, Q3B7T8, Q3V0J1, Q5PQX1, Q5R6R3, Q5T5J6, Q5ZM60, Q640L3, Q640U0, Q66H73, Q6PAV5, Q6PG04, Q7ZX27, Q7ZXV6, Q8K4Q9, Q8N4S0, Q8TDY2, Q90314, Q90WN7, Q91892, Q921T2, Q95M19, Q95MD2, Q95N18

Diamond homologs: Q8TDY2, Q9ESK9

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
ATG13	up-regulates	RB1CC1	binding
ULK1	up-regulates	RB1CC1	phosphorylation
RB1CC1	“form complex”	ULK1/Atg13/Fip200	binding
ULK2	“up-regulates activity”	RB1CC1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 124 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	5	42.3×	6e-06
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	5	37.3×	1e-05
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	5	37.3×	1e-05
Activation of BH3-only proteins	5	27.6×	4e-05
RHO GTPases activate PKNs	7	24.7×	2e-06
Autophagy	12	19.8×	2e-10
Macroautophagy	15	19.2×	6e-13
Selective autophagy	6	18.6×	4e-05

GO biological processes:

GO term	Partners	Fold	FDR
piecemeal microautophagy of the nucleus	6	52.0×	3e-07
mitophagy	10	29.4×	5e-10
autophagosome assembly	13	27.1×	1e-12
cellular response to glucose starvation	6	18.7×	1e-04
negative regulation of TORC1 signaling	6	18.0×	1e-04
macroautophagy	8	17.8×	2e-06
protein targeting	5	17.0×	8e-04
autophagosome maturation	5	16.2×	9e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	180
Likely benign	13
Benign	10

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
3976	NC_000008.11:g.52623770_52685461del	Pathogenic
3977	nsv1067861	Pathogenic
1685423	NM_014781.5(RB1CC1):c.1702C>T (p.Arg568Ter)	Likely pathogenic

SpliceAI

4166 predictions. Top by Δscore:

Variant	Effect	Δscore
8:52628030:ACCAC:A	donor_gain	1.0000
8:52628031:CCACC:C	donor_gain	1.0000
8:52630468:A:AC	donor_gain	1.0000
8:52630469:C:CC	donor_gain	1.0000
8:52630469:CT:C	donor_gain	1.0000
8:52630469:CTCT:C	donor_gain	1.0000
8:52630526:CAT:C	acceptor_gain	1.0000
8:52630529:C:CC	acceptor_gain	1.0000
8:52634917:TTAC:T	donor_loss	1.0000
8:52634918:TACCA:T	donor_loss	1.0000
8:52634919:A:AC	donor_gain	1.0000
8:52634920:C:CC	donor_gain	1.0000
8:52634920:C:T	donor_loss	1.0000
8:52634920:CCAGT:C	donor_gain	1.0000
8:52634966:TGT:T	acceptor_gain	1.0000
8:52634969:C:CC	acceptor_gain	1.0000
8:52636010:CTT:C	donor_loss	1.0000
8:52636011:TTA:T	donor_loss	1.0000
8:52636012:TAC:T	donor_loss	1.0000
8:52636013:A:AC	donor_gain	1.0000
8:52636013:ACT:A	donor_gain	1.0000
8:52636013:ACTCG:A	donor_loss	1.0000
8:52636014:C:CC	donor_gain	1.0000
8:52636014:CT:C	donor_gain	1.0000
8:52636014:CTC:C	donor_gain	1.0000
8:52636014:CTCG:C	donor_gain	1.0000
8:52636065:TTTCT:T	acceptor_gain	1.0000
8:52636066:TTCT:T	acceptor_gain	1.0000
8:52636068:CT:C	acceptor_gain	1.0000
8:52636070:C:CC	acceptor_gain	1.0000

AlphaMissense

10585 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:52623815:T:A	R1584S	1.000
8:52623815:T:G	R1584S	1.000
8:52623816:C:A	R1584I	1.000
8:52623816:C:G	R1584T	1.000
8:52623817:T:C	R1584G	1.000
8:52623820:A:C	Y1583D	1.000
8:52623821:A:C	F1582L	1.000
8:52623821:A:T	F1582L	1.000
8:52623822:A:C	F1582C	1.000
8:52623822:A:G	F1582S	1.000
8:52623823:A:G	F1582L	1.000
8:52623840:A:T	V1576D	1.000
8:52623845:A:C	F1574L	1.000
8:52623845:A:T	F1574L	1.000
8:52623846:A:C	F1574C	1.000
8:52623846:A:G	F1574S	1.000
8:52623847:A:C	F1574V	1.000
8:52623847:A:G	F1574L	1.000
8:52623847:A:T	F1574I	1.000
8:52623848:T:A	R1573S	1.000
8:52623848:T:G	R1573S	1.000
8:52623849:C:G	R1573T	1.000
8:52623850:T:C	R1573G	1.000
8:52623851:G:C	N1572K	1.000
8:52623851:G:T	N1572K	1.000
8:52624720:T:A	K1568N	1.000
8:52624720:T:G	K1568N	1.000
8:52624721:T:A	K1568I	1.000
8:52624722:T:C	K1568E	1.000
8:52624724:G:T	A1567D	1.000

dbSNP variants (sampled 300 via entrez): RS1000003689 (8:52629915 T>C), RS1000018332 (8:52663189 G>A), RS1000046055 (8:52667549 C>A), RS1000075312 (8:52669724 C>A), RS1000087400 (8:52663404 A>C,T), RS1000152223 (8:52697174 C>T), RS1000160749 (8:52641046 C>G), RS1000206892 (8:52635425 C>A,G), RS1000214057 (8:52681682 G>C), RS1000265650 (8:52697447 A>C,G), RS1000302856 (8:52684572 G>A), RS1000305709 (8:52714771 C>T), RS1000314303 (8:52651512 T>A,C), RS1000321919 (8:52669403 G>A), RS1000335150 (8:52630181 T>G)

Disease associations

OMIM: gene MIM:606837 | disease phenotypes: MIM:114480

GenCC curated gene-disease

Mondo (2): hereditary breast carcinoma (MONDO:0016419), breast adenocarcinoma (MONDO:0004988)

Orphanet (1): Hereditary breast cancer (Orphanet:227535)

HPO phenotypes

3 total (3 of 3 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001442	Typified by somatic mosaicism
HP:0003002	Breast carcinoma

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST004807_1	Immunoglobulin light chain (AL) amyloidosis (liver involvement)	2.000000e-08
GCST007398_1	Mitochondrial DNA copy number (white blood cells)	2.000000e-06
GCST008161_131	Waist circumference adjusted for body mass index	9.000000e-06
GCST010002_299	Refractive error	7.000000e-25
GCST010989_139	Body size at age 10	1.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006312	mitochondrial DNA measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0009819	comparative body size at age 10, self-reported

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C562840	Breast Cancer, Familial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	6
Valproic Acid	decreases expression, decreases methylation, increases expression	3
Cyclosporine	increases expression	3
bisphenol A	affects expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
metarrestin	affects binding, decreases reaction, increases reaction	1
dicrotophos	decreases expression	1
oxybenzone	increases expression	1
kojic acid	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
trovafloxacin	decreases reaction, increases expression	1
monomethylarsonous acid	increases expression	1
K 7174	increases expression	1
abrine	increases expression	1
elesclomol	increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
jinfukang	decreases expression	1
NSC 689534	increases expression, affects binding	1
Bortezomib	increases expression	1
Sunitinib	increases expression	1
Leflunomide	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	increases abundance, increases expression	1
Atrazine	decreases expression	1

Cellosaurus cell lines

7 cell lines: 5 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B9R1	Abcam A-549 RB1CC1 KO	Cancer cell line	Male
CVCL_D1JA	HEK293::TMEM192-3xHA RB1CC1-/- mNEON-YIPF4	Transformed cell line	Female
CVCL_D1KQ	HEK293::TMEM192-3xHA RB1CC1-/-	Transformed cell line	Female
CVCL_D1LA	HeLa S3 RB1CC1 KO	Cancer cell line	Female
CVCL_E0ML	Ubigene HeLa RB1CC1 KO	Cancer cell line	Female
CVCL_E1KW	HyCyte HeLa KO-hRB1CC1	Cancer cell line	Female
CVCL_TI59	HAP1 RB1CC1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05183828	PHASE4	RECRUITING	Effect of HSD3B1 (1245C) Gene Mutation on Treatment of Stage I-III Breast Cancer
NCT00005970	PHASE3	COMPLETED	Doxorubicin Hydrochloride, Cyclophosphamide, and Pacltaxel With or Without Trastuzumab in Treating Women With HER2-Positive Node-Positive or High-Risk Node-Negative Breast Cancer
NCT00310180	PHASE3	ACTIVE_NOT_RECRUITING	Hormone Therapy With or Without Combination Chemotherapy in Treating Women Who Have Undergone Surgery for Node-Negative Breast Cancer (The TAILORx Trial)
NCT00433511	PHASE3	ACTIVE_NOT_RECRUITING	Doxorubicin Hydrochloride, Cyclophosphamide, and Paclitaxel With or Without Bevacizumab in Treating Patients With Lymph Node-Positive or High-Risk, Lymph Node-Negative Breast Cancer
NCT00869206	PHASE3	COMPLETED	Zoledronic Acid in Treating Patients With Metastatic Breast Cancer, Metastatic Prostate Cancer, or Multiple Myeloma With Bone Involvement
NCT02037529	PHASE3	SUSPENDED	Eribulin Mesylate or Paclitaxel as First- or Second-Line Therapy in Treating Patients With Recurrent Stage IIIC-IV Breast Cancer
NCT02115282	PHASE3	ACTIVE_NOT_RECRUITING	Exemestane With or Without Entinostat in Treating Patients With Recurrent Hormone Receptor-Positive Breast Cancer That is Locally Advanced or Metastatic
NCT02488967	PHASE3	ACTIVE_NOT_RECRUITING	Doxorubicin Hydrochloride and Cyclophosphamide Followed by Paclitaxel With or Without Carboplatin in Treating Patients With Triple-Negative Breast Cancer
NCT03199885	PHASE3	TERMINATED	Testing the Drug Atezolizumab or Placebo With Usual Therapy in First-Line HER2-Positive Metastatic Breast Cancer
NCT04300829	PHASE3	UNKNOWN	Cicaderma Efficacy vs Standard Care of Sites in Preventing Radiodermatitis in Non-metastatic Breast Cancer Patients
NCT01245712	PHASE2	ACTIVE_NOT_RECRUITING	Radiation Therapy in Treating Patients With Stage 0-II Breast Cancer
NCT01730833	PHASE2	ACTIVE_NOT_RECRUITING	Pertuzumab, Trastuzumab, and Paclitaxel Albumin-Stabilized Nanoparticle Formulation in Treating Patients With HER2-Positive Advanced Breast Cancer
NCT02067741	PHASE2	TERMINATED	CR1447 in Endocrine Responsive-HER2neg and TN-ARpos Breast Cancer
NCT02282345	PHASE2	COMPLETED	Talazoparib Before Standard Therapy in Treating Patients With Invasive, BRCA-Mutated Breast Cancer
NCT02530489	PHASE2	COMPLETED	Nab-Paclitaxel and Atezolizumab Before Surgery in Treating Patients With Triple Negative Breast Cancer
NCT02957968	PHASE2	ACTIVE_NOT_RECRUITING	Neoadjuvant Pembrolizumab + Decitabine Followed by Std Neoadj Chemo for Locally Advanced HER2- Breast Ca
NCT03094052	PHASE2	COMPLETED	Incidence and Severity of Diarrhea in Patients With HER2 Positive Breast Cancer Treated With Trastuzumab and Neratinib
NCT03666819	PHASE2	WITHDRAWN	Carbon Dioxide Fractional Laser in Treating Participants With Stage 0-III Hormone Receptor-Positive Breast Cancer With Vulvovaginal Atrophy
NCT04197687	PHASE2	UNKNOWN	TPIV100 and Sargramostim for the Treatment of HER2 Positive, Stage II-III Breast Cancer in Patients With Residual Disease After Chemotherapy and Surgery
NCT06538389	PHASE2	RECRUITING	High Cannabidiol Plant Extract (BRC-001) to Improve Aromatase Inhibitor-Induced Arthralgia in Women With Breast Cancer
NCT06671262	PHASE2	RECRUITING	Neoadjuvant Toripalimab and Radiotherapy Treatment in N+ HR+ Breast Cancer
NCT02453620	PHASE1	ACTIVE_NOT_RECRUITING	Entinostat, Nivolumab, and Ipilimumab in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery or Locally Advanced or Metastatic HER2-Negative Breast Cancer
NCT02824575	PHASE1	TERMINATED	Rebastinib Plus Antitubulin Therapy With Paclitaxel or Eribulin in Metastatic Breast Cancer
NCT03432741	PHASE1	TERMINATED	Direct Tumor Microinjection and FDG-PET in Testing Drug Sensitivity in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma, Hodgkin Lymphoma, or Stage IV Breast Cancer
NCT04139993	PHASE1	TERMINATED	RBX7455 Before Surgery for the Treatment of Operable Breast Cancer
NCT04150042	PHASE1	RECRUITING	SHARON: A Clinical Trial for Metastatic Cancer Using Chemotherapy and Patients’ Own Stem Cells
NCT04481113	PHASE1	COMPLETED	Abemaciclib and Niraparib Before Surgery for the Treatment of Hormone Receptor Positive HER2 Negative Breast Cancer
NCT04521764	PHASE1	RECRUITING	A Vaccine (MV-s-NAP) for the Treatment of Patients With Invasive Metastatic Breast Cancer
NCT04535323	PHASE1	COMPLETED	Platelet Rich Plasma for the Treatment of Genitourinary Syndrome of Menopause in Patients With Stage 0-III Breast Cancer
NCT04756505	PHASE1	WITHDRAWN	Immunotherapy (NHS-IL12 & Bintrafusp Alfa) and Radiation Therapy for the Treatment of Hormone Receptor Positive, HER2 Negative Metastatic Breast Cancer, the REINA Trial
NCT06745804	PHASE1	RECRUITING	Study of 68Ga-R10602
NCT07020117	PHASE1	RECRUITING	A Study of [225Ac]Ac-AKY-1189 in Patients With Solid Tumors
NCT00040222	Not specified	COMPLETED	Clinical, Genetic, Behavioral, Laboratory and Epidemiologic Characterization of Individuals and Families at High Risk of Breast/Ovarian Cancer
NCT02557776	Not specified	COMPLETED	Written Genetic Counseling and Mutation Analysis of BRCA1 and BRCA2 to Patients With Breast Cancer
NCT03495544	Not specified	UNKNOWN	Study Estimating Association Between Germline Mutations and PD-L1 Expression in Breast Cancer
NCT03959267	Not specified	COMPLETED	Testing a Culturally Adapted Telephone Genetic Counseling Intervention
NCT04058418	Not specified	COMPLETED	Specialist Recommendation on FBC (Familial Breast Cancer) Chemoprevention Prescribing
NCT04125914	Not specified	ACTIVE_NOT_RECRUITING	Weight Management and Health Behavior Intervention in Lowering Cancer Risk for BRCA Positive and Lynch Syndrome Families
NCT04169542	Not specified	RECRUITING	Impact of COVID-19 Pandemic on Out-of-Pocket Costs, Lost Wages, and Unemployment in Patients With Breast Cancer Undergoing Breast Surgery
NCT04197856	Not specified	ACTIVE_NOT_RECRUITING	Direct Information to At-risk Relatives