CCNF

Summary

CCNF (cyclin F, HGNC:1591) is a protein-coding gene on chromosome 16p13.3, encoding Cyclin-F (P41002). Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.

This gene encodes a member of the cyclin family. Cyclins are important regulators of cell cycle transitions through their ability to bind and activate cyclin-dependent protein kinases. This member also belongs to the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of the ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class and it was one of the first proteins in which the F-box motif was identified.

Source: NCBI Gene 899 — RefSeq curated summary.

At a glance

• Gene–disease (curated): frontotemporal dementia and/or amyotrophic lateral sclerosis 5 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 227 total — 2 pathogenic
• Phenotypes (HPO): 53
• MANE Select transcript: NM_001761

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1591
Approved symbol	CCNF
Name	cyclin F
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Aliases	FBX1, FBXO1
Ensembl gene	ENSG00000162063
Ensembl biotype	protein_coding
OMIM	600227
Entrez	899

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000293968, ENST00000397066, ENST00000564236, ENST00000564333, ENST00000569093, ENST00000916915, ENST00000916916, ENST00000916917, ENST00000916918

RefSeq mRNA: 2 — MANE Select: NM_001761 NM_001323538, NM_001761

CCDS: CCDS10467

Canonical transcript exons

ENST00000397066 — 17 exons

Exon	Start	End
ENSE00001909744	2456545	2458854
ENSE00003500010	2443649	2443800
ENSE00003521359	2455395	2455564
ENSE00003553603	2435806	2435873
ENSE00003584620	2448855	2448978
ENSE00003585010	2432961	2433067
ENSE00003586455	2437129	2437322
ENSE00003597844	2431130	2431284
ENSE00003602428	2449828	2449915
ENSE00003602964	2439353	2439457
ENSE00003615645	2445458	2445622
ENSE00003646896	2439749	2439826
ENSE00003654123	2449282	2449462
ENSE00003687811	2453410	2453537
ENSE00003692048	2438070	2438123
ENSE00003694617	2453210	2453309
ENSE00003842444	2429447	2429497

Expression profiles

Bgee: expression breadth ubiquitous, 213 present calls, max score 86.68.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.2167 / max 145.9400, expressed in 1523 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
152223	9.3501	1409
152222	1.8666	930

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
type B pancreatic cell	CL:0000169	86.68	gold quality
olfactory bulb	UBERON:0002264	86.23	gold quality
hair follicle	UBERON:0002073	85.13	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.57	gold quality
trabecular bone tissue	UBERON:0002483	84.40	gold quality
cervix squamous epithelium	UBERON:0006922	84.01	gold quality
ventricular zone	UBERON:0003053	82.32	gold quality
tongue squamous epithelium	UBERON:0006919	82.24	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	81.22	silver quality
epithelium of nasopharynx	UBERON:0001951	80.99	silver quality
buccal mucosa cell	CL:0002336	80.82	gold quality
bone marrow	UBERON:0002371	80.68	gold quality
gluteal muscle	UBERON:0002000	80.41	gold quality
mucosa of urinary bladder	UBERON:0001259	79.84	gold quality
embryo	UBERON:0000922	79.24	gold quality
vastus lateralis	UBERON:0001379	78.97	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	78.87	silver quality
bone marrow cell	CL:0002092	78.41	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.38	gold quality
ganglionic eminence	UBERON:0004023	78.20	gold quality
stromal cell of endometrium	CL:0002255	78.10	gold quality
thymus	UBERON:0002370	78.09	gold quality
quadriceps femoris	UBERON:0001377	77.78	gold quality
diaphragm	UBERON:0001103	77.69	gold quality
oviduct epithelium	UBERON:0004804	77.35	silver quality
squamous epithelium	UBERON:0006914	77.33	silver quality
epithelial cell of pancreas	CL:0000083	77.09	gold quality
lower esophagus mucosa	UBERON:0035834	76.95	gold quality
gingival epithelium	UBERON:0001949	76.88	silver quality
endometrium epithelium	UBERON:0004811	76.06	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6911	yes	315.83
E-ANND-3	yes	5.08

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): POU5F1

miRNA regulators (miRDB)

54 targeting CCNF, 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-5193	100.00	67.26	1744
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-3136-3P	99.57	66.59	781
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-5009-3P	99.45	69.43	1341
HSA-MIR-519D-5P	99.41	69.30	2057
HSA-MIR-3182	99.40	68.15	2454
HSA-MIR-32-3P	99.36	68.20	2517
HSA-MIR-19A-5P	99.36	66.93	1675
HSA-MIR-19B-1-5P	99.36	67.07	1669
HSA-MIR-19B-2-5P	99.36	67.07	1669
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-3678-3P	99.31	67.10	1432
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-4717-3P	99.06	66.34	1072
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-3926	98.95	69.26	1438

Literature-anchored findings (GeneRIF, showing 32)

• degradation during G2-M by mechanisms fundamentally different from other cyclins (PMID:12122006)
• SCF(Cyclin F)-mediated degradation of CP110 is required for the fidelity of mitosis and genome integrity (PMID:20596027)
• After DNA damage, cyclin F is downregulated in an ATR-dependent manner to allow accumulation of RRM2. Defective elimination of cyclin F delays DNA repair and sensitizes cells to DNA damage, a phenotype that is reverted by expressing a nondegradable RRM2 mutant. (PMID:22632967)
• Cyclin F controls genome stability through ubiquitin-mediated proteolysis. (Review) (PMID:23182110)
• Cyclin F suppresses B-Myb activity to promote cell cycle checkpoint control. (PMID:25557911)
• The SCYL1- BP1 affects the cell cycle through increasing steady state levels of Cyclin F and RRM2 proteins, thus constituting a dual regulatory circuit. (PMID:25980818)
• CDC6 and Cyclin F interact through defined sequence motifs that promote CDC6 ubiquitylation and degradation. (PMID:26818844)
• Data indicate that a missense mutation in cyclin F (CCNF) in a large Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) family. (PMID:27080313)
• These data indicate that the coordinated, temporal ordering of cyclin F and Cdh1 degradation, organized in a double-negative feedback loop, represents a fundamental aspect of cell-cycle control (PMID:27653696)
• Cyclin F-mediated degradation of SLBP limits H2A.X accumulation and apoptosis upon genotoxic stress in G2 cell cycle checkpoint. (PMID:27773672)
• cyclin F is a novel F-box protein that functions as an intrinsic cellular regulator of HIV-1 Vif and has a negative regulatory effect on the maintenance of viral infectivity by restoring APOBEC3G expression (PMID:28184007)
• Our result indicates that the mutation of CCNF is rare in patients with amyotrophic lateral sclerosis and frontotemporal dementia from Mainland China (PMID:28281833)
• Authors demonstrated a significant correlation between the severity of the CCNF-induced axonopathy and a reduced motor response to a light stimulus (photomotor response). (PMID:28444311)
• A single missense mutation in cyclin F causes hyper-ubiquitylation of proteins that can indirectly impair the autophagy degradation pathway, which is implicated in amyotrophic lateral sclerosis pathogenesis. (PMID:28852778)
• Mutational spectrum of CCNF emphasizes the pathogenic role of CCNF mutations in ALS. (PMID:29102476)
• Cyclin F and ribonucleotide reductase family member 2 (RRM2) compose a functional axis responsible for nucleotide metabolism. Impairment in this pathway may contribute to increased DNA damage repair and drug resistance. Additionally, we analyzed the expression of RRM2 mRNA and discovered that high expression of RRM2 is associated with worse overall survival. (PMID:29767233)
• the cyclin F-RBPJ axis has a key role in response to metabolic stress in cancer cells (PMID:30254149)
• Cyclin F is regulated by proteolysis through beta-TrCP at the G2/M transition. (PMID:30257202)
• Higher mRNA expression levels of FBXO1, FBXO31, SKP2, and FBXO5 were significantly associated with worse prognosis for breast cancer patients. (Review) (PMID:30341246)
• Cyclin F controls cell-cycle transcriptional outputs by directing the degradation of the E2F1, E2F2, and E2F3a. (PMID:31130363)
• Pathogenic mutations in the ALS gene CCNF cause cytoplasmic mislocalization of Cyclin F and elevated VCP ATPase activity (PMID:31577344)
• ALS/FTD-causing mutation in cyclin F causes the dysregulation of SFPQ. (PMID:33729478)
• Increased expression of Cyclin F in liver cancer predicts poor prognosis: A study based on TCGA database. (PMID:34397798)
• Cyclin F, Neurodegeneration, and the Pathogenesis of ALS/FTD. (PMID:36062310)
• ALS-linked loss of Cyclin-F function affects HSP90. (PMID:36114006)
• The Skp1-Cullin1-FBXO1 complex is a pleiotropic regulator required for the formation of gametes and motile forms in Plasmodium berghei. (PMID:36898988)
• Genetic and Phenotypic Spectrum of Amyotrophic Lateral Sclerosis Patients with CCNF Variants from a Large Chinese Cohort. (PMID:37171577)
• ALS-linked CCNF variant disrupts motor neuron ubiquitin homeostasis. (PMID:37220877)
• The E3 Ubiquitin Ligase SCF Cyclin F Promotes Sequestosome-1/p62 Insolubility and Foci Formation and is Dysregulated in ALS and FTD Pathogenesis. (PMID:37243816)
• ALS/FTD-associated mutation in cyclin F inhibits ER-Golgi trafficking, inducing ER stress, ERAD and Golgi fragmentation. (PMID:37993492)
• Overexpression of cyclin F/CCNF as an independent prognostic factor for poor survival in clear cell renal cell carcinoma. (PMID:38654021)
• Cyclin F-EXO1 axis controls cell cycle-dependent execution of double-strand break repair. (PMID:39121215)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	ccnf	ENSDARG00000105046
mus_musculus	Ccnf	ENSMUSG00000072082
rattus_norvegicus	Ccnf	ENSRNOG00000007483
drosophila_melanogaster	CycB	FBGN0000405
drosophila_melanogaster	CycD	FBGN0010315
drosophila_melanogaster	CycE	FBGN0010382
caenorhabditis_elegans		WBGENE00000865
caenorhabditis_elegans		WBGENE00000866
caenorhabditis_elegans	cyb-2.2	WBGENE00000867
caenorhabditis_elegans		WBGENE00000870
caenorhabditis_elegans	cye-1	WBGENE00000871

Paralogs (18): CCNE1 (ENSG00000105173), CCNP (ENSG00000105219), CCNJ (ENSG00000107443), CCND1 (ENSG00000110092), CCND3 (ENSG00000112576), CCNG1 (ENSG00000113328), CCNI (ENSG00000118816), CCND2 (ENSG00000118971), CCNA1 (ENSG00000133101), CCNB1 (ENSG00000134057), CCNJL (ENSG00000135083), CCNG2 (ENSG00000138764), CCNA2 (ENSG00000145386), CCNB3 (ENSG00000147082), CCNO (ENSG00000152669), CCNB2 (ENSG00000157456), CCNE2 (ENSG00000175305), CCNI2 (ENSG00000205089)

Protein

Protein identifiers

Cyclin-F — P41002 (reviewed: P41002)

Alternative names: F-box only protein 1

All UniProt accessions (3): P41002, H0Y2P7, H3BUD3

UniProt curated annotations — full annotation on UniProt →

Function. Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. The SCF(CCNF) E3 ubiquitin-protein ligase complex is an integral component of the ubiquitin proteasome system (UPS) and links proteasome degradation to the cell cycle. Mediates the substrate recognition and the proteasomal degradation of various target proteins involved in the regulation of cell cycle progression and in the maintenance of genome stability. Mediates the ubiquitination and proteasomal degradation of CP110 during G2 phase, thereby acting as an inhibitor of centrosome reduplication. In G2, mediates the ubiquitination and subsequent degradation of ribonucleotide reductase RRM2, thereby maintaining a balanced pool of dNTPs and genome integrity. In G2, mediates the ubiquitination and proteasomal degradation of CDC6, thereby suppressing DNA re-replication and preventing genome instability. Involved in the ubiquitination and degradation of the substrate adapter CDH1 of the anaphase-promoting complex (APC/C), thereby acting as an antagonist of APC/C in regulating G1 progression and S phase entry. May play a role in the G2 cell cycle checkpoint control after DNA damage, possibly by promoting the ubiquitination of MYBL2/BMYB.

Subunit / interactions. Component of the SCF(CCNF) complex consisting of CUL1, RBX1, SKP1 and CCNF. Interacts with SKP1. Interacts with CUL1. Interacts with CCNB1; interaction is required for nuclear localization of CCNB1. Interacts with CCP110; this interaction leads to CCP110 ubiquitination and degradation via the proteasome pathway. Interacts (via the Cyclin N-terminal domain) with MYBL2/BMYB. Interacts with FZR1/CDH1 (via N-terminus). Interacts with RRM2 (via Cy motif and when phosphorylated at ‘Thr-33’); the interaction occurs exclusively in G2 and early M. Interacts with CDC6 (via Cy motif); the interaction takes place during G2 and M phase.

Subcellular location. Nucleus. Cytoplasm. Perinuclear region. Cytoskeleton. Microtubule organizing center. Centrosome. Centriole.

Tissue specificity. Widely expressed, with expression detected in the heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.

Post-translational modifications. Degraded when the spindle assembly checkpoint is activated during the G2-M transition. Degradation depends on the C-terminal PEST sequence. Phosphorylated just before cells enter into mitosis. Ubiquitinated by the anaphase-promoting complex (APC/C); leading to its degradation by the proteasome.

Disease relevance. Frontotemporal dementia and/or amyotrophic lateral sclerosis 5 (FTDALS5) [MIM:619141] A neurodegenerative disorder characterized by frontotemporal dementia and/or amyotrophic lateral sclerosis in affected individuals. There is high intrafamilial variation. Frontotemporal dementia is characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Amyotrophic lateral sclerosis is characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. FTDALS5 is an autosomal dominant form with age-dependent penetrance. Penetrance is estimated to be 50% by age 56 and 100% by age 61. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The nuclear localization signals mediate the localization to the nucleus and are required for CCNB1 localization to the nucleus. The D box motifs 1-5 (amino acid sequence RxxL) are involved in substrate binding, such as FZR1/CDH1, and may be ubiquitinated.

Induction. Down-regulated in an ATR-dependent manner in response to DNA damage induced by doxorubicin, camptothecin, UV-C, methyl methanesulfonate, nocodazole, or gamma-irradiation. Down-regulation in response to DNA damage is required to allow RRM2 accumulation within the nucleus and for efficient DNA repair.

Miscellaneous. Founding member of the F-box domain protein family, which obtained its name from cyclin-F. Member of the cyclin family, however, unlike most members of the cyclin family, it does not bind or activate a cyclin-dependent kinase.

Similarity. Belongs to the cyclin family. Cyclin AB subfamily.

RefSeq proteins (2): NP_001310467, NP_001752* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001810	F-box_dom	Domain
IPR004367	Cyclin_C-dom	Domain
IPR006671	Cyclin_N	Domain
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR013763	Cyclin-like_dom	Domain
IPR036047	F-box-like_dom_sf	Homologous_superfamily
IPR036915	Cyclin-like_sf	Homologous_superfamily
IPR039361	Cyclin	Family
IPR048258	Cyclins_cyclin-box	Conserved_site

Pfam: PF00134, PF02984, PF12937

UniProt features (84 total): helix 35, sequence variant 10, mutagenesis site 9, short sequence motif 7, sequence conflict 7, turn 5, region of interest 3, strand 3, domain 2, compositionally biased region 2, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9CB3	ELECTRON MICROSCOPY	3.47

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P41002-F1	72.34	0.51

Functional residue map

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

Mutagenesis-validated functional residues (9):

Position	Phenotype
35–36	impairs interaction with skp1 and cul1 and prevents degradation of cp110, leading to promote the formation of micronucle
309–310	reduces the interaction with mybl2/bmyb. disrupts the interaction with cdc6. does not disrupt interaction with cul1.
309	reduced degradation of rrm2 after uv-induced dna-damage. abolishes the interaction with cp110 and rrm2; when associated
310–313	reduces the interaction with fzr1/cdh1. reduced ubiquitination. abolishes the interaction with fzr1/cdh1; when associate
343–346	reduces the interaction with fzr1/cdh1.
349–352	reduces the interaction with fzr1/cdh1.
351–354	reduces the interaction with fzr1/cdh1. abolishes the interaction with fzr1/cdh1; when associated with 310-r–l-313. los
352	abolishes the interaction with cp110 and rrm2; when associated with a-309.
767–770	reduces the interaction with fzr1/cdh1.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-8951664	Neddylation
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 407 (showing top): MODULE_52, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GNF2_CENPF, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, MORF_MSH3, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, MODULE_45, MORF_BRCA1, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GNF2_H2AFX, MODULE_453

GO Biological Process (8): G1/S transition of mitotic cell cycle (GO:0000082), re-entry into mitotic cell cycle (GO:0000320), placenta development (GO:0001890), negative regulation of centrosome duplication (GO:0010826), protein ubiquitination (GO:0016567), SCF-dependent proteasomal ubiquitin-dependent protein catabolic process (GO:0031146), cell division (GO:0051301), regulation of cell cycle (GO:0051726)

GO Molecular Function (4): anaphase-promoting complex binding (GO:0010997), cyclin-dependent protein serine/threonine kinase regulator activity (GO:0016538), ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (11): cyclin-dependent protein kinase holoenzyme complex (GO:0000307), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), centrosome (GO:0005813), centriole (GO:0005814), microtubule organizing center (GO:0005815), cytosol (GO:0005829), SCF ubiquitin ligase complex (GO:0019005), perinuclear region of cytoplasm (GO:0048471), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Post-translational protein modification	1
Class I MHC mediated antigen processing & presentation	1
Immune System	1
Metabolism of proteins	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
microtubule organizing center	2
intracellular membraneless organelle	2
cytoplasm	2
mitotic cell cycle	1
mitotic cell cycle phase transition	1
cell cycle G1/S phase transition	1
cell cycle process	1
animal organ development	1
regulation of centrosome duplication	1
negative regulation of centrosome cycle	1
centrosome duplication	1
protein modification by small protein conjugation	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
cellular process	1
cell cycle	1
regulation of cellular process	1
protein-containing complex binding	1
cyclin-dependent protein serine/threonine kinase activity	1
cyclin-dependent protein kinase regulator activity	1
enzyme-substrate adaptor activity	1
binding	1
serine/threonine protein kinase complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
centriole	1
microtubule cytoskeleton	1
cullin-RING ubiquitin ligase complex	1

Protein interactions and networks

STRING

2870 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CCNF	SKP1	P34991	998
CCNF	SKP2	Q13309	939
CCNF	CCP110	O43303	928
CCNF	BTRC	Q9Y297	921
CCNF	CUL1	Q13616	839
CCNF	FBXW11	Q9UKB1	830
CCNF	FBXL7	Q9UJT9	730
CCNF	RRM2	P31350	724
CCNF	CDC6	Q99741	719
CCNF	FBXL4	Q9UKA2	708
CCNF	CDK1	P06493	703
CCNF	KDM2A	Q9Y2K7	703
CCNF	FBXO8	Q9NRD0	684
CCNF	FBXO6	Q9NRD1	677
CCNF	FBXL3	Q9UKT7	676

IntAct

39 interactions, top by confidence:

A	B	Type	Score
RRM2	RRM1	psi-mi:“MI:0914”(association)	0.850
CCNF	CCP110	psi-mi:“MI:0914”(association)	0.790
CCP110	CCNF	psi-mi:“MI:0915”(physical association)	0.790
CCP110	CCNF	psi-mi:“MI:0914”(association)	0.790
CCNF	SKP1	psi-mi:“MI:0914”(association)	0.740
CCNF	SKP1	psi-mi:“MI:0915”(physical association)	0.740
CCNF	RRM2	psi-mi:“MI:0914”(association)	0.710
RRM2	CCNF	psi-mi:“MI:0403”(colocalization)	0.710
CCNF	RRM2	psi-mi:“MI:0915”(physical association)	0.710
RRM2	CCNF	psi-mi:“MI:0915”(physical association)	0.710
CCNF	CUL1	psi-mi:“MI:0915”(physical association)	0.660
CCNF	SKP1	psi-mi:“MI:0915”(physical association)	0.640
SKP1	MYCBP2	psi-mi:“MI:0914”(association)	0.640
RRM2	HSPA8	psi-mi:“MI:0914”(association)	0.640
CCNF	CCP110	psi-mi:“MI:0915”(physical association)	0.400
SKP1	CCNF	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (3717): CCNF (Two-hybrid), CCNF (Affinity Capture-Western), CCNF (Reconstituted Complex), CCNF (Affinity Capture-Western), MYBL2 (Affinity Capture-Western), MYBL2 (Reconstituted Complex), CDC6 (Affinity Capture-Western), CCNF (Affinity Capture-Western), CCNF (Reconstituted Complex), CDC6 (Biochemical Activity), CCNF (Affinity Capture-Western), CCNF (Affinity Capture-MS), CCNF (Affinity Capture-Western), SLBP (Affinity Capture-Western), CCNF (Affinity Capture-RNA)

ESM2 similar proteins: A0JM59, A2BGT0, A4QNN3, A5PK16, A5PMR2, A5PN09, A6QNM7, A7Z056, B1AY15, B1WBD7, D2HBJ8, D3ZPG5, E2RK09, E7F6T8, E9QG68, F1SRY5, P41002, P51944, Q28CN3, Q2KJ09, Q3UN04, Q5F479, Q5R5Z6, Q5RE63, Q5REG5, Q5XGZ2, Q6NTR6, Q6ZWE6, Q70CQ3, Q70CQ4, Q70EK9, Q810L3, Q86T82, Q8BM47, Q8BW70, Q8C0R0, Q8C2S0, Q8C6M1, Q8K296, Q8K387

Diamond homologs: A0MEB5, A5PK16, O48790, P18606, P20248, P25010, P25011, P30274, P34638, P34800, P34801, P37881, P39963, P41002, P43062, P47827, P51943, P51944, P51986, P78396, Q01J96, Q0DJR9, Q0INT0, Q0JPA4, Q38819, Q39069, Q39071, Q3ECW2, Q5A1N6, Q5XGG5, Q61456, Q6AY13, Q6NYX6, Q7F830, Q7T0L6, Q7TMA5, Q7XSJ6, Q8K4F8, Q92161, Q9C6A9

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
AKT	“up-regulates activity”	CCNF	phosphorylation
APC-c	“down-regulates quantity by destabilization”	CCNF	ubiquitination
CCNF	“down-regulates quantity by destabilization”	FZR1	ubiquitination
CCNF	“down-regulates quantity by destabilization”	CCP110	ubiquitination
CSNK2A1	“down-regulates activity”	CCNF	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	115
Likely benign	42
Benign	43

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
992593	NM_001761.3(CCNF):c.1175G>C (p.Arg392Thr)	Pathogenic
992594	NM_001761.3(CCNF):c.1870G>A (p.Glu624Lys)	Pathogenic

SpliceAI

2356 predictions. Top by Δscore:

Variant	Effect	Δscore
16:2429494:GGCG:G	donor_gain	1.0000
16:2429495:GCG:G	donor_gain	1.0000
16:2429495:GCGG:G	donor_gain	1.0000
16:2429497:GGT:G	donor_loss	1.0000
16:2429498:G:GG	donor_gain	1.0000
16:2429498:GTGA:G	donor_loss	1.0000
16:2429499:T:G	donor_loss	1.0000
16:2431128:A:AG	acceptor_gain	1.0000
16:2431128:AGT:A	acceptor_gain	1.0000
16:2431128:AGTG:A	acceptor_gain	1.0000
16:2431129:G:GA	acceptor_gain	1.0000
16:2431129:GT:G	acceptor_gain	1.0000
16:2431129:GTG:G	acceptor_gain	1.0000
16:2431129:GTGG:G	acceptor_gain	1.0000
16:2431129:GTGGT:G	acceptor_gain	1.0000
16:2431280:GAGCT:G	donor_gain	1.0000
16:2431281:AGCT:A	donor_gain	1.0000
16:2431282:GCT:G	donor_gain	1.0000
16:2431282:GCTG:G	donor_gain	1.0000
16:2431282:GCTGT:G	donor_loss	1.0000
16:2431283:CT:C	donor_gain	1.0000
16:2431283:CTGT:C	donor_loss	1.0000
16:2431284:TG:T	donor_loss	1.0000
16:2431285:G:GG	donor_gain	1.0000
16:2431285:GTAAG:G	donor_loss	1.0000
16:2431286:TAAGT:T	donor_loss	1.0000
16:2435800:TTTCA:T	acceptor_loss	1.0000
16:2435801:TTCA:T	acceptor_loss	1.0000
16:2435802:TCA:T	acceptor_loss	1.0000
16:2435804:A:AG	acceptor_gain	1.0000

AlphaMissense

5128 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:2437277:G:C	K165N	1.000
16:2437277:G:T	K165N	1.000
16:2445474:T:A	W316R	1.000
16:2445474:T:C	W316R	1.000
16:2445476:G:C	W316C	1.000
16:2445476:G:T	W316C	1.000
16:2448899:T:C	L380P	1.000
16:2437251:T:A	W157R	0.999
16:2437251:T:C	W157R	0.999
16:2445466:T:C	L313P	0.999
16:2445472:A:T	D315V	0.999
16:2445478:T:C	L317P	0.999
16:2445594:G:C	G356R	0.999
16:2445595:G:A	G356D	0.999
16:2448887:A:T	E376V	0.999
16:2448889:G:C	A377P	0.999
16:2448890:C:A	A377D	0.999
16:2433033:T:A	W82R	0.998
16:2433033:T:C	W82R	0.998
16:2435846:G:C	G107R	0.998
16:2437275:A:C	K165Q	0.998
16:2437276:A:T	K165M	0.998
16:2445472:A:C	D315A	0.998
16:2445553:T:C	L342P	0.998
16:2445583:T:C	L352P	0.998
16:2448881:T:A	I374N	0.998
16:2448895:T:A	W379R	0.998
16:2448895:T:C	W379R	0.998
16:2448905:A:T	D382V	0.998
16:2448919:T:C	Y387H	0.998

dbSNP variants (sampled 300 via entrez): RS1000052798 (16:2448270 T>C), RS1000058777 (16:2448622 C>T), RS1000066615 (16:2440213 C>T), RS1000165188 (16:2439569 C>G,T), RS1000263535 (16:2446204 G>A), RS1000346409 (16:2441622 C>T), RS1000417932 (16:2430639 C>T), RS1000475127 (16:2450961 G>A), RS1000726056 (16:2432198 A>C), RS1000851182 (16:2429917 G>A,C), RS1000901936 (16:2429721 C>A,T), RS1000928869 (16:2452844 G>C), RS1000998985 (16:2455137 C>T), RS1001158593 (16:2432007 T>C), RS1001200093 (16:2431609 G>A)

Disease associations

OMIM: gene MIM:600227 | disease phenotypes: MIM:308350, MIM:605021, MIM:614617, MIM:616044, MIM:619141

GenCC curated gene-disease

Disease	Classification	Inheritance
frontotemporal dementia and/or amyotrophic lateral sclerosis 5	Strong	Autosomal dominant
amyotrophic lateral sclerosis	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
frontotemporal dementia and/or amyotrophic lateral sclerosis 5	Limited	AD

Mondo (8): developmental and epileptic encephalopathy, 1 (MONDO:0010632), familial infantile myoclonic epilepsy (MONDO:0011506), autosomal recessive nonsyndromic hearing loss 86 (MONDO:0013826), autosomal dominant nonsyndromic hearing loss 65 (MONDO:0014470), amyotrophic lateral sclerosis (MONDO:0004976), frontotemporal dementia (MONDO:0017276), frontotemporal dementia and/or amyotrophic lateral sclerosis 5 (MONDO:0030875), polyneuropathy (MONDO:0001824)

Orphanet (5): Familial infantile myoclonic epilepsy (Orphanet:352582), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), Amyotrophic lateral sclerosis (Orphanet:803), Frontotemporal dementia (Orphanet:282)

HPO phenotypes

53 total (30 of 53 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000217	Xerostomia
HP:0000708	Atypical behavior
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000739	Anxiety
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001308	Tongue fasciculations
HP:0001324	Muscle weakness
HP:0001347	Hyperreflexia
HP:0001618	Dysphonia
HP:0001824	Weight loss
HP:0002015	Dysphagia
HP:0002094	Dyspnea
HP:0002145	Frontotemporal dementia
HP:0002180	Neurodegeneration
HP:0002307	Drooling
HP:0002313	Spastic paraparesis
HP:0002360	Sleep disturbance
HP:0002380	Fasciculations
HP:0002463	Language impairment
HP:0002878	Respiratory failure
HP:0003202	Skeletal muscle atrophy
HP:0003324	Generalized muscle weakness
HP:0003376	Steppage gait
HP:0003394	Muscle spasm
HP:0003470	Paralysis
HP:0003484	Upper limb muscle weakness
HP:0003487	Babinski sign

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST008163_391	Height	2.000000e-06
GCST010244_396	Triglyceride levels	2.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
D057180	Frontotemporal Dementia	C10.228.140.380.266.299; C10.574.950.300.299; C18.452.845.800.300.299; F03.615.400.380.299
D011115	Polyneuropathies	C10.668.829.800

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, decreases expression	5
bisphenol A	decreases expression, increases expression	2
polyhexamethyleneguanidine	affects expression, decreases expression	2
chromium hexavalent ion	decreases expression, increases abundance	2
2,2’,4,4’-tetrabromodiphenyl ether	affects expression, decreases expression	2
Arsenic Trioxide	decreases expression, decreases methylation, increases expression	2
Cadmium	decreases expression	2
Cisplatin	decreases expression, increases expression	2
Formaldehyde	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tretinoin	decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
2-methyl-4-isothiazolin-3-one	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
aflatoxin B2	increases methylation	1
hydroquinone	decreases expression	1
vanadyl sulfate	decreases expression	1
diallyl trisulfide	decreases expression	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	decreases expression, affects cotreatment	1

Cellosaurus cell lines

1 cell lines: 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_VF31	UOWi005-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00542412	PHASE4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	PHASE4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	PHASE4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	PHASE4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	PHASE4	RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT00021697	PHASE3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	PHASE3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	PHASE3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	PHASE3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00136110	PHASE3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	PHASE3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00372879	PHASE3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
NCT00415519	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III
NCT00424463	PHASE3	COMPLETED	Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00868166	PHASE3	COMPLETED	Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
NCT00965497	PHASE3	COMPLETED	Escitalopram (Lexapro) for Depression MS or ALS
NCT01016522	PHASE3	TERMINATED	Safety and Tolerability of the Ketogenic Diet in Amyotrophic Lateral Sclerosis (ALS)
NCT01160263	PHASE3	COMPLETED	Study of Dopamine and Serotonin Transporters in Patients With Amyotrophic Lateral Sclerosis and Controls
NCT01281189	PHASE3	COMPLETED	Phase 3 Study of Dexpramipexole in ALS
NCT01492686	PHASE3	COMPLETED	Phase 3 Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis
NCT01583088	PHASE3	TERMINATED	Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation
NCT01622088	PHASE3	TERMINATED	Phase 3 Extension Study of Dexpramipexole in ALS
NCT02496767	PHASE3	COMPLETED	Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
NCT02623699	PHASE3	COMPLETED	An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
NCT02936635	PHASE3	COMPLETED	A Study for Patients Who Completed VITALITY-ALS (CY 4031)
NCT03127267	PHASE3	RECRUITING	Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients
NCT03280056	PHASE3	COMPLETED	Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients
NCT03491462	PHASE3	COMPLETED	Arimoclomol in Amyotropic Lateral Sclerosis
NCT03505021	PHASE3	COMPLETED	Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
NCT03548311	PHASE3	COMPLETED	Clinical Trial of Ultra-high Dose Methylcobalamin for ALS
NCT03690791	PHASE3	UNKNOWN	Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease
NCT03800524	PHASE3	UNKNOWN	Safety and Efficacy of TUDCA as add-on Treatment in Patients Affected by ALS
NCT03836716	PHASE3	TERMINATED	Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial
NCT03948178	PHASE3	TERMINATED	Effects of Oral Levosimendan on Respiratory Function in Patients With Amyotrophic Lateral Sclerosis (ALS): Open-Label Extension
NCT04165824	PHASE3	COMPLETED	Safety Study of Oral Edaravone Administered in Subjects With ALS
NCT04248465	PHASE3	TERMINATED	An Efficacy and Safety Study of Ravulizumab in ALS Participants
NCT04569084	PHASE3	TERMINATED	Efficacy and Safety Study of Oral Edaravone Administered in Subjects With ALS