CDKN1C

Summary

CDKN1C (cyclin dependent kinase inhibitor 1C, HGNC:1786) is a protein-coding gene on chromosome 11p15.4, encoding Cyclin-dependent kinase inhibitor 1C (P49918). Potent tight-binding inhibitor of several G1 cyclin/CDK complexes (cyclin E-CDK2, cyclin D2-CDK4, and cyclin A-CDK2) and, to lesser extent, of the mitotic cyclin B-CDC2. It is haploinsufficient (ClinGen: sufficient evidence).

This gene is imprinted, with preferential expression of the maternal allele. The encoded protein is a tight-binding, strong inhibitor of several G1 cyclin/Cdk complexes and a negative regulator of cell proliferation. Mutations in this gene are implicated in sporadic cancers and Beckwith-Wiedemann syndorome, suggesting that this gene is a tumor suppressor candidate. Three transcript variants encoding two different isoforms have been found for this gene.

Source: NCBI Gene 1028 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Beckwith-Wiedemann syndrome (Definitive, GenCC) — +5 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 1,280 total — 104 pathogenic, 20 likely-pathogenic
• Phenotypes (HPO): 89
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001122630

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1786
Approved symbol	CDKN1C
Name	cyclin dependent kinase inhibitor 1C
Location	11p15.4
Locus type	gene with protein product
Status	Approved
Aliases	P57, KIP2
Ensembl gene	ENSG00000129757
Ensembl biotype	protein_coding
OMIM	600856
Entrez	1028

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 8 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000380725, ENST00000414822, ENST00000430149, ENST00000440480, ENST00000471157, ENST00000647251, ENST00000681969, ENST00000891443, ENST00000953340, ENST00000953341

RefSeq mRNA: 5 — MANE Select: NM_001122630 NM_000076, NM_001122630, NM_001122631, NM_001362474, NM_001362475

CCDS: CCDS44519, CCDS7738, CCDS86169

Canonical transcript exons

ENST00000313407 — 0 exons

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.3919 / max 769.2825, expressed in 1376 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
118243	21.1974	1320
118242	1.1945	589

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
placenta	UBERON:0001987	99.35	gold quality
adrenal tissue	UBERON:0018303	98.92	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.14	gold quality
right ovary	UBERON:0002118	98.11	gold quality
left ovary	UBERON:0002119	98.08	gold quality
right adrenal gland cortex	UBERON:0035827	98.08	gold quality
right adrenal gland	UBERON:0001233	97.89	gold quality
ovary	UBERON:0000992	97.43	gold quality
tibial nerve	UBERON:0001323	97.33	gold quality
left adrenal gland cortex	UBERON:0035825	97.26	gold quality
left adrenal gland	UBERON:0001234	96.83	gold quality
omental fat pad	UBERON:0010414	96.66	gold quality
left uterine tube	UBERON:0001303	96.42	gold quality
adipose tissue	UBERON:0001013	96.34	gold quality
subcutaneous adipose tissue	UBERON:0002190	96.10	gold quality
adult mammalian kidney	UBERON:0000082	95.97	gold quality
endocervix	UBERON:0000458	95.83	gold quality
adrenal gland	UBERON:0002369	95.78	gold quality
body of uterus	UBERON:0009853	95.65	gold quality
apex of heart	UBERON:0002098	95.56	gold quality
mucosa of stomach	UBERON:0001199	95.23	gold quality
metanephros cortex	UBERON:0010533	94.71	gold quality
fundus of stomach	UBERON:0001160	94.70	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.66	gold quality
lower esophagus	UBERON:0013473	94.64	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.24	gold quality
myometrium	UBERON:0001296	94.10	gold quality
right lung	UBERON:0002167	94.03	gold quality
kidney	UBERON:0002113	93.86	gold quality
thoracic mammary gland	UBERON:0005200	93.78	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-MTAB-10662	yes	4127.60
E-HCAD-56	yes	710.79
E-GEOD-149689	yes	516.42
E-MTAB-9221	yes	473.22
E-MTAB-6701	yes	82.33
E-GEOD-135922	yes	47.49
E-GEOD-100618	yes	24.46
E-MTAB-6678	yes	17.74
E-ANND-3	yes	16.06
E-MTAB-9388	yes	11.47
E-MTAB-8060	no	1677.06

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BCL11B, CEBPB, CTCF, CTNNB1, E2F1, EGR1, ESR1, EWSR1, EZH2, FLI1, FOXC1, FOXO1, FOXO3, FOXP1, HES1, HEY1, HIF1A, HLX, HOXA10, ID2, KLF4, MYOD1, NFKBIA, NOG, NR3C1, NR4A2, PAX3, PAX6, PLAGL1, PROX1, RNF141, RUNX1, SMARCA1, SOX17, SP1, SSRP1, TCF3, TCF4, TP63, TP73

miRNA regulators (miRDB)

55 targeting CDKN1C, 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-4283	100.00	66.42	2097
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-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-557	99.96	70.01	1640
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-129-5P	99.88	70.26	3273
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-26A-5P	99.78	73.52	2303

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Identification and functional characterization of an intragenic DNA binding site for the spumaretroviral trans-activator in the human p57Kip2 gene (PMID:11815601)
• Induction of p57(KIP2) expression by p73beta (PMID:11891335)
• Down-regulation of p57 may play a role in the dedifferentiation of thyroid carcinoma. (PMID:11891530)
• DNA methylation and histone deacetylation of p57KIP2 promoter results in gene silencing of p57KIP2 in human tumors (PMID:11965547)
• aberrant DNA methylation of the gene occurs in the promoter region in lymphoid malignancies of B-cell phenotype (PMID:12239171)
• findings support the hypothesis that misexpression of p57 is involved in the abnormal development of androgenetic complete moles (PMID:12514787)
• Expression of p57kip2, Rb protein and PCNA and their relationships with clinicopathology in human pancreatic cancer. (PMID:12532471)
• P57/KIP2 is a determinant pro-survival factor for cell protection from green tea polyphenol-induced apoptosis. (PMID:12553041)
• frequently methylated in adult patients with ALL, and that inactivation of a pathway composed of p73, p15, and p57KIP2 predicts for poor prognosis in Ph-negative patients (PMID:12586619)
• identified a functional glucocorticoid response element, located 5 kilo bases upstream of the transcription start site in the human p57(Kip2) promoter (PMID:12790805)
• SCFSkp2 complex plays an important role in cell-cycle progression by determining the abundance of p57Kip2 and that of the related CDK inhibitor p27Kip1. (PMID:12925736)
• it is evident that B-Myb protein may promote cell proliferation by a non-transcriptional mechanism that involves release of active cyclin/cyclin dependent kinase 2 from cyclin-dependent inhibitor 1C p57(KIP2) (PMID:12947099)
• p57KIP2 modulates stress-activated signaling by functioning as an endogenous inhibitor of JNK/SAPK (PMID:12963725)
• p57 may act as a key regulator in embryogenesis by regulating cell cycle through binding to Cdks and the regulating actin dynamics through binding to LIMK-1 (PMID:14530263)
• loss of p57KIP2 expression appears associated with colorectal carcinogenesis (PMID:14612924)
• An epimutation at KvDMR1, the absence of maternal methylation, causes the aberrant silencing of CDKN1C, some 180 kb away on the maternal chromosome. (PMID:14627666)
• Diminished CDKN1C expression is associated with loss of methylation of CpG & H3K9 at DMR-LIT1, & is involved in esophageal cancer. DMR-LIT1 epigenetically regulates CDKN1C expression through histone modifications at DMR-LIT1 promoter. (PMID:15007390)
• p57KIP2 was weakly expressed in 4/6 glioblastoma (GBM) specimens by western blot. p57KIP2 immunoreactivity was positive in 8/40 GBMs, and was primarily nuclear in location. The motility of glioma cells was significantly reduced after p57KIP2 induction. (PMID:15332324)
• Aberrant methylation of p57KIP2 gene is associated with lung and breast cancers and malignant mesotheliomas (PMID:15492797)
• p57 is up-regulated in the process of decidualization. (PMID:15749785)
• Variants in CDKN1C may contribute to the inter-individual variation in birth weight. (PMID:15821902)
• p57KIP2 is part of an imprinted gene network that may play a role in Beckwith-Wiedemann syndrome. (PMID:15888726)
• endothelial cells of infantile hemangiomas not associated with Beckwith-Wiedemann syndrome normally express p57(KIP2) while chorioangiomas do not (PMID:15900410)
• The Cyclin-Dependent Kinase Inhibitor p57 plays key roles in cell cycle regulation, and was methylation-negative in myeloid neoplasia. (PMID:15936816)
• Transcripts of P57KIP2, imprinted genes related to BWS, were detected in human oocytes and at all stages of preimplantation embryos. (PMID:15952111)
• The P57 was methylated in 2 (10%) pediatric patients , compared to 20 (37%)respectively in adult patients. (PMID:15978938)
• identification of a novel p73-Kip2/p57 pathway that coordinates mitotic exit and transition to G1 (PMID:15985436)
• The absence of methylation and repressive chromatin structure at the CDKN1C promoter in Beckwith-Wiedemann Syndrome patients with loss of methylation at KvDMR1 suggests a direct role of this epimutation in silencing CDKN1C. (PMID:16061564)
• The decreased expression of p57(kip2) and/or overexpression of cyclinE protein and PCNA may contribute to the occurrence and progression of pancreatic cancer. (PMID:16124066)
• Methylation of p57(KIP2) may contribute to the malignant progression of gastric MALT lymphomas. (PMID:16357845)
• Recent advances in epigenetic control of the CDKN1C/KCNQ1OT1 imprinted domain in both humans and mice, causing Beckwith-Wiedemann syndrome and cancer. (review) (PMID:16575194)
• Global gene expression analysis in neuroblastoma cells engineered to acutely express the E protein E47 and Id2, showed that p57Kip2 is a target of E47. (PMID:16705184)
• These results suggest that the tumor suppressive properties of p57KIP2 in leukemia may depend on the intrinsic promoter DNA methylation status of the gene. (PMID:16936778)
• TGF-beta1 and/or TGF-beta2 inhibit proliferation of primary cultured human limbal epithelial cells, and p57 and p15 play roles in this process. (PMID:16943770)
• CTIP2 associates with the NuRD complex on the promoter of p57KIP2, a newly identified CTIP2 target gene. (PMID:16950772)
• findings suggest p57kip2 may play a role in the regulation of meiotic progression of early spermatocytes & cell cycle arrest & differentiation of spermatids (PMID:17050328)
• These data demonstrate the role of BMP2 compared to BMP6 in the inhibition of growth and induction of differentiation of keratinocytes; p57(Kip2) and p21(Cip1) have a BMP2/6-induced expression. (PMID:17112701)
• Genetic evidence links the association between DNA-variants in the CDKN1C gene with a risk of atherosclerosis and myocardial infarction. (PMID:17351341)
• mechanism whereby p57(Kip2) influences the mitochondrial apoptotic cell death pathway in cancer cells (PMID:17464323)
• In this study, P57kip2 immunostaining was absent in the trophoblastic layers of CHM and was positive in the trophoblast layer of nonmolar villi and MD. (PMID:17572845)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	cdkn1ca	ENSDARG00000010878
danio_rerio	cdkn1cb	ENSDARG00000104903
mus_musculus	Cdkn1c	ENSMUSG00000037664
rattus_norvegicus	Cdkn1c	ENSRNOG00000059500

Paralogs (2): CDKN1B (ENSG00000111276), CDKN1A (ENSG00000124762)

Protein

Protein identifiers

Cyclin-dependent kinase inhibitor 1C — P49918 (reviewed: P49918)

Alternative names: Cyclin-dependent kinase inhibitor p57, p57Kip2

All UniProt accessions (3): A0A2R8YFP9, A6NK88, P49918

UniProt curated annotations — full annotation on UniProt →

Function. Potent tight-binding inhibitor of several G1 cyclin/CDK complexes (cyclin E-CDK2, cyclin D2-CDK4, and cyclin A-CDK2) and, to lesser extent, of the mitotic cyclin B-CDC2. Negative regulator of cell proliferation. May play a role in maintenance of the non-proliferative state throughout life.

Subunit / interactions. Interacts with PCNA.

Subcellular location. Nucleus.

Tissue specificity. Expressed in the heart, brain, lung, skeletal muscle, kidney, pancreas and testis. Expressed in the eye. High levels are seen in the placenta while low levels are seen in the liver.

Disease relevance. Beckwith-Wiedemann syndrome (BWS) [MIM:130650] A disorder characterized by anterior abdominal wall defects including exomphalos (omphalocele), pre- and postnatal overgrowth, and macroglossia. Additional less frequent complications include specific developmental defects and a predisposition to embryonal tumors. The disease is caused by variants affecting the gene represented in this entry. Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies (IMAGE) [MIM:614732] A rare condition characterized by intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies. Patients with this condition may present shortly after birth with severe adrenal insufficiency, which can be life-threatening if not recognized early and commenced on steroid replacement therapy. Other reported features in this condition include, hypercalciuria and/or hypercalcemia, craniosynostosis, cleft palate, and scoliosis. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Paternally imprinted, therefore most expression comes from the maternal allele.

Similarity. Belongs to the CDI family.

Isoforms (2)

UniProt ID	Names	Canonical?
P49918-1	Long	yes
P49918-2	Short

RefSeq proteins (5): NP_000067, NP_001116102, NP_001116103, NP_001349403, NP_001349404 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003175	CDI_dom	Domain
IPR044898	CDI_dom_sf	Homologous_superfamily

Pfam: PF02234

UniProt features (37 total): sequence variant 15, repeat 9, region of interest 4, compositionally biased region 4, modified residue 2, chain 1, short sequence motif 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49918-F1	63.93	0.17

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 (2): 107, 268

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-69231	Cyclin D associated events in G1
R-HSA-9661069	Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)
R-HSA-1640170	Cell Cycle
R-HSA-1643685	Disease
R-HSA-453279	Mitotic G1 phase and G1/S transition
R-HSA-69236	G1 Phase
R-HSA-69278	Cell Cycle, Mitotic
R-HSA-9659787	Aberrant regulation of mitotic G1/S transition in cancer due to RB1 defects
R-HSA-9675126	Diseases of mitotic cell cycle
R-HSA-9687139	Aberrant regulation of mitotic cell cycle due to RB1 defects

MSigDB gene sets: 609 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GOBP_MYELOID_CELL_DIFFERENTIATION, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, FLECHNER_PBL_KIDNEY_TRANSPLANT_REJECTED_VS_OK_UP, GOBP_LENS_FIBER_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, FREAC2_01, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, YAO_HOXA10_TARGETS_VIA_PROGESTERONE_UP, PEREZ_TP63_TARGETS, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_NEURON_MATURATION

GO Biological Process (24): negative regulation of transcription by RNA polymerase II (GO:0000122), skeletal system development (GO:0001501), kidney development (GO:0001822), regulation of exit from mitosis (GO:0007096), myeloid cell differentiation (GO:0030099), adrenal gland development (GO:0030325), positive regulation of transforming growth factor beta receptor signaling pathway (GO:0030511), multicellular organism growth (GO:0035264), neuron maturation (GO:0042551), camera-type eye development (GO:0043010), negative regulation of mitotic cell cycle (GO:0045930), negative regulation of epithelial cell proliferation (GO:0050680), digestive system development (GO:0055123), uterus development (GO:0060065), embryonic placenta morphogenesis (GO:0060669), genomic imprinting (GO:0071514), regulation of lens fiber cell differentiation (GO:1902746), placenta development (GO:0001890), negative regulation of kinase activity (GO:0033673), negative regulation of phosphorylation (GO:0042326), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), regulation of cell cycle (GO:0051726), negative regulation of cyclin-dependent protein kinase activity (GO:1904030)

GO Molecular Function (5): cyclin-dependent protein serine/threonine kinase inhibitor activity (GO:0004861), protein-containing complex binding (GO:0044877), molecular function inhibitor activity (GO:0140678), protein kinase inhibitor activity (GO:0004860), protein binding (GO:0005515)

GO Cellular Component (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
G1 Phase	1
Aberrant regulation of mitotic G1/S transition in cancer due to RB1 defects	1
Cell Cycle, Mitotic	1
Mitotic G1 phase and G1/S transition	1
Cell Cycle	1
Aberrant regulation of mitotic cell cycle due to RB1 defects	1
Disease	1
Diseases of mitotic cell cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
animal organ development	3
system development	2
binding	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
renal system development	1
exit from mitosis	1
regulation of mitotic cell cycle phase transition	1
hemopoiesis	1
cell differentiation	1
endocrine system development	1
gland development	1
transforming growth factor beta receptor signaling pathway	1
regulation of transforming growth factor beta receptor signaling pathway	1
positive regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
positive regulation of cellular response to transforming growth factor beta stimulus	1
multicellular organismal process	1
developmental growth	1
cell maturation	1
neuron development	1
eye development	1
mitotic cell cycle	1
regulation of mitotic cell cycle	1
negative regulation of cell cycle	1
negative regulation of cell population proliferation	1
epithelial cell proliferation	1
regulation of epithelial cell proliferation	1
reproductive structure development	1
embryonic placenta development	1
embryonic morphogenesis	1
germ cell development	1
epigenetic programming of gene expression	1
regulation of epithelial cell differentiation	1
lens fiber cell differentiation	1
kinase activity	1
negative regulation of phosphorylation	1
negative regulation of catalytic activity	1
regulation of kinase activity	1
phosphorylation	1

Protein interactions and networks

STRING

2148 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CDKN1C	CDK2	P24941	970
CDKN1C	PHLDA2	Q53GA4	928
CDKN1C	CCNA2	P20248	928
CDKN1C	KCNQ1	P51787	918
CDKN1C	IGF2	P01344	903
CDKN1C	SLC67A1	Q96BI1	890
CDKN1C	CCNA1	P78396	882
CDKN1C	CDK6	Q00534	782
CDKN1C	CIB1	Q99828	781
CDKN1C	CDK4	P11802	780
CDKN1C	ASCL2	Q99929	768
CDKN1C	CDKN2D	P55273	764
CDKN1C	BMP10	O95393	762
CDKN1C	DYNC1I2	Q13409	759
CDKN1C	CCNL2	Q96S94	754

IntAct

41 interactions, top by confidence:

A	B	Type	Score
CCND1	CDK4	psi-mi:“MI:0914”(association)	0.990
CCND3	CDK4	psi-mi:“MI:0914”(association)	0.980
CCND2	CDK4	psi-mi:“MI:0914”(association)	0.960
CDK2	CCNE2	psi-mi:“MI:0914”(association)	0.940
CCND1	CDK2	psi-mi:“MI:0914”(association)	0.880
CDK2	CCNB2	psi-mi:“MI:0914”(association)	0.860
CDK1	CCNB2	psi-mi:“MI:0914”(association)	0.840
CCNB2	CDKN1B	psi-mi:“MI:0914”(association)	0.670
CCND3	CDK1	psi-mi:“MI:0914”(association)	0.640
CCNA2	GMNN	psi-mi:“MI:0914”(association)	0.640
CCND1	CDK1	psi-mi:“MI:0914”(association)	0.640
CDK2	GMNN	psi-mi:“MI:0914”(association)	0.640
CDK4	CDKN1C	psi-mi:“MI:0915”(physical association)	0.560
CDK6	CCNT1	psi-mi:“MI:0914”(association)	0.530
CDK3	GMNN	psi-mi:“MI:0914”(association)	0.530
CDK4	GUSB	psi-mi:“MI:0914”(association)	0.530
CDK1	GMNN	psi-mi:“MI:0914”(association)	0.530
MCM7	CDKN1C	psi-mi:“MI:0915”(physical association)	0.530
MCM7	CDKN1C	psi-mi:“MI:0407”(direct interaction)	0.530
CDKN1C	FBXL12	psi-mi:“MI:0915”(physical association)	0.520
FBXL12	CDKN1C	psi-mi:“MI:0915”(physical association)	0.520

BioGRID (86): CDKN1C (Biochemical Activity), AKT1 (Affinity Capture-Western), CDKN1C (Affinity Capture-Western), CDKN1C (Biochemical Activity), CDKN1C (Affinity Capture-MS), CDKN1C (Affinity Capture-MS), CDKN1C (Affinity Capture-MS), CDKN1C (Affinity Capture-MS), CDKN1C (Affinity Capture-MS), CDKN1C (Affinity Capture-MS), CDKN1C (Affinity Capture-MS), CDKN1C (Affinity Capture-MS), CDKN1C (Affinity Capture-MS), CDKN1C (Affinity Capture-MS), LIMK1 (Two-hybrid)

ESM2 similar proteins: A2AI08, A5D7L8, D3YXK1, O08550, O18805, O19002, O35613, O35615, P38936, P39689, P49918, P49919, Q07266, Q0D2K3, Q1LZD3, Q1W1Y5, Q2WG77, Q4FZU8, Q4KMQ1, Q4R5U8, Q5I034, Q5TJE1, Q5XHX2, Q68DK7, Q6PAN7, Q6PDM1, Q6SPE9, Q6SPF0, Q6ZS17, Q7TSX9, Q7TT28, Q80VC9, Q80Y50, Q8BG26, Q8BLS7, Q8CHM3, Q8IZL8, Q8N1G1, Q8VIB2, Q96BT3

Diamond homologs: O19001, O19002, P38936, P39689, P46414, P46527, P46529, P49918, P49919, Q60439, Q6SLL5

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
MAPK14	up-regulates	CDKN1C	phosphorylation
AKT	down-regulates	CDKN1C	phosphorylation
AKT1	down-regulates	CDKN1C	phosphorylation
VHL	“up-regulates quantity by expression”	CDKN1C	“transcriptional regulation”
HLX	“up-regulates quantity by expression”	CDKN1C	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 24 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
Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)	8	230.7×	2e-16
Aberrant regulation of mitotic cell cycle due to RB1 defects	8	148.3×	6e-15
TP53 Regulates Transcription of Cell Cycle Genes	6	148.3×	3e-11
G1 Phase	8	143.2×	6e-15
Diseases of mitotic cell cycle	8	143.2×	6e-15
Mitotic G1 phase and G1/S transition	12	100.5×	4e-20
G1/S Transition	9	95.3×	6e-15
Cyclin D associated events in G1	8	84.8×	5e-13

GO biological processes:

GO term	Partners	Fold	FDR
G1/S transition of mitotic cell cycle	13	113.4×	1e-22
cell division	13	26.1×	3e-14
DNA damage response	5	11.6×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1280 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	104
Likely pathogenic	20
Uncertain significance	589
Likely benign	484
Benign	4

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070416	NM_001122630.2(CDKN1C):c.199C>T (p.Gln67Ter)	Pathogenic
1071226	NM_001122630.2(CDKN1C):c.399_415del (p.Ala134fs)	Pathogenic
1071455	NM_001122630.2(CDKN1C):c.325G>T (p.Glu109Ter)	Pathogenic
1072486	NM_001122630.2(CDKN1C):c.203G>A (p.Trp68Ter)	Pathogenic
1074899	NM_001122630.2(CDKN1C):c.95_96insA (p.Ser32fs)	Pathogenic
1076545	NM_001122630.2(CDKN1C):c.748_749del (p.Gly250fs)	Pathogenic
132848	NM_001122630.2(CDKN1C):c.300dup (p.Ala101fs)	Pathogenic
132850	NM_001122630.2(CDKN1C):c.367dup (p.Glu123fs)	Pathogenic
132860	NM_001122630.2(CDKN1C):c.643C>T (p.Gln215Ter)	Pathogenic
132861	NM_001122630.2(CDKN1C):c.655C>T (p.Gln219Ter)	Pathogenic
132862	NM_001122630.2(CDKN1C):c.670C>T (p.Gln224Ter)	Pathogenic
132864	NM_001122630.2(CDKN1C):c.688C>T (p.Gln230Ter)	Pathogenic
132866	NM_001122630.2(CDKN1C):c.698C>A (p.Ser233Ter)	Pathogenic
1372013	NM_001122630.2(CDKN1C):c.193_200dup (p.Gln67fs)	Pathogenic
1372071	NM_001122630.2(CDKN1C):c.205del (p.Thr69fs)	Pathogenic
1374542	NM_001122630.2(CDKN1C):c.745_757del (p.Asn249fs)	Pathogenic
1379126	NM_001122630.2(CDKN1C):c.60_61del (p.Ser21fs)	Pathogenic
1391208	NM_001122630.2(CDKN1C):c.809_810del (p.Arg270fs)	Pathogenic
1396638	NM_001122630.2(CDKN1C):c.204G>A (p.Trp68Ter)	Pathogenic
1401271	NM_001122630.2(CDKN1C):c.244G>T (p.Glu82Ter)	Pathogenic
1402309	NM_001122630.2(CDKN1C):c.578del (p.Pro193fs)	Pathogenic
1417762	NM_001122630.2(CDKN1C):c.410del (p.Pro137fs)	Pathogenic
143246	NM_001122630.2(CDKN1C):c.*5+2T>C	Pathogenic
1454485	NC_000011.9:g.(?2905228)(2906725_?)del	Pathogenic
1454500	NM_001122630.2(CDKN1C):c.132del (p.Glu45fs)	Pathogenic
1455010	NM_001122630.2(CDKN1C):c.133G>T (p.Glu45Ter)	Pathogenic
1455648	NM_001122630.2(CDKN1C):c.174dup (p.Pro59fs)	Pathogenic
1455977	NM_001122630.2(CDKN1C):c.421_422insA (p.Pro141fs)	Pathogenic
1708131	NM_001122630.2(CDKN1C):c.832_835delinsCTGCGCCTGA (p.Gly278_Asp279delinsLeuArgLeuAsn)	Pathogenic
18446	NM_001122630.2(CDKN1C):c.812C>A (p.Ser271Ter)	Pathogenic

SpliceAI

424 predictions. Top by Δscore:

Variant	Effect	Δscore
11:2883995:TCAC:T	donor_loss	1.0000
11:2883996:CACTT:C	donor_loss	1.0000
11:2883997:A:AC	donor_gain	1.0000
11:2883997:ACTT:A	donor_loss	1.0000
11:2883998:C:CT	donor_gain	1.0000
11:2883998:CTTGG:C	donor_gain	1.0000
11:2883798:CG:C	donor_gain	0.9900
11:2883798:CGCTG:C	donor_gain	0.9900
11:2883991:GTACT:G	donor_loss	0.9900
11:2883992:TACT:T	donor_loss	0.9900
11:2883993:ACTC:A	donor_loss	0.9900
11:2883994:CTCA:C	donor_gain	0.9900
11:2883998:CT:C	donor_gain	0.9900
11:2883990:TGTAC:T	donor_loss	0.9800
11:2883998:CTT:C	donor_gain	0.9800
11:2883998:CTTG:C	donor_gain	0.9800
11:2883792:A:C	donor_gain	0.9700
11:2883828:TGC:T	donor_gain	0.9700
11:2884664:GCTCA:G	donor_loss	0.9700
11:2884665:CTCA:C	donor_loss	0.9700
11:2884666:TCA:T	donor_loss	0.9700
11:2884667:CA:C	donor_loss	0.9700
11:2884668:A:AT	donor_loss	0.9700
11:2883797:A:C	donor_gain	0.9600
11:2883911:CTAAA:C	acceptor_gain	0.9600
11:2883993:A:AC	donor_gain	0.9600
11:2883994:C:CC	donor_gain	0.9600
11:2884132:AATCT:A	acceptor_loss	0.9600
11:2884133:ATC:A	acceptor_loss	0.9600
11:2884134:TCTG:T	acceptor_loss	0.9600

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000071892 (11:2886205 A>C), RS1000373562 (11:2884316 C>G), RS1000851334 (11:2886514 A>G), RS1001326354 (11:2886581 T>G), RS1002372400 (11:2885567 C>A,T), RS1002947962 (11:2887594 C>T), RS1003077907 (11:2887257 G>C,T), RS1003549223 (11:2886873 G>A), RS1005267880 (11:2887553 TC>T), RS1005463139 (11:2883629 TTTTC>T), RS1007312392 (11:2884544 C>G), RS1007467250 (11:2885618 G>A), RS1008355932 (11:2886545 C>T), RS1008606799 (11:2885226 G>A,T), RS1008694306 (11:2886740 G>A)

Disease associations

OMIM: gene MIM:600856 | disease phenotypes: MIM:130650, MIM:614732, MIM:180860

GenCC curated gene-disease

Disease	Classification	Inheritance
Beckwith-Wiedemann syndrome	Definitive	Autosomal dominant
IMAGe syndrome	Definitive	Autosomal dominant
rhabdomyosarcoma	Moderate	Autosomal dominant
Beckwith-Wiedemann syndrome due to CDKN1C mutation	Supportive	Autosomal dominant
intrauterine growth restriction-short stature-early adult-onset diabetes syndrome	Supportive	Autosomal dominant
Silver-Russell syndrome	Limited	Autosomal dominant

Mondo (7): Beckwith-Wiedemann syndrome (MONDO:0007534), IMAGe syndrome (MONDO:0013873), Silver-Russell syndrome 1 (MONDO:0020796), Beckwith-Wiedemann syndrome due to CDKN1C mutation (MONDO:0016476), Silver-Russell syndrome (MONDO:0008394), rhabdomyosarcoma (MONDO:0005212), intrauterine growth restriction-short stature-early adult-onset diabetes syndrome (MONDO:0018573)

Orphanet (4): Beckwith-Wiedemann syndrome (Orphanet:116), IMAGe syndrome (Orphanet:85173), Silver-Russell syndrome (Orphanet:813), Beckwith-Wiedemann syndrome due to CDKN1C mutation (Orphanet:231120)

HPO phenotypes

89 total (30 of 89 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000045	Abnormal scrotum morphology
HP:0000047	Hypospadias
HP:0000048	Bifid scrotum
HP:0000054	Micropenis
HP:0000076	Vesicoureteral reflux
HP:0000078	Abnormality of the genital system
HP:0000105	Enlarged kidney
HP:0000121	Nephrocalcinosis
HP:0000126	Hydronephrosis
HP:0000135	Hypogonadism
HP:0000150	Gonadoblastoma
HP:0000158	Macroglossia
HP:0000175	Cleft palate
HP:0000239	Large fontanelles
HP:0000256	Macrocephaly
HP:0000269	Prominent occiput
HP:0000280	Coarse facial features
HP:0000325	Triangular face
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000520	Proptosis
HP:0000750	Delayed speech and language development
HP:0000787	Nephrolithiasis
HP:0000803	Renal cortical cysts
HP:0000821	Hypothyroidism
HP:0000824	Decreased response to growth hormone stimulation test
HP:0000835	Adrenal hypoplasia

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST000769_7	Calcium levels	5.000000e-06
GCST008362_122	Birth weight	6.000000e-09
GCST010725_20	Malaria	4.000000e-69
GCST010725_33	Malaria	2.000000e-67
GCST010725_51	Malaria	1.000000e-55
GCST90014023_31	Type 1 diabetes	4.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004838	calcium measurement
EFO:0004344	birth weight

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D001506	Beckwith-Wiedemann Syndrome	C16.131.077.133; C16.131.260.080; C16.320.180.080; C16.320.447.375
D012208	Rhabdomyosarcoma	C04.557.450.590.550.660; C04.557.450.795.550.660
D056730	Silver-Russell Syndrome	C05.660.207.925; C16.131.077.855; C16.131.260.870; C16.320.180.870; C16.320.240.937; C16.320.447.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects cotreatment, decreases expression, increases expression	7
Valproic Acid	increases expression, increases methylation, affects expression, decreases expression	6
(+)-JQ1 compound	affects cotreatment, decreases reaction, increases cleavage, decreases expression, increases expression	4
Decitabine	affects expression, affects methylation, increases expression, affects cotreatment	4
Vorinostat	affects cotreatment, decreases reaction, increases cleavage, increases expression, decreases expression	4
bisphenol A	increases expression, increases methylation, affects cotreatment	3
Benzo(a)pyrene	decreases expression, increases expression, affects methylation	3
Copper	increases expression, affects binding, decreases expression	3
Oxygen	increases expression	3
Smoke	increases abundance, increases expression, decreases expression	3
methylmercuric chloride	decreases expression, increases expression	2
methylselenic acid	affects expression, increases expression	2
trichostatin A	affects cotreatment, increases expression, decreases expression	2
dinophysistoxin 1	increases expression	2
Resveratrol	increases expression	2
Acetaminophen	increases expression, affects expression	2
Air Pollutants	increases expression, decreases expression, increases abundance	2
Atrazine	affects cotreatment, increases expression	2
Dexamethasone	increases expression, affects cotreatment	2
Hydrogen Peroxide	affects expression	2
Nickel	decreases expression	2
Quercetin	increases expression	2
Silicon Dioxide	decreases expression, increases expression	2
Tobacco Smoke Pollution	increases expression, increases methylation	2
Tretinoin	decreases expression	2
Zinc	affects cotreatment, affects expression, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
Cadmium Chloride	increases expression	2
Genistein	decreases expression, increases expression	2
tert-Butylhydroperoxide	affects cotreatment, increases expression, decreases reaction, affects binding, increases reaction (+1 more)	2

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8DI	Abcam HCT 116 CDKN1C KO	Cancer cell line	Male
CVCL_B9FR	Abcam A-549 CDKN1C KO	Cancer cell line	Male
CVCL_B9VF	Abcam HeLa CDKN1C KO	Cancer cell line	Female
CVCL_D2EC	Abcam MCF-7 CDKN1C KO	Cancer cell line	Female
CVCL_SI57	HAP1 CDKN1C (-) 1	Cancer cell line	Male
CVCL_XM69	HAP1 CDKN1C (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00339118	PHASE4	UNKNOWN	EpSSG (European Soft Tissue Sarcoma Study Group) Protocol for Non-Metastatic Rhabdomyosarcoma in Children
NCT04854018	PHASE4	COMPLETED	Indo-cyanine Green (ICG) in Paediatric Oncology MIS
NCT06457906	PHASE3	RECRUITING	SRS/SRT/Hypo-RT Versus HA-WBRT for No More Than 10 Brain Metastases in SCLC
NCT00945009	PHASE3	ACTIVE_NOT_RECRUITING	Combination Chemotherapy and Surgery in Treating Young Patients With Wilms Tumor
NCT00162695	PHASE3	TERMINATED	Rhabdomyosarcoma and Malignant Soft Tissue Tumours of Childhood
NCT00354835	PHASE3	COMPLETED	Combination Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Rhabdomyosarcoma
NCT02567435	PHASE3	ACTIVE_NOT_RECRUITING	Combination Chemotherapy With or Without Temsirolimus in Treating Patients With Intermediate Risk Rhabdomyosarcoma
NCT04994132	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Compare Early Use of Vinorelbine and Maintenance Therapy for Patients With High Risk Rhabdomyosarcoma
NCT06836492	PHASE3	RECRUITING	A Prospective Clinical Cohort Study on Stratified Treatment of Rhabdomyosarcoma Based on Risk Factors.
NCT07466316	PHASE3	NOT_YET_RECRUITING	A Study Comparing Higher Dose Chemotherapy Over a Shorter Amount of Time to Lower Dose Chemotherapy Plus Maintenance Over a Longer Amount of Time in Patients With Newly Diagnosed Intermediate-Risk Rhabdomyosarcoma (IR RMS)
NCT04180501	PHASE2	UNKNOWN	SRS Sequential Sindilimab in Brain Metastasis of NSLSC
NCT04899908	PHASE2	ACTIVE_NOT_RECRUITING	Stereotactic Brain-directed Radiation With or Without Aguix Gadolinium-Based Nanoparticles in Brain Metastases
NCT07162246	PHASE2	RECRUITING	Combined Gamma Knife/Linac Radiosurgery for Large Brain Tumors / Metastases
NCT00001335	PHASE2	COMPLETED	New Therapeutic Strategies for Patients With Ewing’s Sarcoma Family of Tumors, High Risk Rhabdomyosarcoma, and Neuroblastoma
NCT00001564	PHASE2	COMPLETED	A Pilot Study of Tumor-Specific Peptide Vaccination and IL-2 With or Without Autologous T Cell Transplantation in Recurrent Pediatric Sarcomas
NCT00001566	PHASE2	COMPLETED	A Pilot Study of Autologous T-Cell Transplantation With Vaccine Driven Expansion of Anti-Tumor Effectors After Cytoreductive Therapy in Metastatic Pediatric Sarcomas
NCT00180947	PHASE2	UNKNOWN	Study of Vinorelbine and Cyclofosfamide Among Patients With Refractory Tumours or in Relapse
NCT00186992	PHASE2	ACTIVE_NOT_RECRUITING	Radiation Therapy to Treat Musculoskeletal Tumors
NCT00464620	PHASE2	COMPLETED	Trial of Dasatinib in Advanced Sarcomas
NCT00520936	PHASE2	COMPLETED	A Study of Pemetrexed in Children With Recurrent Cancer
NCT00668148	PHASE2	COMPLETED	A Five-Tier, Open-Label Study of IMC-A12 in Advanced Sarcoma
NCT00840047	PHASE2	ACTIVE_NOT_RECRUITING	Methionine PET/CT Studies In Patients With Cancer
NCT01336803	PHASE2	COMPLETED	Differentiation of Bone Sarcomas and Osteomyelitis With Ferumoxytol-Enhanced MRI
NCT01355445	PHASE2	COMPLETED	Vincristine and Irinotecan With or Without Temozolomide in Children and Adults With Refractory/Relapsed Rhabdomyosarcoma
NCT01614795	PHASE2	COMPLETED	Cixutumumab and Temsirolimus in Treating Younger Patients With Recurrent or Refractory Sarcoma
NCT01807468	PHASE2	UNKNOWN	Haploidentical Stem Cell Transplantation and NK Cell Therapy in Patients With High-risk Solid Tumors
NCT01871766	PHASE2	ACTIVE_NOT_RECRUITING	Risk-Adapted Focal Proton Beam Radiation and/or Surgery in Patients With Low, Intermediate and High Risk Rhabdomyosarcoma Receiving Standard or Intensified Chemotherapy
NCT02011126	PHASE2	WITHDRAWN	Imetelstat Sodium in Treating Younger Patients With Relapsed or Refractory Solid Tumors
NCT02048371	PHASE2	COMPLETED	SARC024: A Blanket Protocol to Study Oral Regorafenib in Patients With Selected Sarcoma Subtypes
NCT02100891	PHASE2	TERMINATED	Phase 2 STIR Trial: Haploidentical Transplant and Donor Natural Killer Cells for Solid Tumors
NCT02452554	PHASE2	COMPLETED	Lorvotuzumab Mertansine in Treating Younger Patients With Relapsed or Refractory Wilms Tumor, Rhabdomyosarcoma, Neuroblastoma, Pleuropulmonary Blastoma, Malignant Peripheral Nerve Sheath Tumor, or Synovial Sarcoma
NCT02509598	PHASE2	COMPLETED	A Study of Lymphoseek® as a Lymphoid Tissue Targeting Agent in Pediatric Patients With Melanoma, Rhabdomyosarcoma, or Other Solid Tumors Who Are Undergoing Lymph Node Mapping
NCT02624388	PHASE2	TERMINATED	Study of Genistein in Pediatric Oncology Patients (UVA-Gen001)
NCT02689336	PHASE2	WITHDRAWN	Erlotinib in Combination With Temozolomide in Treating Relapsed/Recurrent/Refractory Pediatric Solid Tumors
NCT02867592	PHASE2	ACTIVE_NOT_RECRUITING	Cabozantinib-S-Malate in Treating Younger Patients With Recurrent, Refractory, or Newly Diagnosed Sarcomas, Wilms Tumor, or Other Rare Tumors
NCT02945800	PHASE2	COMPLETED	Nab-Paclitaxel and Gemcitabine for Recurrent/Refractory Sarcoma
NCT03155620	PHASE2	ACTIVE_NOT_RECRUITING	Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
NCT03213652	PHASE2	ACTIVE_NOT_RECRUITING	Ensartinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With ALK or ROS1 Genomic Alterations (A Pediatric MATCH Treatment Trial)
NCT03213665	PHASE2	COMPLETED	Tazemetostat in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With EZH2, SMARCB1, or SMARCA4 Gene Mutations (A Pediatric MATCH Treatment Trial)
NCT03213678	PHASE2	COMPLETED	Samotolisib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With TSC or PI3K/MTOR Mutations (A Pediatric MATCH Treatment Trial)