CDKN2C

Summary

CDKN2C (cyclin dependent kinase inhibitor 2C, HGNC:1789) is a protein-coding gene on chromosome 1p32.3, encoding Cyclin-dependent kinase 4 inhibitor C (P42773). Interacts strongly with CDK6, weakly with CDK4.

The protein encoded by this gene is a member of the INK4 family of cyclin-dependent kinase inhibitors. This protein has been shown to interact with CDK4 or CDK6, and prevent the activation of the CDK kinases, thus function as a cell growth regulator that controls cell cycle G1 progression. Ectopic expression of this gene was shown to suppress the growth of human cells in a manner that appears to correlate with the presence of a wild-type RB1 function. Studies in the knockout mice suggested the roles of this gene in regulating spermatogenesis, as well as in suppressing tumorigenesis. Two alternatively spliced transcript variants of this gene, which encode an identical protein, have been reported.

Source: NCBI Gene 1031 — RefSeq curated summary.

At a glance

• GWAS associations: 32
• Clinical variants (ClinVar): 33 total — 1 likely-pathogenic
• Cancer driver (intOGen): activating (oncogene-like) across 3 cancer types
• MANE Select transcript: NM_078626

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1789
Approved symbol	CDKN2C
Name	cyclin dependent kinase inhibitor 2C
Location	1p32.3
Locus type	gene with protein product
Status	Approved
Aliases	INK4C, p18
Ensembl gene	ENSG00000123080
Ensembl biotype	protein_coding
OMIM	603369
Entrez	1031

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000262662, ENST00000371761, ENST00000396148, ENST00000855560, ENST00000855561

RefSeq mRNA: 3 — MANE Select: NM_078626 NM_001262, NM_001429675, NM_078626

CCDS: CCDS555

Canonical transcript exons

ENST00000371761 — 2 exons

Exon	Start	End
ENSE00001456048	50973893	50974634
ENSE00001456052	50970245	50970497

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 93.97.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.7593 / max 735.0411, expressed in 1501 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
2828	8.2809	937
2822	3.1721	851
2824	2.2935	777
2819	1.8635	662
2821	0.9421	420
2823	0.6898	313
2827	0.6833	368
2818	0.2757	132
2820	0.2304	108
2826	0.1786	65

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	93.97	gold quality
popliteal artery	UBERON:0002250	93.63	gold quality
tibial artery	UBERON:0007610	93.62	gold quality
adipose tissue	UBERON:0001013	93.51	gold quality
trabecular bone tissue	UBERON:0002483	93.39	gold quality
connective tissue	UBERON:0002384	93.23	gold quality
adipose tissue of abdominal region	UBERON:0007808	93.03	gold quality
omental fat pad	UBERON:0010414	92.75	gold quality
peritoneum	UBERON:0002358	92.72	gold quality
superficial temporal artery	UBERON:0001614	92.44	gold quality
right coronary artery	UBERON:0001625	92.31	gold quality
subcutaneous adipose tissue	UBERON:0002190	91.52	gold quality
aorta	UBERON:0000947	91.34	gold quality
left coronary artery	UBERON:0001626	91.32	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.27	gold quality
thoracic mammary gland	UBERON:0005200	90.82	gold quality
coronary artery	UBERON:0001621	90.77	gold quality
left ovary	UBERON:0002119	90.65	gold quality
mammary gland	UBERON:0001911	90.58	gold quality
thymus	UBERON:0002370	90.39	gold quality
descending thoracic aorta	UBERON:0002345	90.29	gold quality
lower esophagus muscularis layer	UBERON:0035833	90.17	gold quality
lower esophagus	UBERON:0013473	90.15	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	90.07	gold quality
olfactory bulb	UBERON:0002264	90.06	gold quality
ganglionic eminence	UBERON:0004023	89.98	gold quality
right ovary	UBERON:0002118	89.97	gold quality
bone element	UBERON:0001474	89.53	gold quality
smooth muscle tissue	UBERON:0001135	89.42	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	89.37	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.51
E-GEOD-99795	no	96.35

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DNMT3A, E2F1, E2F4, ESR1, FOXC1, GATA3, GLI3, KLF1, MAFK, MEN1, NR4A2, RUNX1, SP1, YY1

miRNA regulators (miRDB)

31 targeting CDKN2C, 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-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-609	99.82	64.26	505
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-5580-3P	99.70	69.41	2052
HSA-MIR-4804-3P	99.65	67.78	866
HSA-MIR-657	99.48	66.02	848
HSA-MIR-4666A-5P	99.41	69.72	1887
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-892C-5P	99.16	70.56	2116
HSA-MIR-6074	98.89	69.64	2187
HSA-MIR-5000-3P	98.79	65.63	1251
HSA-MIR-3161	98.71	67.14	816
HSA-MIR-4720-3P	98.50	68.88	988
HSA-MIR-676-5P	98.49	68.87	1492
HSA-MIR-4773	98.35	67.30	1710
HSA-MIR-4436A	98.05	64.83	1140
HSA-MIR-4275	97.96	68.42	1549
HSA-MIR-10526-3P	97.86	64.97	1342
HSA-MIR-101-5P	96.84	65.66	649

Literature-anchored findings (GeneRIF, showing 40)

• conclude that E2F proteins and Sp1 play an important role in the control of p18 expression (PMID:12077144)
• Deletions in the CDKN2C locus and hypermethylation in the CDKN2C promoter region play a role in ovarian granulosa cell tumorogenesis. (PMID:12203782)
• Inhibitor shows antitumor effect on glioma cells. (PMID:12698196)
• p18INK4c may function as a tumor suppressor in Hodgkin lymphoma, and inactivation may contribute to cell cycle deregulation and defective terminal differentiation of the Reed-Sternberg cells. (PMID:14645011)
• protein kinase C promotes human cancer cell growth through downregulation of p18(INK4c) (PMID:15107819)
• p18(INK4C) loss may contribute to medulloblastoma formation in children (PMID:16260494)
• Transfer of the p16(INK4a) and p18(INK4c) genes and CDK4I suppressed the production of MMP-3 and MCP-1. (PMID:16802342)
• data suggest that p27 and p18 are unlikely to present classic tumor-suppressor genes in sporadic pancreatic endocrine tumors (PMID:17710155)
• Expression of p15, p18 and p27 was not generally related to the MEN1 gene mutational status of the investigated 18 pancreatic endocrine tumours. (PMID:17803708)
• oncogenic RET and loss of p18 cooperate in the multistep tumorigenesis of medullary thyroid carcinoma (PMID:18316595)
• These findings uncover a feedback regulatory circuit in the astrocytic lineage and demonstrate tumor suppressor role for p18(INK4C) in human glioblastoma wherein it functions cooperatively with other INK4 family. (PMID:18394558)
• NaBu-mediated p18( INK4C ) regulation played a role in cell cycle arrest and erythroid differentiation in K562 cells. (PMID:18642058)
• deletions of CDKN2C are important in the progression and clinical outcome of myeloma (PMID:18829482)
• P18 is a tumor suppressor gene involved in human medullary thyroid carcinoma and pheochromocytoma (PMID:18942719)
• Purpose was to investigate genetic alterations of CDKN2C gene in 38 pituitary adenomas. The absence of CDKN2C protein was correlated with LOH of the CDKN2C locus on chromosome 1 and with methylation of the CDKN2C promoter. (PMID:18973139)
• The down-regulation of p18(INK4C) expression may contribute to the tumorigenesis of pituitary adenomas. (PMID:19401813)
• p18(INK4C) is a downstream target of GATA3, constrains luminal progenitor cell expansion, and suppresses luminal tumorigenesis in the mammary gland (PMID:19411068)
• Results identified a molecular basis for CDK inhibitors to exert an antitumor effect in p18-deficient cancers and support the clinical use of CDK inhibitors. (PMID:19509251)
• review presents the recent advances in MEN-4 and other multiple endocrine neoplasias and summarises the current knowledge of how P27KIP1 and p18-INK4C may be implicated in endocrine neoplasia [review] (PMID:20833334)
• results demonstrate for the first time that N-Myc is a downstream target of RET2A signaling, and propose that induction of N-Myc by RET2A is a key step leading to lower p18 levels during MEN2A tumorigenesis (PMID:21112821)
• Data indicate that the role of CDKN2C in the adverse outcome of cases with hemizygous deletion was less certain. (PMID:21994415)
• propose that the contrasting behavior of the two very similar INK4 proteins could reflect their respective roles in senescence versus differentiation (PMID:22080569)
• up-regulated HULC promotes proliferation of hepatoma cells through suppressing p18 (PMID:22685290)
• Analysis of B1a lymphocyte phenotypes of p18-deficient C57BL/6 mice finds that p18 is a key regulator of the size of the B1a cell pool. (PMID:22896639)
• in 85 sporadic parathyroid adenomas, study identified alterations in 5 adenomas: 2 contained heterozygous changes in CDKN1A, 1 germline and 1 of undetermined germline status; 1 had a CDKN2B germline alteration, accompanied by loss of the normal allele in the tumor (LOH); 2 had variants of CDKN2C, 1 somatic and 1 germline with LOH (PMID:23715670)
• this studydemonstrated abundant levels of the critical negative cell-cycle regulators, p27(Kip1), its phosphorylated form, p-p27(S10), p18Ink4c, and GSK-3, in beta-cells of both adult human and mouse pancreatic islets, which contribute to maintenance of beta-cell quiescence. (PMID:23896637)
• Mutations in CDKN2C is associated with sporadic parathyroid adenoma. (PMID:24127162)
• DNA methyltransferase 3A promotes cell proliferation by silencing CDK inhibitor p18INK4C in gastric carcinogenesis (PMID:26350239)
• Data suggest that cell cycle-dependent kinase inhibitors CDKN2C/p18 and CDKN1A/p21 facilitate cell cycle entry/cell proliferation of quiescent adult human pancreatic beta cells in primary culture (from tissues obtained from organ donors). (PMID:26740620)
• The differences in p18(INK4c)and p57(Kip2)activities in chronic myeloid leukemia and normal stem cells suggest a different cell cycle regulation. (PMID:26985855)
• Our study suggests that p18 is a limiting factor for the noncanonical HSC differentiation path in lymphoid lineages. (PMID:27287689)
• genetic association studies in population in Houston TX: Data suggest that CDKN2C copy number variations are associated with sporadic medullary thyroid carcinoma; these associations include presence of distant metastasis at presentation and decreased overall survival. (PMID:27610696)
• CDKN2C gene deletion is associated with plasma cell post-transplantation lymphoproliferative disorders. (PMID:27750397)
• CDKN2C inactivation contributes to the leukemogenesis in acute promyelocytic leukemia. (PMID:27888400)
• Cycling hypoxia could induce significant changes in CLDN1 and CLDN7 expression in nasopharyngeal cancer cells, indirectly regulation P18 expression and affecting cell invasion/proliferation. (PMID:28055967)
• Low P18 expression is associated with multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors. (PMID:29134609)
• an oncogenic role for the protein lysine methyltransferase SETDB2 in leukemia pathogenesis. It is overexpressed in pre-BCR(+) ALL and required for their maintenance in vitro and in vivo. SETDB2 expression is maintained as a direct target gene of the chimeric transcription factor E2A-PBX1 in a subset of ALL and suppresses expression of the cell-cycle inhibitor CDKN2C through histone H3K9 tri-methylation. (PMID:29694893)
• miR-21-5p promotes cell proliferation and G1/S transition in melanoma by targeting CDKN2C. (PMID:32090490)
• MCL1 binding to the reverse BH3 motif of P18INK4C couples cell survival to cell proliferation. (PMID:32111816)
• A genome-wide gain-of-function screen identifies CDKN2C as a HBV host factor. (PMID:32483149)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cdkn2c	ENSDARG00000057610
mus_musculus	Cdkn2c	ENSMUSG00000028551
rattus_norvegicus	Cdkn2c	ENSRNOG00000008956

Paralogs (2): CDKN2D (ENSG00000129355), ANKRD39 (ENSG00000213337)

Protein

Protein identifiers

Cyclin-dependent kinase 4 inhibitor C — P42773 (reviewed: P42773)

Alternative names: Cyclin-dependent kinase 6 inhibitor, p18-INK4c, p18-INK6

All UniProt accessions (2): P42773, Q6ICV4

UniProt curated annotations — full annotation on UniProt →

Function. Interacts strongly with CDK6, weakly with CDK4. Inhibits cell growth and proliferation with a correlated dependence on endogenous retinoblastoma protein RB.

Subunit / interactions. Heterodimer of p18 with CDK6.

Tissue specificity. Highest levels found in skeletal muscle. Also found in pancreas and heart.

Similarity. Belongs to the CDKN2 cyclin-dependent kinase inhibitor family.

RefSeq proteins (3): NP_001253, NP_001416604, NP_523240* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002110	Ankyrin_rpt	Repeat
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR050776	Ank_Repeat/CDKN_Inhibitor	Family

Pfam: PF12796, PF13637

UniProt features (21 total): helix 10, repeat 4, turn 2, strand 2, sequence variant 2, chain 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
1IHB	X-RAY DIFFRACTION	1.95
1MX4	X-RAY DIFFRACTION	2
1MX6	X-RAY DIFFRACTION	2
1MX2	X-RAY DIFFRACTION	2.25
1G3N	X-RAY DIFFRACTION	2.9
1BU9	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P42773-F1	92.36	0.85

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-2559580	Oxidative Stress Induced Senescence
R-HSA-2559582	Senescence-Associated Secretory Phenotype (SASP)
R-HSA-2559585	Oncogene Induced Senescence
R-HSA-69231	Cyclin D associated events in G1
R-HSA-1640170	Cell Cycle
R-HSA-2262752	Cellular responses to stress
R-HSA-2559583	Cellular Senescence
R-HSA-453279	Mitotic G1 phase and G1/S transition
R-HSA-69236	G1 Phase
R-HSA-69278	Cell Cycle, Mitotic
R-HSA-8953897	Cellular responses to stimuli

MSigDB gene sets: 430 (showing top): MODULE_52, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, BENPORATH_ES_WITH_H3K27ME3, CHIBA_RESPONSE_TO_TSA_UP, MYOGENIN_Q6, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_GROWTH, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, FRASOR_RESPONSE_TO_SERM_OR_FULVESTRANT_DN, SCHLESINGER_METHYLATED_DE_NOVO_IN_CANCER, GOBP_NEUROGENESIS, MODULE_16, CHX10_01

GO Biological Process (7): negative regulation of cell population proliferation (GO:0008285), negative regulation of cell growth (GO:0030308), oligodendrocyte differentiation (GO:0048709), stem cell proliferation (GO:0072089), regulation of G1/S transition of mitotic cell cycle (GO:2000045), negative regulation of stem cell proliferation (GO:2000647), cell population proliferation (GO:0008283)

GO Molecular Function (3): cyclin-dependent protein serine/threonine kinase inhibitor activity (GO:0004861), protein kinase binding (GO:0019901), protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Cellular Senescence	3
G1 Phase	1
Cellular responses to stimuli	1
Cellular responses to stress	1
Cell Cycle, Mitotic	1
Mitotic G1 phase and G1/S transition	1
Cell Cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell population proliferation	2
negative regulation of cellular process	2
cellular anatomical structure	2
regulation of cell population proliferation	1
regulation of cell growth	1
cell growth	1
negative regulation of growth	1
central nervous system development	1
glial cell differentiation	1
stem cell division	1
G1/S transition of mitotic cell cycle	1
regulation of mitotic cell cycle phase transition	1
regulation of cell cycle G1/S phase transition	1
negative regulation of cell population proliferation	1
stem cell proliferation	1
regulation of stem cell proliferation	1
cellular process	1
cyclin-dependent protein serine/threonine kinase activity	1
cyclin-dependent protein serine/threonine kinase regulator activity	1
protein serine/threonine kinase inhibitor activity	1
kinase binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

2136 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CDKN2C	CDK4	P11802	997
CDKN2C	CDK6	Q00534	997
CDKN2C	CDKN1B	P46527	915
CDKN2C	CCNL2	Q96S94	845
CDKN2C	CDKN1A	P38936	812
CDKN2C	CCND1	P24385	741
CDKN2C	CCND3	P30281	726
CDKN2C	CDKN1C	P49918	725
CDKN2C	MYCN	P04198	718
CDKN2C	MEN1	O00255	717
CDKN2C	CDK2	P24941	625
CDKN2C	CIB1	Q99828	609
CDKN2C	CKS1B	P33551	590
CDKN2C	CCND2	P30279	588
CDKN2C	TP53	P04637	586

IntAct

208 interactions, top by confidence:

A	B	Type	Score
CDK4	CDKN2C	psi-mi:“MI:0915”(physical association)	0.970
CDK6	CDKN2C	psi-mi:“MI:0915”(physical association)	0.970
CDKN2C	CDK6	psi-mi:“MI:0915”(physical association)	0.970
CDKN2C	CDK4	psi-mi:“MI:0915”(physical association)	0.970
CDKN2C	CDK4	psi-mi:“MI:0914”(association)	0.970

BioGRID (161): CDKN2C (Two-hybrid), CDKN2C (Two-hybrid), REL (Two-hybrid), TCF4 (Two-hybrid), TCF12 (Two-hybrid), AHCYL1 (Two-hybrid), NAGK (Two-hybrid), NIF3L1 (Two-hybrid), CDKN2C (Affinity Capture-MS), CDKN2C (Affinity Capture-MS), CDKN2C (Affinity Capture-MS), CDKN2C (Affinity Capture-MS), CDKN2C (Affinity Capture-MS), ANGPTL4 (Two-hybrid), GREB1 (Two-hybrid)

ESM2 similar proteins: A0PJZ0, A6NHY2, A7E2S9, C7B178, D3J162, G5E8K5, P42570, P42773, P53355, Q08E43, Q10311, Q14DN9, Q18297, Q2T9W8, Q3EC11, Q4R3S3, Q4R544, Q4UJC4, Q4UJJ2, Q5EFR1, Q5I126, Q5I148, Q5I155, Q5I159, Q5I160, Q5R6D7, Q5RCK5, Q5TYM7, Q5VYY1, Q60772, Q60773, Q6XJU9, Q80YE7, Q86WC6, Q91ZT9, Q91ZU0, Q92527, Q9BGT9, Q9CQM6, Q9D119

Diamond homologs: A0A084B9Z8, B4E2M5, P42773, Q03017, Q4FE45, Q4JHE0, Q502M6, Q60772, Q61982, Q6RI86, Q8BLA8, Q9R172, Q9UM47, F1M5M3, O77617, P42771, P42772, P51480, P55271, P55272, P55273, Q29RV0, Q2KJD8, Q38998, Q60773, Q91ZU1, Q9R0Z3, Q18297, Q28FJ2, Q6ZVH7, Q5R4M7, Q69ZR2, Q9NWX5, Q9ULT8, Q9VL06, Q25338, Q5ZLC8, Q8BTI7, Q8NB46, Q9J5I7

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
MEN1	“up-regulates quantity by expression”	CDKN2C	“transcriptional regulation”
DNMT3A	“down-regulates quantity by repression”	CDKN2C	“transcriptional regulation”
CDKN2C	down-regulates	CDK4	binding
CDKN2C	down-regulates	CDK6	binding
KLF1	“up-regulates quantity by expression”	CDKN2C	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 84 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)	5	52.9×	4e-06
G1 Phase	6	39.4×	1e-06
Aberrant regulation of mitotic cell cycle due to RB1 defects	5	34.0×	2e-05
Diseases of mitotic cell cycle	5	32.8×	2e-05
Oncogene Induced Senescence	5	28.0×	4e-05
Cyclin D associated events in G1	7	27.2×	1e-06
Regulation of TP53 Degradation	5	24.4×	7e-05
Mitotic G1 phase and G1/S transition	7	21.5×	4e-06

GO biological processes:

GO term	Partners	Fold	FDR
G1/S transition of mitotic cell cycle	8	21.1×	4e-06
animal organ morphogenesis	5	12.6×	5e-03
protein stabilization	7	6.2×	9e-03
cell division	9	5.5×	5e-03
positive regulation of gene expression	10	5.1×	3e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 3 cancer types — BL, HGGNOS, LGGNOS.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	16
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
800342	NM_078626.3(CDKN2C):c.230C>A (p.Ala77Glu)	Likely pathogenic

SpliceAI

450 predictions. Top by Δscore:

Variant	Effect	Δscore
1:50973887:TTCCA:T	acceptor_loss	0.9900
1:50973888:TCCA:T	acceptor_loss	0.9900
1:50973889:CCA:C	acceptor_loss	0.9900
1:50973890:CAG:C	acceptor_loss	0.9900
1:50973891:A:AG	acceptor_gain	0.9900
1:50973891:AG:A	acceptor_gain	0.9900
1:50973891:AGG:A	acceptor_loss	0.9900
1:50973892:G:A	acceptor_loss	0.9900
1:50973892:G:GG	acceptor_gain	0.9900
1:50973892:GG:G	acceptor_gain	0.9900
1:50973892:GGTT:G	acceptor_gain	0.9900
1:50973892:GGTTA:G	acceptor_gain	0.9900
1:50973892:GGT:G	acceptor_gain	0.9800
1:50960800:AAAG:A	donor_loss	0.9700
1:50960801:AAG:A	donor_loss	0.9700
1:50960802:AGGT:A	donor_loss	0.9700
1:50960803:GGTAA:G	donor_loss	0.9700
1:50960804:G:T	donor_loss	0.9700
1:50960791:G:GT	donor_gain	0.9400
1:50973881:C:G	acceptor_gain	0.9400
1:50968777:A:AG	acceptor_gain	0.9300
1:50960799:GAAAG:G	donor_gain	0.9100
1:50968778:A:G	acceptor_gain	0.9100
1:50972363:G:T	donor_gain	0.9100
1:50973880:A:AG	acceptor_gain	0.9000
1:50960806:A:C	donor_loss	0.8900
1:50969898:GG:G	donor_gain	0.8900
1:50969899:GG:G	donor_gain	0.8900
1:50972267:A:G	donor_gain	0.8900
1:50960829:G:GT	donor_gain	0.8600

AlphaMissense

1101 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:50974061:G:C	D100H	0.997
1:50973933:T:C	L57P	0.996
1:50973996:C:A	A78D	0.996
1:50974095:C:A	A111D	0.996
1:50973930:T:C	L56P	0.995
1:50974062:A:C	D100A	0.995
1:50974062:A:T	D100V	0.995
1:50974080:C:A	P106H	0.995
1:50974094:G:C	A111P	0.995
1:50974165:C:A	N134K	0.995
1:50974165:C:G	N134K	0.995
1:50970430:T:C	L21P	0.993
1:50974080:C:G	P106R	0.993
1:50974092:C:A	A110D	0.993
1:50974128:T:C	L122P	0.992
1:50974061:G:T	D100Y	0.991
1:50974063:T:A	D100E	0.991
1:50974063:T:G	D100E	0.991
1:50974164:A:T	N134I	0.991
1:50974005:G:T	G81V	0.989
1:50970473:T:A	N35K	0.988
1:50970473:T:G	N35K	0.988
1:50970485:G:C	R39S	0.988
1:50970485:G:T	R39S	0.988
1:50973972:G:T	G70V	0.988
1:50973995:G:C	A78P	0.988
1:50973963:A:T	D67V	0.987
1:50974029:T:C	L89S	0.987
1:50974032:T:C	L90P	0.987
1:50974091:G:C	A110P	0.987

dbSNP variants (sampled 300 via entrez): RS1000741886 (1:50971795 T>C), RS1001048828 (1:50971209 C>T), RS1001143288 (1:50971584 A>G), RS1001387016 (1:50969451 C>G,T), RS1001949939 (1:50974843 T>A), RS1001966623 (1:50969884 A>G), RS1002637494 (1:50967136 A>G), RS10028 (1:50974577 G>T), RS1003030607 (1:50974279 A>G), RS1003642499 (1:50968620 G>T), RS1003671721 (1:50973793 AAAAT>A), RS1003757141 (1:50968858 G>C), RS1004416535 (1:50968918 G>A), RS1004766480 (1:50969077 G>A), RS1005052999 (1:50968956 AG>A,AGG)

Disease associations

OMIM: gene MIM:603369 | disease phenotypes: MIM:254500

GenCC curated gene-disease

Mondo (1): plasma cell myeloma (MONDO:0009693)

Orphanet (2): Multiple myeloma (Orphanet:29073), AL amyloidosis (Orphanet:85443)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

32 associations (top):

Study	Trait	p-value
GCST000872_3	QRS duration	3.000000e-10
GCST003322_3	Ischemic stroke (large artery atherosclerosis)	4.000000e-08
GCST003598_19	QRS duration	5.000000e-06
GCST003598_46	QRS duration	9.000000e-09
GCST003844_23	QRS duration	1.000000e-11
GCST003872_9	QRS complex (12-leadsum)	2.000000e-08
GCST005306_4	Atrial fibrillation	2.000000e-11
GCST005935_1	Ventricular ectopy or supraventricular ectopy (pleiotropy)	1.000000e-08
GCST005937_4	Ventricular ectopy	3.000000e-06
GCST006661_33	Male-pattern baldness	9.000000e-12
GCST006881_6	Hippocampal tail volume (corrected for total hippocampal volume)	4.000000e-10
GCST007269_13	Pulse pressure	4.000000e-11
GCST008839_67	Height	3.000000e-25
GCST009963_1	Cataracts (operation)	5.000000e-11
GCST010653_53	Thyroid stimulating hormone levels	4.000000e-12
GCST010696_17	Cortical thickness (min-P)	9.000000e-11
GCST010697_16	Cortical surface area (min-P)	5.000000e-09
GCST010698_74	Subcortical volume (min-P)	2.000000e-13
GCST010699_35	Brain morphology (min-P)	9.000000e-09
GCST010700_50	Cortical thickness (MOSTest)	2.000000e-10
GCST010701_119	Cortical surface area (MOSTest)	5.000000e-11
GCST010702_4	Subcortical volume (MOSTest)	3.000000e-08
GCST010703_110	Brain morphology (MOSTest)	6.000000e-20
GCST012013_5	Cataracts	8.000000e-07
GCST012227_1060	Hip circumference adjusted for BMI	4.000000e-10
GCST012227_1061	Hip circumference adjusted for BMI	1.000000e-23
GCST90013466_40	Height	1.000000e-12
GCST90013466_63	Height	3.000000e-21
GCST90013467_12	Height	5.000000e-07
GCST90013468_6	Height	7.000000e-08

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0005054	QRS complex
EFO:0007742	QRS amplitude
EFO:0009275	premature cardiac contractions
EFO:0009276	ventricular ectopy
EFO:0009277	supraventricular ectopy
EFO:0005763	pulse pressure measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009101	Multiple Myeloma	C04.557.595.500; C14.907.454.460; C15.378.147.780.650; C15.378.463.515.460; C20.683.515.845; C20.683.780.650

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects cotreatment, increases expression	7
Estradiol	decreases expression	4
bisphenol A	affects expression, decreases expression	3
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	3
Arsenic Trioxide	increases expression, decreases expression	3
Benzo(a)pyrene	affects methylation, decreases expression	3
Cyclosporine	decreases expression	3
Particulate Matter	decreases expression, increases abundance	3
manganese chloride	decreases expression, increases abundance, affects cotreatment	2
perfluorooctane sulfonic acid	decreases expression, increases expression	2
cylindrospermopsin	decreases expression	2
perfluoro-n-nonanoic acid	decreases expression	2
Troglitazone	decreases expression, increases expression	2
Air Pollutants	decreases expression, increases abundance	2
Cannabidiol	decreases expression	2
Copper	affects binding, decreases expression	2
Coumestrol	affects cotreatment, increases expression, increases reaction	2
Doxorubicin	affects response to substance, increases expression, affects reaction	2
Manganese	decreases expression, increases abundance, affects cotreatment	2
Quercetin	decreases expression, increases expression	2
Tobacco Smoke Pollution	decreases expression	2
Tretinoin	increases expression	2
propionaldehyde	decreases expression	1
kaempferol	decreases expression	1
geraniol	decreases expression	1
titanium dioxide	affects binding, decreases expression	1
nimesulide	decreases expression, decreases reaction	1
beta-lapachone	decreases expression	1
arsenite	affects binding, increases reaction	1
cobaltous chloride	decreases expression	1

Cellosaurus cell lines

4 cell lines: 2 spontaneously immortalized cell line, 2 telomerase immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C0ZS	MCF10A_CDKN2C_161	Spontaneously immortalized cell line	Female
CVCL_C0ZT	MCF10A_CDKN2C_163	Spontaneously immortalized cell line	Female
CVCL_C1AU	RPE1_CDKN2C_241	Telomerase immortalized cell line	Female
CVCL_C1AV	RPE1_CDKN2C_242	Telomerase immortalized cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00104104	PHASE4	COMPLETED	A Multiple Myeloma Trial in Patients With Bone Metastases
NCT00211211	PHASE4	COMPLETED	FREE Study - Fracture Reduction Evaluation
NCT00242528	PHASE4	WITHDRAWN	Open-label Study, to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Bone Lesions Secondary to Multiple Myeloma.
NCT00257114	PHASE4	COMPLETED	Evaluation of VELCADE Given as Retreatment to Multiple Myeloma Patients for Efficacy, Safety and Tolerability
NCT00352703	PHASE4	COMPLETED	PROMPT - Palifermin in Reduction of Oral Mucositis in PBSC Transplantation
NCT00361140	PHASE4	COMPLETED	Busulfan Safety/Efficacy as Conditioning Prior to Hematopoietic Cell Transplantation (HCT)
NCT00622505	PHASE4	COMPLETED	Zoledronic Acid Treatment (Every 4 or 12 Weeks) to Prevent Skeletal Complications in Advanced Multiple Myeloma Participants
NCT00652041	PHASE4	COMPLETED	Bortezomib/Adriamycine/Melfalan/Prednisone (VAMP)/Thalidomide/Cyclophosphamide/Dexamethasone (TaCyDex) or Bortezomib/Melfalan/Prednisone (V-MP)/TaCyDex) in Refractary or Relapsed Multiple Myeloma
NCT00733538	PHASE4	COMPLETED	Stage I Multiple Myeloma Treatment
NCT01087008	PHASE4	COMPLETED	Zoledronic Acid in Patients With Multiple Myeloma and Asymptomatic Biochemical Relapse
NCT01249690	PHASE4	UNKNOWN	Efficacy Study of PAD and TAD in Newly Diagnosed Multiple Myeloma
NCT01410929	PHASE4	WITHDRAWN	Evaluation of Vertebral Compression Fracture Fixation With RF Kyphoplasty in Patients With Multiple Myeloma
NCT01731886	PHASE4	COMPLETED	Lenalidomide and Dexamethasone With/Without Stem Cell Transplant in Patients With Multiple Myeloma
NCT01868828	PHASE4	UNKNOWN	A Study of PAD Versus Velcade, Cyclophosphamide and Dexamethasone (VCD) Treatment in Subjects With Multiple Myeloma
NCT02268890	PHASE4	COMPLETED	A Pharmacokinetic Study of Bortezomib in Taiwanese Participants With Multiple Myeloma
NCT02286830	PHASE4	COMPLETED	Prolonged Protection From Bone Disease in Multiple Myeloma
NCT02559154	PHASE4	UNKNOWN	Modified Bortezomib-based Combination Therapy for Multiple Myeloma
NCT02577783	PHASE4	UNKNOWN	PDD vs PAD to Treat Initially Diagnosed MM
NCT02773550	PHASE4	TERMINATED	Treatment With a Scheme With Low Doses of Bortezomib / Melphalan / Prednisone (MPV) in Patients With Multiple Myeloma
NCT02958969	PHASE4	COMPLETED	Apixaban for Primary Prevention of Venous Thromboembolism in Patients With Multiple Myeloma
NCT03173092	PHASE4	TERMINATED	A Study of Ixazomib (NINLARO®) in Combination With Lenalidomide and Dexamethasone (IRD) for the Treatment of Participants With Multiple Myeloma (MM)
NCT03619252	PHASE4	COMPLETED	Pneumococcal Vaccination of Multiple Myeloma Patients on Novel Agents
NCT03768960	PHASE4	COMPLETED	A Study of DARZALEX (Daratumumab) In Indian Participants With Relapsed and Refractory Multiple Myeloma, Whose Prior Therapy Included a Proteasome Inhibitor and an Immunomodulatory Agent
NCT03829371	PHASE4	ACTIVE_NOT_RECRUITING	STUDY COMPARING TWO STANDARD TREATMENTS IN AUTOLOGOUS STEM CELL TRANSPLANTATION INELIGIBLE POPULATION AFFECTED BY MULTIPLE MYELOMA
NCT03908138	PHASE4	UNKNOWN	RDD Versus VDD in Newly Diagnosed Patients With Multiple Myeloma
NCT04217967	PHASE4	COMPLETED	Ixazomib, Lenalidomide, and Combination for Maintenance in NDMM Patients
NCT04952766	PHASE4	COMPLETED	Study Evaluating SARS-CoV-2 (COVID-19) Humoral Response After BNT162b2 Vaccine in Immunocompromised Adults Compared to Healthy Adults
NCT04989140	PHASE4	UNKNOWN	Study of Pomalidomide, Oral Dexamethasone and Ixazomib in Patients With Relapsed MM Who Have Received Lenalidomide
NCT05183139	PHASE4	WITHDRAWN	A Multicenter In-class Transition Study of Ixazomib Combined With Pomalidomide and Dexamethasone or With Lenalidomide and Dexamethasone in Adults With Relapsed/Refractory Multiple Myeloma
NCT05201781	PHASE4	RECRUITING	A Long-term Study for Participants Previously Treated With Ciltacabtagene Autoleucel
NCT05429515	PHASE4	NOT_YET_RECRUITING	Effect of HFR-SUPRA in the Treatment of Multiple Myeloma-related Acute Kidney Injury
NCT05511428	PHASE4	COMPLETED	Home Based Daratumumab Administration for Patients With Multiple Myeloma
NCT05545202	PHASE4	UNKNOWN	A Randomized, Comparative, Double-blind Trial of Pentaisomaltose and Dimethyl Sulphoxide for Cryoprotection of Hematopoietic Stem Cells in Subjects With Multiple Myeloma or Malignant Lymphoma With a Need for Autologous Transplantation
NCT05555329	PHASE4	COMPLETED	Alternative Dosing Scheme of Pomalidomide 4 mg Every Other Day Versus Pomalidomide 2 mg and 4 mg Every Day; the POMAlternative Study
NCT05722405	PHASE4	RECRUITING	Ixazomib Plus Low-dose Lenalidomide Versus Ixazomib Alone for Maintenance Treatment of High Risk Multiple Myeloma
NCT05855122	PHASE4	UNKNOWN	Safety and ASCT-related Symptom Burden Optimization of Tocilizumab in ASCT Following HD Melphalan Conditioning for Multiple Myeloma Patients
NCT05944783	PHASE4	NOT_YET_RECRUITING	Bioequivalence Studies of Dasatinib 100 Mg
NCT06057402	PHASE4	RECRUITING	Elranatamab Post Trial Access Study for Participants With Multiple Myeloma (MM)
NCT06251076	PHASE4	RECRUITING	Plan Development for Giving Teclistamab in the Outpatient Setting