CDKN2D

Summary

CDKN2D (cyclin dependent kinase inhibitor 2D, HGNC:1790) is a protein-coding gene on chromosome 19p13.2, encoding Cyclin-dependent kinase 4 inhibitor D (P55273). Interacts strongly with CDK4 and CDK6 and inhibits them.

The protein encoded by this gene is a member of the INK4 family of cyclin-dependent kinase inhibitors. This protein has been shown to form a stable complex 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. The abundance of the transcript of this gene was found to oscillate in a cell-cycle dependent manner with the lowest expression at mid G1 and a maximal expression during S phase. The negative regulation of the cell cycle involved in this protein was shown to participate in repressing neuronal proliferation, as well as spermatogenesis. Two alternatively spliced variants of this gene, which encode an identical protein, have been reported.

Source: NCBI Gene 1032 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 16 total
• GTEx eGene: eQTL in 29 tissues, sQTL in 1 (q < 0.05)
• Constraint (gnomAD): pLI 0.24 (intermediate), LOEUF 1.43 (unconstrained)
• MANE Select transcript: NM_001800

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1790
Approved symbol	CDKN2D
Name	cyclin dependent kinase inhibitor 2D
Location	19p13.2
Locus type	gene with protein product
Status	Approved
Aliases	INK4D, p19
Ensembl gene	ENSG00000129355
Ensembl biotype	protein_coding
OMIM	600927
Entrez	1032

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

MANE Select: ENST00000393599

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2

ENST00000393599, ENST00000335766, ENST00001125730, ENST00001136901

RefSeq mRNA: 2 — MANE Select: NM_001800 NM_001800, NM_079421

CCDS: CCDS12244

Canonical transcript exons

ENST00000393599 — 2 exons

Exon	Start	End
ENSE00000888297	10566460	10567417
ENSE00001515998	10568513	10568979

Expression profiles

Bgee: expression breadth ubiquitous, 200 present calls, max score 97.97.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.6772 / max 385.2168, expressed in 1485 samples.

Highest expression (Bgee): monocyte, cortical plate, mononuclear cell, leukocyte, granulocyte.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CDKN2D is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 29 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 30 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Testis	eqtl	1.3e-52	-0.65	19:10573918:C:G
Muscle Skeletal	eqtl	1.5e-28	-0.34	19:10569427:A:G
Skin Not Sun Exposed Suprapubic	eqtl	2.4e-18	+0.26	19:10558277:G:A
Brain Cerebellum	eqtl	3.5e-14	-0.43	19:10569056:A:C
Cells Cultured fibroblasts	eqtl	2.6e-13	-0.19	19:10569056:A:C
Skin Sun Exposed Lower leg	eqtl	1.3e-12	+0.21	19:10540146:G:A
Adipose Subcutaneous	eqtl	5.5e-12	-0.28	19:10560988:T:C
Nerve Tibial	eqtl	2.2e-09	-0.20	19:10529830:G:A
Brain Cerebellar Hemisphere	eqtl	4.0e-09	-0.27	19:10581324:T:C
Pituitary	eqtl	1.4e-08	-0.28	19:10539973:C:T
Artery Tibial	eqtl	6.3e-08	-0.17	19:10569427:A:G
Whole Blood	eqtl	6.1e-06	+0.09	19:10549564:T:C
Breast Mammary Tissue	eqtl	6.4e-06	-0.19	19:10570965:A:G
Colon Sigmoid	eqtl	1.4e-05	-0.21	19:10592604:G:A
Heart Atrial Appendage	eqtl	1.5e-05	-0.29	19:10560988:T:C
Heart Left Ventricle	eqtl	2.0e-05	-0.25	19:10579533:TA:T
Brain Cortex	eqtl	1.2e-04	+0.14	19:10576483:C:T
Stomach	eqtl	2.1e-04	-0.22	19:10557997:A:G
Brain Caudate basal ganglia	eqtl	2.4e-04	-0.13	19:10560988:T:C
Esophagus Muscularis	eqtl	7.0e-04	-0.18	19:10550773:A:C

FANTOM5 promoters

6 alternative TSS:

Promoter ID	TPM avg	Samples expressed
179158	2.5154	859
179154	2.4434	461
179156	1.3439	529
179157	0.9763	351
179155	0.3263	116
179159	0.0719	29

Top tissues by expression

showing 100 of 283 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	97.97	gold quality
cortical plate	UBERON:0005343	97.69	gold quality
mononuclear cell	CL:0000842	97.53	gold quality
leukocyte	CL:0000738	97.43	gold quality
granulocyte	CL:0000094	96.79	gold quality
right frontal lobe	UBERON:0002810	96.46	gold quality
cingulate cortex	UBERON:0003027	96.41	gold quality
anterior cingulate cortex	UBERON:0009835	96.41	gold quality
prefrontal cortex	UBERON:0000451	95.86	gold quality
amygdala	UBERON:0001876	94.57	gold quality
nucleus accumbens	UBERON:0001882	94.45	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.30	gold quality
caudate nucleus	UBERON:0001873	94.08	gold quality
blood	UBERON:0000178	94.00	gold quality
Brodmann (1909) area 9	UBERON:0013540	93.78	gold quality
neocortex	UBERON:0001950	93.30	gold quality
frontal cortex	UBERON:0001870	93.12	gold quality
putamen	UBERON:0001874	92.80	gold quality
cerebellar hemisphere	UBERON:0002245	92.26	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.19	gold quality
cerebellar cortex	UBERON:0002129	92.15	gold quality
cerebral cortex	UBERON:0000956	91.57	gold quality
telencephalon	UBERON:0001893	91.27	gold quality
ganglionic eminence	UBERON:0004023	91.23	gold quality
Brodmann (1909) area 10	UBERON:0013541	91.16	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.15	gold quality
frontal pole	UBERON:0002795	90.57	gold quality
cerebellum	UBERON:0002037	90.52	gold quality
bone marrow	UBERON:0002371	90.37	gold quality
hypothalamus	UBERON:0001898	90.23	gold quality
forebrain	UBERON:0001890	90.15	gold quality
left testis	UBERON:0004533	89.64	gold quality
brain	UBERON:0000955	89.46	gold quality
right testis	UBERON:0004534	89.46	gold quality
central nervous system	UBERON:0001017	89.32	gold quality
right lung	UBERON:0002167	89.01	gold quality
Ammon’s horn	UBERON:0001954	88.96	gold quality
temporal lobe	UBERON:0001871	88.46	gold quality
spleen	UBERON:0002106	88.14	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	87.88	gold quality
apex of heart	UBERON:0002098	86.81	gold quality
testis	UBERON:0000473	86.64	gold quality
mucosa of stomach	UBERON:0001199	86.34	gold quality
bone marrow cell	CL:0002092	86.18	gold quality
upper lobe of left lung	UBERON:0008952	85.65	gold quality
popliteal artery	UBERON:0002250	85.34	gold quality
tibial artery	UBERON:0007610	85.33	gold quality
superior frontal gyrus	UBERON:0002661	85.18	gold quality
spinal cord	UBERON:0002240	85.09	gold quality
gastrocnemius	UBERON:0001388	85.06	gold quality
aorta	UBERON:0000947	85.02	gold quality
ascending aorta	UBERON:0001496	85.00	gold quality
ventricular zone	UBERON:0003053	84.99	gold quality
thoracic aorta	UBERON:0001515	84.90	gold quality
middle frontal gyrus	UBERON:0002702	84.60	silver quality
substantia nigra	UBERON:0002038	84.51	gold quality
lymph node	UBERON:0000029	84.16	gold quality
muscle of leg	UBERON:0001383	84.13	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	83.98	gold quality
hindlimb stylopod muscle	UBERON:0004252	83.61	gold quality
mucosa of transverse colon	UBERON:0004991	83.49	gold quality
descending thoracic aorta	UBERON:0002345	83.48	gold quality
skin of abdomen	UBERON:0001416	83.27	gold quality
heart left ventricle	UBERON:0002084	83.27	gold quality
right coronary artery	UBERON:0001625	83.04	gold quality
skin of leg	UBERON:0001511	82.84	gold quality
lower esophagus muscularis layer	UBERON:0035833	82.84	gold quality
lower esophagus	UBERON:0013473	82.82	gold quality
adenohypophysis	UBERON:0002196	82.77	gold quality
cardiac ventricle	UBERON:0002082	82.73	gold quality
midbrain	UBERON:0001891	82.69	gold quality
upper lobe of lung	UBERON:0008948	82.42	gold quality
lower esophagus mucosa	UBERON:0035834	82.27	gold quality
Brodmann (1909) area 46	UBERON:0006483	82.23	gold quality
left coronary artery	UBERON:0001626	82.17	gold quality
paraflocculus	UBERON:0005351	82.13	gold quality
muscle layer of sigmoid colon	UBERON:0035805	82.11	gold quality
postcentral gyrus	UBERON:0002581	81.77	gold quality
primary visual cortex	UBERON:0002436	81.69	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.64	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	81.57	gold quality
omental fat pad	UBERON:0010414	81.40	gold quality
left uterine tube	UBERON:0001303	81.38	gold quality
peritoneum	UBERON:0002358	81.34	gold quality
esophagus	UBERON:0001043	81.17	gold quality
coronary artery	UBERON:0001621	81.03	gold quality
pituitary gland	UBERON:0000007	80.75	gold quality
stromal cell of endometrium	CL:0002255	80.61	gold quality
entorhinal cortex	UBERON:0002728	80.55	gold quality
adipose tissue of abdominal region	UBERON:0007808	80.43	gold quality
anatomical system	UBERON:0000467	80.24	gold quality
esophagus mucosa	UBERON:0002469	80.21	gold quality
tibial nerve	UBERON:0001323	80.20	gold quality
right atrium auricular region	UBERON:0006631	80.16	gold quality
right adrenal gland	UBERON:0001233	80.14	gold quality
parietal lobe	UBERON:0001872	80.02	gold quality
heart	UBERON:0000948	80.01	gold quality
small intestine Peyer’s patch	UBERON:0003454	79.89	gold quality
transverse colon	UBERON:0001157	79.84	gold quality
multicellular organism	UBERON:0000468	79.82	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	42.94
E-HCAD-6	yes	34.09
E-MTAB-9221	yes	17.45
E-HCAD-10	yes	16.63
E-HCAD-1	yes	6.02
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Group enriched

showing 60 of 77 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Bone marrow	tissue	267.8	high
Thymus	tissue	72.6
Postcentral gyrus	tissue	70.4
Frontal cortex	tissue	62.5
Locus coeruleus	tissue	60.9
Hippocampus	tissue	54.6	not detected
Caudate putamen	tissue	54.0
Nucleus accumbens	tissue	50.5
Cerebral cortex	tissue	46.7	not detected
Motor cortex	tissue	46.7
Somatosensory cortex	tissue	43.8
Prefrontal cortex	tissue	42.7
Occipital cortex	tissue	41.4
Retrosplenial cortex	tissue	40.0
Hippocampal formation	tissue	39.2
Entorhinal cortex	tissue	39.2
Retrosplenial and cingulate cortex	tissue	39.1
Temporal cortex	tissue	36.9
Insular cortex	tissue	35.1
Pons	tissue	32.6
Basal ganglia	tissue	30.4	not detected
Thalamus	tissue	29.7
Putamen	tissue	28.8
Septum	tissue	28.5
Amygdala	tissue	27.2
Superior colliculi	tissue	26.3
Ventral forebrain	tissue	26.1
Hypothalamus	tissue	23.8
Midbrain	tissue	23.0
Lymph node	tissue	22.3	medium
Substantia nigra	tissue	21.8
Testis	tissue	20.1	high
Medulla oblongata	tissue	18.6
Periaqueductal gray	tissue	17.6
Spleen	tissue	17.5	low
Cerebellum	tissue	15.9	not detected
Retina	tissue	15.2
Tonsil	tissue	15.0	medium
Pituitary gland	tissue	14.8
Tongue	tissue	14.8
Olfactory bulb	tissue	14.8
Spinal cord	tissue	14.7
Vagina	tissue	12.5	not detected
Appendix	tissue	12.5	not detected
Skeletal muscle	tissue	12.0	not detected
Choroid plexus	tissue	11.9
Corpus callosum	tissue	11.7
Skin 1	tissue	10.3	not detected
Lung	tissue	9.3	not detected
Heart muscle	tissue	9.2	not detected
Adipose tissue	tissue	8.9	not detected
Placenta	tissue	7.7	not detected
Smooth muscle	tissue	7.3	not detected
Adrenal gland	tissue	7.2	not detected
Urinary bladder	tissue	6.9	not detected
Colon	tissue	6.0	not detected
Gallbladder	tissue	6.0	not detected
Duodenum	tissue	5.9	not detected
Esophagus	tissue	5.7	not detected
Small intestine	tissue	5.3	not detected

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Olfactory area (83.0), Temporal pole (70.3), Posterior cingulate cortex (69.7), Perirhinal gyrus (69.1), Olfactory tubercle (68.9).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DNMT3A, E2F1, FOXO1, FOXO3, MSX1, PAX6, SP1, SP3, STAT3

miRNA regulators (miRDB)

Targeting CDKN2D by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

18 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-8064	99.45	66.92	875
HSA-MIR-4506	99.34	67.47	526
HSA-MIR-449B-3P	99.20	67.24	1047
HSA-MIR-6794-3P	98.76	66.99	894
HSA-MIR-5197-3P	98.71	67.05	1905
HSA-MIR-2115-5P	98.66	68.07	1191
HSA-MIR-3135B	98.61	65.33	1470
HSA-MIR-4463	98.56	66.05	1071
HSA-MIR-1248	98.47	67.54	1314
HSA-MIR-4722-5P	98.46	66.34	1611
HSA-MIR-4433B-3P	97.22	63.62	663
HSA-MIR-3197	94.02	63.47	85

Functional genomics

gnomAD constraint: pLI 0.239, LOEUF 1.43, missense Z 0.707 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000393599 — one region, missense o/e 0.85.

Literature-anchored findings (GeneRIF, showing 32)

• protein folding and stability (PMID:11786024)
• The human p19(INK4d) gene is under the control of TATA-less promoter and the Sp1 binding site is involved in the transcription. (PMID:12062451)
• Deletions in the CDKN2D locus and hypermethylation in the CDKN2D promoter region plays a role in ovarian granulosa cell tumorogenesis. (PMID:12203782)
• Inhibitor shows antitumor effect on glioma cells. (PMID:12698196)
• p19(INK4d) in addition to p21(WAF1/Cip1) is an important molecular target of HDAC inhibitors inducing growth arrest (PMID:15107822)
• In addition to its role as cell cycle inhibitor, p19INK4d is involved in maintenance of DNA integrity and, therefore, would contribute to cancer prevention. (PMID:15750620)
• Data suggest that the graded stability and the facile unfolding of repeats 1 and 2 is a prerequisite for the down-regulation of the inhibitory activity of p19(INK4d) during the cell-cycle. (PMID:17804013)
• p19(INK4D) knockdown led to a moderate increase (31.7% +/- 5%) in the mean ploidy of megakaryocytes suggesting a role of p19(INK4D) in the endomitotic arrest. (PMID:18276842)
• The study shows that mimicking the phosphorylation site of p19INK4d by a glutamate substitution at position 76 dramatically decreases the stability of the native but not an intermediate state. (PMID:19063602)
• Results show that overexpression of CDK4, cyclin D1, and Rb proteins, and loss of expression of proteins p16, p27, and p19 were statistically significant in NPC tissues compared with non-cancerous NPE (P<0.05) by real-time RT-PCR and tissue microarray. (PMID:19430707)
• p19INK4d is transcriptionally regulated by E2F1 through two response elements present in the p19INK4d promoter. (PMID:21765927)
• expression of p19INK4D may be an effective predictor of clinical behavior in hepatocellular carcinoma, and therefore, a new prognostic marker (PMID:21901251)
• E2F1 is involved in the induction of p19INK4d following UV irradiation (PMID:22476863)
• CDK2 and PKA mediated-sequential phosphorylation is critical for p19INK4d function in the DNA damage response to ensure cell survival. (PMID:22558186)
• Up-regulation of CDKN2D during in-vitro passages of human amniotic fluid-derived mesenchymal stromal cells may indicate the begging of early senescence process in a p53-independent mechanism. (PMID:22747700)
• PTB plays as a negative regulator in H1299 cell proliferation at least by inducing p19(Ink4d) expression at transcriptional and post-transcriptional levels. (PMID:23536791)
• P19(INK4d) expression is a poor prognostic factor in ovarian cancer patients. (PMID:24022213)
• Mutations in CDKN2D is associated with sporadic parathyroid adenoma. (PMID:24127162)
• CDKN2D-WDFY2 fusion could be an important molecular signature for understanding and classifying sub-lineages among heterogeneous high-grade serous ovarian carcinomas. (PMID:24675677)
• p19-INK4d inhibits neuroblastoma cell growth, induces differentiation and is hypermethylated and downregulated in MYCN-amplified neuroblastomas. (PMID:25104850)
• Data indicate that upon oxidative DNA damage, cyclin-dependent kinase inhibitor p19INK4d strongly binds to and relaxes chromatin. (PMID:25204969)
• CDKN2D repression by PML/RARalpha disrupts both cell proliferation and differentiation in the pathogenesis of acute promyelocytic leukemia. (PMID:25275592)
• MiR-451 inhibited the proliferation of esophageal squamous cell carcinoma cells by targeting CDKN2D and MAP3K1 expression. (PMID:26019450)
• p19 may play an important role in the ototoxic effects of cisplatin and is probably involved in the pathogenesis of hearing loss. (PMID:26722409)
• p19(INK4D) is one of the key mediators of miR-125b activity during the onset of megakaryocyte polyploidization. (PMID:27763644)
• We unexpectedly found that p19INK4d plays an important role in human terminal erythropoiesis (PMID:27879259)
• p19(INK4d) plays an active role during human tooth development along with MSX1 and MSX2 (PMID:28933666)
• he results support the concept that P19ink4d may play an important role in the pathogenesis and development of noise induced hearing loss. (PMID:30808142)
• p19INK4d: More than Just a Cyclin-Dependent Kinase Inhibitor. (PMID:31400265)
• p19(INK4d) inhibits proliferation and enhances imatinib efficacy through BCR-ABL signaling pathway in chronic myeloid leukemia. (PMID:32711219)
• Identification of Cdk8 and Cdkn2d as New Prame-Target Genes in 2C-like Embryonic Stem Cells. (PMID:36292630)
• Deregulation of the p19/CDK4/CDK6 axis in Jak2[V617F] megakaryocytes accelerates the development of myelofibrosis. (PMID:38378843)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cdkn2d	ENSDARG00000094176
mus_musculus	Cdkn2d	ENSMUSG00000096472
rattus_norvegicus	Cdkn2d	ENSRNOG00000064248

Paralogs (2): CDKN2C (ENSG00000123080), ANKRD39 (ENSG00000213337)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:105387) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 18 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal spermatogenesis	2
abnormal apoptosis	1
increased circulating follicle stimulating hormone level	1
oligozoospermia	1
testicular atrophy	1
cochlear hair cell degeneration	1
decreased cochlear inner hair cell number	1
cochlear inner hair cell degeneration	1
decreased cochlear outer hair cell number	1
cochlear outer hair cell degeneration	1
abnormal cochlear hair cell physiology	1
absent distortion product otoacoustic emissions	1
sensorineural hearing loss	1
nonsyndromic hearing loss	1
abnormal male meiosis	1
increased or absent threshold for auditory brainstem response	1
increased male germ cell apoptosis	1
multinucleated giant male germ cells	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	Q29RV0	89.2%	Diamond
Monodelphis domestica	O77617	70.4%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
S1PR5	protein-coding	53637
KRI1	protein-coding	65095
ATG4D	protein-coding	84971
SLC44A2	protein-coding	57153
AP1M2	protein-coding	10053
ILF3-DT	ncRNA	147727
MIR1238	ncRNA	100302226
KEAP1	protein-coding	9817

Protein

Protein identifiers

Cyclin-dependent kinase 4 inhibitor D — P55273 (reviewed: P55273)

Alternative names: p19-INK4d

All UniProt accessions (1): P55273

UniProt curated annotations — full annotation on UniProt →

Function. Interacts strongly with CDK4 and CDK6 and inhibits them.

Subunit / interactions. Interacts with CDK6.

Subcellular location. Nucleus. Cytoplasm.

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

RefSeq proteins (2): NP_001791, NP_524145 (=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

UniProt features (19 total): helix 12, repeat 4, chain 1, modified residue 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures by resolution:

PDB	Title	Method	Resolution (Å)
1BD8	STRUCTURE OF CDK INHIBITOR P19INK4D	X-RAY DIFFRACTION	1.8
1BI8	MECHANISM OF G1 CYCLIN DEPENDENT KINASE INHIBITION FROM THE STRUCTURES CDK6-P19INK4D …	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P55273-F1	95.91	0.93

Human Protein Atlas

Protein class: Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm; cytosol

Antibody reliability (HPA): IH enhanced · IF supported

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 (1)

Type	Positions
N-acetylmethionine	1

Function

Pathways and Gene Ontology

Reactome pathways

4 curated (TAS) of 11; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

11 pathways:

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

MSigDB gene sets: 309 (showing top): GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, GOBP_CELL_CYCLE_PHASE_TRANSITION, RIZ_ERYTHROID_DIFFERENTIATION_CCNE1, GOBP_GROWTH, IVANOVA_HEMATOPOIESIS_MATURE_CELL, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, GOBP_NEGATIVE_REGULATION_OF_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_IN_RESPONSE_TO_DNA_DAMAGE, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_NEGATIVE_REGULATION_OF_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE_PROCESS, GOBP_APOPTOTIC_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE, FISCHER_G2_M_CELL_CYCLE, GOBP_REGULATION_OF_CELL_CYCLE

GO Biological Process (11): DNA synthesis involved in DNA repair (GO:0000731), negative regulation of cell population proliferation (GO:0008285), response to UV (GO:0009411), negative regulation of cell growth (GO:0030308), response to retinoic acid (GO:0032526), response to vitamin D (GO:0033280), autophagic cell death (GO:0048102), negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage (GO:1902230), regulation of G1/S transition of mitotic cell cycle (GO:2000045), negative regulation of G1/S transition of mitotic cell cycle (GO:2000134), negative regulation of cell cycle G1/S phase transition (GO:1902807)

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 (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), cyclin D2-CDK4 complex (GO:0097129)

Reactome top-level categories

7 top-level categories:

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

36 GO namespaces:

Category	Terms
cellular anatomical structure	3
negative regulation of cellular process	2
response to lipid	2
response to oxygen-containing compound	2
G1/S transition of mitotic cell cycle	2
regulation of cell cycle G1/S phase transition	2
DNA repair	1
DNA biosynthetic process	1
cell population proliferation	1
regulation of cell population proliferation	1
response to light stimulus	1
regulation of cell growth	1
cell growth	1
negative regulation of growth	1
response to vitamin	1
programmed cell death	1
macroautophagy	1
intrinsic apoptotic signaling pathway in response to DNA damage	1
regulation of intrinsic apoptotic signaling pathway in response to DNA damage	1
negative regulation of intrinsic apoptotic signaling pathway	1
regulation of mitotic cell cycle phase transition	1
negative regulation of mitotic cell cycle phase transition	1
negative regulation of cell cycle G1/S phase transition	1
regulation of G1/S transition of mitotic cell cycle	1
cell cycle G1/S phase transition	1
negative regulation of cell cycle phase transition	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
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
cyclin-dependent protein kinase holoenzyme complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 16 of 19 annotations. The rest are phylogenetic / computational / electronic (IEA).

16 experimentally-supported GO terms:

GO term	NS	Evidence
DNA synthesis involved in DNA repair	BP	mutant phenotype
autophagic cell death	BP	mutant phenotype
negative regulation of G1/S transition of mitotic cell cycle	BP	direct assay
negative regulation of cell growth	BP	direct assay
negative regulation of cell population proliferation	BP	direct assay
negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage	BP	mutant phenotype
regulation of G1/S transition of mitotic cell cycle	BP	direct assay
response to UV	BP	mutant phenotype
response to retinoic acid	BP	mutant phenotype
response to vitamin D	BP	mutant phenotype
cytoplasm	CC	direct assay
cytosol	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
cyclin-dependent protein serine/threonine kinase inhibitor activity	MF	direct assay
protein kinase binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 772 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CDKN2D	CDKN1B	P46527	848
CDKN2D	CDK6	Q00534	841
CDKN2D	CDK4	P11802	829
CDKN2D	CCNL2	Q96S94	789
CDKN2D	CDKN1C	P49918	719
CDKN2D	CDK2	P24941	715
CDKN2D	CDKN1A	P38936	715
CDKN2D	CCND3	P30281	664
CDKN2D	SLC44A2	Q8IWA5	635
CDKN2D	CCND2	P30279	619
CDKN2D	CIB1	Q99828	606
CDKN2D	CCNE1	P24864	554
CDKN2D	CCNH	P51946	553
CDKN2D	CCNA2	P20248	526
CDKN2D	KEAP1	Q14145	503

IntAct

Human interaction partners of CDKN2D in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 54 partners by confidence:

Partner	Interaction type	MIscore	Records
CDK4	physical association	0.970	25
CDK6	physical association	0.960	21
HSD17B14	physical association	0.790	8
INCA1	physical association	0.780	9
IKZF3	physical association	0.740	6
C1orf94	physical association	0.740	5
NR4A2	physical association	0.670	7
NR4A1	physical association	0.670	4
CCND3	physical association	0.560	3
CFAP90	physical association	0.560	3
CGGBP1	physical association	0.560	3
CTBP1	physical association	0.560	3
DDIT4L	physical association	0.560	3
DYNLT2B	physical association	0.560	3
EIF4G1	physical association	0.560	3
FAM228A	physical association	0.560	3
FAM86C1P	physical association	0.560	3
GATAD2B	physical association	0.560	3
GLYR1	physical association	0.560	3
GORASP2	physical association	0.560	3
GSC2	physical association	0.560	3
KRT75	physical association	0.560	3
LNX1	physical association	0.560	3
LONRF1	physical association	0.560	3
MEI4	physical association	0.560	3
MEOX2	physical association	0.560	3
MSS51	physical association	0.560	3
MTF2	physical association	0.560	3
NDUFB7	physical association	0.560	3
NIF3L1	physical association	0.560	3

BioGRID (113 interactions; top human partners by supporting records): CDK4 (Two-hybrid; 15 records), CDK6 (Two-hybrid; 12 records), BRCA1 (Affinity Capture-Western; 4 records), HSD17B14 (Two-hybrid; 3 records), C1orf94 (Two-hybrid; 2 records), IKZF3 (Two-hybrid; 2 records), INCA1 (Two-hybrid; 2 records), NR4A2 (Two-hybrid; 2 records), AK2 (Affinity Capture-MS), APP (Reconstituted Complex), BTG1 (Two-hybrid), C5orf49 (Two-hybrid), CCND3 (Two-hybrid), CDC37 (Affinity Capture-MS), CDC42BPA (Affinity Capture-MS)

SIGNOR signaling

showing 5 of 7 signaling interactions:

A	Effect	B	Mechanism
FOXO1	“up-regulates quantity by expression”	CDKN2D	“transcriptional regulation”
CDK2	up-regulates	CDKN2D	phosphorylation
PRKCA	up-regulates	CDKN2D	phosphorylation
FOXO	“up-regulates quantity by expression”	CDKN2D	“transcriptional regulation”
DNMT3A	“down-regulates quantity by repression”	CDKN2D	“transcriptional regulation”

Disease & clinical

Genetic variants

Variant evidence for CDKN2D: 16 ClinVar records (0 pathogenic / likely pathogenic); 11 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	15
Likely benign	0
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 24 predictions of 291):

Position(s)	Effect	Δscore	Sites
19:10568511–10568512	donor_loss	1.0000	5
19:10567418–10567419	acceptor_loss	0.9900	6
19:10567422	acceptor_gain	0.9900
19:10568528	donor_gain	0.9800
19:10567420	acceptor_loss	0.9600
19:10568945–10568946	donor_loss	0.9200	6
19:10568942	donor_loss	0.9100
19:10568950	donor_gain	0.9100
19:10568942	donor_loss	0.9000
19:10567957	donor_gain	0.8900

AlphaMissense

347 missense substitutions predicted likely pathogenic (of 1,066 scored), across 104 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D71	8	0.918	0.981
D136	7	0.906	0.954
F51	7	0.894	0.977
N39	7	0.877	0.989
F125	7	0.860	0.961
F41	7	0.856	0.967
D104	7	0.837	0.913
H112	7	0.786	0.875
D36	7	0.706	0.864
D80	7	0.663	0.788
K43	6	0.879	0.964
M49	6	0.850	0.929
F86	6	0.844	0.966
H79	6	0.805	0.899
G19	6	0.793	0.950
D10	6	0.766	0.851
G85	5	0.915	0.974
P110	5	0.909	0.983
S13	5	0.881	0.962
G52	5	0.826	0.949

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	0.000548
Kidney Chromophobe (TCGA)	unfavorable	0.000904

Disease associations

OMIM: gene MIM:600927 | disease phenotypes:

GWAS associations

11 associations:

Study	Trait	p-value
GCST90002392_608	Mean corpuscular volume	2e-27
GCST90002397_778	Mean spheric corpuscular volume	3e-22
GCST90002404_159	Red cell distribution width	3e-21
GCST90002392_609	Mean corpuscular volume	2e-19
GCST90002390_462	Mean corpuscular hemoglobin	4e-18
GCST90002390_463	Mean corpuscular hemoglobin	7e-17
GCST90002396_117	Mean reticulocyte volume	1e-15
GCST90002404_160	Red cell distribution width	5e-15
GCST90002389_285	Lymphocyte percentage of white cells	5e-13
GCST90002403_5	Red blood cell count	5e-12
GCST90002403_643	Red blood cell count	5e-9

EFO canonical traits (from GWAS)

5 canonical traits:

EFO ID	Trait name
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0004527	mean corpuscular hemoglobin
EFO:0010701	mean reticulocyte volume
EFO:0004305	erythrocyte count
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression, increases expression	3
Arsenic Trioxide	increases expression, affects cotreatment	3
Estradiol	affects cotreatment, increases expression, decreases expression	3
Hydrogen Peroxide	affects expression, decreases expression	3
Cadmium Chloride	decreases expression, increases expression	3
bisphenol A	increases expression, affects cotreatment	2
methylselenic acid	affects expression, increases expression	2
Decitabine	increases expression	2
Acetaminophen	increases expression	2
Calcitriol	affects cotreatment, decreases expression, increases expression	2
Phenylmercuric Acetate	increases expression, affects cotreatment	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Tretinoin	affects cotreatment, increases expression	2
Particulate Matter	increases abundance, affects expression, decreases expression	2
aristolochic acid I	increases expression	1
alpha phellandrene	increases expression	1
triphenyl phosphate	affects expression	1
testosterone undecanoate	affects cotreatment, increases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
3,3’-diindolylmethane	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression	1
potassium chromate(VI)	increases expression	1
4-hydroxy-2-nonenal	decreases expression	1
nickel sulfate	increases expression	1
avobenzone	increases expression	1
gardenoside	affects binding, decreases reaction, increases expression	1
chromium hexavalent ion	increases expression	1
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	affects expression, affects reaction	1
CGP 52608	increases reaction, affects binding	1

Cellosaurus cell lines

14 cell lines: 10 cancer cell line, 3 embryonic stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_3768	OV-90	Cancer cell line	Female
CVCL_4Z23	OV90C-A	Cancer cell line	Female
CVCL_4Z24	OV90C-D	Cancer cell line	Female
CVCL_4Z25	OV90D-6	Cancer cell line	Female
CVCL_4Z26	OV90D-7	Cancer cell line	Female
CVCL_4Z27	OV90P-3	Cancer cell line	Female
CVCL_4Z28	OV90P-7	Cancer cell line	Female
CVCL_A0M8	SEES3-1V human CDKN2D, clone1	Embryonic stem cell	Male
CVCL_A0M9	SEES3-1V human CDKN2D, clone2	Embryonic stem cell	Male
CVCL_A0N0	SEES3-1V human CDKN2D, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.