CNOT2

Summary

CNOT2 (CCR4-NOT transcription complex subunit 2, HGNC:7878) is a protein-coding gene on chromosome 12q15, encoding CCR4-NOT transcription complex subunit 2 (Q9NZN8). Component of the CCR4-NOT complex which is one of the major cellular mRNA deadenylases and is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational initiation and general transcription regul…. It is a selective cancer dependency (DepMap: 32.4% of cell lines).

This gene encodes a subunit of the multi-component CCR4-NOT complex. The CCR4-NOT complex regulates mRNA synthesis and degradation and is also thought to be involved in mRNA splicing, transport and localization. The encoded protein interacts with histone deacetylases and functions as a repressor of polymerase II transcription. Alternatively spliced transcript variants have been observed for this gene.

Source: NCBI Gene 4848 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies (Strong, GenCC)
• GWAS associations: 5
• Clinical variants (ClinVar): 95 total — 5 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 21
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 32.4% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_014515

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7878
Approved symbol	CNOT2
Name	CCR4-NOT transcription complex subunit 2
Location	12q15
Locus type	gene with protein product
Status	Approved
Aliases	CDC36, NOT2H
Ensembl gene	ENSG00000111596
Ensembl biotype	protein_coding
OMIM	604909
Entrez	4848

Gene structure

Transcript identifiers

Ensembl transcripts: 49 — 26 protein_coding, 8 protein_coding_CDS_not_defined, 8 retained_intron, 7 nonsense_mediated_decay

ENST00000229195, ENST00000418359, ENST00000546673, ENST00000547149, ENST00000547321, ENST00000547780, ENST00000547867, ENST00000548021, ENST00000548159, ENST00000548230, ENST00000548338, ENST00000548599, ENST00000548686, ENST00000548741, ENST00000548863, ENST00000548939, ENST00000549443, ENST00000549705, ENST00000549709, ENST00000549750, ENST00000549947, ENST00000550155, ENST00000550160, ENST00000550194, ENST00000550641, ENST00000550705, ENST00000551043, ENST00000551132, ENST00000551179, ENST00000551434, ENST00000551483, ENST00000551661, ENST00000551710, ENST00000551873, ENST00000552151, ENST00000552319, ENST00000552422, ENST00000552483, ENST00000552599, ENST00000552915, ENST00000553020, ENST00000553078, ENST00000868453, ENST00000868454, ENST00000868455, ENST00000932301, ENST00000932302, ENST00000932303, ENST00000953274

RefSeq mRNA: 15 — MANE Select: NM_014515 NM_001199302, NM_001199303, NM_001414651, NM_001414652, NM_001414653, NM_001414654, NM_001414655, NM_001414656, NM_001414657, NM_001414658, NM_001414659, NM_001414660, NM_001414661, NM_001414662, NM_014515

CCDS: CCDS31857

Canonical transcript exons

ENST00000229195 — 16 exons

Exon	Start	End
ENSE00001478811	70353829	70354993
ENSE00002382800	70243433	70243480
ENSE00003471844	70346180	70346324
ENSE00003503428	70344128	70344228
ENSE00003546590	70338666	70338822
ENSE00003560571	70342258	70342307
ENSE00003566335	70337389	70337513
ENSE00003588175	70310895	70311017
ENSE00003608556	70329423	70329570
ENSE00003614498	70330287	70330469
ENSE00003644637	70338443	70338563
ENSE00003652343	70278132	70278274
ENSE00003681241	70319298	70319364
ENSE00003722615	70335438	70335563
ENSE00003786384	70332767	70332846
ENSE00003786487	70342107	70342168

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 98.75.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 50.2196 / max 800.2977, expressed in 1820 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
126780	45.5903	1815
126774	2.1681	896
126781	1.3028	792
126773	0.6352	210
126782	0.2132	49
126783	0.1424	37
126776	0.0849	33
126775	0.0642	18
126784	0.0183	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	98.75	gold quality
secondary oocyte	CL:0000655	98.24	gold quality
cervix squamous epithelium	UBERON:0006922	97.81	gold quality
calcaneal tendon	UBERON:0003701	97.58	gold quality
nipple	UBERON:0002030	97.41	gold quality
epithelium of nasopharynx	UBERON:0001951	97.18	gold quality
nasopharynx	UBERON:0001728	97.16	gold quality
penis	UBERON:0000989	96.86	gold quality
tendon	UBERON:0000043	96.81	gold quality
colonic epithelium	UBERON:0000397	96.74	gold quality
adrenal tissue	UBERON:0018303	96.63	gold quality
ganglionic eminence	UBERON:0004023	96.57	gold quality
cortical plate	UBERON:0005343	96.53	gold quality
skin of abdomen	UBERON:0001416	96.48	gold quality
cerebellar cortex	UBERON:0002129	96.48	gold quality
cerebellar hemisphere	UBERON:0002245	96.48	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.41	gold quality
sperm	CL:0000019	96.27	gold quality
gingival epithelium	UBERON:0001949	96.23	gold quality
corpus callosum	UBERON:0002336	96.22	gold quality
tibia	UBERON:0000979	96.12	gold quality
cerebellum	UBERON:0002037	96.10	gold quality
embryo	UBERON:0000922	96.08	gold quality
skin of leg	UBERON:0001511	96.08	gold quality
pericardium	UBERON:0002407	96.00	gold quality
zone of skin	UBERON:0000014	95.99	gold quality
germinal epithelium of ovary	UBERON:0001304	95.91	gold quality
monocyte	CL:0000576	95.79	gold quality
gingiva	UBERON:0001828	95.72	gold quality
tonsil	UBERON:0002372	95.69	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-89232	yes	2707.25
E-MTAB-6678	yes	26.48
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NCOR1, NCOR2, NR0B1, THRA

miRNA regulators (miRDB)

194 targeting CNOT2, 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-5011-5P	100.00	83.46	5820
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 32.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 13)

• major repression function of CNOT2 is localized in a specialized protein motif, the Not-Box (PMID:14707134)
• These findings suggest that CDK11 may contribute to apoptosis by regulating the activity of NOT2 independent of its kinase activity. (PMID:16039607)
• This study shows that SMRT/NCoR-HDAC3 complex is a cofactor of CNOT2-mediated repression and suggests that transcriptional regulation by the Ccr4-Not complex involves regulation of chromatin modification. (PMID:16712523)
• human CNOT2 is important for maintaining the deadenylase activity and structural integrity of the CCR4-NOT complex, thereby affecting cell viability. (PMID:21299754)
• Cnot1, Cnot2, and Cnot3 represent a novel component of the core self-renewal and pluripotency circuitry conserved in mouse and human ESCs. (PMID:22367759)
• The CNOT2-CNOT3 heterodimer is stabilized and tightly anchored to the surface of CNOT1 through an unexpected intertwined arrangement of peptide regions lacking defined secondary structure. (PMID:24121232)
• ERG is recruited to mRNAs via interaction with the RNA-binding protein RBPMS, and it promotes mRNA decay by binding CNOT2, a component of the CCR4-NOT deadenylation complex. (PMID:27273514)
• Increased expression of MHC II genes after knock-down or knock-out of either CNOT1, CNOT2, or CNOT3 subunit was seen in a variety of cell systems and also in naive macrophages from CNOT3 conditional knock-out mice. (PMID:28615693)
• CNOT2 promotes proliferation and angiogenesis via VEGF signaling in MDA-MB-231 breast cancer cells. (PMID:29024811)
• CNOT2 is a novel negative regulator of the JAK-STAT pathway and supports dengue virus infection. (PMID:31155293)
• CCR4NOT transcription complex subunit 2 regulates TRAIL sensitivity in nonsmallcell lung cancer cells via the STAT3 pathway. (PMID:31894259)
• CNOT2 haploinsufficiency in a 40-year-old man with intellectual disability, autism, and seizures. (PMID:34018673)
• Inhibition of CNOT2 Induces Apoptosis via MID1IP1 in Colorectal Cancer Cells by Activating p53. (PMID:34680125)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cnot2	ENSDARG00000061802
mus_musculus	Cnot2	ENSMUSG00000020166
rattus_norvegicus	Cnot2	ENSRNOG00000004909
drosophila_melanogaster	Rga	FBGN0017550
drosophila_melanogaster	CG15262	FBGN0028852
caenorhabditis_elegans		WBGENE00003825

Paralogs (1): CNOT3 (ENSG00000088038)

Protein

Protein identifiers

CCR4-NOT transcription complex subunit 2 — Q9NZN8 (reviewed: Q9NZN8)

Alternative names: CCR4-associated factor 2

All UniProt accessions (22): Q9NZN8, A0A087X050, F8VPX5, F8VQD8, F8VQF4, F8VRJ3, F8VRS8, F8VS14, F8VSK9, F8VUB4, F8VV05, F8VV52, F8VVD4, F8VVY1, F8VWH8, F8VX63, F8W145, H0YH84, H0YHT6, H0YHT8, H0YI11, H0YI80

UniProt curated annotations — full annotation on UniProt →

Function. Component of the CCR4-NOT complex which is one of the major cellular mRNA deadenylases and is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational initiation and general transcription regulation. Additional complex functions may be a consequence of its influence on mRNA expression. Required for the CCR4-NOT complex structural integrity. Can repress transcription and may link the CCR4-NOT complex to transcriptional regulation; the repressive function may specifically involve the N-Cor repressor complex containing HDAC3, NCOR1 and NCOR2. Involved in the maintenance of embryonic stem (ES) cell identity.

Subunit / interactions. Component of the CCR4-NOT complex; distinct complexes seem to exist that differ in the participation of probably mutually exclusive catalytic subunits. In the complex interacts directly with CNOT3. Interacts with NCOR1, NCOR2. HDAC3 and GPS2.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Ubiquitous. Highly expressed in brain, heart, thymus, spleen, kidney, liver, small intestine, placenta, lung and peripheral blood leukocytes.

Disease relevance. Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies (IDNADFS) [MIM:618608] An autosomal dominant disorder characterized by delayed development, speech delay with nasal speech, and characteristic facial features including upslanted palpebral fissures, anteverted nares, a thin upper lip, and micrognathia. Some patients may have skeletal anomalies, such as brachydactyly, toe syndactyly and flat feet. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. May be due to an intron retention. May be due to an intron retention.

Similarity. Belongs to the CNOT2/3/5 family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9NZN8-1	1	yes
Q9NZN8-2	2
Q9NZN8-3	3
Q9NZN8-4	4
Q9NZN8-5	5

RefSeq proteins (15): NP_001186231, NP_001186232, NP_001401580, NP_001401581, NP_001401582, NP_001401583, NP_001401584, NP_001401585, NP_001401586, NP_001401587, NP_001401588, NP_001401589, NP_001401590, NP_001401591, NP_055330* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007282	NOT2/3/5_C	Domain
IPR038635	CCR4-NOT_su2/3/5_C_sf	Homologous_superfamily
IPR040168	Not2/3/5	Family

Pfam: PF04153

UniProt features (42 total): helix 12, modified residue 7, splice variant 5, strand 5, turn 4, region of interest 3, compositionally biased region 3, sequence variant 2, chain 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
4C0F	X-RAY DIFFRACTION	2.4
5FU6	X-RAY DIFFRACTION	2.9
5FU7	X-RAY DIFFRACTION	3.1
4C0D	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZN8-F1	60.35	0.26

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 (7): 165, 169, 242, 274, 93, 126, 157

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-429947	Deadenylation of mRNA
R-HSA-6804115	TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain
R-HSA-9820841	M-decay: degradation of maternal mRNAs by maternally stored factors

MSigDB gene sets: 384 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOMF_RNA_NUCLEASE_ACTIVITY, GOBP_P_BODY_ASSEMBLY, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOMF_NUCLEASE_ACTIVITY, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_ESTROGEN_RECEPTOR_SIGNALING_PATHWAY, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_REGULATION_OF_INTRACELLULAR_STEROID_HORMONE_RECEPTOR_SIGNALING_PATHWAY, GENTILE_RESPONSE_CLUSTER_D3, GOBP_BLASTOCYST_FORMATION, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION

GO Biological Process (10): negative regulation of transcription by RNA polymerase II (GO:0000122), nuclear-transcribed mRNA poly(A) tail shortening (GO:0000289), trophectodermal cell differentiation (GO:0001829), regulation of transcription by RNA polymerase II (GO:0006357), regulation of translation (GO:0006417), positive regulation of cytoplasmic mRNA processing body assembly (GO:0010606), regulatory ncRNA-mediated gene silencing (GO:0031047), negative regulation of intracellular estrogen receptor signaling pathway (GO:0033147), regulation of stem cell population maintenance (GO:2000036), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (4): transcription corepressor binding (GO:0001222), transcription coregulator activity (GO:0003712), poly(A)-specific ribonuclease activity (GO:0004535), protein binding (GO:0005515)

GO Cellular Component (9): P-body (GO:0000932), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), CCR4-NOT complex (GO:0030014), CCR4-NOT core complex (GO:0030015)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Deadenylation-dependent mRNA decay	1
TP53 Regulates Transcription of Cell Cycle Genes	1
Maternal to zygotic transition (MZT)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
transcription by RNA polymerase II	2
intracellular protein-containing complex	2
regulation of transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	1
nuclear-transcribed mRNA catabolic process	1
blastocyst formation	1
cell differentiation	1
regulation of DNA-templated transcription	1
translation	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
regulation of cytoplasmic mRNA processing body assembly	1
P-body assembly	1
positive regulation of organelle assembly	1
negative regulation of gene expression	1
estrogen receptor signaling pathway	1
negative regulation of intracellular steroid hormone receptor signaling pathway	1
regulation of intracellular estrogen receptor signaling pathway	1
stem cell population maintenance	1
regulation of developmental process	1
regulation of multicellular organismal process	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
transcription coregulator binding	1
transcription regulator activity	1
3’-5’-RNA exonuclease activity	1
binding	1
cytoplasmic ribonucleoprotein granule	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1
CCR4-NOT complex	1

Protein interactions and networks

STRING

1893 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CNOT2	CNOT1	A5YKK6	999
CNOT2	CNOT4	O95628	999
CNOT2	CNOT9	Q92600	998
CNOT2	CNOT7	Q9UIV1	997
CNOT2	CNOT10	Q9H9A5	995
CNOT2	CNOT8	Q9UFF9	995
CNOT2	CNOT3	O75175	993
CNOT2	CNOT11	Q9UKZ1	992
CNOT2	CNOT6	Q9ULM6	981
CNOT2	CNOT6L	Q96LI5	977
CNOT2	TMEM214	Q6NUQ4	902
CNOT2	EXD2	Q9NVH0	898
CNOT2	SEC61B	P38390	832
CNOT2	SEC61G	P38384	655
CNOT2	SEC62	Q99442	649

IntAct

202 interactions, top by confidence:

A	B	Type	Score
CNOT3	CNOT2	psi-mi:“MI:0915”(physical association)	0.940
CNOT2	CNOT3	psi-mi:“MI:0915”(physical association)	0.940
CNOT7	CNOT1	psi-mi:“MI:0914”(association)	0.880
CNOT6L	CNOT1	psi-mi:“MI:0914”(association)	0.810
CNOT11	CNOT1	psi-mi:“MI:0914”(association)	0.770
CNOT2	CNOT1	psi-mi:“MI:0914”(association)	0.740
CNOT2	CNOT6L	psi-mi:“MI:0915”(physical association)	0.740
CNOT3	CNOT1	psi-mi:“MI:0914”(association)	0.740
CNOT2	CNOT1	psi-mi:“MI:0915”(physical association)	0.740
TOB1	CNOT1	psi-mi:“MI:0914”(association)	0.710
CAPZB	CNOT1	psi-mi:“MI:0914”(association)	0.640
CAPZA2	CNOT1	psi-mi:“MI:0914”(association)	0.640
TNRC6C	CNOT1	psi-mi:“MI:0914”(association)	0.620
CNOT2	TNRC6C	psi-mi:“MI:0915”(physical association)	0.620

BioGRID (314): CNOT2 (Affinity Capture-Western), CNOT1 (Affinity Capture-Western), CNOT3 (Affinity Capture-Western), CNOT8 (Affinity Capture-Western), CNOT2 (Affinity Capture-Western), CNOT2 (Affinity Capture-MS), CNOT2 (Affinity Capture-MS), CNOT2 (Affinity Capture-MS), CNOT2 (Affinity Capture-MS), CNOT3 (Two-hybrid), CNOT2 (Affinity Capture-MS), CNOT2 (Affinity Capture-Western), CNOT2 (Affinity Capture-Western), CNOT2 (Affinity Capture-Western), CNOT2 (Affinity Capture-Western)

ESM2 similar proteins: A1ZAU8, A2ICN5, A2VDZ3, A8MPH9, B3MI72, B3NA01, B4GCP2, B4HQT6, B4J6N6, B4KND9, B4LMA2, B4MR74, B4P1N5, B5E1I4, G5EFT5, G5EGU9, O61735, P21525, P22813, P34545, P40791, P41846, Q02078, Q03413, Q06A37, Q20733, Q20898, Q21955, Q22366, Q24535, Q24573, Q29A33, Q2MJT0, Q5REW7, Q60929, Q61L47, Q758Y4, Q7JRJ1, Q86MD3, Q8C5L3

Diamond homologs: O13870, O75175, P06102, P87240, Q12514, Q52JK6, Q8C5L3, Q8K0V4, Q9NZN8, P06100, Q94547, Q9FPW4

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CNOT2	“form complex”	“CCR4-NOT complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 128 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
TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain	9	61.5×	2e-12
Deadenylation of mRNA	9	52.0×	7e-12
M-decay: degradation of maternal mRNAs by maternally stored factors	11	47.2×	9e-14
Regulation of MECP2 expression and activity	7	33.9×	1e-07
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	6	24.4×	9e-06
Transcriptional Regulation by MECP2	5	20.9×	1e-04
Ca2+ pathway	5	11.7×	2e-03
TP53 Regulates Metabolic Genes	6	10.2×	7e-04

GO biological processes:

GO term	Partners	Fold	FDR
nuclear-transcribed mRNA poly(A) tail shortening	10	73.6×	2e-14
positive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	7	72.2×	5e-10
regulatory ncRNA-mediated gene silencing	8	49.5×	5e-10
nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	5	48.3×	5e-06
miRNA-mediated gene silencing by inhibition of translation	5	40.7×	1e-05
negative regulation of translation	9	16.2×	7e-07
regulation of translation	7	14.1×	6e-05
regulation of circadian rhythm	5	11.9×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	6
Uncertain significance	53
Likely benign	10
Benign	1

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
3146607	NM_014515.7(CNOT2):c.683C>A (p.Ser228Ter)	Pathogenic
3369381	NM_014515.7(CNOT2):c.203_211delinsACCATCTACA (p.Leu68fs)	Pathogenic
59023	GRCh38/hg38 12q15(chr12:70029314-70599455)x1	Pathogenic
691599	NC_000012.11:g.70672317_70757341del	Pathogenic
691600	NM_014515.7(CNOT2):c.946A>T (p.Lys316Ter)	Pathogenic
1064799	NM_014515.7(CNOT2):c.1621dup (p.Ter541LeuextTer?)	Likely pathogenic
3063251	GRCh37/hg19 12q15(chr12:70430549-70988542)x1	Likely pathogenic
3338647	NM_014515.7(CNOT2):c.1369del (p.Gln457fs)	Likely pathogenic
394428	GRCh37/hg19 12q15(chr12:70588735-71366869)x1	Likely pathogenic
4278472	NM_014515.7(CNOT2):c.49-2A>G	Likely pathogenic
443535	GRCh37/hg19 12q15-21.1(chr12:70575476-73344659)x1	Likely pathogenic

SpliceAI

3327 predictions. Top by Δscore:

Variant	Effect	Δscore
12:70243478:GCG:G	donor_gain	1.0000
12:70278130:A:AG	acceptor_gain	1.0000
12:70278131:G:GG	acceptor_gain	1.0000
12:70278199:C:CA	acceptor_gain	1.0000
12:70310889:GTTTA:G	acceptor_loss	1.0000
12:70310891:TTAG:T	acceptor_loss	1.0000
12:70310892:TAGGT:T	acceptor_loss	1.0000
12:70310893:A:AT	acceptor_loss	1.0000
12:70310894:G:GC	acceptor_loss	1.0000
12:70311013:AAGAT:A	donor_gain	1.0000
12:70311014:AGAT:A	donor_gain	1.0000
12:70311015:GAT:G	donor_gain	1.0000
12:70311015:GATG:G	donor_gain	1.0000
12:70311016:AT:A	donor_gain	1.0000
12:70311017:TG:T	donor_loss	1.0000
12:70311018:G:GG	donor_gain	1.0000
12:70311018:GTA:G	donor_loss	1.0000
12:70311019:TAAG:T	donor_loss	1.0000
12:70319365:G:GG	donor_gain	1.0000
12:70332758:T:G	acceptor_gain	1.0000
12:70332765:A:AG	acceptor_gain	1.0000
12:70332766:G:GG	acceptor_gain	1.0000
12:70332766:GT:G	acceptor_gain	1.0000
12:70335436:A:AG	acceptor_gain	1.0000
12:70335436:AGAC:A	acceptor_gain	1.0000
12:70335437:G:GG	acceptor_gain	1.0000
12:70335437:GACG:G	acceptor_gain	1.0000
12:70335506:G:T	donor_gain	1.0000
12:70335510:G:GT	donor_gain	1.0000
12:70335549:G:GT	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000031984 (12:70250121 T>C), RS1000046330 (12:70346189 T>A), RS1000063298 (12:70255860 T>C), RS1000123015 (12:70286510 C>T), RS1000153966 (12:70286121 C>T), RS1000158442 (12:70255652 G>T), RS1000215682 (12:70327604 G>A), RS1000217105 (12:70324524 C>T), RS1000222933 (12:70317772 A>C), RS1000223762 (12:70337602 C>A,G), RS1000232990 (12:70332451 G>T), RS1000244414 (12:70332123 G>C), RS1000258392 (12:70249916 T>C), RS1000275432 (12:70317525 A>G), RS1000277677 (12:70339051 C>A,T)

Disease associations

OMIM: gene MIM:604909 | disease phenotypes: MIM:618608, MIM:615873

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies	Strong	Autosomal dominant

Mondo (3): neurodevelopmental disorder (MONDO:0700092), intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies (MONDO:0032832), ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder (MONDO:0014379)

Orphanet (3): Helsmoortel-Van der Aa syndrome (Orphanet:404448), Intellectual disability-nasal speech-craniofacial dysmorphism syndrome (Orphanet:697760), Intellectual disability-nasal speech-craniofacial dysmorphism syndrome due to CNOT2 mutation (Orphanet:697764)

HPO phenotypes

21 total (21 of 21 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000219	Thin upper lip vermilion
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000463	Anteverted nares
HP:0000527	Long eyelashes
HP:0000574	Thick eyebrow
HP:0000582	Upslanted palpebral fissure
HP:0000692	Tooth malposition
HP:0000750	Delayed speech and language development
HP:0001007	Hirsutism
HP:0001270	Motor delay
HP:0001290	Generalized hypotonia
HP:0001611	Hypernasal speech
HP:0002650	Scoliosis
HP:0004209	Clinodactyly of the 5th finger
HP:0004691	2-3 toe syndactyly
HP:0008872	Feeding difficulties in infancy
HP:0009237	Short 5th finger
HP:0011228	Horizontal eyebrow

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001663_7	Amyotrophic lateral sclerosis (age of onset)	5.000000e-06
GCST007094_146	Diastolic blood pressure	4.000000e-08
GCST007239_21	Ovarian cancer	9.000000e-07
GCST007239_22	Ovarian cancer	3.000000e-06
GCST010173_168	Triglyceride levels	1.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004847	age at onset
EFO:0006336	diastolic blood pressure
EFO:0004530	triglyceride measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105920 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, decreases methylation	5
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	3
trichostatin A	affects expression, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
dicrotophos	decreases expression	1
bisphenol A	increases methylation	1
cinnamaldehyde	decreases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
butyraldehyde	decreases expression	1
manganese chloride	decreases expression	1
ochratoxin A	decreases acetylation, decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
4-phenylbutyric acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
bisphenol S	affects cotreatment, decreases methylation	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	decreases expression	1
Arsenic Trioxide	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Caffeine	decreases phosphorylation	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Estradiol	decreases expression	1
Formaldehyde	decreases expression	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Manganese	decreases expression	1
Methyl Methanesulfonate	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4012558	Binding	Binding affinity to CCR4-NOT transcription complex subunit 2 in human INA-6 cells after 3 hrs by nanoLC-MS/MS method	Ugi Reaction-Derived α-Acyl Aminocarboxamides Bind to Phosphatidylinositol 3-Kinase-Related Kinases, Inhibit HSF1-Dependent Heat Shock Response, and Induce Apoptosis in Multiple Myeloma Cells. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E0AF	Ubigene HeLa CNOT2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice