CNOT3

Summary

CNOT3 (CCR4-NOT transcription complex subunit 3, HGNC:7879) is a protein-coding gene on chromosome 19q13.42, encoding CCR4-NOT transcription complex subunit 3 (O75175). 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 common-essential gene (DepMap: required in 99.2% of cancer cell lines).

Involved in regulation of stem cell population maintenance. Part of CCR4-NOT complex.

Source: NCBI Gene 4849 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 459 total — 44 pathogenic, 24 likely-pathogenic
• Phenotypes (HPO): 42
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 2 cancer types
• Cancer dependency (DepMap): dependent in 99.2% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_014516

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7879
Approved symbol	CNOT3
Name	CCR4-NOT transcription complex subunit 3
Location	19q13.42
Locus type	gene with protein product
Status	Approved
Aliases	NOT3H, KIAA0691, LENG2
Ensembl gene	ENSG00000088038
Ensembl biotype	protein_coding
OMIM	604910
Entrez	4849

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 23 protein_coding, 3 nonsense_mediated_decay, 3 retained_intron

ENST00000221232, ENST00000358389, ENST00000440571, ENST00000457463, ENST00000471126, ENST00000496327, ENST00000613073, ENST00000617930, ENST00000618939, ENST00000642159, ENST00000644245, ENST00000644707, ENST00000646002, ENST00000647082, ENST00000896564, ENST00000896565, ENST00000896566, ENST00000933501, ENST00000933502, ENST00000933503, ENST00000933504, ENST00000933505, ENST00000933506, ENST00000933507, ENST00000933508, ENST00000933509, ENST00000933510, ENST00000933511, ENST00000933512

RefSeq mRNA: 1 — MANE Select: NM_014516 NM_014516

CCDS: CCDS12880

Canonical transcript exons

ENST00000221232 — 18 exons

Exon	Start	End
ENSE00001357714	54153715	54153840
ENSE00003458553	54142929	54143003
ENSE00003460544	54148620	54148743
ENSE00003468629	54155309	54155681
ENSE00003487460	54152226	54152325
ENSE00003520390	54144237	54144332
ENSE00003555014	54145598	54145817
ENSE00003579808	54146601	54146657
ENSE00003597022	54148148	54148535
ENSE00003597188	54143442	54143516
ENSE00003647472	54144006	54144134
ENSE00003651012	54152428	54152626
ENSE00003658561	54143660	54143749
ENSE00003670826	54145910	54146043
ENSE00003672512	54143119	54143186
ENSE00003677484	54152867	54152999
ENSE00003679131	54149560	54149758
ENSE00003830018	54137762	54137993

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 95.82.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.9845 / max 179.6179, expressed in 1821 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
177469	30.0201	1820
177468	0.7895	493
177470	0.1748	73

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	95.82	gold quality
pituitary gland	UBERON:0000007	94.84	gold quality
granulocyte	CL:0000094	94.59	gold quality
right uterine tube	UBERON:0001302	94.48	gold quality
adenohypophysis	UBERON:0002196	94.38	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.26	gold quality
ventricular zone	UBERON:0003053	93.91	gold quality
left lobe of thyroid gland	UBERON:0001120	93.88	gold quality
right lobe of thyroid gland	UBERON:0001119	93.84	gold quality
cerebellar hemisphere	UBERON:0002245	93.73	gold quality
cerebellum	UBERON:0002037	93.71	gold quality
cerebellar cortex	UBERON:0002129	93.70	gold quality
blood	UBERON:0000178	93.67	gold quality
left testis	UBERON:0004533	93.64	gold quality
thyroid gland	UBERON:0002046	93.54	gold quality
right testis	UBERON:0004534	93.41	gold quality
right adrenal gland cortex	UBERON:0035827	93.21	gold quality
left ovary	UBERON:0002119	93.17	gold quality
endocervix	UBERON:0000458	93.16	gold quality
lower esophagus mucosa	UBERON:0035834	93.14	gold quality
right adrenal gland	UBERON:0001233	93.07	gold quality
right ovary	UBERON:0002118	93.06	gold quality
testis	UBERON:0000473	93.05	gold quality
ganglionic eminence	UBERON:0004023	92.97	gold quality
metanephros cortex	UBERON:0010533	92.89	gold quality
spleen	UBERON:0002106	92.81	gold quality
body of uterus	UBERON:0009853	92.77	gold quality
prostate gland	UBERON:0002367	92.76	gold quality
ovary	UBERON:0000992	92.70	gold quality
right coronary artery	UBERON:0001625	92.52	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.85

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
PRPF31
TNFRSF11A	Repression

miRNA regulators (miRDB)

24 targeting CNOT3, 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-3646	100.00	73.56	5283
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-516A-3P	99.46	67.96	1378
HSA-MIR-516B-3P	99.46	67.96	1378
HSA-MIR-7162-5P	99.46	68.08	1368
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-664A-3P	99.22	71.08	2696
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-6769B-5P	98.73	64.91	1092
HSA-MIR-6769A-5P	97.99	64.16	851
HSA-MIR-6765-3P	97.83	64.59	1165
HSA-MIR-3194-5P	96.80	64.90	1027

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 99.2% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 22)

• TBP-interacting protein 120B binds to NOT3 (PMID:12207886)
• A high density SNP genotyping approach within the 19q13 chromosome region identifies an association of a CNOT3 polymorphism with ankylosing spondylitis. (PMID:22294640)
• CNOT3 depletion stabilizes the MAD1 mRNA, and MAD1 knockdown attenuates the CNOT3 depletion-induced increase of the mitotic index. (PMID:22342980)
• Cnot1, Cnot2, and Cnot3 represent a novel component of the core self-renewal and pluripotency circuitry conserved in mouse and human ESCs. (PMID:22367759)
• In asymptomatic carriers CNOT3 is expressed at low levels, allowing higher amounts of wild-type PRPF31 transcripts to be produced and preventing manifestation of retinal degeneration. (PMID:23144630)
• CNOT3 is a tumor suppressor mutated in 7 of 89 (7.9%) adult T-cell acute lymphoblastic leukemias, and its knockdown causes tumors in a sensitized Drosophila melanogaster model. (PMID:23263491)
• A mutation in PRPF31 is hypostatic to a trait acting on CNOT3, with the RP11 phenotype only being observed when there is homozygous (recessive) inheritance of the higher expressivity CNOT3 (“symptomatic” or risk) allele. (PMID:24116917)
• 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)
• our findings implicate CNOT3 in the coordination of colonic epithelial cell self-renewal, suggesting this factor as a new biomarker for molecular and prognostic classification of early-stage colorectal cancer (PMID:27899379)
• Cnot3 enhances cardiomyocyte proliferation by promoting cell cycle inhibitor mRNA degradation. (PMID:28473716)
• 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)
• The up-regulation of CNOT3 facilitates the development of non-small cell lung cancer. (PMID:30531840)
• CCR4-NOT transcription complex subunit 3 (CNOT3) is up-regulated in lung cancer tissues and is associated with poor prognosis of the patients. Knocking down CNOT3 expression sensitizes cisplatin-resistant A549 (A549/DDP) cells to cisplatin-induced apoptosis. CNOT3 depletion up-regulates the expression level of RIPK3 and the enhanced apoptosis is mediated by the elevated RIPK3 to further trigger Caspase 8 activation. (PMID:31177396)
• De novo variants in CNOT3 cause a variable neurodevelopmental disorder. (PMID:31201375)
• The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy. (PMID:31474762)
• Inherited cases of CNOT3-associated intellectual developmental disorder with speech delay, autism, and dysmorphic facies. (PMID:32720325)
• A Genetic Study of Cerebral Atherosclerosis Reveals Novel Associations with NTNG1 and CNOT3. (PMID:34073619)
• CNOT3 interacts with the Aurora B and MAPK/ERK kinases to promote survival of differentiating mesendodermal progenitor cells. (PMID:34613789)
• Determinants of Disease Penetrance in PRPF31-Associated Retinopathy. (PMID:34680937)
• Clinical features of CNOT3-associated neurodevelopmental disorder in three Chinese patients. (PMID:36802310)
• CCR4-NOT differentially controls host versus virus poly(a)-tail length and regulates HCMV infection. (PMID:37846490)
• Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis. (PMID:38491013)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cnot3a	ENSDARG00000007135
danio_rerio	cnot3b	ENSDARG00000019842
mus_musculus	Cnot3	ENSMUSG00000035632
rattus_norvegicus	Cnot3	ENSRNOG00000053234
drosophila_melanogaster	Not3	FBGN0033029
caenorhabditis_elegans		WBGENE00003826

Paralogs (1): CNOT2 (ENSG00000111596)

Protein

Protein identifiers

CCR4-NOT transcription complex subunit 3 — O75175 (reviewed: O75175)

Alternative names: CCR4-associated factor 3, Leukocyte receptor cluster member 2

All UniProt accessions (10): O75175, A0A087X0F9, A0A2R8Y4W0, A0A2R8Y691, A0A2R8Y6N5, A0A2R8Y7Z8, B7Z6J7, H0Y5X7, H7C148, H7C5J4

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. May be involved in metabolic regulation; may be involved in recruitment of the CCR4-NOT complex to deadenylation target mRNAs involved in energy metabolism. Involved in mitotic progression and regulation of the spindle assembly checkpoint by regulating the stability of MAD1L1 mRNA. Can repress transcription and may link the CCR4-NOT complex to transcriptional regulation; the repressive function may involve histone deacetylases. 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 CNOT2. Interacts with TIP120B and NANOS2. Interacts with EBF1. Interacts in an RNA-independent manner with BICC1 (via KH domains). Interacts with HELZ.

Subcellular location. Cytoplasm. Nucleus. P-body.

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

Disease relevance. Intellectual developmental disorder with speech delay, autism and dysmorphic facies (IDDSADF) [MIM:618672] An autosomal dominant disorder characterized by mild to severe intellectual disability, developmental delay, delayed or absent speech, hypotonia, short stature, autistic features, and highly variable dysmorphic facial features. The disease is caused by variants affecting the gene represented in this entry.

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

RefSeq proteins (1): NP_055331* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007207	Not_N	Domain
IPR007282	NOT2/3/5_C	Domain
IPR012270	CCR4-NOT_su3/5	Family
IPR038635	CCR4-NOT_su2/3/5_C_sf	Homologous_superfamily
IPR040168	Not2/3/5	Family

Pfam: PF04065, PF04153

UniProt features (51 total): helix 13, compositionally biased region 10, sequence variant 9, strand 8, turn 5, modified residue 3, region of interest 2, chain 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
9C3H	ELECTRON MICROSCOPY	2
4C0G	X-RAY DIFFRACTION	2.4
5FU6	X-RAY DIFFRACTION	2.9
5FU7	X-RAY DIFFRACTION	3.1
9C3I	ELECTRON MICROSCOPY	3.1
4C0D	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75175-F1	68.53	0.42

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 (3): 292, 299, 542

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: 278 (showing top): MORF_MTA1, AGGAAGC_MIR5163P, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MORF_HDAC2, GOBP_BLASTOCYST_FORMATION, YY1_Q6, PUJANA_CHEK2_PCC_NETWORK, GOBP_TRANSLATION, GOBP_SPECIFICATION_OF_SYMMETRY, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, E2F_Q3, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT, GOBP_REGULATION_OF_CATABOLIC_PROCESS

GO Biological Process (9): nuclear-transcribed mRNA poly(A) tail shortening (GO:0000289), trophectodermal cell differentiation (GO:0001829), regulation of DNA-templated transcription (GO:0006355), mRNA catabolic process (GO:0006402), regulation of translation (GO:0006417), determination of left/right symmetry (GO:0007368), regulatory ncRNA-mediated gene silencing (GO:0031047), positive regulation of cold-induced thermogenesis (GO:0120162), regulation of stem cell population maintenance (GO:2000036)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (6): P-body (GO:0000932), nucleus (GO:0005634), cytosol (GO:0005829), CCR4-NOT complex (GO:0030014), CCR4-NOT core complex (GO:0030015), cytoplasm (GO:0005737)

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
negative regulation of gene expression	2
cellular anatomical structure	2
intracellular protein-containing complex	2
nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	1
nuclear-transcribed mRNA catabolic process	1
blastocyst formation	1
cell differentiation	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
RNA catabolic process	1
mRNA metabolic process	1
translation	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
determination of bilateral symmetry	1
left/right pattern formation	1
positive regulation of multicellular organismal process	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	1
stem cell population maintenance	1
regulation of developmental process	1
regulation of multicellular organismal process	1
binding	1
cytoplasmic ribonucleoprotein granule	1
intracellular membrane-bounded organelle	1
cytoplasm	1
CCR4-NOT complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1909 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CNOT3	CNOT1	A5YKK6	999
CNOT3	CNOT4	O95628	999
CNOT3	CNOT9	Q92600	997
CNOT3	CNOT8	Q9UFF9	997
CNOT3	CNOT10	Q9H9A5	995
CNOT3	CNOT7	Q9UIV1	995
CNOT3	CNOT2	Q9NZN8	993
CNOT3	CNOT11	Q9UKZ1	991
CNOT3	CNOT6	Q9ULM6	987
CNOT3	CNOT6L	Q96LI5	975
CNOT3	PRPF31	Q8WWY3	689
CNOT3	EDC3	Q96F86	670
CNOT3	CNOT12	Q9C0C2	664
CNOT3	ZFX	P17010	644
CNOT3	TNRC6A	Q8NDV7	622

IntAct

158 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
CNOT11	CNOT1	psi-mi:“MI:0914”(association)	0.770
CNOT2	CNOT1	psi-mi:“MI:0914”(association)	0.740
CNOT3	CNOT1	psi-mi:“MI:0914”(association)	0.740
CNOT3	CNOT1	psi-mi:“MI:0915”(physical association)	0.740
CNOT3	CNOT8	psi-mi:“MI:0915”(physical association)	0.730
CNOT8	CNOT3	psi-mi:“MI:0915”(physical association)	0.730
CNOT3	TOB1	psi-mi:“MI:0914”(association)	0.710
CNOT3	TOB1	psi-mi:“MI:0915”(physical association)	0.710
TOB1	CNOT1	psi-mi:“MI:0914”(association)	0.710
TNRC6C	CNOT1	psi-mi:“MI:0914”(association)	0.690
CNOT6	CNOT3	psi-mi:“MI:0915”(physical association)	0.670
CAPZA2	CNOT1	psi-mi:“MI:0914”(association)	0.640
CAPZB	CNOT1	psi-mi:“MI:0914”(association)	0.640
TNRC6C	CNOT1	psi-mi:“MI:0914”(association)	0.620

BioGRID (251): CNOT3 (Reconstituted Complex), CNOT3 (Affinity Capture-Western), CNOT3 (Affinity Capture-MS), CNOT3 (Affinity Capture-Western), CNOT3 (Affinity Capture-Western), CNOT3 (Affinity Capture-Western), CNOT3 (Affinity Capture-Western), CNOT3 (Affinity Capture-Western), CNOT3 (Affinity Capture-Western), CNOT3 (Affinity Capture-Western), CNOT3 (Affinity Capture-MS), CNOT3 (Affinity Capture-MS), CNOT3 (Affinity Capture-MS), CNOT3 (Two-hybrid), CNOT3 (Affinity Capture-Western)

ESM2 similar proteins: A3KN83, A5DDB7, A8JUV0, B3M301, B3P8A3, B4G437, B4HGG6, B4JII0, B4K799, B4M0H8, B4NBP4, B4PL32, B4QSF0, O01737, O01835, O74842, O75175, P25992, P30181, P34333, P34447, P35187, P41846, P48479, P52654, P93755, Q09811, Q24546, Q298L4, Q5BJL5, Q5F371, Q689Z5, Q6AW06, Q6E3C9, Q6E3D2, Q6E3D4, Q6E3D5, Q7QBW0, Q7YZA2, Q8I0P1

Diamond homologs: O13870, O75175, P06100, P06102, Q12514, Q52JK6, Q8K0V4, P87240, Q8C5L3, Q9NZN8, Q5AD56, Q94547, Q9FPW4

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
CNOT3	“form complex”	“CCR4-NOT complex”	binding
CNOT3	unknown	CAND2	binding
CNOT3	“down-regulates quantity by repression”	TNFRSF11A	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 109 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	75.3×	4e-13
Deadenylation of mRNA	8	56.7×	9e-11
M-decay: degradation of maternal mRNAs by maternally stored factors	9	47.4×	3e-11
SARS-CoV-1-host interactions	6	17.0×	1e-04
SARS-CoV-1 Infection	6	13.8×	4e-04
Cellular responses to stress	10	5.9×	4e-04
Cellular responses to stimuli	10	5.1×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
nuclear-transcribed mRNA poly(A) tail shortening	8	73.8×	5e-11
regulatory ncRNA-mediated gene silencing	5	38.7×	3e-05
negative regulation of translation	9	20.3×	2e-07
negative regulation of neuron differentiation	5	15.6×	1e-03
regulation of translation	6	15.1×	2e-04
cytoplasmic translation	5	10.6×	7e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 2 cancer types — CLLSLL, PRAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	44
Likely pathogenic	24
Uncertain significance	216
Likely benign	97
Benign	24

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1285584	NM_014516.4(CNOT3):c.929_939del (p.Ser310fs)	Pathogenic
1685643	NM_014516.4(CNOT3):c.1706-2A>G	Pathogenic
1694942	NM_014516.4(CNOT3):c.1373del (p.Pro458fs)	Pathogenic
1707474	NM_014516.4(CNOT3):c.1242dup (p.Ser415fs)	Pathogenic
1707497	NM_014516.4(CNOT3):c.2089C>T (p.Arg697Ter)	Pathogenic
1708348	NM_014516.4(CNOT3):c.1941dup (p.Tyr648fs)	Pathogenic
1806021	NM_014516.4(CNOT3):c.1865G>A (p.Trp622Ter)	Pathogenic
2526437	NM_014516.4(CNOT3):c.76dup (p.Glu26fs)	Pathogenic
2572243	NM_014516.4(CNOT3):c.566del (p.Met189fs)	Pathogenic
2573108	NM_014516.4(CNOT3):c.1155_1168dup (p.Pro390fs)	Pathogenic
2577980	NM_014516.4(CNOT3):c.821_825dup (p.Asn276fs)	Pathogenic
2579182	GRCh38/hg38 19q13.42(chr19:54152129-54161358)x1	Pathogenic
3064115	NM_014516.4(CNOT3):c.1373dup (p.Ser459fs)	Pathogenic
3065994	NM_014516.4(CNOT3):c.1579C>T (p.Gln527Ter)	Pathogenic
3234781	NM_014516.4(CNOT3):c.766C>T (p.Gln256Ter)	Pathogenic
3242695	NC_000019.9:g.(?54621659)(54659145_?)del	Pathogenic
3242697	NC_000019.9:g.(?54625219)(54659145_?)del	Pathogenic
3338643	Single allele	Pathogenic
3347417	NM_014516.4(CNOT3):c.2014TTC[1] (p.Phe673del)	Pathogenic
3385389	NM_014516.4(CNOT3):c.1892_1893del (p.Asp630_Ser631insTer)	Pathogenic
3387805	NM_014516.4(CNOT3):c.586del (p.Leu196fs)	Pathogenic
3387806	NM_014516.4(CNOT3):c.1127_1145del (p.Ala376fs)	Pathogenic
3387807	NM_014516.4(CNOT3):c.1232del (p.Ser411fs)	Pathogenic
3387808	NM_014516.4(CNOT3):c.1395_1399dup (p.Ser467fs)	Pathogenic
3387809	NM_014516.4(CNOT3):c.1406+1G>A	Pathogenic
3387811	NM_014516.4(CNOT3):c.1705+2T>G	Pathogenic
3387812	NM_014516.4(CNOT3):c.1836_1837insATCA (p.Tyr613fs)	Pathogenic
3387813	NM_014516.4(CNOT3):c.1893_1894del (p.Glu632fs)	Pathogenic
3387816	NM_014516.4(CNOT3):c.2043_2050del (p.Lys682fs)	Pathogenic
3387820	NM_014516.4(CNOT3):c.70C>T (p.Gln24Ter)	Pathogenic

SpliceAI

3266 predictions. Top by Δscore:

Variant	Effect	Δscore
19:54143437:CTCA:C	acceptor_loss	1.0000
19:54143438:TCA:T	acceptor_loss	1.0000
19:54143440:A:AG	acceptor_gain	1.0000
19:54143441:G:GA	acceptor_gain	1.0000
19:54143441:G:GT	acceptor_loss	1.0000
19:54143441:GCTC:G	acceptor_gain	1.0000
19:54143441:GCTCC:G	acceptor_gain	1.0000
19:54143495:G:GT	donor_gain	1.0000
19:54143499:G:GT	donor_gain	1.0000
19:54143500:A:T	donor_gain	1.0000
19:54143507:G:GT	donor_gain	1.0000
19:54143511:C:G	donor_gain	1.0000
19:54143517:G:GG	donor_gain	1.0000
19:54143522:GGGGC:G	donor_gain	1.0000
19:54143652:A:AG	acceptor_gain	1.0000
19:54143652:ATCT:A	acceptor_gain	1.0000
19:54143653:T:G	acceptor_gain	1.0000
19:54143655:T:A	acceptor_gain	1.0000
19:54143657:CA:C	acceptor_loss	1.0000
19:54143658:A:AC	acceptor_loss	1.0000
19:54143658:A:AG	acceptor_gain	1.0000
19:54143658:AGC:A	acceptor_gain	1.0000
19:54143658:AGCG:A	acceptor_gain	1.0000
19:54143659:G:GA	acceptor_gain	1.0000
19:54143659:GC:G	acceptor_gain	1.0000
19:54143659:GCG:G	acceptor_gain	1.0000
19:54143659:GCGG:G	acceptor_gain	1.0000
19:54143659:GCGGC:G	acceptor_gain	1.0000
19:54143746:GACG:G	donor_gain	1.0000
19:54143747:ACGG:A	donor_loss	1.0000

AlphaMissense

4955 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:54142985:G:C	D3H	1.000
19:54142991:C:A	R5S	1.000
19:54142991:C:T	R5C	1.000
19:54142992:G:A	R5H	1.000
19:54142992:G:C	R5P	1.000
19:54142994:A:G	K6E	1.000
19:54142996:A:C	K6N	1.000
19:54142996:A:T	K6N	1.000
19:54142998:T:A	L7H	1.000
19:54142998:T:C	L7P	1.000
19:54143003:G:C	G9R	1.000
19:54143121:G:A	E10K	1.000
19:54143122:A:T	E10V	1.000
19:54143125:T:A	I11N	1.000
19:54143125:T:G	I11S	1.000
19:54143127:G:C	D12H	1.000
19:54143130:C:A	R13S	1.000
19:54143130:C:T	R13C	1.000
19:54143131:G:C	R13P	1.000
19:54143133:T:C	C14R	1.000
19:54143134:G:A	C14Y	1.000
19:54143135:C:G	C14W	1.000
19:54143137:T:C	L15P	1.000
19:54143139:A:G	K16E	1.000
19:54143141:G:C	K16N	1.000
19:54143141:G:T	K16N	1.000
19:54143142:A:G	K17E	1.000
19:54143144:G:C	K17N	1.000
19:54143144:G:T	K17N	1.000
19:54143145:G:A	V18M	1.000

dbSNP variants (sampled 300 via entrez): RS1000179476 (19:54153352 C>A,T), RS1000201134 (19:54155547 G>A), RS1000454441 (19:54143602 C>A,G,T), RS1000578340 (19:54152162 G>A,C), RS1001098404 (19:54138698 G>A,C), RS1001308531 (19:54139009 T>C), RS1001383602 (19:54138763 G>A,C,T), RS1001459525 (19:54149259 G>C), RS1001733868 (19:54153646 C>T), RS1002204382 (19:54153382 C>T), RS1002805847 (19:54154561 G>A), RS1003143421 (19:54154770 C>T), RS1003431585 (19:54135795 G>A,T), RS1003651642 (19:54140036 T>A,C), RS1003723817 (19:54139809 G>C)

Disease associations

OMIM: gene MIM:604910 | disease phenotypes: MIM:618672

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual developmental disorder with speech delay, autism, and dysmorphic facies	Definitive	Autosomal dominant
complex neurodevelopmental disorder	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (5): intellectual developmental disorder with speech delay, autism, and dysmorphic facies (MONDO:0032864), breast ductal adenocarcinoma (MONDO:0005590), autism spectrum disorder (MONDO:0005258), complex neurodevelopmental disorder (MONDO:0100038), intellectual disability (MONDO:0001071)

Orphanet (3): Non-specific syndromic intellectual disability (Orphanet:528084), NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

42 total (30 of 42 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000248	Brachycephaly
HP:0000268	Dolichocephaly
HP:0000269	Prominent occiput
HP:0000272	Malar flattening
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000369	Low-set ears
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000457	Depressed nasal ridge
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000540	Hypermetropia
HP:0000582	Upslanted palpebral fissure
HP:0000601	Hypotelorism
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000729	Autistic behavior
HP:0001182	Tapered finger
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001357	Plagiocephaly
HP:0001385	Hip dysplasia
HP:0001763	Pes planus
HP:0002079	Hypoplasia of the corpus callosum
HP:0002162	Low posterior hairline

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST007540_11	PEG-asparaginase hypersensitivity without enzyme activity in childhood acute lymphoblastic leukaemia	5.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004881	asparaginase hypersensitivity

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105769 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs73062673	CNOT3		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression	4
methylmercuric chloride	increases expression, affects cotreatment	3
entinostat	decreases expression, affects cotreatment	2
Benzo(a)pyrene	decreases expression, decreases methylation	2
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
trichostatin A	decreases expression	1
sodium arsenite	decreases expression	1
benzo(e)pyrene	increases methylation	1
methacrylaldehyde	affects cotreatment, increases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
ICG 001	decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Oxaliplatin	increases expression	1
Acrolein	affects cotreatment, increases expression	1
Air Pollutants	increases abundance, increases expression	1
Atrazine	increases expression	1
Haloperidol	decreases expression	1
Ivermectin	decreases expression	1
Lead	affects expression	1
Mercury	increases expression	1
Methapyrilene	increases methylation	1
Methotrexate	affects response to substance	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
CHEMBL4012561	Binding	Binding affinity to CCR4-NOT transcription complex subunit 3 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

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	PHASE3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD