CNOT4

Summary

CNOT4 (CCR4-NOT transcription complex subunit 4, HGNC:7880) is a protein-coding gene on chromosome 7q33, encoding CCR4-NOT transcription complex subunit 4 (O95628). Has E3 ubiquitin ligase activity, promoting ubiquitination and degradation of target proteins.

The protein encoded by this gene is a subunit of the CCR4-NOT complex, a global transcriptional regulator. The encoded protein interacts with CNOT1 and has E3 ubiquitin ligase activity. Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 4850 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 73 total — 1 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_001190850

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7880
Approved symbol	CNOT4
Name	CCR4-NOT transcription complex subunit 4
Location	7q33
Locus type	gene with protein product
Status	Approved
Aliases	CLONE243, NOT4H
Ensembl gene	ENSG00000080802
Ensembl biotype	protein_coding
OMIM	604911
Entrez	4850

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 11 protein_coding, 4 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000315544, ENST00000361528, ENST00000414802, ENST00000423368, ENST00000428680, ENST00000451834, ENST00000465721, ENST00000473470, ENST00000491203, ENST00000498534, ENST00000541284, ENST00000707062, ENST00000707063, ENST00000707064, ENST00000870230, ENST00000912981

RefSeq mRNA: 12 — MANE Select: NM_001190850 NM_001008225, NM_001190847, NM_001190848, NM_001190849, NM_001190850, NM_001393370, NM_001393371, NM_001393372, NM_001393373, NM_001393374, NM_001393375, NM_013316

CCDS: CCDS43650, CCDS47719, CCDS55164, CCDS55165, CCDS55166, CCDS55167

Canonical transcript exons

ENST00000541284 — 12 exons

Exon	Start	End
ENSE00000977793	135422156	135422353
ENSE00001334775	135393918	135394415
ENSE00001353213	135415176	135415262
ENSE00002260857	135361795	135363186
ENSE00003626167	135363854	135364066
ENSE00003659085	135438158	135438423
ENSE00003733956	135414331	135414432
ENSE00003735784	135395634	135395883
ENSE00003736347	135398169	135398226
ENSE00003745356	135410515	135410648
ENSE00003748634	135413488	135413613
ENSE00003928816	135509889	135510102

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 92.28.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.2138 / max 234.5660, expressed in 1808 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
86362	25.2138	1808

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	92.28	gold quality
calcaneal tendon	UBERON:0003701	90.63	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.10	gold quality
tendon	UBERON:0000043	88.63	gold quality
gastrocnemius	UBERON:0001388	88.44	gold quality
parietal pleura	UBERON:0002400	88.37	gold quality
muscle of leg	UBERON:0001383	88.35	gold quality
corpus callosum	UBERON:0002336	88.21	gold quality
medial globus pallidus	UBERON:0002477	87.96	gold quality
sural nerve	UBERON:0015488	87.90	gold quality
cortical plate	UBERON:0005343	87.83	gold quality
endothelial cell	CL:0000115	87.78	gold quality
pleura	UBERON:0000977	87.78	gold quality
hindlimb stylopod muscle	UBERON:0004252	87.65	gold quality
palpebral conjunctiva	UBERON:0001812	87.36	gold quality
eye	UBERON:0000970	87.17	gold quality
visceral pleura	UBERON:0002401	87.14	gold quality
middle temporal gyrus	UBERON:0002771	87.07	gold quality
nipple	UBERON:0002030	86.96	gold quality
sperm	CL:0000019	86.75	gold quality
globus pallidus	UBERON:0001875	86.67	gold quality
Brodmann (1909) area 23	UBERON:0013554	86.63	gold quality
pigmented layer of retina	UBERON:0001782	86.52	gold quality
retina	UBERON:0000966	86.50	gold quality
epithelial cell of pancreas	CL:0000083	86.40	gold quality
skeletal muscle organ	UBERON:0014892	86.40	gold quality
muscle organ	UBERON:0001630	86.39	gold quality
CA1 field of hippocampus	UBERON:0003881	86.16	gold quality
superior surface of tongue	UBERON:0007371	86.09	gold quality
esophagus squamous epithelium	UBERON:0006920	86.08	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.91
E-MTAB-8060	no	74.68

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
APP

miRNA regulators (miRDB)

108 targeting CNOT4, 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-126-5P	100.00	72.71	3180
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-153-5P	99.89	73.86	6317

Literature-anchored findings (GeneRIF, showing 14)

• Data show that binding of the CNOT4 RING finger to the ubiquitin-conjugating enzyme (E2) UbcH5B is highly selective (PMID:15001359)
• Data show that Ccr4-Not function in RNA splicing and nuclear export, and that CNOT4 binds CNOT1 in yeast two-hybrid assays. (PMID:19558367)
• Data show that Not4/CNOT4 is a novel positive regulator of the JAK/STAT pathway in Drosophila and in humans. (PMID:22159038)
• Single nucleotide polymorphism in CNOT4 gene is associated with osteosarcoma susceptibility. (PMID:25663449)
• CNOT4 controls the degradation of chromatin-unbound PAF1 via the 26S proteasome. (PMID:25933433)
• These results indicate that CNOT4 is a ubiquitin ligase of influenza A virus nucleoprotein, and ubiquitination of the nucleoprotein plays a positive role in viral RNA replication. (PMID:28536288)
• conserved RNA recognition motif and C3H1 domain of the Not4 (PMID:29802328)
• Damage-induced ubiquitination of ABCE1 protein by NOT4 generates poly-ubiquitin signals that attract autophagy receptors to mitochondrial outer membrane to initiate mitophagy. (PMID:29861391)
• the C-terminal regions of human and D. melanogaster NOT4 contain a conserved sequence motif that directly binds the CAF40 subunit of the CCR4-NOT complex (CAF40-binding motif [CBM]). (PMID:30692204)
• CNOT4 enhances the efficacy of anti-PD-1 immunotherapy in a model of non-small cell lung cancer. (PMID:33034149)
• The Interplay between HGF/c-met Axis and Nox4 in BRAF Mutated Melanoma. (PMID:33451139)
• CNOT4 suppresses non-small cell lung cancer progression and is required for effector cytolytic T lymphocytes cell responses to lung cancer cells. (PMID:33592572)
• Aberrant expression of MYD88 via RNA-controlling CNOT4 and EXOSC3 in colonic mucosa impacts generation of colonic cancer. (PMID:34626022)
• CNOT4 suppresses nonsmall cell lung cancer progression by promoting the degradation of PAF1. (PMID:37493105)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cnot4a	ENSDARG00000007045
danio_rerio	cnot4b	ENSDARG00000007639
mus_musculus	Cnot4	ENSMUSG00000038784
rattus_norvegicus	Cnot4	ENSRNOG00000010795
drosophila_melanogaster	Cnot4	FBGN0051716
caenorhabditis_elegans		WBGENE00003827

Protein

Protein identifiers

CCR4-NOT transcription complex subunit 4 — O95628 (reviewed: O95628)

Alternative names: CCR4-associated factor 4, E3 ubiquitin-protein ligase CNOT4, Potential transcriptional repressor NOT4Hp, RING-type E3 ubiquitin transferase CNOT4

All UniProt accessions (3): O95628, A0A9L9PY48, A0A9L9PY79

UniProt curated annotations — full annotation on UniProt →

Function. Has E3 ubiquitin ligase activity, promoting ubiquitination and degradation of target proteins. Involved in activation of the JAK/STAT pathway. Catalyzes ubiquitination of methylated RBM15. Plays a role in quality control of translation of mitochondrial outer membrane-localized mRNA. As part of the PINK1-regulated signaling, upon mitochondria damage, ubiquitinates ABCE1 and thereby recruits autophagy receptors to the mitochondrial outer membrane to initiate mitophagy.

Subunit / interactions. Interacts with CNOT1 via its C-terminus but does not stably associate with the CCR4-NOT complex. Interacts (via RING domain) with UBE2D2. Interacts with ABCE1, PINK1 and PELO.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Autoubiquitinated.

Pathway. Protein modification; protein ubiquitination.

Isoforms (10)

UniProt ID	Names	Canonical?
O95628-1	1	yes
O95628-2	2
O95628-3	3
O95628-4	4
O95628-5	5
O95628-6	6
O95628-7	7
O95628-8	8
O95628-9	9
O95628-10	10

RefSeq proteins (12): NP_001008226, NP_001177776, NP_001177777, NP_001177778, NP_001177779, NP_001380299, NP_001380300, NP_001380301, NP_001380302, NP_001380303, NP_001380304, NP_037448 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000504	RRM_dom	Domain
IPR000571	Znf_CCCH	Domain
IPR001841	Znf_RING	Domain
IPR003954	RRM_euk-type	Domain
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR034261	CNOT4_RRM	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily
IPR039515	NOT4_mRING-HC-C4C4	Domain
IPR039780	Mot2	Family

Pfam: PF00076, PF14570

UniProt features (49 total): mutagenesis site 11, modified residue 8, splice variant 8, sequence conflict 5, compositionally biased region 4, region of interest 3, turn 3, zinc finger region 2, chain 1, domain 1, sequence variant 1, helix 1, coiled-coil region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1E4U	SOLUTION NMR
1UR6	SOLUTION NMR, THEORETICAL MODEL

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95628-F1	62.54	0.21

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 (8): 71, 301, 324, 432, 475, 483, 490, 497

Mutagenesis-validated functional residues (11):

Position	Phenotype
16	abolishes interaction with e2 ubiquitin ligases.
17	abolishes interaction with e2 ubiquitin ligases.
18	strongly reduces interaction with e2 ubiquitin ligases.
33	abolishes interaction with e2 ubiquitin ligases.
42	strongly reduces interaction with e2 ubiquitin ligases.
44	strongly reduces interaction with e2 ubiquitin ligases.
45	strongly reduces interaction with e2 ubiquitin ligases.
49	strongly reduces interaction with e2 ubiquitin ligases.
49	strongly reduced interaction with ube2d2.
54	strongly reduces interaction with e2 ubiquitin ligases.
57	strongly reduces interaction with e2 ubiquitin ligases.

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): GOBP_MYELOID_CELL_DIFFERENTIATION, MULLIGHAN_NPM1_SIGNATURE_3_UP, TGCGCANK_UNKNOWN, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, TGCACTT_MIR519C_MIR519B_MIR519A, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, ACTGCAG_MIR173P, GGGTGGRR_PAX4_03, GGAMTNNNNNTCCY_UNKNOWN, USF_C, RODRIGUES_NTN1_TARGETS_DN, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_REGULATION_OF_HEMOPOIESIS

GO Biological Process (5): nuclear-transcribed mRNA poly(A) tail shortening (GO:0000289), ubiquitin-dependent protein catabolic process (GO:0006511), protein ubiquitination (GO:0016567), regulation of megakaryocyte differentiation (GO:0045652), protein autoubiquitination (GO:0051865)

GO Molecular Function (8): RNA binding (GO:0003723), ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), nucleic acid binding (GO:0003676), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (4): nucleus (GO:0005634), cytosol (GO:0005829), CCR4-NOT complex (GO:0030014), 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
protein ubiquitination	2
binding	2
cellular anatomical structure	2
nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	1
nuclear-transcribed mRNA catabolic process	1
modification-dependent protein catabolic process	1
protein modification by small protein conjugation	1
megakaryocyte differentiation	1
regulation of myeloid cell differentiation	1
nucleic acid binding	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
cytoplasm	1
intracellular protein-containing complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1538 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CNOT4	CNOT2	Q9NZN8	999
CNOT4	CNOT1	A5YKK6	999
CNOT4	CNOT3	O75175	999
CNOT4	CNOT9	Q92600	996
CNOT4	UBE2D2	P51669	991
CNOT4	CNOT8	Q9UFF9	972
CNOT4	CNOT7	Q9UIV1	968
CNOT4	CNOT10	Q9H9A5	906
CNOT4	CNOT11	Q9UKZ1	867
CNOT4	CNOT6	Q9ULM6	845
CNOT4	CNOT6L	Q96LI5	806
CNOT4	ECPAS	Q5VYK3	771
CNOT4	LTN1	O94822	744
CNOT4	KDM5C	P41229	648
CNOT4	XRN1	Q8IZH2	644

IntAct

18 interactions, top by confidence:

A	B	Type	Score
YWHAB	PIK3C2A	psi-mi:“MI:0914”(association)	0.800
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
YWHAE	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
UBE2D2	CNOT4	psi-mi:“MI:0915”(physical association)	0.370
UBE2D3	CNOT4	psi-mi:“MI:0915”(physical association)	0.370
UBE2D4	CNOT4	psi-mi:“MI:0915”(physical association)	0.370
CNOT4	UBE2E3	psi-mi:“MI:0915”(physical association)	0.370
CNOT4	UBE2N	psi-mi:“MI:0915”(physical association)	0.370
UBE2W	CNOT4	psi-mi:“MI:0915”(physical association)	0.370
CNOT4	EP300	psi-mi:“MI:0915”(physical association)	0.370
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
MYC		psi-mi:“MI:0914”(association)	0.350
YWHAQ	MCRIP1	psi-mi:“MI:0914”(association)	0.350
CLIC3	CNOT4	psi-mi:“MI:0914”(association)	0.350
LIN28B	MEX3A	psi-mi:“MI:2364”(proximity)	0.270
DDX6	RPSA2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (103): CNOT4 (Affinity Capture-MS), CNOT4 (Affinity Capture-MS), CNOT4 (Affinity Capture-Western), RBM15 (Biochemical Activity), UBE2D2 (Reconstituted Complex), CNOT4 (Protein-peptide), CNOT1 (Affinity Capture-Western), CNOT4 (Affinity Capture-MS), CNOT4 (Affinity Capture-MS), CNOT6 (Reconstituted Complex), CNOT1 (Affinity Capture-Western), CNOT2 (Affinity Capture-Western), CNOT3 (Affinity Capture-Western), CNOT6 (Affinity Capture-Western), CNOT1 (Reconstituted Complex)

ESM2 similar proteins: A1YFY6, A2T6X9, A6H7I8, B2RUJ5, F1M5F3, F1N2W9, O35430, O35431, O95487, O95628, O95644, P0C6S7, P14316, P17863, P22681, P22682, P23798, P23906, P35227, P81133, P98084, Q02410, Q0IHY4, Q13469, Q14190, Q14432, Q1L994, Q3UR85, Q52L14, Q5CD77, Q5RD33, Q60591, Q61045, Q61079, Q66JB6, Q69ZT9, Q6NRE7, Q6QB00, Q8BIZ1, Q8BT14

Diamond homologs: O95628, P34909, Q09818, Q8BT14, Q94EH8, A2SW84, A8WLV5, B0W939, B1WC40, B3LYP1, B3P0D7, B4GLK8, B4IBA4, B4JUT1, B4KCD5, B4LZ88, B4M205, B4NB54, B4PL68, B4QV17, B5FXN8, B5G279, B7P877, C0H859, C1BY64, O01671, O08583, O17310, O22173, O61374, O97018, P19339, P52272, P52298, P52299, Q0U1G2, Q13595, Q177H0, Q19706, Q1HE01

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
CNOT4	“form complex”	“CCR4-NOT complex”	binding
Ub:E2	“up-regulates activity”	CNOT4	ubiquitination
CNOT4	“down-regulates quantity by destabilization”	RBM15	ubiquitination
CNOT4	“down-regulates quantity by destabilization”	KDM5C	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 23 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
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	223.9×	2e-11
Activation of BAD and translocation to mitochondria	5	211.5×	1e-09
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	5	186.6×	2e-09
Activation of BH3-only proteins	5	137.9×	9e-09
RHO GTPases activate PKNs	5	88.1×	8e-08
Intrinsic Pathway for Apoptosis	5	81.3×	1e-07
Transcriptional and post-translational regulation of MITF-M expression and activity	5	49.6×	1e-06
SARS-CoV-1-host interactions	5	48.8×	1e-06

GO biological processes:

GO term	Partners	Fold	FDR
intracellular protein localization	5	24.9×	8e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	55
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1330183	GRCh37/hg19 7q33-35(chr7:133848099-145814115)x1	Pathogenic

SpliceAI

2718 predictions. Top by Δscore:

Variant	Effect	Δscore
7:135363184:TAC:T	acceptor_gain	1.0000
7:135363184:TACC:T	acceptor_loss	1.0000
7:135363187:C:CC	acceptor_gain	1.0000
7:135363849:GTTAC:G	donor_loss	1.0000
7:135363850:TTAC:T	donor_loss	1.0000
7:135363851:TA:T	donor_loss	1.0000
7:135364076:T:C	acceptor_gain	1.0000
7:135364076:T:TC	acceptor_gain	1.0000
7:135364080:C:CT	acceptor_gain	1.0000
7:135364081:A:T	acceptor_gain	1.0000
7:135364083:C:CT	acceptor_gain	1.0000
7:135364084:A:T	acceptor_gain	1.0000
7:135364090:A:AC	acceptor_gain	1.0000
7:135364090:A:C	acceptor_gain	1.0000
7:135364097:A:C	acceptor_gain	1.0000
7:135388777:T:A	donor_gain	1.0000
7:135394411:TGTTT:T	acceptor_gain	1.0000
7:135394412:GTTT:G	acceptor_gain	1.0000
7:135394413:TTT:T	acceptor_gain	1.0000
7:135394414:TT:T	acceptor_gain	1.0000
7:135394416:C:CC	acceptor_gain	1.0000
7:135394416:C:CG	acceptor_loss	1.0000
7:135394419:T:TC	acceptor_gain	1.0000
7:135395883:TCT:T	acceptor_loss	1.0000
7:135398227:C:CC	acceptor_gain	1.0000
7:135398229:A:C	acceptor_gain	1.0000
7:135410506:AATAC:A	donor_loss	1.0000
7:135410507:ATACT:A	donor_loss	1.0000
7:135410508:TACT:T	donor_loss	1.0000
7:135410509:ACTTA:A	donor_loss	1.0000

AlphaMissense

4707 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:135394292:A:G	L418P	1.000
7:135394299:C:G	A416P	1.000
7:135394301:A:G	L415S	1.000
7:135394384:C:A	W387C	1.000
7:135394384:C:G	W387C	1.000
7:135394386:A:G	W387R	1.000
7:135394386:A:T	W387R	1.000
7:135410617:A:G	L240P	1.000
7:135410625:T:A	E237D	1.000
7:135410625:T:G	E237D	1.000
7:135410627:C:T	E237K	1.000
7:135410630:A:C	Y236D	1.000
7:135410637:G:C	H233Q	1.000
7:135410637:G:T	H233Q	1.000
7:135410638:T:C	H233R	1.000
7:135410639:G:C	H233D	1.000
7:135410639:G:T	H233N	1.000
7:135410644:C:T	G231D	1.000
7:135410645:C:G	G231R	1.000
7:135410648:C:G	A230P	1.000
7:135413492:A:C	M228R	1.000
7:135413492:A:G	M228T	1.000
7:135413492:A:T	M228K	1.000
7:135413500:T:A	K225N	1.000
7:135413500:T:G	K225N	1.000
7:135413501:T:A	K225I	1.000
7:135413502:T:C	K225E	1.000
7:135413504:G:A	T224I	1.000
7:135413506:G:C	F223L	1.000
7:135413506:G:T	F223L	1.000

dbSNP variants (sampled 300 via entrez): RS1000000471 (7:135395746 G>A), RS1000001496 (7:135363731 C>A,T), RS1000043925 (7:135373031 T>C), RS1000120784 (7:135441505 T>C), RS1000123146 (7:135507389 T>C), RS1000138433 (7:135488297 A>G), RS1000152589 (7:135432269 G>A), RS1000157525 (7:135367782 G>A), RS1000200938 (7:135412603 A>G), RS1000206412 (7:135447308 A>T), RS1000209487 (7:135480746 T>G), RS1000212059 (7:135369600 TAAAC>T), RS1000236027 (7:135407141 C>G,T), RS1000248223 (7:135476714 G>A), RS1000263344 (7:135480311 T>C)

Disease associations

OMIM: gene MIM:604911 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST006979_216	Heel bone mineral density	3.000000e-09
GCST009322_4	Numerical cognitive ability	9.000000e-06
GCST009524_135	Household income (MTAG)	5.000000e-08
GCST009524_196	Household income (MTAG)	5.000000e-09
GCST010143_39	Meat-related diet	2.000000e-08
GCST012277_3	Clostridioides difficle infection	3.000000e-07
GCST90000025_311	Appendicular lean mass	5.000000e-13
GCST90000026_12	Appendicular lean mass	4.000000e-08
GCST90000027_38	Appendicular lean mass	2.000000e-06
GCST90013407_116	Liver enzyme levels (gamma-glutamyl transferase)	3.000000e-13

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0008354	cognitive function measurement
EFO:0009695	household income
EFO:0008111	diet measurement
EFO:0009130	clostridium difficile infection
EFO:0004980	appendicular lean mass
EFO:0004532	serum gamma-glutamyl transferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105770 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3812265	CNOT4		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression	6
trichostatin A	affects cotreatment, decreases expression	3
sodium arsenite	affects binding, increases reaction, increases abundance, increases expression	3
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
mercuric bromide	decreases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, increases expression	1
dicrotophos	increases expression	1
testosterone enanthate	affects expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
salinomycin	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
aflatoxin B2	increases methylation	1
beta-methylcholine	affects expression	1
pentanal	decreases expression	1
di-n-butylphosphoric acid	affects expression	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	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
Panobinostat	affects cotreatment, decreases expression	1
Arsenic	increases abundance, increases expression	1
Benzo(a)pyrene	decreases expression	1
Cadmium	increases abundance, decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	decreases 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
CHEMBL4012562	Binding	Binding affinity to CCR4-NOT transcription complex subunit 4 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)

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