CNOT6L

Summary

CNOT6L (CCR4-NOT transcription complex subunit 6 like, HGNC:18042) is a protein-coding gene on chromosome 4q21.1, encoding CCR4-NOT transcription complex subunit 6-like (Q96LI5). Has 3’-5’ poly(A) exoribonuclease activity for synthetic poly(A) RNA substrate.

Predicted to enable 3’-5’-RNA exonuclease activity. Involved in positive regulation of cell population proliferation and positive regulation of cytoplasmic mRNA processing body assembly. Located in cytosol and nucleus. Part of CCR4-NOT complex.

Source: NCBI Gene 246175 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 69 total
• Druggable target: yes
• MANE Select transcript: NM_144571

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18042
Approved symbol	CNOT6L
Name	CCR4-NOT transcription complex subunit 6 like
Location	4q21.1
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp434K098, Ccr4b
Ensembl gene	ENSG00000138767
Ensembl biotype	protein_coding
OMIM	618069
Entrez	246175

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000504123, ENST00000504804, ENST00000505983, ENST00000506166, ENST00000508371, ENST00000512485, ENST00000515506, ENST00000649644, ENST00000873612

RefSeq mRNA: 13 — MANE Select: NM_144571 NM_001286790, NM_001365006, NM_001365007, NM_001387835, NM_001387836, NM_001387837, NM_001387838, NM_001387839, NM_001387840, NM_001387841, NM_001387842, NM_001387843, NM_144571

CCDS: CCDS93552, CCDS93553

Canonical transcript exons

ENST00000504123 — 12 exons

Exon	Start	End
ENSE00001126764	77713387	77720643
ENSE00001485986	77819304	77819368
ENSE00003460150	77744718	77744875
ENSE00003461278	77728854	77729081
ENSE00003482014	77726167	77726369
ENSE00003516619	77748316	77748384
ENSE00003541471	77776271	77776392
ENSE00003597653	77773081	77773166
ENSE00003617819	77742141	77742295
ENSE00003689646	77774530	77774716
ENSE00003693330	77731387	77731538
ENSE00003787197	77756862	77756951

Expression profiles

Bgee: expression breadth ubiquitous, 256 present calls, max score 99.53.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.5419 / max 554.8343, expressed in 1814 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
52713	17.1987	1790
52712	9.7379	1653
52707	3.9285	1040
52711	1.6819	575
52714	1.6085	978
52709	0.2396	93
52710	0.0854	41
52708	0.0516	8
52695	0.0098	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.53	gold quality
oocyte	CL:0000023	97.17	gold quality
ileal mucosa	UBERON:0000331	96.19	gold quality
oviduct epithelium	UBERON:0004804	95.44	gold quality
superficial temporal artery	UBERON:0001614	95.20	gold quality
tibialis anterior	UBERON:0001385	95.00	gold quality
bone marrow cell	CL:0002092	94.64	gold quality
thymus	UBERON:0002370	94.40	gold quality
corpus epididymis	UBERON:0004359	94.16	gold quality
kidney epithelium	UBERON:0004819	93.99	gold quality
tonsil	UBERON:0002372	93.31	gold quality
jejunal mucosa	UBERON:0000399	93.29	gold quality
bone marrow	UBERON:0002371	92.89	gold quality
colonic epithelium	UBERON:0000397	92.75	gold quality
esophagus squamous epithelium	UBERON:0006920	92.64	gold quality
oral cavity	UBERON:0000167	92.63	gold quality
caput epididymis	UBERON:0004358	92.20	gold quality
pancreatic ductal cell	CL:0002079	92.19	gold quality
lymph node	UBERON:0000029	91.92	gold quality
adrenal tissue	UBERON:0018303	91.85	gold quality
placenta	UBERON:0001987	91.79	gold quality
cauda epididymis	UBERON:0004360	91.59	gold quality
palpebral conjunctiva	UBERON:0001812	91.57	gold quality
pericardium	UBERON:0002407	91.51	gold quality
mucosa of paranasal sinus	UBERON:0005030	91.40	gold quality
trabecular bone tissue	UBERON:0002483	91.28	gold quality
calcaneal tendon	UBERON:0003701	91.09	gold quality
mammalian vulva	UBERON:0000997	90.99	gold quality
buccal mucosa cell	CL:0002336	90.97	gold quality
mammary duct	UBERON:0001765	90.82	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-119	yes	47.13
E-GEOD-135922	yes	27.33
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

500 targeting CNOT6L, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4789-3P	99.99	70.75	2484

Literature-anchored findings (GeneRIF, showing 11)

• CCR4b may be involved in various cellular events that include cell proliferation. (PMID:17452450)
• show that the nuclease domain of CNOT6L exhibits full Mg(2+)-dependent deadenylase activity with strict poly(A) RNA substrate specificity. (PMID:20628353)
• Results identified CNOT6/CNOT6L as a key regulator of insulin-like growth factor-binding protein 5, which mediates cell cycle arrest and senescence via a p53-dependent pathway. (PMID:21233283)
• Cnot6L, a validated target of miR-146a, affects the stability of Zeb1 mRNA. (PMID:23591815)
• Data show that CNOT6L protein-interleukin 8 (IL-8) is a signaling axis in myogenesis. (PMID:26608607)
• Structural analysis shows that all inhibitors occupy the substrate and magnesium-binding sites of CNOT6L, suggesting that inhibitors compete with both substrate and divalent magnesium ions for overlapping binding sites. (PMID:27013054)
• Studied hepatic role in metabolic homeostasis of fibroblast growth factor 21(FGF21) and the “CCR4-NOT complex” (a multisubunit protein complex composed of “CCR4-NOT transcription complex subunit 6 like” (CNOT6L) and “CCR4-NOT transcription complex subunit 6” (CNOT6). Results show CNOT6L plays a major role in regulation FGF21 levels. (PMID:30926667)
• Active 1-hydroxy-xanthines inhibit both isolated Caf1 (CNOT7) enzyme and human Caf1-containing complexes that also contain the second nuclease subunit Ccr4 (CNOT6L) to a similar extent, indicating that the active site of the Caf1 nuclease subunit does not undergo substantial conformational change when bound to other Ccr4-Not subunits. (PMID:30984545)
• We show that knockdown of human XRN1, CNOT6 and ETF1 genes in HepG2 cells led to significant alteration in stability of specific mRNAs, alterations in half-life were inversely associated with transcription rates, mostly not resulting in changes in abundance (PMID:31116665)
• Deadenylase-dependent mRNA decay of GDF15 and FGF21 orchestrates food intake and energy expenditure. (PMID:35385705)
• Exosomal circCNOT6L Regulates Astrocyte Apoptotic Signals Induced by Hypoxia Exposure Through miR99a-5p/SERPINE1 and Alleviates Ischemic Stroke Injury. (PMID:37531026)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	cnot6l	ENSDARG00000054597
mus_musculus	Cnot6l	ENSMUSG00000034724
rattus_norvegicus	Cnot6l	ENSRNOG00000002075
drosophila_melanogaster	twin	FBGN0011725
drosophila_melanogaster	angel	FBGN0016762
caenorhabditis_elegans		WBGENE00000376
caenorhabditis_elegans		WBGENE00020955

Paralogs (5): ANGEL1 (ENSG00000013523), CNOT6 (ENSG00000113300), NOCT (ENSG00000151014), ANGEL2 (ENSG00000174606), PDE12 (ENSG00000174840)

Protein

Protein identifiers

CCR4-NOT transcription complex subunit 6-like — Q96LI5 (reviewed: Q96LI5)

Alternative names: Carbon catabolite repressor protein 4 homolog B

All UniProt accessions (4): Q96LI5, D6RIW9, H0Y9C1, H0Y9Z5

UniProt curated annotations — full annotation on UniProt →

Function. Has 3’-5’ poly(A) exoribonuclease activity for synthetic poly(A) RNA substrate. Catalytic 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 the deadenylation-dependent degradation of mRNAs through the 3’-UTR AU-rich element-mediated mechanism. Involved in deadenylation-dependent degradation of CDKN1B mRNA. Its mRNA deadenylase activity can be inhibited by TOB1. Mediates cell proliferation and cell survival and prevents cellular senescence.

Subunit / interactions. Component of the CCR4-NOT complex; distinct complexes seem to exist that differ in the participation of probably mutually exclusive catalytic subunits; the complex contains two deadenylase subunits, CNOT6 or CNOT6L, and CNOT7 or CNOT8. Interacts with CNOT1, CNOT3, CNOT7, CNOT8 and CNOT9. Interacts with TOB1. Interacts with NANOS2. Interacts with ZFP36. Interacts with ZFP36L2. Interacts with RBM46.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Highly expressed in placenta, skeletal muscle, pancreas, testis and leukocytes. Weakly expressed in heart, spleen and thymus.

Activity regulation. Inhibited by free AMP, and with lesser efficiency also by CMP, GMP, UMP, ATP and neomycin.

Cofactor. Binds 2 magnesium ions, but the ions interact each with only 1 or 2 residues.

Miscellaneous. Depletion of CNOT6L causes cell growth defect.

Similarity. Belongs to the CCR4/nocturin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96LI5-1	1	yes
Q96LI5-2	2

RefSeq proteins (13): NP_001273719, NP_001351935, NP_001351936, NP_001374764, NP_001374765, NP_001374766, NP_001374767, NP_001374768, NP_001374769, NP_001374770, NP_001374771, NP_001374772, NP_653172* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001611	Leu-rich_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR005135	Endo/exonuclease/phosphatase	Domain
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR034967	Deadenylase_CCR4b	Domain
IPR036691	Endo/exonu/phosph_ase_sf	Homologous_superfamily
IPR050410	CCR4/nocturin_mRNA_transcr	Family

Pfam: PF03372, PF13855

Enzyme classification (BRENDA):

• EC 3.1.13.4 — poly(A)-specific ribonuclease (BRENDA: 15 organisms, 67 substrates, 89 inhibitors, 9 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
POLY(A) RNA	—	7
POLY(A)	0.0051	1

UniProt features (67 total): strand 20, helix 15, binding site 9, mutagenesis site 6, turn 5, repeat 4, splice variant 3, region of interest 2, chain 1, sequence conflict 1, active site 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
3NGQ	X-RAY DIFFRACTION	1.8
5DV4	X-RAY DIFFRACTION	1.8
5DV2	X-RAY DIFFRACTION	2.07
9WQ1	X-RAY DIFFRACTION	2.09
3NGO	X-RAY DIFFRACTION	2.2
3NGN	X-RAY DIFFRACTION	2.4
9WQ4	X-RAY DIFFRACTION	2.4
7VOI	X-RAY DIFFRACTION	4.38

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96LI5-F1	90.12	0.78

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 410 (proton donor/acceptor)

Ligand- & substrate-binding residues (9): 276; 360; 365; 410; 412; 479; 484; 240; 240

Mutagenesis-validated functional residues (6):

Position	Phenotype
240	loss of deadenylase activity.
365	decreased deadenylase activity.
410	loss of deadenylase activity.
484	loss of deadenylase activity.
489	loss of deadenylase activity.
529	loss of deadenylase activity.

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: 369 (showing top): GOMF_RNA_NUCLEASE_ACTIVITY, GOBP_P_BODY_ASSEMBLY, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, MODULE_255, GOMF_NUCLEASE_ACTIVITY, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MODULE_317, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, CHANDRAN_METASTASIS_DN, GOBP_TRANSLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_POSITIVE_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_REGULATION_OF_CATABOLIC_PROCESS

GO Biological Process (8): nuclear-transcribed mRNA poly(A) tail shortening (GO:0000289), mRNA processing (GO:0006397), regulation of translation (GO:0006417), positive regulation of cell population proliferation (GO:0008284), positive regulation of cytoplasmic mRNA processing body assembly (GO:0010606), regulatory ncRNA-mediated gene silencing (GO:0031047), nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay (GO:0000288), mRNA destabilization (GO:0061157)

GO Molecular Function (8): 3’-5’-RNA exonuclease activity (GO:0000175), poly(A)-specific ribonuclease activity (GO:0004535), metal ion binding (GO:0046872), catalytic activity (GO:0003824), nuclease activity (GO:0004518), exonuclease activity (GO:0004527), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (4): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), CCR4-NOT complex (GO:0030014)

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
nuclear-transcribed mRNA catabolic process	2
negative regulation of gene expression	2
cellular anatomical structure	2
nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	1
RNA processing	1
mRNA metabolic process	1
translation	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
regulation of cytoplasmic mRNA processing body assembly	1
P-body assembly	1
positive regulation of organelle assembly	1
mRNA destabilization	1
regulation of mRNA stability	1
RNA destabilization	1
positive regulation of mRNA catabolic process	1
3’-5’ exonuclease activity	1
RNA exonuclease activity, producing 5’-phosphomonoesters	1
3’-5’-RNA exonuclease activity	1
cation binding	1
molecular_function	1
catalytic activity, acting on a nucleic acid	1
nuclease activity	1
hydrolase activity, acting on ester bonds	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1
intracellular protein-containing complex	1

Protein interactions and networks

STRING

1034 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CNOT6L	CNOT7	Q9UIV1	997
CNOT6L	CNOT8	Q9UFF9	997
CNOT6L	CNOT1	A5YKK6	988
CNOT6L	CNOT9	Q92600	980
CNOT6L	CNOT2	Q9NZN8	977
CNOT6L	CNOT3	O75175	975
CNOT6L	CNOT6	Q9ULM6	972
CNOT6L	CNOT10	Q9H9A5	951
CNOT6L	CNOT11	Q9UKZ1	872
CNOT6L	CNOT4	O95628	806
CNOT6L	PARN	O95453	769
CNOT6L	SERINC1	Q9NRX5	663
CNOT6L	BTG4	Q9NY30	646
CNOT6L	PABPC1	P11940	631
CNOT6L	VAPA	Q9P0L0	626

IntAct

104 interactions, top by confidence:

A	B	Type	Score
CNOT7	CNOT6L	psi-mi:“MI:0915”(physical association)	0.880
CNOT6L	CNOT7	psi-mi:“MI:0915”(physical association)	0.880
CNOT7	CNOT1	psi-mi:“MI:0914”(association)	0.880
CNOT7	CNOT6L	psi-mi:“MI:0914”(association)	0.880
CNOT6L	CNOT1	psi-mi:“MI:0914”(association)	0.810
CNOT6L	CNOT1	psi-mi:“MI:0915”(physical association)	0.810
CNOT11	CNOT1	psi-mi:“MI:0914”(association)	0.770
CNOT8	CNOT6L	psi-mi:“MI:0915”(physical association)	0.750
CNOT6L	CNOT8	psi-mi:“MI:0915”(physical association)	0.750
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
CNOT6L	TOB1	psi-mi:“MI:0914”(association)	0.710
TOB1	CNOT6L	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
CNOT6L	TNKS1BP1	psi-mi:“MI:0915”(physical association)	0.660
CNOT10	CNOT6L	psi-mi:“MI:0915”(physical association)	0.660
CAPZB	CNOT1	psi-mi:“MI:0914”(association)	0.640
CAPZA2	CNOT1	psi-mi:“MI:0914”(association)	0.640

BioGRID (172): CNOT6L (Reconstituted Complex), CNOT6L (Affinity Capture-Western), CNOT6L (Affinity Capture-MS), CNOT6L (Affinity Capture-MS), CNOT6L (Affinity Capture-MS), CNOT6L (Affinity Capture-Western), CNOT6L (Affinity Capture-Western), CNOT6L (Affinity Capture-Western), CNOT6L (Affinity Capture-Western), CNOT6L (Affinity Capture-MS), CNOT6L (Affinity Capture-MS), CNOT6L (Affinity Capture-MS), CNOT6L (Affinity Capture-MS), CNOT6L (Affinity Capture-Western), ZFP36 (Affinity Capture-Western)

ESM2 similar proteins: A0A2R8QFQ6, A0A2R8RWN9, A0JN27, D3Z7P3, F1LTR1, O15294, O60907, O89050, O94925, P13264, P56558, P81436, Q07G17, Q13042, Q13888, Q15303, Q27HV0, Q28D01, Q2TBV5, Q3ULA2, Q4R8H1, Q4R9A8, Q4VC33, Q5F398, Q5JUK3, Q5R532, Q5RB35, Q5RKJ1, Q5SP67, Q5SRY7, Q61527, Q62956, Q6GR10, Q6P1K8, Q7L5Y9, Q7RTP6, Q7SXR3, Q8C6G8, Q8CGY8, Q8CJ19

Diamond homologs: A1CIJ6, A1CW67, A2BHJ4, A2Q9L0, B7XK66, C4V7I7, O74874, P0CP22, P0CP23, P31384, Q0CT27, Q0U7W4, Q1EA11, Q2UUI3, Q4P9T3, Q4WQG5, Q5A761, Q5B778, Q5BJ41, Q5XH73, Q6AXU9, Q6BMM5, Q6CEJ6, Q6CJU4, Q6FRT2, Q6IR85, Q75BI3, Q8K3P5, Q8SU52, Q8VEG6, Q8W0Z9, Q96LI5, Q9C2R2, Q9M2F8, Q9ULM6, A8JQX3, B2RYM0, P79942, Q8K1C0, Q8VCU0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CNOT6L	“form complex”	“CCR4-NOT complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 58 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	10	173.0×	2e-19
Deadenylation of mRNA	9	131.8×	3e-16
M-decay: degradation of maternal mRNAs by maternally stored factors	11	119.6×	2e-19
Estrogen-dependent gene expression	5	12.6×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
nuclear-transcribed mRNA poly(A) tail shortening	9	153.7×	4e-16
positive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	6	143.4×	1e-10
regulatory ncRNA-mediated gene silencing	8	114.7×	2e-13
negative regulation of translation	7	29.2×	2e-07
regulation of translation	6	27.9×	3e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	37
Likely benign	2
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

2726 predictions. Top by Δscore:

Variant	Effect	Δscore
4:77726165:A:AC	donor_gain	1.0000
4:77726166:C:CC	donor_gain	1.0000
4:77726367:CAC:C	acceptor_gain	1.0000
4:77726368:ACC:A	acceptor_loss	1.0000
4:77726369:CCT:C	acceptor_loss	1.0000
4:77726369:CCTGG:C	acceptor_gain	1.0000
4:77726370:C:CC	acceptor_gain	1.0000
4:77726371:T:C	acceptor_loss	1.0000
4:77726373:G:GC	acceptor_gain	1.0000
4:77726378:A:AC	acceptor_gain	1.0000
4:77728849:AATAC:A	donor_loss	1.0000
4:77728850:ATAC:A	donor_loss	1.0000
4:77728851:TACCT:T	donor_loss	1.0000
4:77728852:A:T	donor_loss	1.0000
4:77731382:CTCA:C	donor_loss	1.0000
4:77731383:TCA:T	donor_loss	1.0000
4:77731386:C:CA	donor_loss	1.0000
4:77731386:CCTG:C	donor_gain	1.0000
4:77731539:C:CC	acceptor_gain	1.0000
4:77742135:A:C	donor_gain	1.0000
4:77742135:ACTT:A	donor_loss	1.0000
4:77742136:CT:C	donor_loss	1.0000
4:77742137:T:TC	donor_loss	1.0000
4:77742138:T:TC	donor_loss	1.0000
4:77742139:A:AC	donor_gain	1.0000
4:77742139:A:AG	donor_loss	1.0000
4:77742140:C:CA	donor_gain	1.0000
4:77742140:CT:C	donor_gain	1.0000
4:77742140:CTT:C	donor_gain	1.0000
4:77742140:CTTTT:C	donor_gain	1.0000

AlphaMissense

3648 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:77720512:G:C	H529Q	1.000
4:77720512:G:T	H529Q	1.000
4:77720513:T:A	H529L	1.000
4:77720513:T:G	H529P	1.000
4:77720514:G:C	H529D	1.000
4:77720516:T:A	D528V	1.000
4:77720516:T:G	D528A	1.000
4:77720517:C:G	D528H	1.000
4:77720537:G:T	P521Q	1.000
4:77720543:C:T	G519E	1.000
4:77720633:T:A	D489V	1.000
4:77726170:G:C	F484L	1.000
4:77726170:G:T	F484L	1.000
4:77726171:A:G	F484S	1.000
4:77726172:A:G	F484L	1.000
4:77726185:A:C	N479K	1.000
4:77726185:A:T	N479K	1.000
4:77726189:G:A	T478I	1.000
4:77728869:A:G	S413P	1.000
4:77728870:G:C	N412K	1.000
4:77728870:G:T	N412K	1.000
4:77728872:T:C	N412D	1.000
4:77728876:A:C	D410E	1.000
4:77728876:A:T	D410E	1.000
4:77728877:T:A	D410V	1.000
4:77728877:T:C	D410G	1.000
4:77728877:T:G	D410A	1.000
4:77728878:C:G	D410H	1.000
4:77728984:C:A	Q374H	1.000
4:77728984:C:G	Q374H	1.000

dbSNP variants (sampled 300 via entrez): RS1000020821 (4:77736714 G>A), RS1000042180 (4:77788548 C>A,T), RS1000091946 (4:77809146 T>G), RS1000122971 (4:77805868 A>T), RS1000133117 (4:77715899 T>C), RS1000133609 (4:77765126 T>G), RS1000147367 (4:77784314 A>G), RS1000158672 (4:77784619 G>A,C), RS1000182358 (4:77738590 C>T), RS1000216986 (4:77763080 A>C), RS1000315440 (4:77803270 T>A), RS1000350742 (4:77769908 A>G), RS1000360849 (4:77723593 AG>A), RS1000372536 (4:77800916 C>T), RS1000384947 (4:77745591 G>A)

Disease associations

OMIM: gene MIM:618069 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST002198_20	Tuberculosis	3.000000e-07

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105957 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression	5
trichostatin A	affects cotreatment, increases expression	3
bisphenol A	increases methylation, decreases expression, affects cotreatment	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
decabromobiphenyl ether	decreases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
manganese chloride	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
torcetrapib	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
jinfukang	decreases expression	1
Arsenic Trioxide	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	increases expression	1
Cadmium	increases abundance, increases expression	1
Demecolcine	decreases expression	1
Formaldehyde	decreases expression	1
Gallic Acid	decreases expression	1
Manganese	increases expression	1
Methyl Methanesulfonate	increases expression	1
Dronabinol	increases expression	1
Vincristine	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
CHEMBL4012559	Binding	Binding affinity to CCR4-NOT transcription complex subunit 6-like 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.