CNOT9

Summary

CNOT9 (CCR4-NOT transcription complex subunit 9, HGNC:10445) is a protein-coding gene on chromosome 2q35, encoding CCR4-NOT transcription complex subunit 9 (Q92600). 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: 52.1% of cell lines).

This gene encodes a member of the highly conserved RCD1 protein family. The encoded protein is a transcriptional cofactor and a core protein of the CCR4-NOT complex. It may be involved in signal transduction as well as retinoic acid-regulated cell differentiation and development. Alternatively spliced transcript variants have been described for this gene.

Source: NCBI Gene 9125 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Limited, ClinGen)
• GWAS associations: 3
• Clinical variants (ClinVar): 35 total — 1 pathogenic, 2 likely-pathogenic
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 2 cancer types
• Cancer dependency (DepMap): dependent in 52.1% of screened cell lines
• MANE Select transcript: NM_005444

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10445
Approved symbol	CNOT9
Name	CCR4-NOT transcription complex subunit 9
Location	2q35
Locus type	gene with protein product
Status	Approved
Aliases	RCD1, RCD1+, CT129, CAF40
Ensembl gene	ENSG00000144580
Ensembl biotype	protein_coding
OMIM	612054
Entrez	9125

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 8 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000273064, ENST00000295701, ENST00000418808, ENST00000432877, ENST00000433439, ENST00000473626, ENST00000489687, ENST00000627282, ENST00000875549, ENST00000934108, ENST00000934109, ENST00000934110

RefSeq mRNA: 3 — MANE Select: NM_005444 NM_001271634, NM_001271635, NM_005444

CCDS: CCDS33379, CCDS63122, CCDS63123

Canonical transcript exons

ENST00000273064 — 8 exons

Exon	Start	End
ENSE00000965964	218587586	218587695
ENSE00000965966	218592616	218592707
ENSE00001144492	218594108	218597080
ENSE00001183547	218580561	218580740
ENSE00001278428	218584612	218584721
ENSE00003521850	218592304	218592402
ENSE00003690499	218582971	218583086
ENSE00003901273	218568839	218568978

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 93.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 52.6032 / max 270.0191, expressed in 1823 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
25349	35.6672	1821
25348	8.1763	1740
25350	3.7768	1542
25352	2.4561	980
25351	1.4076	746
25353	1.1193	424

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	93.89	gold quality
gingival epithelium	UBERON:0001949	93.23	gold quality
epithelium of nasopharynx	UBERON:0001951	93.03	gold quality
ganglionic eminence	UBERON:0004023	92.92	gold quality
right uterine tube	UBERON:0001302	92.84	gold quality
lymph node	UBERON:0000029	92.62	gold quality
stromal cell of endometrium	CL:0002255	92.51	gold quality
mucosa of stomach	UBERON:0001199	92.01	gold quality
calcaneal tendon	UBERON:0003701	91.89	gold quality
adenohypophysis	UBERON:0002196	91.88	gold quality
rectum	UBERON:0001052	91.80	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.61	gold quality
ventricular zone	UBERON:0003053	91.59	gold quality
vermiform appendix	UBERON:0001154	91.52	gold quality
cortical plate	UBERON:0005343	91.51	gold quality
caecum	UBERON:0001153	91.42	gold quality
pituitary gland	UBERON:0000007	91.30	gold quality
tonsil	UBERON:0002372	91.28	gold quality
gingiva	UBERON:0001828	91.07	gold quality
right testis	UBERON:0004534	90.97	gold quality
islet of Langerhans	UBERON:0000006	90.96	gold quality
smooth muscle tissue	UBERON:0001135	90.96	gold quality
granulocyte	CL:0000094	90.84	gold quality
left uterine tube	UBERON:0001303	90.73	gold quality
skin of abdomen	UBERON:0001416	90.61	gold quality
left testis	UBERON:0004533	90.60	gold quality
left adrenal gland cortex	UBERON:0035825	90.56	gold quality
left adrenal gland	UBERON:0001234	90.54	gold quality
nipple	UBERON:0002030	90.51	gold quality
left ovary	UBERON:0002119	90.51	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.13
E-MTAB-5061	no	3.15

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYB, WT1

miRNA regulators (miRDB)

167 targeting CNOT9, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-548AN	99.97	70.91	2817
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
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-96-5P	99.95	72.80	2140

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 52.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 11)

• mammalian protein is a novel transcriptional cofactor that mediates retinoic acid-induced cell differentiation (PMID:12356739)
• CCR4 plays a role in the regulation of certain endogenous RARalpha target genes and RCD1 and CCR4 might mediate their function through their interaction with NIF-1 (PMID:18180299)
• Report involvement of RQCD1 overexpression, a novel cancer-testis antigen, in the Akt pathway in breast cancer cells. (PMID:19724902)
• Our findings in this study imply the functional mechanism of RQCD1 in the Akt activity regulation as a mediator in the EGFR-signaling pathway (PMID:20878056)
• Crystal structures of the DDX6, CNOT1 and CNOT9 complexes. (PMID:24768538)
• Crystal structure of the DDX6, CNOT9 and CNOT1 complex. (PMID:24768540)
• Data indicate a recurrent somatic C > T change causing a P131L mutation in the RQCD1 (Required for Cell Differentiation1 Homolog) gene identified through whole exome sequencing of 20 metastatic melanomas. (PMID:25544760)
• Authors show that a novel interaction between TTP and the CCR4-NOT subunit, CNOT9, is required for recruitment of the deadenylase complex. In addition to CNOT1, CNOT9 is now included in the identified CCR4-NOT subunits shown to interact with TTP. (PMID:29291391)
• overexpression of miR-361-5p might act as a suppressor in triple-negative breast cancer by targeting RQCD1 to inhibit the EGFR/PI3K/Akt signaling pathway (PMID:29924958)
• Data suggest that the CCR4-NOT transcription complex subunit 1 (CNOT1)-CCR4-NOT transcription complex subunit 9 (CNOT9) components stimulate deadenylation by the nuclease module. (PMID:30309886)
• De novo variants in CNOT9 cause a neurodevelopmental disorder with or without epilepsy. (PMID:37092538)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cnot9	ENSDARG00000033855
mus_musculus	Cnot9	ENSMUSG00000026174
rattus_norvegicus	Cnot9	ENSRNOG00000016034
drosophila_melanogaster	Rcd-1	FBGN0031047
drosophila_melanogaster	Rcd-1r	FBGN0032089
caenorhabditis_elegans		WBGENE00016139

Protein

Protein identifiers

CCR4-NOT transcription complex subunit 9 — Q92600 (reviewed: Q92600)

Alternative names: Cell differentiation protein RQCD1 homolog

All UniProt accessions (5): Q92600, D5MQE1, F8WBZ6, F8WCV7, H7C0W0

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. Involved in down-regulation of MYB- and JUN-dependent transcription. May play a role in cell differentiation. Can bind oligonucleotides, such as poly-G, poly-C or poly-T (in vitro), but the physiological relevance of this is not certain. Does not bind poly-A. Enhances ligand-dependent transcriptional activity of nuclear hormone receptors, including RARA, expect ESR1-mediated transcription that is not only slightly increased, if at all.

Subunit / interactions. Homodimer. Component of the CCR4-NOT complex; distinct complexes seem to exist that differ in the participation of probably mutually exclusive catalytic subunits. Interacts with MYB, ATF2, RARA, RARB, RARG, RXRA, RXRB and RXRG. Identified in a complex with ATF2 bound to target DNA. Interacts with NANOS2. Directly interacts with ZNF335.

Subcellular location. Nucleus. Cytoplasm. P-body.

Tissue specificity. Detected in spleen, thymus, prostate, testis, ovary and intestine.

Similarity. Belongs to the CNOT9 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q92600-1	1	yes
Q92600-2	2
Q92600-3	3

RefSeq proteins (3): NP_001258563, NP_001258564, NP_005435* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007216	CNOT9	Family
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily

Pfam: PF04078

UniProt features (32 total): helix 19, turn 4, splice variant 3, strand 2, chain 1, modified residue 1, sequence variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
4CRU	X-RAY DIFFRACTION	1.65
4CT7	X-RAY DIFFRACTION	1.9
9JNJ	X-RAY DIFFRACTION	2
4CRV	X-RAY DIFFRACTION	2.05
4CT6	X-RAY DIFFRACTION	2.1
6HOM	X-RAY DIFFRACTION	2.1
5LSW	X-RAY DIFFRACTION	2.15
2FV2	X-RAY DIFFRACTION	2.2
6HON	X-RAY DIFFRACTION	2.2
9JNM	X-RAY DIFFRACTION	2.2
9JNL	X-RAY DIFFRACTION	2.4
9FL8	X-RAY DIFFRACTION	2.64
5ONA	X-RAY DIFFRACTION	2.7
5ONB	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92600-F1	92.83	0.89

Functional residue map

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

Post-translational modifications (1): 1

Mutagenesis-validated functional residues (1):

Position	Phenotype
227	loss of dna binding.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-429947	Deadenylation of mRNA
R-HSA-5617472	Activation of anterior HOX genes in hindbrain development during early embryogenesis
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: 307 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, RNGTGGGC_UNKNOWN, E2F_Q4, GOBP_REGULATION_OF_ERBB_SIGNALING_PATHWAY, TGCGCANK_UNKNOWN, E2F4DP1_01, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GAANYNYGACNY_UNKNOWN, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_PEPTIDYL_SERINE_MODIFICATION, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_ESTROGEN_RECEPTOR_SIGNALING_PATHWAY, GOBP_MACROMOLECULE_CATABOLIC_PROCESS

GO Biological Process (11): nuclear-transcribed mRNA poly(A) tail shortening (GO:0000289), sex differentiation (GO:0007548), negative regulation of translation (GO:0017148), cytokine-mediated signaling pathway (GO:0019221), regulatory ncRNA-mediated gene silencing (GO:0031047), positive regulation of peptidyl-serine phosphorylation (GO:0033138), negative regulation of intracellular estrogen receptor signaling pathway (GO:0033147), positive regulation of epidermal growth factor receptor signaling pathway (GO:0045742), mRNA catabolic process (GO:0006402), regulation of translation (GO:0006417), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (6): transcription coactivator activity (GO:0003713), epidermal growth factor receptor binding (GO:0005154), kinase binding (GO:0019900), protein domain specific binding (GO:0019904), protein homodimerization activity (GO:0042803), protein binding (GO:0005515)

GO Cellular Component (8): P-body (GO:0000932), nucleus (GO:0005634), cytosol (GO:0005829), membrane (GO:0016020), CCR4-NOT complex (GO:0030014), CCR4-NOT core complex (GO:0030015), protein-containing complex (GO:0032991), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Deadenylation-dependent mRNA decay	1
Activation of HOX genes during differentiation	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	3
cellular anatomical structure	3
translation	2
intracellular protein-containing complex	2
nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	1
nuclear-transcribed mRNA catabolic process	1
developmental process involved in reproduction	1
regulation of translation	1
negative regulation of protein metabolic process	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
positive regulation of protein phosphorylation	1
peptidyl-serine phosphorylation	1
regulation of peptidyl-serine phosphorylation	1
estrogen receptor signaling pathway	1
negative regulation of intracellular steroid hormone receptor signaling pathway	1
regulation of intracellular estrogen receptor signaling pathway	1
epidermal growth factor receptor signaling pathway	1
regulation of epidermal growth factor receptor signaling pathway	1
positive regulation of ERBB signaling pathway	1
RNA catabolic process	1
mRNA metabolic process	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	1
growth factor receptor binding	1
enzyme binding	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
binding	1
cytoplasmic ribonucleoprotein granule	1
intracellular membrane-bounded organelle	1
cytoplasm	1
CCR4-NOT complex	1
cellular_component	1

Protein interactions and networks

STRING

1228 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CNOT9	CNOT2	Q9NZN8	998
CNOT9	CNOT6	Q9ULM6	998
CNOT9	CNOT1	A5YKK6	997
CNOT9	CNOT3	O75175	997
CNOT9	CNOT4	O95628	996
CNOT9	CNOT10	Q9H9A5	994
CNOT9	CNOT7	Q9UIV1	990
CNOT9	CNOT11	Q9UKZ1	988
CNOT9	CNOT8	Q9UFF9	988
CNOT9	CNOT6L	Q96LI5	980
CNOT9	TNRC6A	Q8NDV7	939
CNOT9	CNOT12	Q9C0C2	779
CNOT9	TNRC6C	Q9HCJ0	730
CNOT9	MYB	P10242	691
CNOT9	GIGYF1	O75420	671

IntAct

125 interactions, top by confidence:

A	B	Type	Score
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
CNOT3	CNOT1	psi-mi:“MI:0914”(association)	0.740
TOB1	CNOT1	psi-mi:“MI:0914”(association)	0.710
TNRC6C	CNOT1	psi-mi:“MI:0914”(association)	0.690
TOB1	CNOT9	psi-mi:“MI:0914”(association)	0.640
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
CNOT6L	CNOT9	psi-mi:“MI:0915”(physical association)	0.560
ANXA2R	CNOT1	psi-mi:“MI:0914”(association)	0.540
VASN	AP3B1	psi-mi:“MI:0914”(association)	0.530
MINK1	CNOT1	psi-mi:“MI:0914”(association)	0.530
TNKS1BP1	CNOT1	psi-mi:“MI:0914”(association)	0.530
CNOT10	CNOT1	psi-mi:“MI:0914”(association)	0.530

BioGRID (344): RQCD1 (Affinity Capture-MS), RQCD1 (Affinity Capture-MS), RQCD1 (Affinity Capture-MS), RQCD1 (Affinity Capture-MS), RQCD1 (Affinity Capture-MS), RQCD1 (Affinity Capture-MS), CNOT1 (Co-fractionation), CNOT7 (Co-fractionation), PPP2R5C (Co-fractionation), RQCD1 (Co-fractionation), RQCD1 (Co-fractionation), RQCD1 (Affinity Capture-MS), RQCD1 (Synthetic Lethality), RQCD1 (Proximity Label-MS), RQCD1 (Proximity Label-MS)

ESM2 similar proteins: A4FV68, A7MB47, B4F766, O04375, O04376, O18211, O35638, P14068, P22892, P53829, Q08AM6, Q15173, Q16537, Q28647, Q28BM0, Q3KQ45, Q4R347, Q5PQL2, Q5R6Z6, Q5R9G4, Q5RAW5, Q5ZLW3, Q61151, Q68F38, Q6DCP6, Q6DGR4, Q6IP65, Q6NWL4, Q6P819, Q6PD28, Q704U0, Q7RTS9, Q80W83, Q84ZC0, Q8CHY3, Q8LF36, Q8WVM7, Q92368, Q92600, Q99NF8

Diamond homologs: A7MB47, P53829, Q4R347, Q5PQL2, Q5R6Z6, Q6IP65, Q6NWL4, Q6P819, Q92368, Q92600, Q9JKY0

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
CNOT9	“up-regulates activity”	GIGYF2	binding
CNOT9	“up-regulates activity”	GIGYF1	binding
CNOT9	“form complex”	“CCR4-NOT complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 104 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	8	61.1×	8e-11
Deadenylation of mRNA	8	51.7×	2e-10
M-decay: degradation of maternal mRNAs by maternally stored factors	9	43.2×	8e-11

GO biological processes:

GO term	Partners	Fold	FDR
nuclear-transcribed mRNA poly(A) tail shortening	8	73.0×	6e-11
regulatory ncRNA-mediated gene silencing	6	46.0×	1e-06
regulation of translation	6	14.9×	4e-04
negative regulation of translation	5	11.1×	7e-03

Disease & clinical

Cancer significance

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

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	2
Uncertain significance	23
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1706475	NM_005444.3(CNOT9):c.874C>T (p.Arg292Trp)	Pathogenic
1707499	NM_005444.3(CNOT9):c.136C>G (p.Arg46Gly)	Likely pathogenic
74445	NM_005444.3(CNOT9):c.392C>T (p.Pro131Leu)	Likely pathogenic

SpliceAI

1252 predictions. Top by Δscore:

Variant	Effect	Δscore
2:218580553:A:AG	acceptor_gain	1.0000
2:218580553:ATCT:A	acceptor_gain	1.0000
2:218580554:T:G	acceptor_gain	1.0000
2:218580556:T:TA	acceptor_gain	1.0000
2:218580560:GCCT:G	acceptor_gain	1.0000
2:218580660:C:G	donor_gain	1.0000
2:218581050:GTACT:G	donor_gain	1.0000
2:218584719:TTGGT:T	donor_loss	1.0000
2:218584720:TGGT:T	donor_loss	1.0000
2:218584721:GGT:G	donor_loss	1.0000
2:218584722:G:A	donor_loss	1.0000
2:218584722:G:GG	donor_gain	1.0000
2:218584723:T:G	donor_loss	1.0000
2:218587582:TTA:T	acceptor_loss	1.0000
2:218587583:TA:T	acceptor_loss	1.0000
2:218587584:A:AT	acceptor_loss	1.0000
2:218587584:AGG:A	acceptor_gain	1.0000
2:218587585:G:GA	acceptor_loss	1.0000
2:218587585:GGG:G	acceptor_gain	1.0000
2:218587612:G:GT	donor_gain	1.0000
2:218587676:G:GT	donor_gain	1.0000
2:218587693:ACA:A	donor_gain	1.0000
2:218587694:CA:C	donor_gain	1.0000
2:218587696:GTAT:G	donor_gain	1.0000
2:218592301:CAGGT:C	acceptor_loss	1.0000
2:218592302:AGGT:A	acceptor_loss	1.0000
2:218592303:G:A	acceptor_loss	1.0000
2:218592303:GGTT:G	acceptor_gain	1.0000
2:218592399:CTTGG:C	donor_loss	1.0000
2:218592401:TGGT:T	donor_loss	1.0000

AlphaMissense

1921 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:218580622:T:C	L29P	1.000
2:218580640:G:T	R35M	1.000
2:218580641:G:C	R35S	1.000
2:218580641:G:T	R35S	1.000
2:218580649:C:A	A38D	1.000
2:218580652:T:C	L39S	1.000
2:218580652:T:G	L39W	1.000
2:218580655:T:C	L40P	1.000
2:218580661:T:A	L42Q	1.000
2:218580661:T:C	L42P	1.000
2:218580661:T:G	L42R	1.000
2:218580673:G:C	R46P	1.000
2:218580675:G:A	E47K	1.000
2:218580691:T:A	L52H	1.000
2:218580691:T:C	L52P	1.000
2:218580694:C:A	A53E	1.000
2:218580703:T:C	L56P	1.000
2:218580705:T:A	W57R	1.000
2:218580705:T:C	W57R	1.000
2:218580718:G:A	G61D	1.000
2:218580733:T:C	L66P	1.000
2:218582971:G:A	E69K	1.000
2:218583011:T:G	L82W	1.000
2:218583025:T:C	S87P	1.000
2:218583026:C:A	S87Y	1.000
2:218583026:C:T	S87F	1.000
2:218583028:A:G	N88D	1.000
2:218583030:C:A	N88K	1.000
2:218583030:C:G	N88K	1.000
2:218583033:A:C	R89S	1.000

dbSNP variants (sampled 300 via entrez): RS1000079946 (2:218569737 C>G), RS1000113410 (2:218577300 G>A,C), RS1000463999 (2:218567935 G>A), RS1000540838 (2:218573394 A>G), RS1000552143 (2:218572667 A>C,G), RS1000575093 (2:218573676 A>G), RS1000990083 (2:218585999 A>G), RS1001008999 (2:218593376 T>C), RS1001553702 (2:218585821 G>A), RS1001566858 (2:218568688 G>A,T), RS1001629408 (2:218572469 G>A), RS1001760914 (2:218593551 G>T), RS1001815733 (2:218578567 C>T), RS1001828947 (2:218581156 TTTTG>T), RS1001876856 (2:218568893 C>G,T)

Disease associations

OMIM: gene MIM:612054 | disease phenotypes:

GenCC curated gene-disease

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Limited	AD

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST006661_114	Male-pattern baldness	2.000000e-16
GCST010989_209	Body size at age 10	6.000000e-09
GCST90002383_350	Hematocrit	7.000000e-37

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009819	comparative body size at age 10, self-reported
EFO:0004348	hematocrit

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105961 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.54	Kd	28.7	nM	CHEMBL5653589
7.53	ED50	29.8	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 5 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149319: Binding affinity to human RQCD1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0287	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, affects expression, decreases expression	3
bisphenol A	decreases expression, decreases methylation	2
Arsenic Trioxide	affects binding, decreases reaction, decreases expression	2
Nickel	increases expression	2
trichostatin A	affects expression	1
arsenite	affects binding, increases reaction	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
CGP 52608	affects binding, increases reaction	1
ICG 001	increases expression	1
Vorinostat	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Arsenic	affects methylation	1
Atrazine	increases expression	1
Dinitrochlorobenzene	affects binding	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	decreases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Ozone	affects expression, increases abundance	1
Quercetin	decreases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Thimerosal	increases expression	1
Thiram	decreases expression	1
Valproic Acid	affects expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	decreases methylation, increases expression	1
Asbestos, Amosite	increases methylation	1
Antirheumatic Agents	decreases expression	1
Okadaic Acid	increases expression	1
Copper Sulfate	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4012587	Binding	Binding affinity to RCD1 protein 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

2 cell lines: 1 transformed cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A5EE	HEK293T-CAF40-null	Transformed cell line	Female
CVCL_B1NR	Abcam HeLa CNOT9 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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