CNOT9

protein-coding

CCR4-NOT transcription complex subunit 9, the group of CCR4-NOT transcription complex|Armadillo like helical domain containing

Gene summary

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. [provided by RefSeq, Oct 2012]

Previous symbols:

RQCD1

MANE transcript

NM_005444.3

Inheritance

ClinVar variants

P:5U:22

Top phenotype

CNOT9-associated neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr2:218,568,580-218,597,080

External References & Databases

Ensembl (ENSG00000144580)

Transcript & Mutation Effects

hg38 • Region Span ~28.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*CNOT9* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2023 (von Wintzingerode et al., PMID: 37092538). Phenotypic features reported in affected individuals include developmental delay, prominent speech delay, intellectual disability, seizures, anxiety, impulsivity, hyperactivity, and ophthalmological and skeletal abnormalities (PMID: 37092538). Four *de novo* missense variants that have been reported in seven probands in one publication (PMID: 37092538) are included in this curation. Molecular modeling suggests that these variants can lead to reduced protein stability or impaired interaction with other proteins within the CCR4-NOT complex (PMID: 37092538). There is also experimental evidence such as biochemical and protein interaction (PMIDs: 30309886, 24768540). In summary, there is limited evidence to support the gene-disease relationship between *CNOT9* and autosomal dominant complex neurodevelopmental disorder. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 1, 2025 (SOP Version 11).

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CNOT9 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 22

CNOT9-associated neurodevelopmental disorderTotal: 5

Inborn genetic diseasesTotal: 2

CNOT9-related disorderTotal: 1

not specifiedTotal: 1

CNOT9-related conditionTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005444.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous						0
missense	1 clinvar	4 clinvar	16 clinvar			21
nonsense			2 clinvar			2
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	1	4	22	0	0	27

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 43 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005444.3	RefSeq	NP_005435.1	8	MANE Select
ENST00000273064.11	Ensembl	ENSP00000273064.6	8	MANE Select
NM_001271634.2	RefSeq	NP_001258563.1	9	Standard
NM_001271635.2	RefSeq	NP_001258564.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

RNA degradation - Homo sapiens (human)
miR-targeted genes in lymphocytes - TarBase
miR-targeted genes in muscle cell - TarBase
Gene expression (Transcription)
Generic Transcription Pathway

Biological Process

nuclear-transcribed mRNA poly(A) tail shortening
DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest
sex differentiation
negative regulation of translation
cytokine-mediated signaling pathway

Molecular Function

epidermal growth factor receptor binding
protein binding
kinase binding
protein domain specific binding
protein homodimerization activity

Cellular Component

P-body
nucleus
cytosol
membrane
CCR4-NOT complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000273064
Coding exons: 8
Length: 28501
Individuals with no LoFs: 125739
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125741
p: 0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.28	48	167	0.287	0.00000916	1919
Missense (PolyPhen)		6	64.515	0.093001		832
Synonymous	1.32	50	63.3	0.789	0.00000322	615
Loss of Function	3.63	1	17.3	0.0579	9.60e-7	194

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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 (By similarity). 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. {ECO:0000250, ECO:0000269|PubMed:17189474, ECO:0000269|PubMed:18180299}.;

Recessive Scores

pRec: 0.152

Intolerance Scores

RVIS EVS: -0.12
RVIS percentile EVS: 44.54