CNOT1

protein-coding

CCR4-NOT transcription complex subunit 1, the group of CCR4-NOT transcription complex|Small nucleolar RNA protein coding host genes|Armadillo like helical domain containing|MIF4G domain containing proteins

Gene summary

Enables armadillo repeat domain binding activity; molecular adaptor activity; and nuclear receptor binding activity. Contributes to poly(A)-specific ribonuclease activity. Involved in several processes, including negative regulation of intracellular signal transduction; positive regulation of cytoplasmic mRNA processing body assembly; and regulation of gene expression. Located in P-body. Part of CCR4-NOT complex. Implicated in Vissers-Bodmer syndrome and holoprosencephaly 12. [provided by Alliance of Genome Resources, Jun 2026]

Previous symbols:

NOT1

MANE transcript

NM_016284.5

Inheritance

ClinVar variants

P:54U:509B:186

Top phenotype

Holoprosencephaly 12, with or without pancreatic agenesis

gnomAD constraint

pLI —, LoF o/e 0.01

Max pathogenic AF

—

Genomic locus

chr16:58,519,951-58,629,885

External References & Databases

Ensembl (ENSG00000125107)

Transcript & Mutation Effects

hg38 • Region Span ~109.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

holoprosencephaly 12 with or without pancreatic agenesisMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032787

Submitter: Ambry Genetics

Vissers-Bodmer syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033618

Submitter: Ambry Genetics

Vissers-Bodmer syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033618

Submitter: Labcorp Genetics (formerly Invitae)

holoprosencephaly 12 with or without pancreatic agenesisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032787

Submitter: G2P

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*CNOT1* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2020 (Vissers et al., PMID: 32553196). Individuals present with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral problems. Individuals with *CNOT1* p.Arg535Cys variants have been reported with holoprosencephaly and pancreatic agenesis without neurodevelopmental delay (De Franco et al., PMID: 31006513). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in phenotypic variability. Therefore, probands with this variant have not been included in this curation. Thirty-nine variants (missense, in-frame indel, nonsense, frameshift, large deletion) that have been reported in thirty-seven probands in one publication (PMID: 32553196) are included in this curation. More evidence is available in the publication, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity appears to be *de novo* haploinsufficiency. This gene-disease relationship is also supported by experimental evidence. A GAL4-UAS Drosophila model designed with reportedly pathogenic *CNOT1* variants demonstrated memory deficits, which were rescued when wild-type *CNOT1* was introduced (PMID: 32553196). In summary, there is definitive evidence to support the relationship between *CNOT1* and autosomal dominant complex neurodevelopmental disorder. This gene-disease relationship was first evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 4, 2023 with a classification of strong (SOP 9). This relationship was reevaluated on September 19, 2023 and upgraded to a classification of definitive given that three years have now passed since the first report of this gene-disease relationship (SOP 9).

Vissers-Bodmer syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033618

Submitter: G2P

holoprosencephaly 12 with or without pancreatic agenesisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032787

Submitter: Labcorp Genetics (formerly Invitae)

holoprosencephaly 12 with or without pancreatic agenesisLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0032787

Submitter: ClinGen

*CNOT1* was originally reported in cases of holoprosencephaly and/or pancreatic agenesis/insufficiency in 2019 (PMID: 31006513, 31006510). One of the papers included 3 individuals with heterozygous p.Arg535Cys (PMID: 31006513), confirmed to be de novo in 2 individuals. One of these individuals was not scored due to a lack of documentation of holoprosencephaly. The other paper included 2 individuals with de novo p.Arg535Cys, both of whom with holoprosencephaly. A knock-in mouse model of this variant showed neurological and pancreatic abnormalities at E14.5, and this evidence was used to augment the genetic evidence. A mouse brain expression study (PMID: 31006510) was scored as functional evidence. In total, there is Limited evidence to support the gene-disease relationship between *CNOT1* and holoprosencephaly with or without pancreatic agenesis. Of note, this gene has also been implicated in Vissers-Bodmer syndrome, which is characterized by global developmental delay and behavioral abnormalities apparent from infancy. As the condition is clinically distinct from holoprosencephaly and/or pancreatic agenesis/insufficiency, lacks specific structural brain anomalies, and likely has different molecular mechanisms, this will be/have been assessed separately. This curation was approved by the Brain Malformation Panel on 2/14/2023.

Clinical Genomic Database (CGD)

Holoprosencephaly 12, with or without pancreatic agenesisAD

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Endocrine; Gastrointestinal; Musculoskeletal; Neurologic

Intervention: Audiologic/Otolaryngologic; Endocrine

Rationale: In addition to other findings, the condition has been described as sometimes involving congenital absence of the pancreas, which leads to medical interventions to manage early-onset insulin-dependent diabetes mellitus and the need for pancreatic enzyme replacement; In some individuals, early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 28525974; 31006510; 32553196

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CNOT1 variants in ClinVar

16 Conditions Cataloged

not providedTotal: 648

Inborn genetic diseasesTotal: 172

Vissers-Bodmer syndromeTotal: 70

not specifiedTotal: 59

CNOT1-related disorderTotal: 55

Holoprosencephaly 12 with or without pancreatic agenesisTotal: 24

See casesTotal: 4

Neurodevelopmental delayTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016284.5. 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			9 clinvar	154 clinvar	9 clinvar	172
missense	4 clinvar	8 clinvar	475 clinvar	21 clinvar	1 clinvar	509
nonsense	4 clinvar	10 clinvar	3 clinvar			17
start loss						0
frameshift	7 clinvar	11 clinvar	4 clinvar			22
splice donor/acceptor (+/-2bp)	4 clinvar	6 clinvar	18 clinvar	1 clinvar		29
Total	19	35	509	176	10	749

Highest pathogenic variant AF is 0.0000020521716

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 34 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016284.5	RefSeq	NP_057368.3	48	MANE Select
ENST00000317147.10	Ensembl	ENSP00000320949.5	48	MANE Select
NM_001265612.2	RefSeq	NP_001252541.1	48	Standard
NM_206999.3	RefSeq	NP_996882.1	30	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
cnot1	Danio rerio	Structure: anatomical system Quality: quality abnormal

Gene / Model

Organism

Observed Phenotype

cnot1

Danio rerio

Structure: anatomical system

Quality: quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

RNA degradation - Homo sapiens (human)
Gene expression (Transcription)
Generic Transcription Pathway
RNA Polymerase II Transcription
Metabolism of RNA

Biological Process

negative regulation of transcription by RNA polymerase II
nuclear-transcribed mRNA poly(A) tail shortening
DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest
multicellular organism development
positive regulation of cytoplasmic mRNA processing body assembly

Molecular Function

RNA binding
poly(A)-specific ribonuclease activity
protein binding
protein domain specific binding
estrogen receptor binding

Cellular Component

P-body
extracellular space
nucleus
cytosol
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000317147
Coding exons: 48
Length: 109936
Individuals with no LoFs: 125740
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125744
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	7.25	561	1.30e+3	0.433	0.0000691	15670
Missense (PolyPhen)		51	290.68	0.17545		3560
Synonymous	-0.514	470	456	1.03	0.0000240	4564
Loss of Function	10.3	1	125	0.00800	0.00000681	1440

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	0.000055	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000026	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Scaffolding 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. Its scaffolding function implies its interaction with the catalytic complex module and diverse RNA-binding proteins mediating the complex recruitment to selected mRNA 3'UTRs. Involved in degradation of AU-rich element (ARE)-containing mRNAs probably via association with ZFP36. Mediates the recruitment of the CCR4-NOT complex to miRNA targets and to the RISC complex via association with TNRC6A, TNRC6B or TNRC6C. Acts as a transcriptional repressor. Represses the ligand-dependent transcriptional activation by nuclear receptors. Involved in the maintenance of emryonic stem (ES) cell identity. {ECO:0000269|PubMed:10637334, ECO:0000269|PubMed:16778766, ECO:0000269|PubMed:21278420, ECO:0000269|PubMed:21976065, ECO:0000269|PubMed:21984185, ECO:0000269|PubMed:22367759, ECO:0000269|PubMed:23644599}.;

Recessive Scores

pRec: 0.135

Intolerance Scores

LoFtool: 0.191
RVIS EVS: -1.9
RVIS percentile EVS: 1.97

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.927

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium