CNOT1

Chr 16AD

CCR4-NOT transcription complex subunit 1

Also known as: AD-005, CDC39, HPE12, NOT1, NOT1H, VIBOS

NCBI Gene: 23019ENSG00000125107UniProt: A5YKK6

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 and cytosol. Part of CCR4-NOT complex. Implicated in Vissers-Bodmer syndrome and holoprosencephaly 12. [provided by Alliance of Genome Resources, Jul 2025]

Primary Disease Associations & Inheritance

Holoprosencephaly 12, with or without pancreatic agenesisMIM #618500
AD
Vissers-Bodmer syndromeMIM #619033
AD
544
ClinVar variants
43
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— CNOT1
🧬
Gene-Disease Validity (ClinGen)
holoprosencephaly 12 with or without pancreatic agenesis · ADLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
43 Pathogenic / Likely Pathogenic· 335 VUS of 544 total submissions
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.04LOEUF
pLI 1.000
Z-score 10.28
OE 0.01 (0.00–0.04)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
7.25Z-score
OE missense 0.43 (0.40–0.46)
561 obs / 1295.9 exp
Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.01 (0.00–0.04)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.43 (0.40–0.46)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.03
0≤1.21.6
LoF obs/exp: 1 / 125.0Missense obs/exp: 561 / 1295.9Syn Z: -0.51

ClinVar Variant Classifications

544 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19
Likely Pathogenic24
VUS335
Likely Benign106
Benign57
Conflicting3
19
Pathogenic
24
Likely Pathogenic
335
VUS
106
Likely Benign
57
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
9
2
8
0
19
Likely Pathogenic
10
3
11
0
24
VUS
6
303
22
4
335
Likely Benign
0
8
37
61
106
Benign
1
1
52
3
57
Conflicting
—3
Total2631713068544

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

CNOT1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

CNOT1-related neurodevelopmental disorder

strong
ADUndeterminedUncertain
Dev. Disorders
G2P ↗

CNOT1-related holoprosencephaly with or without pancreatic agenesis

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Holoprosencephaly 12, with or without pancreatic agenesis

MIM #618500

Molecular basis of disorder known

Autosomal dominant

Vissers-Bodmer syndrome

MIM #619033

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — CNOT1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay.
Vissers LELM et al.·Am J Hum Genet
2020
Pathogenicity analysis and splicing rescue of a classical splice site variant (c.1343+1G>T) of CNOT1 gene associated with neurodevelopmental disorders.
Dong Y et al.·Am J Med Genet A
2023
[Clinical and genetic analysis of a Chinese pedigree affected with Vissers-Bodmer syndrome due to variant of CNOT1 gene and a literature review.].
Jiao Y et al.·Zhonghua Yi Xue Yi Chuan Xue Za Zhi
2025Review
Fetal Description of the Pancreatic Agenesis and Holoprosencephaly Syndrome Associated to a Specific CNOT1 Variant.
Cospain A et al.·Pediatr Dev Pathol
2022
The central region of CNOT1 and CNOT9 stimulates deadenylation by the Ccr4-Not nuclease module.
Pavanello L et al.·Biochem J
2018
CNOT1 p.Arg535Cys variant in holoprosencephaly with late onset diabetes mellitus.
de Queiroz Júnior AF et al.·Am J Med Genet A
2024Case report
A CCR4-NOT Transcription Complex, Subunit 1, CNOT1, Variant Associated with Holoprosencephaly.
Kruszka P et al.·Am J Hum Genet
2019Case report
CNOT1 cooperates with LMNA to aggravate osteosarcoma tumorigenesis through the Hedgehog signaling pathway.
Cheng DD et al.·Mol Oncol
2017
Importance of the Conserved Carboxyl-Terminal CNOT1 Binding Domain to Tristetraprolin Activity In Vivo.
Lai WS et al.·Mol Cell Biol
2019
Vissers-Bodmer syndrome caused by a novel de novo CNOT1 frameshift variant.
Wu T et al.·Am J Med Genet A
2024Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools