CNOT1

Chr 16AD

CCR4-NOT transcription complex subunit 1

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

NCBI Gene: 23019 ENSG00000125107 UniProt: A5YKK6 OMIM: 604917

CNOT1 encodes a scaffolding component of the CCR4-NOT complex, a major cellular mRNA deadenylase that regulates mRNA degradation, translational repression, and transcription. Mutations cause autosomal dominant holoprosencephaly 12 (with or without pancreatic agenesis) and Vissers-Bodmer syndrome, affecting brain development and other organ systems. This gene is highly constrained against loss-of-function variants (pLI = 1.0), indicating intolerance to protein-disrupting mutations.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.042 OMIM phenotypes

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

47 unique Pathogenic / Likely Pathogenic· 460 VUS of 953 total submissions

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — CNOT1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.01 (0.00–0.04)

0≤0.351.4

Missense OE?0.43 (0.40–0.46)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 1 / 125.0Missense obs/exp: 561 / 1295.9Syn Z: -0.51

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCNOT1-related neurodevelopmental disorderOTHERAD

strongCNOT1-related holoprosencephaly with or without pancreatic agenesisOTHERAD

This gene — mechanism propensity

0.2099th %ile

GOF

0.3193th %ile

LOF

0.82top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 81% of P/LP variants are LoF · LOEUF 0.04 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFAn integrated omics approach of patient-derived genomics and transcriptomics data suggested only minimal effects on endonucleolytic nonsense-mediated mRNA decay components, suggesting that de novo CNOT1 variants are likely haploinsufficient hypomorph or neomorph, rather than dominant negative.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 32553196 ↗

ClinVar Variant Classifications

953 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic18

Likely Pathogenic29

VUS460

Likely Benign275

Benign104

Conflicting11

Pathogenic

Likely Pathogenic

460

VUS

275

Likely Benign

104

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	14	4	0	0	18
Likely Pathogenic	24	4	1	0	29
VUS	11	417	25	7	460
Likely Benign	2	15	110	148	275
Benign	3	2	82	17	104
Conflicting	—				11
Total	54	442	218	172	897

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

View in ClinVar →

24 pathogenic / likely-pathogenic (of 35) ClinVar copy-number / structural variants overlap CNOT1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →