CNOT4

Chr 7

CCR4-NOT transcription complex subunit 4

Also known as: CLONE243, NOT4, NOT4H

NCBI Gene: 4850ENSG00000080802UniProt: O95628

The protein encoded by this gene is a subunit of the CCR4-NOT complex, a global transcriptional regulator. The encoded protein interacts with CNOT1 and has E3 ubiquitin ligase activity. Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jul 2010]

93
ClinVar variants
33
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— CNOT4
⚡
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
33 Pathogenic / Likely Pathogenic· 59 VUS of 93 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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.
0.14LOEUF
pLI 1.000
Z-score 5.17
OE 0.03 (0.01–0.14)
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.
3.49Z-score
OE missense 0.51 (0.46–0.57)
207 obs / 404.6 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.03 (0.01–0.14)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.51 (0.46–0.57)
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.0.96
0≤1.21.6
LoF obs/exp: 1 / 33.1Missense obs/exp: 207 / 404.6Syn Z: 0.35

ClinVar Variant Classifications

93 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic32
Likely Pathogenic1
VUS59
Likely Benign1
32
Pathogenic
1
Likely Pathogenic
59
VUS
1
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
32
0
32
Likely Pathogenic
0
0
1
0
1
VUS
0
54
5
0
59
Likely Benign
0
0
1
0
1
Benign
0
0
0
0
0
Total05439093

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

View in ClinVar →

Protein Context — Lollipop Plot

CNOT4 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
CNOT4 enhances the efficacy of anti-PD-1 immunotherapy in a model of non-small cell lung cancer.
Zhang B et al.·FEBS Open Bio
2020Functional
The contribution of 7q33 copy number variations for intellectual disability.
Lopes F et al.·Neurogenetics
2018
TNKS1BP1 mediates AECII senescence and radiation induced lung injury through suppressing EEF2 degradation.
Zhu J et al.·Respir Res
2024
Erythrocyte miRNA-92a-3p interactions with PfEMP1 as determinants of clinical malaria.
Prabhu SR et al.·Funct Integr Genomics
2023
The miR-1206 microRNA variant is associated with methotrexate-induced oral mucositis in pediatric acute lymphoblastic leukemia.
Gutierrez-Camino A et al.·Pharmacogenet Genomics
2017
Unique MicroRNAs Signature of Lymphocyte of Yang and Yin Syndromes in Acute Ischemic Stroke Patients.
Zhao HP et al.·Chin J Integr Med
2019Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Auxin-induced depletion of human CCR4-NOT subunits reveals opposing functions of CNOT1 and CNOT4 in mRNA metabolism.
Kulkarni S et al.·J Biol Chem
2025🔓 Open Access
Cnot4 heterozygosity attenuates high fat diet-induced obesity in mice and impairs PPARγ-mediated adipocyte differentiation.
Yamaguchi T et al.·PLoS One
2025🔓 Open Access
Ubiquitination-deficit of Cnot4 impairs the capacity of proliferation and differentiation in mouse embryonic stem cells.
Ding W et al.·Biochem Biophys Res Commun
2025Functional
TNKS1BP1 facilitates ubiquitination of CNOT4 by TRIM21 to promote hepatocellular carcinoma progression and immune evasion.
Wang Y et al.·Cell Death Dis
2024🔓 Open Access
Stalled translation by mitochondrial stress upregulates a CNOT4-ZNF598 ribosomal quality control pathway important for tissue homeostasis.
Geng J et al.·Nat Commun
2024🔓 Open Access
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