CNOT3

Chr 19

CCR4-NOT transcription complex subunit 3

Also known as: IDDSADF, LENG2, NOT3, NOT3H

NCBI Gene: 4849ENSG00000088038UniProt: O75175

Involved in regulation of stem cell population maintenance. Part of CCR4-NOT complex. [provided by Alliance of Genome Resources, Jul 2025]

Primary Disease Associations & Inheritance

UniProtIntellectual developmental disorder with speech delay, autism and dysmorphic facies
460
ClinVar variants
88
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— CNOT3
🧬
Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
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
88 Pathogenic / Likely Pathogenic· 221 VUS of 460 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
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.
0.08LOEUF
pLI 1.000
Z-score 5.81
OE 0.00 (0.00–0.08)
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.
3.76Z-score
OE missense 0.50 (0.45–0.56)
230 obs / 456.3 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.0.00 (0.00–0.08)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.50 (0.45–0.56)
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.1.05
0≤1.21.6
LoF obs/exp: 0 / 39.3Missense obs/exp: 230 / 456.3Syn Z: -0.56

ClinVar Variant Classifications

460 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic59
Likely Pathogenic29
VUS221
Likely Benign108
Benign25
Conflicting18
59
Pathogenic
29
Likely Pathogenic
221
VUS
108
Likely Benign
25
Benign
18
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
27
1
31
0
59
Likely Pathogenic
8
12
7
2
29
VUS
1
178
36
6
221
Likely Benign
0
15
34
59
108
Benign
0
5
14
6
25
Conflicting
—18
Total3621112273460

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

View in ClinVar →

Protein Context — Lollipop Plot

CNOT3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

CNOT3-related neurodevelopmental disorder

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
T-Cell Acute Lymphoblastic Leukemia: Biomarkers and Their Clinical Usefulness.
Bardelli V et al.·Genes (Basel)
2021Review
Comprehensive analysis of CNOT3-related neurodevelopmental disorders: phenotypic and genotypic characterization.
Engel C et al.·Eur J Hum Genet
2025
Clinical features of CNOT3-associated neurodevelopmental disorder in three Chinese patients.
Zhao P et al.·Neurogenetics
2023Cohort
Transcriptional Regulator CNOT3 Defines an Aggressive Colorectal Cancer Subtype.
Cejas P et al.·Cancer Res
2017
Determinants of Disease Penetrance in PRPF31-Associated Retinopathy.
McLenachan S et al.·Genes (Basel)
2021
Genetic etiology of ventriculomegaly in 73 fetuses identified by High-Throughput sequencing.
Chenyue Z et al.·Sci Rep
2025
Dilated aorta in CNOT3 -related neurodevelopmental disorder: 'expanding' the phenotype.
Lau SHM et al.·Clin Dysmorphol
2024Case report
A novel pathogenic variant in CNOT3 causing neurodevelopmental delay and epilepsy.
Lv J et al.·Seizure
2023Case report
CNOT3 contributes to cisplatin resistance in lung cancer through inhibiting RIPK3 expression.
Jing L et al.·Apoptosis
2019
De novo variants in CNOT3 cause a variable neurodevelopmental disorder.
Martin R et al.·Eur J Hum Genet
2019
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
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10

External Resources

Links to major genomics databases and tools