CNOT3

Chr 19AD

CCR4-NOT transcription complex subunit 3

Also known as: IDDSADF, LENG2, NOT3, NOT3H

NCBI Gene: 4849 ENSG00000088038 UniProt: O75175 OMIM: 604910

CNOT3 encodes a component of the CCR4-NOT complex, a major cellular mRNA deadenylase that regulates mRNA degradation, translational repression, and transcriptional regulation, and is involved in stem cell maintenance and mitotic progression. Mutations cause autosomal dominant intellectual developmental disorder with speech delay, autism, and dysmorphic facies. The gene is highly constrained against loss-of-function variants (pLI >0.99, LOEUF 0.076), indicating that even single functional copies are critical for normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.081 OMIM phenotype

Clinical Summary— CNOT3

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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ClinVar Variants

72 unique Pathogenic / Likely Pathogenic· 212 VUS of 457 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.00 (0.00–0.08)

0≤0.351.4

Missense OE?0.50 (0.45–0.56)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 0 / 39.3Missense obs/exp: 230 / 456.3Syn Z: -0.56

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCNOT3-related neurodevelopmental disorderLOFAD

This gene — mechanism propensity

0.2499th %ile

GOF

0.2696th %ile

LOF

0.84top 5%

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

LOFprediction above median · 1 literature citation · 69% of P/LP variants are LoF · LOEUF 0.08

Literature Evidence

LOFHaploinsufficiency appears to be the most likely mechanism of action, with eight cases found to have protein-truncating variants.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 31201375 ↗

ClinVar Variant Classifications

457 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic43

Likely Pathogenic29

VUS212

Likely Benign110

Benign24

Conflicting19

Pathogenic

Likely Pathogenic

212

VUS

110

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	39	2	2	0	43
Likely Pathogenic	11	15	1	2	29
VUS	3	182	21	6	212
Likely Benign	0	18	33	59	110
Benign	0	4	14	6	24
Conflicting	—				19
Total	53	221	71	73	437

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 25) ClinVar copy-number / structural variants overlap CNOT3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →