Is CNOT3 p.Gln583Pro (c.1748A>C) pathogenic?

CNOT3 p.Gln583Pro (c.1748A>C) is classified Conflicting classifications of pathogenicity in CNOT3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-10-30). AlphaMissense: likely benign (0.0648); Very rare (popmax 0.00322%, nfe); Associated with complex neurodevelopmental disorder.

What condition is associated with CNOT3 p.Gln583Pro (c.1748A>C)?

CNOT3 p.Gln583Pro (c.1748A>C) is associated with complex neurodevelopmental disorder (ClinVar).

How common is CNOT3 p.Gln583Pro (c.1748A>C) in the general population?

CNOT3 p.Gln583Pro (c.1748A>C) is very rare (popmax 0.00322%, nfe) (gnomAD).

How is Non-specific syndromic intellectual disability inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CNOT3 p.Gln583Pro (c.1748A>C)?

AlphaMissense predicts likely benign (score 0.0648) — an in-silico prediction, not a clinical call.

CNOT3 p.Gln583Pro

c.1748A>C · rs772101793 · VCV3146614

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0648 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00322%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

complex neurodevelopmental disorder

Computational evidence

Protein change
AlphaMissense	0.0648	likely benign
REVEL	0.141	moderately benign-leaning
SaProt	LLR -4.10	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP -0.05, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 7,004 bp · p 0.37 · regional, not allelic
Overall
CADD	19.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00322% European (non-Finnish) · 38/1,180,028 alleles

Filtering AF 0.00239% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.00254% 41/1,614,042 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,828
European (non-Finnish)grpmax	0.00322%	31,053

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CNOT3
Protein: p.Gln583Pro
Coding: c.1748A>C
MANE Select: NM_014516
dbSNP: rs772101793
Type: single nucleotide variant
Location: chr19:54152470 (GRCh38)
Gene constraint: LOEUF 0.057 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.53 · 6 PDB

Full CNOT3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

complex neurodevelopmental disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Non-specific syndromic intellectual disability (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Childhood, Infancy

Similar variants

CNOT3 p.Pro244Leu Uncertain significance ★★ ⚠ same condition
CNOT3 p.Asn276Thr Benign ★★ same condition
CNOT3 p.Gly304Ser Conflicting classifications of pathogenicity ★ ⚠ same condition
CNOT3 c.1904+2T>C Pathogenic/Likely pathogenic ★★ same type
CNOT3 p.Arg697Ter Pathogenic ★★ same type
CNOT3 p.Arg81Ser Likely pathogenic ★★ same type
CNOT3 p.Arg96Ter Pathogenic/Likely pathogenic ★★ same type
CNOT3 p.Thr86= Likely pathogenic ★★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cnot3-p-gln583pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown