Is CNOT3 p.Pro584= (c.1752G>A) pathogenic?

CNOT3 p.Pro584= (c.1752G>A) is classified Conflicting classifications of pathogenicity in CNOT3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-11-15). Very rare (popmax 0.00768%, sas); Associated with intellectual developmental disorder with speech delay, autism, and dysmorphic facies.

How common is CNOT3 p.Pro584= (c.1752G>A) in the general population?

CNOT3 p.Pro584= (c.1752G>A) is very rare (popmax 0.00768%, sas) (gnomAD).

CNOT3 p.Pro584=

Q: What condition is associated with CNOT3 p.Pro584= (c.1752G>A)?

CNOT3 p.Pro584= (c.1752G>A) is associated with intellectual developmental disorder with speech delay, autism, and dysmorphic facies (ClinVar).

c.1752G>A · rs1406807767 · VCV2688802

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00768%, sas)

Conditions

intellectual developmental disorder with speech delay, autism, and dysmorphic facies

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.005	strongly benign-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP -9.8	GERP -2
Overall
CADD	0.338	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00768% South Asian · 7/91,088 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00396%

Overall 0.00489% 79/1,614,050 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00768%	13,013
African / African-American	0.00667%	14,986
European (non-Finnish)	0.00542%	18,438
Remaining individualsnot grpmax-eligible	0.0048%	20,828

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.Pro584=
Coding: c.1752G>A
MANE Select: NM_014516
dbSNP: rs1406807767
Type: single nucleotide variant
Location: chr19:54152474 (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

intellectual developmental disorder with speech delay, autism, and dysmorphic facies — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CNOT3 p.Pro584Leu Likely benign ★ ⚠ same residue
CNOT3 c.1904+2T>C Pathogenic/Likely pathogenic ★★ same condition
CNOT3 p.Arg697Ter Pathogenic ★★ same condition
CNOT3 p.Arg81Ser Likely pathogenic ★★ same condition
CNOT3 p.Arg96Ter Pathogenic/Likely pathogenic ★★ same condition
CNOT3 p.Thr86= Likely pathogenic ★★ same condition
CNOT3 c.483+6T>G Uncertain significance ★★ same condition
CNOT3 p.Arg665His Uncertain significance ★★ ⚠ same condition

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-pro584 (accessed [today's date]).

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