Is CNOT3 p.Ser245fs (c.732dup) pathogenic?

CNOT3 p.Ser245fs (c.732dup) is classified Pathogenic/Likely pathogenic in CNOT3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-05-21). Very rare (popmax 0.000425%, nfe); Associated with intellectual developmental disorder with speech delay, autism, and dysmorphic facies.

How common is CNOT3 p.Ser245fs (c.732dup) in the general population?

CNOT3 p.Ser245fs (c.732dup) is very rare (popmax 0.000425%, nfe) (gnomAD).

CNOT3 p.Ser245fs

Q: What condition is associated with CNOT3 p.Ser245fs (c.732dup)?

CNOT3 p.Ser245fs (c.732dup) is associated with intellectual developmental disorder with speech delay, autism, and dysmorphic facies (ClinVar).

c.732dup · rs753475896 · VCV694669

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000425%, nfe)

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.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 9 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.1	GERP 1.6, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000425% European (non-Finnish) · 5/1,177,854 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00418% 61/1,457,614 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0878%	1,139
Remaining individualsnot grpmax-eligible	0.00321%	31,178
European (non-Finnish)grpmax	0.000425%	235,571

Finnish 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.Ser245fs
Coding: c.732dup
MANE Select: NM_014516
dbSNP: rs753475896
Type: Indel
Location: chr19:54145930 (GRCh38)
Gene constraint: LOEUF 0.057 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.53 · 6 PDB
Residue 245: the 'disordered' region

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.Ser245Cys Uncertain significance ★ same residue
CNOT3 p.Pro314fs Likely pathogenic ★ same condition
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.Asn276fs Pathogenic ★★ same condition
CNOT3 p.Thr86= Likely pathogenic ★★ 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-ser245fs (accessed [today's date]).

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