Is CNOT2 p.Gln457fs (c.1369del) pathogenic?

CNOT2 p.Gln457fs (c.1369del) is classified Likely pathogenic in CNOT2 (ClinVar, Single submitter, 1 submitter). Associated with intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies.

CNOT2 p.Gln457fs

Q: What condition is associated with CNOT2 p.Gln457fs (c.1369del)?

CNOT2 p.Gln457fs (c.1369del) is associated with intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies (ClinVar).

c.1369del · VCV3338647

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies

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 14 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1

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

Variant & gene context

Gene: CNOT2
Protein: p.Gln457fs
Coding: c.1369del
MANE Select: NM_014515
Type: Deletion
Location: chr12:70344206 (GRCh38)
Gene constraint: LOEUF 0.211 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 60.35 · 4 PDB
Residue 457: a UniProt-annotated variant site (in idnadfs); the 'repressor domain' region; an α-helix

Full CNOT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CNOT2 p.Tyr494Cys Uncertain significance ★★ ⚠ same condition
CNOT2 p.His526fs Likely pathogenic ★ same condition
CNOT2 p.Leu376fs Likely pathogenic ★ same condition
CNOT2 p.Gln411Arg Uncertain significance ★ ⚠ same condition
CNOT2 p.Pro136Ser Uncertain significance ★ ⚠ same condition
CNOT2 p.Lys316Ter Pathogenic same condition
CNOT2 p.Ter541= Conflicting classifications of pathogenicity ★ ⚠ same type
CNOT2 p.Tyr500fs Uncertain significance ★ 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/cnot2-p-gln457fs (accessed [today's date]).

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