Is CNOT3 p.Arg697Gln (c.2090G>A) pathogenic?

CNOT3 p.Arg697Gln (c.2090G>A) is classified Uncertain significance in CNOT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-18). AlphaMissense: likely pathogenic (0.9997); Absent from gnomAD v4.1.

How common is CNOT3 p.Arg697Gln (c.2090G>A) in the general population?

CNOT3 p.Arg697Gln (c.2090G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CNOT3 p.Arg697Gln (c.2090G>A)?

AlphaMissense predicts likely pathogenic (score 0.9997) — an in-silico prediction, not a clinical call.

CNOT3 p.Arg697Gln

c.2090G>A · VCV4883599

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9997 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9997	likely pathogenic · top 10% in CNOT3
REVEL	0.295	indeterminate
SaProt	LLR -14.54	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1, phastCons 1
Regional constraint	o/e 0.05	constrained · MANE · 95 bp · p 1e-09 · regional, not allelic
Overall
CADD	28.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CNOT3
Protein: p.Arg697Gln
Coding: c.2090G>A
MANE Select: NM_014516
Type: single nucleotide variant
Location: chr19:54153767 (GRCh38)
Gene constraint: LOEUF 0.057 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.53 · 6 PDB
Residue 697: the 'repressor domain' region; a UniProt-annotated variant site (in iddsadf); a UniProt-annotated variant site (in iddsadf; uncertain significance); a β-strand

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

Similar variants

CNOT3 p.Arg697Ter Pathogenic ★★ same residue
CNOT3 c.1904+2T>C Pathogenic/Likely 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
CNOT3 c.1905-7C>G Uncertain significance ★★ same type
CNOT3 c.483+6T>G Uncertain significance ★★ same type
CNOT3 p.Ala376Thr 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/cnot3-p-arg697gln (accessed [today's date]).

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