Is CNOT3 p.Arg290Cys (c.868C>T) pathogenic?

CNOT3 p.Arg290Cys (c.868C>T) is classified Uncertain significance in CNOT3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-28). AlphaMissense: likely pathogenic (0.709); Very rare (popmax 8.78e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CNOT3 p.Arg290Cys (c.868C>T)?

CNOT3 p.Arg290Cys (c.868C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CNOT3 p.Arg290Cys (c.868C>T) in the general population?

CNOT3 p.Arg290Cys (c.868C>T) is very rare (popmax 8.78e-05%, nfe) (gnomAD).

What do computational predictors say about CNOT3 p.Arg290Cys (c.868C>T)?

AlphaMissense predicts likely pathogenic (score 0.709) — an in-silico prediction, not a clinical call.

CNOT3 p.Arg290Cys

c.868C>T · VCV3372733

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.709 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.78e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.709	likely pathogenic
REVEL	0.222	benign-leaning
SaProt	LLR -7.33	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 7,004 bp · p 0.37 · regional, not allelic
Overall
CADD	28.9	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 8.78e-05% European (non-Finnish) · 1/1,138,500 alleles

Overall 7.06e-05% 1/1,416,132 alleles · very rare

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.Arg290Cys
Coding: c.868C>T
MANE Select: NM_014516
Type: single nucleotide variant
Location: chr19:54146631 (GRCh38)
Gene constraint: LOEUF 0.057 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.53 · 6 PDB
Residue 290: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CNOT3 p.Ala438Val Uncertain significance ★★ ⚠ same condition
CNOT3 p.Glu533Gln Uncertain significance ★★ ⚠ same condition
CNOT3 p.Gly405Ser Uncertain significance ★★ ⚠ same condition
CNOT3 p.Met182Val Uncertain significance ★★ ⚠ same condition
CNOT3 p.Pro244Ala Uncertain significance ★★ ⚠ same condition
CNOT3 p.Pro320Leu Uncertain significance ★★ ⚠ same condition
CNOT3 p.Pro510Ser Uncertain significance ★★ ⚠ same condition
CNOT3 p.Pro579Leu 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-arg290cys (accessed [today's date]).

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