Is CNOT2 p.Lys473Arg (c.1418A>G) pathogenic?

CNOT2 p.Lys473Arg (c.1418A>G) is classified Uncertain significance in CNOT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-20). AlphaMissense: likely benign (0.2258); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with CNOT2 p.Lys473Arg (c.1418A>G)?

CNOT2 p.Lys473Arg (c.1418A>G) is associated with Inborn genetic diseases (ClinVar).

How common is CNOT2 p.Lys473Arg (c.1418A>G) in the general population?

CNOT2 p.Lys473Arg (c.1418A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CNOT2 p.Lys473Arg (c.1418A>G)?

AlphaMissense predicts likely benign (score 0.2258) — an in-silico prediction, not a clinical call.

CNOT2 p.Lys473Arg

c.1418A>G · VCV3494478

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2258 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2258	likely benign
REVEL	0.321	indeterminate
SaProt	LLR -10.96	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 12 kb · p 5.2e-16 · regional, not allelic
Overall
CADD	28.6	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 0.00223% East Asian · 1/44,816 alleles

Overall 0.000186% 3/1,610,316 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,816
Admixed American	0.00167%	59,840
African / African-American	0.00133%	74,924

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: CNOT2
Protein: p.Lys473Arg
Coding: c.1418A>G
MANE Select: NM_014515
Type: single nucleotide variant
Location: chr12:70346206 (GRCh38)
Gene constraint: LOEUF 0.211 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 60.35 · 4 PDB
Residue 473: a UniProt-annotated variant site (in idnadfs); the 'repressor domain' region; a turn

Full CNOT2 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

CNOT2 p.Arg183Gln Uncertain significance ★★ ⚠ same condition
CNOT2 p.Gly32Glu Likely benign ★★ same condition
CNOT2 p.Met49Val Likely benign ★★ same condition
CNOT2 p.Ser228Ter Pathogenic ★ same condition
CNOT2 p.Ala253Gly Uncertain significance ★ ⚠ same condition
CNOT2 p.Ala266Gly Uncertain significance ★ ⚠ same condition
CNOT2 p.Arg236Gly Uncertain significance ★ ⚠ same condition
CNOT2 p.Arg53Gln 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/cnot2-p-lys473arg (accessed [today's date]).

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