Is CNOT8 p.Lys280Arg (c.839A>G) pathogenic?

CNOT8 p.Lys280Arg (c.839A>G) is classified Uncertain significance in CNOT8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-26). AlphaMissense: likely benign (0.0947); Very rare (popmax 0.00666%, amr).

How common is CNOT8 p.Lys280Arg (c.839A>G) in the general population?

CNOT8 p.Lys280Arg (c.839A>G) is very rare (popmax 0.00666%, amr) (gnomAD).

What do computational predictors say about CNOT8 p.Lys280Arg (c.839A>G)?

AlphaMissense predicts likely benign (score 0.0947) — an in-silico prediction, not a clinical call.

CNOT8 p.Lys280Arg

c.839A>G · rs200582500 · VCV2292679

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0947 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0947	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -6.38	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 59 bp · p 0.56 · regional, not allelic
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00666% Admixed American · 4/60,016 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00118% 19/1,614,068 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00666%	15,004
African / African-American	0.00267%	37,520
European (non-Finnish)	0.0011%	90,770

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: CNOT8
Protein: p.Lys280Arg
Coding: c.839A>G
MANE Select: NM_001301073
dbSNP: rs200582500
Type: single nucleotide variant
Location: chr5:154875399 (GRCh38)
Gene constraint: LOEUF 0.776 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 90.51 · 1 PDB

Full CNOT8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNOT8 c.729+1G>T Uncertain significance ★ same type
CNOT8 p.Ala285Val Uncertain significance ★ ⚠ same type
CNOT8 p.Arg173Cys Uncertain significance ★ ⚠ same type
CNOT8 p.Asn289Ile Uncertain significance ★ ⚠ same type
CNOT8 p.Asp70Ala Uncertain significance ★ same type
CNOT8 p.Cys256Arg Uncertain significance ★ ⚠ same type
CNOT8 p.Gln219Glu Uncertain significance ★ ⚠ same type
CNOT8 p.Gln278Pro 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/cnot8-p-lys280arg (accessed [today's date]).

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