Is CNOT6 p.Ile285Val (c.853A>G) pathogenic?

CNOT6 p.Ile285Val (c.853A>G) is classified Uncertain significance in CNOT6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-17). AlphaMissense: likely benign (0.0609); Ultra-rare (popmax 0.0618%, afr).

How common is CNOT6 p.Ile285Val (c.853A>G) in the general population?

CNOT6 p.Ile285Val (c.853A>G) is ultra-rare (popmax 0.0618%, afr) (gnomAD).

What do computational predictors say about CNOT6 p.Ile285Val (c.853A>G)?

AlphaMissense predicts likely benign (score 0.0609) — an in-silico prediction, not a clinical call.

CNOT6 p.Ile285Val

c.853A>G · rs147748063 · VCV3146634

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0609 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0618%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0609	likely benign
REVEL	0.409	indeterminate
SaProt	LLR -9.11	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 0.79, phastCons 1
Regional constraint	o/e 0.28	constrained · MANE · 822 bp · p 3.3e-11 · regional, not allelic
Overall
CADD	18.35	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 0.0618% African / African-American · 46/74,416 alleles

Filtering AF 0.0475% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0426%

Overall 0.00535% 86/1,606,038 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0618%	1,618
Admixed American	0.0192%	5,214
Remaining individualsnot grpmax-eligible	0.0145%	6,907
South Asian	0.00224%	44,561
East Asian	0.00223%	44,814
European (non-Finnish)	0.00144%	69,298

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: CNOT6
Protein: p.Ile285Val
Coding: c.853A>G
MANE Select: NM_001370472
dbSNP: rs147748063
Type: single nucleotide variant
Location: chr5:180567223 (GRCh38)
Gene constraint: LOEUF 0.32 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.51 · 1 PDB
Residue 285: a β-strand; the 'nuclease domain' region

Full CNOT6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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CCR4 p.Ala246Val Uncertain significance ★ ⚠ same type
CCR4 p.Arg147Trp Uncertain significance ★ ⚠ same type
CCR4 p.Cys178Arg Uncertain significance ★ ⚠ same type
CCR4 p.Cys329Gly Uncertain significance ★ ⚠ same type
CCR4 p.Gln230Lys Uncertain significance ★ ⚠ same type
CCR4 p.His357Arg Uncertain significance ★ ⚠ same type
CCR4 p.Ile15Val 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/cnot6-p-ile285val (accessed [today's date]).

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