Is CNOT9 p.Lys188Asn (c.564G>C) pathogenic?

CNOT9 p.Lys188Asn (c.564G>C) is classified Uncertain significance in CNOT9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-15). AlphaMissense: likely pathogenic (0.9998); Absent from gnomAD v4.1.

How common is CNOT9 p.Lys188Asn (c.564G>C) in the general population?

CNOT9 p.Lys188Asn (c.564G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CNOT9 p.Lys188Asn (c.564G>C)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

CNOT9 p.Lys188Asn

c.564G>C · VCV4537831

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9998 · 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	0.9998	likely pathogenic
REVEL	0.638	indeterminate
SaProt	LLR -16.49	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 6.5	GERP 0.85, phastCons 1
Regional constraint	o/e 0.36	constrained · MANE · 14 kb · p 7.3e-31 · regional, not allelic
Overall
CADD	26.8	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: CNOT9
Protein: p.Lys188Asn
Coding: c.564G>C
MANE Select: NM_005444
Type: single nucleotide variant
Location: chr2:218592327 (GRCh38)
Gene constraint: LOEUF 0.523 · pLI 0.96 (gnomAD)
Structure: AlphaFold pLDDT 92.83 · 14 PDB
Residue 188: an α-helix

Full CNOT9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNOT9 p.Arg227His Pathogenic/Likely pathogenic ★★ same type
CNOT9 p.Arg292Trp Pathogenic ★★ ⚠ same type
CNOT9 p.Arg46Gln Likely pathogenic ★ same type
CNOT9 p.Arg46Gly Likely pathogenic ★ same type
CNOT9 p.Pro131Leu Likely pathogenic ★ same type
CNOT9 c.541-1G>T Uncertain significance ★ same type
CNOT9 p.Ala101Thr Uncertain significance ★ ⚠ same type
CNOT9 p.Arg169Gln 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/cnot9-p-lys188asn (accessed [today's date]).

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