Is CNOT8 p.Cys256Arg (c.766T>C) pathogenic?

CNOT8 p.Cys256Arg (c.766T>C) is classified Uncertain significance in CNOT8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-27). AlphaMissense: ambiguous (0.5414); Ultra-rare (popmax 0.0101%, nfe).

How common is CNOT8 p.Cys256Arg (c.766T>C) in the general population?

CNOT8 p.Cys256Arg (c.766T>C) is ultra-rare (popmax 0.0101%, nfe) (gnomAD).

What do computational predictors say about CNOT8 p.Cys256Arg (c.766T>C)?

AlphaMissense predicts ambiguous (score 0.5414) — an in-silico prediction, not a clinical call.

CNOT8 p.Cys256Arg

c.766T>C · VCV4654987

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5414 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0101%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5414	ambiguous
REVEL	0.504	indeterminate
SaProt	LLR -7.22	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 12 kb · p 1.8e-19 · regional, not allelic
Overall
CADD	24.3	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 0.0101% European (non-Finnish) · 119/1,180,046 alleles

Filtering AF 0.00859% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00803%

Overall 0.00781% 126/1,614,050 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0101%	9,916
Remaining individualsnot grpmax-eligible	0.0064%	15,621
African / African-American	0.004%	24,977

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.Cys256Arg
Coding: c.766T>C
MANE Select: NM_001301073
Type: single nucleotide variant
Location: chr5:154875326 (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.Gln219Glu Uncertain significance ★ ⚠ same type
CNOT8 p.Gln278Pro Uncertain significance ★ ⚠ same type
CNOT8 p.Glu29Gln 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-cys256arg (accessed [today's date]).

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