Is CNOT8 p.Asp70Ala (c.209A>C) pathogenic?

CNOT8 p.Asp70Ala (c.209A>C) is classified Uncertain significance in CNOT8 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-09). AlphaMissense: likely pathogenic (0.993); Absent from gnomAD v4.1.

How common is CNOT8 p.Asp70Ala (c.209A>C) in the general population?

CNOT8 p.Asp70Ala (c.209A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CNOT8 p.Asp70Ala (c.209A>C)?

AlphaMissense predicts likely pathogenic (score 0.993) — an in-silico prediction, not a clinical call.

CNOT8 p.Asp70Ala

c.209A>C · VCV4972777

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.993 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.993	likely pathogenic
REVEL	0.78	moderately pathogenic-leaning
SaProt	LLR -13.79	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 12 kb · p 1.8e-19 · regional, not allelic
Overall
CADD	28.7	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: CNOT8
Protein: p.Asp70Ala
Coding: c.209A>C
MANE Select: NM_001301073
Type: single nucleotide variant
Location: chr5:154865283 (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.Cys256Arg 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-asp70ala (accessed [today's date]).

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