Is CNOT1 p.Ala333Val (c.998C>T) pathogenic?

CNOT1 p.Ala333Val (c.998C>T) is classified Uncertain significance in CNOT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-19). AlphaMissense: likely benign (0.0868); Very rare (popmax 0.00135%, afr).

How common is CNOT1 p.Ala333Val (c.998C>T) in the general population?

CNOT1 p.Ala333Val (c.998C>T) is very rare (popmax 0.00135%, afr) (gnomAD).

What do computational predictors say about CNOT1 p.Ala333Val (c.998C>T)?

AlphaMissense predicts likely benign (score 0.0868) — an in-silico prediction, not a clinical call.

CNOT1 p.Ala333Val

c.998C>T · VCV3689816

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0868 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00135%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0868	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -6.01	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 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 43 kb · p 6e-23 · regional, not allelic
Overall
CADD	25.3	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 0.00135% African / African-American · 1/74,168 alleles

Overall 0.000657% 1/152,140 alleles · very rare

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: CNOT1
Protein: p.Ala333Val
Coding: c.998C>T
MANE Select: NM_016284
Type: single nucleotide variant
Location: chr16:58582839 (GRCh38)
Gene constraint: LOEUF 0.064 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.22 · 21 PDB
Residue 333: a UniProt-annotated variant site (in vibos)

Full CNOT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNOT1 c.434-2A>G Pathogenic ★★ same type
CNOT1 p.Arg26Ter Pathogenic/Likely pathogenic ★★ same type
CNOT1 p.Arg535Cys Pathogenic ★★ same type
CNOT1 c.310-3C>G Uncertain significance ★★ same type
CNOT1 c.5895+4T>C Uncertain significance ★★ same type
CNOT1 p.Ala1368Val Uncertain significance ★★ ⚠ same type
CNOT1 p.Ala1503Thr Uncertain significance ★★ ⚠ same type
CNOT1 p.Ala1604Gly 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/cnot1-p-ala333val (accessed [today's date]).

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