Is CNOT6 p.Leu394Pro (c.1181T>C) pathogenic?

CNOT6 p.Leu394Pro (c.1181T>C) is classified Uncertain significance in CNOT6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-14). AlphaMissense: likely benign (0.136); Absent from gnomAD v4.1.

How common is CNOT6 p.Leu394Pro (c.1181T>C) in the general population?

CNOT6 p.Leu394Pro (c.1181T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CNOT6 p.Leu394Pro (c.1181T>C)?

AlphaMissense predicts likely benign (score 0.136) — an in-silico prediction, not a clinical call.

CNOT6 p.Leu394Pro

c.1181T>C · VCV3834583

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.136 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.136	likely benign
REVEL	0.165	moderately benign-leaning
SaProt	LLR -11.19	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 0.68, phastCons 0.98
Regional constraint	o/e 0.63	unconstrained · MANE · 3,450 bp · p 4.4e-07 · regional, not allelic
Overall
CADD	22.2	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

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: CNOT6
Protein: p.Leu394Pro
Coding: c.1181T>C
MANE Select: NM_001370472
Type: single nucleotide variant
Location: chr5:180569263 (GRCh38)
Gene constraint: LOEUF 0.32 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.51 · 1 PDB
Residue 394: the 'nuclease domain' region

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

Similar variants

CCR4 p.Ala246Thr Uncertain significance ★ ⚠ same type
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-leu394pro (accessed [today's date]).

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