Is CNOT3 p.Leu671Phe (c.2011C>T) pathogenic?

CNOT3 p.Leu671Phe (c.2011C>T) is classified Uncertain significance in CNOT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-20). AlphaMissense: likely pathogenic (0.9996); Absent from gnomAD v4.1.

How common is CNOT3 p.Leu671Phe (c.2011C>T) in the general population?

CNOT3 p.Leu671Phe (c.2011C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CNOT3 p.Leu671Phe (c.2011C>T)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

CNOT3 p.Leu671Phe

c.2011C>T · rs2514256294 · VCV2499704

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic · top 10% in CNOT3
REVEL	0.773	moderately pathogenic-leaning
SaProt	LLR -13.98	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 4.6	GERP 1, phastCons 1
Regional constraint	o/e 0.46	unconstrained · MANE · 796 bp · p 0.002 · regional, not allelic
Overall
CADD	26.1	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: CNOT3
Protein: p.Leu671Phe
Coding: c.2011C>T
MANE Select: NM_014516
dbSNP: rs2514256294
Type: single nucleotide variant
Location: chr19:54152973 (GRCh38)
Gene constraint: LOEUF 0.057 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.53 · 6 PDB
Residue 671: the 'repressor domain' region; a UniProt-annotated variant site (in iddsadf); an α-helix

Full CNOT3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNOT3 p.Leu671= Likely benign ★ same residue
CNOT3 c.1904+2T>C Pathogenic/Likely pathogenic ★★ same type
CNOT3 p.Arg697Ter Pathogenic ★★ same type
CNOT3 p.Arg81Ser Likely pathogenic ★★ same type
CNOT3 p.Arg96Ter Pathogenic/Likely pathogenic ★★ same type
CNOT3 p.Thr86= Likely pathogenic ★★ same type
CNOT3 c.1905-7C>G Uncertain significance ★★ same type
CNOT3 c.483+6T>G 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/cnot3-p-leu671phe (accessed [today's date]).

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