Is CNOT4 p.Ala649Pro (c.1945G>C) pathogenic?

CNOT4 p.Ala649Pro (c.1945G>C) is classified Uncertain significance in CNOT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-20). Very rare (popmax 0.00167%, amr).

How common is CNOT4 p.Ala649Pro (c.1945G>C) in the general population?

CNOT4 p.Ala649Pro (c.1945G>C) is very rare (popmax 0.00167%, amr) (gnomAD).

CNOT4 p.Ala649Pro

c.1945G>C · rs759859047 · VCV3146625

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.081	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.99	GERP -1.6, phastCons 0.47
Regional constraint	o/e 0.93	unconstrained · MANE · 219 bp · p 0.49 · regional, not allelic
Overall
CADD	18.22	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,994 alleles

Overall 6.84e-05% 1/1,461,850 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: CNOT4
Protein: p.Ala649Pro
Coding: c.1945G>C
MANE Select: NM_001190850
dbSNP: rs759859047
Type: single nucleotide variant
Location: chr7:135363082 (GRCh38)
Gene constraint: LOEUF 0.236 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.54 · 2 PDB

Full CNOT4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNOT4 p.Ala101Ser Uncertain significance ★ ⚠ same type
CNOT4 p.Ala459Thr Uncertain significance ★ ⚠ same type
CNOT4 p.Ala583Thr Uncertain significance ★ same type
CNOT4 p.Ala587Val Uncertain significance ★ same type
CNOT4 p.Ala669Thr Uncertain significance ★ same type
CNOT4 p.Arg323Gln Uncertain significance ★ ⚠ same type
CNOT4 p.Arg342His Uncertain significance ★ ⚠ same type
CNOT4 p.Arg3Cys 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/cnot4-p-ala649pro (accessed [today's date]).

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