Is CNOT4 p.Pro688Gln (c.2063C>A) pathogenic?

CNOT4 p.Pro688Gln (c.2063C>A) is classified Uncertain significance in CNOT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-09). Very rare (popmax 0.000933%, nfe).

How common is CNOT4 p.Pro688Gln (c.2063C>A) in the general population?

CNOT4 p.Pro688Gln (c.2063C>A) is very rare (popmax 0.000933%, nfe) (gnomAD).

CNOT4 p.Pro688Gln

c.2063C>A · rs1794717856 · VCV2235531

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000933%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.255	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 219 bp · p 0.49 · regional, not allelic
Overall
CADD	27.2	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000933% European (non-Finnish) · 11/1,179,140 alleles

Filtering AF 0.000501% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000682% 11/1,612,660 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.Pro688Gln
Coding: c.2063C>A
MANE Select: NM_001190850
dbSNP: rs1794717856
Type: single nucleotide variant
Location: chr7:135362964 (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.Ala649Pro 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

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-pro688gln (accessed [today's date]).

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