Is CNOT3 p.Ala474= (c.1422G>A) pathogenic?

CNOT3 p.Ala474= (c.1422G>A) is classified Likely benign in CNOT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-08). Very rare (popmax 0.00345%, amr).

How common is CNOT3 p.Ala474= (c.1422G>A) in the general population?

CNOT3 p.Ala474= (c.1422G>A) is very rare (popmax 0.00345%, amr) (gnomAD).

CNOT3 p.Ala474=

c.1422G>A · rs774088927 · VCV2875170

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00345%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.03	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4	GERP -2.7
Overall
CADD	5.383	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00345% Admixed American · 2/57,990 alleles

Filtering AF 0.000572% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000214%

Overall 0.00132% 21/1,593,242 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0143%	7,014
Admixed Americangrpmax	0.00345%	28,995
East Asian	0.00224%	44,544
Remaining individualsnot grpmax-eligible	0.00162%	61,548
African / African-American	0.00135%	74,264
European (non-Finnish)	0.000599%	166,854

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CNOT3
Protein: p.Ala474=
Coding: c.1422G>A
MANE Select: NM_014516
dbSNP: rs774088927
Type: single nucleotide variant
Location: chr19:54149575 (GRCh38)
Gene constraint: LOEUF 0.057 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.53 · 6 PDB
Residue 474: the 'disordered' region

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

Similar variants

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
CNOT3 p.Ala376Thr 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-ala474 (accessed [today's date]).

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