Is CNOT3 p.Ala426Val (c.1277C>T) pathogenic?

CNOT3 p.Ala426Val (c.1277C>T) is classified Benign/Likely benign in CNOT3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0997); Rare (popmax 0.291%, nfe).

How common is CNOT3 p.Ala426Val (c.1277C>T) in the general population?

CNOT3 p.Ala426Val (c.1277C>T) is rare (popmax 0.291%, nfe) (gnomAD).

What do computational predictors say about CNOT3 p.Ala426Val (c.1277C>T)?

AlphaMissense predicts likely benign (score 0.0997) — an in-silico prediction, not a clinical call.

CNOT3 p.Ala426Val

c.1277C>T · rs181910878 · VCV1694941

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0997 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.291%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0997	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -6.63	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 0.85, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 7,004 bp · p 0.37 · regional, not allelic
Overall
CADD	24.0	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

Grpmax group 0.291% European (non-Finnish) · 3,345/1,150,592 alleles

Filtering AF 0.282% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.279%

Overall 0.328% 5,124/1,563,026 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	3.9%	26
Remaining individualsnot grpmax-eligible	0.491%	204
Finnishnot grpmax-eligible	0.338%	295
European (non-Finnish)grpmax	0.291%	344
Middle Eastern	0.274%	365
Admixed American	0.164%	608
African / African-American	0.0592%	1,688
South Asian	0.0588%	1,701

Ashkenazi Jewish 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.Ala426Val
Coding: c.1277C>T
MANE Select: NM_014516
dbSNP: rs181910878
Type: single nucleotide variant
Location: chr19:54148530 (GRCh38)
Gene constraint: LOEUF 0.057 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.53 · 6 PDB
Residue 426: 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-ala426val (accessed [today's date]).

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