Is CNOT3 p.Ser491Ala (c.1471T>G) pathogenic?

CNOT3 p.Ser491Ala (c.1471T>G) is classified Benign/Likely benign in CNOT3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.0577); Rare (popmax 0.364%, afr); Associated with Inborn genetic diseases.

What condition is associated with CNOT3 p.Ser491Ala (c.1471T>G)?

CNOT3 p.Ser491Ala (c.1471T>G) is associated with Inborn genetic diseases (ClinVar).

How common is CNOT3 p.Ser491Ala (c.1471T>G) in the general population?

CNOT3 p.Ser491Ala (c.1471T>G) is rare (popmax 0.364%, afr) (gnomAD).

What do computational predictors say about CNOT3 p.Ser491Ala (c.1471T>G)?

AlphaMissense predicts likely benign (score 0.0577) — an in-silico prediction, not a clinical call.

CNOT3 p.Ser491Ala

c.1471T>G · rs10416861 · VCV1971451

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0577 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.364%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0577	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -6.73	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 0.13	GERP -2.7, phastCons 0.004
Regional constraint	o/e 0.96	unconstrained · MANE · 7,004 bp · p 0.37 · regional, not allelic
Overall
CADD	8.626	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 0.364% African / African-American · 273/74,948 alleles

Filtering AF 0.329% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.315%

Overall 0.0198% 319/1,613,496 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.364%	275
Remaining individualsnot grpmax-eligible	0.0368%	2,716
Admixed American	0.025%	3,999
Middle Eastern	0.0165%	6,062
South Asian	0.0011%	90,972
European (non-Finnish)	0.000509%	196,622

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.Ser491Ala
Coding: c.1471T>G
MANE Select: NM_014516
dbSNP: rs10416861
Type: single nucleotide variant
Location: chr19:54149624 (GRCh38)
Gene constraint: LOEUF 0.057 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.53 · 6 PDB
Residue 491: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CNOT3 p.Ser491= Benign ★ same residue
CNOT3 p.Ala438Val Uncertain significance ★★ ⚠ same condition
CNOT3 p.Arg290Cys Uncertain significance ★★ ⚠ same condition
CNOT3 p.Glu533Gln Uncertain significance ★★ ⚠ same condition
CNOT3 p.Gly405Ser Uncertain significance ★★ ⚠ same condition
CNOT3 p.Met182Val Uncertain significance ★★ ⚠ same condition
CNOT3 p.Pro244Ala Uncertain significance ★★ ⚠ same condition
CNOT3 p.Pro320Leu Uncertain significance ★★ ⚠ same condition

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-ser491ala (accessed [today's date]).

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