Is CNOT11 p.Pro57Ser (c.169C>T) pathogenic?

CNOT11 p.Pro57Ser (c.169C>T) is classified Uncertain significance in CNOT11 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely benign (0.0628); Ultra-rare (popmax 0.04%, afr).

How common is CNOT11 p.Pro57Ser (c.169C>T) in the general population?

CNOT11 p.Pro57Ser (c.169C>T) is ultra-rare (popmax 0.04%, afr) (gnomAD).

What do computational predictors say about CNOT11 p.Pro57Ser (c.169C>T)?

AlphaMissense predicts likely benign (score 0.0628) — an in-silico prediction, not a clinical call.

CNOT11 p.Pro57Ser

c.169C>T · VCV4230924

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0628 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.04%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0628	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -5.71	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 0.052	GERP -0.54, phastCons 0.12
Regional constraint	o/e 0.97	unconstrained · MANE · 4,860 bp · p 0.68 · regional, not allelic
Overall
CADD	6.35	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.04% African / African-American · 28/70,034 alleles

Filtering AF 0.0283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0245%

Overall 0.002% 31/1,549,296 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.04%	2,501
Remaining individualsnot grpmax-eligible	0.00336%	29,797
European (non-Finnish)	8.66e-05%	1,155,147

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: CNOT11
Protein: p.Pro57Ser
Coding: c.169C>T
MANE Select: NM_017546
Type: single nucleotide variant
Location: chr2:101253133 (GRCh38)
Gene constraint: LOEUF 0.583 · pLI 0.77 (gnomAD)
Structure: AlphaFold pLDDT 78.45 · 4 PDB
Residue 57: the 'disordered' region

Full CNOT11 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNOT11 p.Ala365Pro Uncertain significance ★ ⚠ same type
CNOT11 p.Arg202Cys Uncertain significance ★ ⚠ same type
CNOT11 p.Arg202His Uncertain significance ★ ⚠ same type
CNOT11 p.Arg286Cys Uncertain significance ★ ⚠ same type
CNOT11 p.Arg60Ser Uncertain significance ★ ⚠ same type
CNOT11 p.Asp307Glu Uncertain significance ★ ⚠ same type
CNOT11 p.Gln203His Uncertain significance ★ ⚠ same type
CNOT11 p.Gly36Ser 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/cnot11-p-pro57ser (accessed [today's date]).

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