Is CNOT10 p.Pro251Leu (c.752C>T) pathogenic?

CNOT10 p.Pro251Leu (c.752C>T) is classified Uncertain significance in CNOT10 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-05). AlphaMissense: likely benign (0.2272); Ultra-rare (popmax 0.015%, afr).

How common is CNOT10 p.Pro251Leu (c.752C>T) in the general population?

CNOT10 p.Pro251Leu (c.752C>T) is ultra-rare (popmax 0.015%, afr) (gnomAD).

What do computational predictors say about CNOT10 p.Pro251Leu (c.752C>T)?

AlphaMissense predicts likely benign (score 0.2272) — an in-silico prediction, not a clinical call.

CNOT10 p.Pro251Leu

c.752C>T · rs755586827 · VCV2544745

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2272 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2272	likely benign
REVEL	0.28	benign-leaning
SaProt	LLR -4.87	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 5.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 84 kb · p 3.3e-05 · regional, not allelic
Overall
CADD	25.6	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 0.015% African / African-American · 11/73,566 alleles

Filtering AF 0.0083% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00644%

Overall 0.000796% 12/1,506,676 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.015%	6,688
European (non-Finnish)	9.07e-05%	1,101,966

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: CNOT10
Protein: p.Pro251Leu
Coding: c.752C>T
MANE Select: NM_015442
dbSNP: rs755586827
Type: single nucleotide variant
Location: chr3:32720121 (GRCh38)
Gene constraint: LOEUF 0.405 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.87 · 2 PDB
Residue 251: an α-helix

Full CNOT10 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNOT10 p.Ala11Gly Uncertain significance ★ ⚠ same type
CNOT10 p.Ala225Val Uncertain significance ★ ⚠ same type
CNOT10 p.Ala250Val Uncertain significance ★ ⚠ same type
CNOT10 p.Ala279Thr Uncertain significance ★ ⚠ same type
CNOT10 p.Ala2Thr Uncertain significance ★ ⚠ same type
CNOT10 p.Ala305Val Uncertain significance ★ ⚠ same type
CNOT10 p.Ala319Ser Uncertain significance ★ ⚠ same type
CNOT10 p.Ala669Val 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/cnot10-p-pro251leu (accessed [today's date]).

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