Is CNOT11 p.Pro2Leu (c.5C>T) pathogenic?

CNOT11 p.Pro2Leu (c.5C>T) is classified Uncertain significance in CNOT11 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-14). AlphaMissense: likely benign (0.1794); Very rare (popmax 0.00968%, amr).

How common is CNOT11 p.Pro2Leu (c.5C>T) in the general population?

CNOT11 p.Pro2Leu (c.5C>T) is very rare (popmax 0.00968%, amr) (gnomAD).

What do computational predictors say about CNOT11 p.Pro2Leu (c.5C>T)?

AlphaMissense predicts likely benign (score 0.1794) — an in-silico prediction, not a clinical call.

CNOT11 p.Pro2Leu

c.5C>T · rs1487573671 · VCV3146603

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1794 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00968%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1794	likely benign
REVEL	0.351	indeterminate
SaProt	LLR -6.90	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP 0.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 4,860 bp · p 0.68 · regional, not allelic
Overall
CADD	22.4	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 0.00968% Admixed American · 4/41,310 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00192%

Overall 0.000475% 7/1,475,068 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00968%	10,327
African / African-American	0.00295%	33,917
European (non-Finnish)	8.92e-05%	1,121,507

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.Pro2Leu
Coding: c.5C>T
MANE Select: NM_017546
dbSNP: rs1487573671
Type: single nucleotide variant
Location: chr2:101252969 (GRCh38)
Gene constraint: LOEUF 0.583 · pLI 0.77 (gnomAD)
Structure: AlphaFold pLDDT 78.45 · 4 PDB
Residue 2: 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-pro2leu (accessed [today's date]).

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