Is CNOT11 p.Pro288Leu (c.863C>T) pathogenic?

CNOT11 p.Pro288Leu (c.863C>T) is classified Uncertain significance in CNOT11 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-22). AlphaMissense: likely benign (0.3189); Ultra-rare (popmax 0.0263%, nfe).

How common is CNOT11 p.Pro288Leu (c.863C>T) in the general population?

CNOT11 p.Pro288Leu (c.863C>T) is ultra-rare (popmax 0.0263%, nfe) (gnomAD).

What do computational predictors say about CNOT11 p.Pro288Leu (c.863C>T)?

AlphaMissense predicts likely benign (score 0.3189) — an in-silico prediction, not a clinical call.

CNOT11 p.Pro288Leu

c.863C>T · rs200697826 · VCV2591006

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3189 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0263%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3189	likely benign
REVEL	0.15	moderately benign-leaning
SaProt	LLR -6.30	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.64 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6	GERP 0.96, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 8,764 bp · p 0.022 · regional, not allelic
Overall
CADD	21.0	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 0.0263% European (non-Finnish) · 310/1,180,010 alleles

Filtering AF 0.0238% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0229%

Overall 0.0211% 341/1,613,954 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0352%	2,840
European (non-Finnish)grpmax	0.0263%	3,806
African / African-American	0.00668%	14,978
East Asian	0.00446%	22,436
Admixed American	0.00167%	59,990
Finnishnot grpmax-eligible	0.00156%	64,026

Remaining individuals 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: CNOT11
Protein: p.Pro288Leu
Coding: c.863C>T
MANE Select: NM_017546
dbSNP: rs200697826
Type: single nucleotide variant
Location: chr2:101264875 (GRCh38)
Gene constraint: LOEUF 0.583 · pLI 0.77 (gnomAD)
Structure: AlphaFold pLDDT 78.45 · 4 PDB
Residue 288: an α-helix

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-pro288leu (accessed [today's date]).

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