Is CNOT1 p.Pro1381Ala (c.4141C>G) pathogenic?

CNOT1 p.Pro1381Ala (c.4141C>G) is classified Conflicting classifications of pathogenicity in CNOT1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.068); Very rare (popmax 0.00094%, nfe); Associated with Vissers-Bodmer syndrome.

What condition is associated with CNOT1 p.Pro1381Ala (c.4141C>G)?

CNOT1 p.Pro1381Ala (c.4141C>G) is associated with Vissers-Bodmer syndrome (ClinVar).

How common is CNOT1 p.Pro1381Ala (c.4141C>G) in the general population?

CNOT1 p.Pro1381Ala (c.4141C>G) is very rare (popmax 0.00094%, nfe) (gnomAD).

What do computational predictors say about CNOT1 p.Pro1381Ala (c.4141C>G)?

AlphaMissense predicts likely benign (score 0.068) — an in-silico prediction, not a clinical call.

CNOT1 p.Pro1381Ala

c.4141C>G · rs779708330 · VCV1335214

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.068 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00094%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Vissers-Bodmer syndrome

Computational evidence

Protein change
AlphaMissense	0.068	likely benign
REVEL	0.105	moderately benign-leaning
SaProt	LLR -6.93	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 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 3,135 bp · p 1.4e-10 · regional, not allelic
Overall
CADD	23.6	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 0.00094% European (non-Finnish) · 11/1,170,824 alleles

Filtering AF 0.000504% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000369%

Overall 0.00076% 11/1,447,936 alleles · very rare

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: CNOT1
Protein: p.Pro1381Ala
Coding: c.4141C>G
MANE Select: NM_016284
dbSNP: rs779708330
Type: single nucleotide variant
Location: chr16:58543900 (GRCh38)
Gene constraint: LOEUF 0.064 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.22 · 21 PDB
Residue 1381: an α-helix; a UniProt-annotated variant site (in vibos); the 'interaction with cnot6, cnot6l, cnot7 and cnot8' region

Full CNOT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Vissers-Bodmer syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CNOT1 c.434-2A>G Pathogenic ★★ same condition
CNOT1 p.Arg26Ter Pathogenic/Likely pathogenic ★★ same condition
CNOT1 p.Arg535Cys Pathogenic ★★ same condition
CNOT1 c.310-3C>G Uncertain significance ★★ same condition
CNOT1 p.Leu1370Val Uncertain significance ★★ ⚠ same condition
CNOT1 p.Lys621Arg Uncertain significance ★★ ⚠ same condition
CNOT1 c.4006+12A>G Benign ★★ same condition
CNOT1 c.5896-5C>T Benign ★★ 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/cnot1-p-pro1381ala (accessed [today's date]).

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