Is CNOT1 p.Leu1462Pro (c.4385T>C) pathogenic?

CNOT1 p.Leu1462Pro (c.4385T>C) is classified Uncertain significance in CNOT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-10). AlphaMissense: likely pathogenic (0.992); Absent from gnomAD v4.1; Associated with Vissers-Bodmer syndrome.

What condition is associated with CNOT1 p.Leu1462Pro (c.4385T>C)?

CNOT1 p.Leu1462Pro (c.4385T>C) is associated with Vissers-Bodmer syndrome (ClinVar).

How common is CNOT1 p.Leu1462Pro (c.4385T>C) in the general population?

CNOT1 p.Leu1462Pro (c.4385T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CNOT1 p.Leu1462Pro (c.4385T>C)?

AlphaMissense predicts likely pathogenic (score 0.992) — an in-silico prediction, not a clinical call.

CNOT1 p.Leu1462Pro

c.4385T>C · VCV3376969

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.992 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Vissers-Bodmer syndrome

Computational evidence

Protein change
AlphaMissense	0.992	likely pathogenic
REVEL	0.603	indeterminate
SaProt	LLR -13.24	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 3,135 bp · p 1.4e-10 · regional, not allelic
Overall
CADD	27.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CNOT1
Protein: p.Leu1462Pro
Coding: c.4385T>C
MANE Select: NM_016284
Type: single nucleotide variant
Location: chr16:58543656 (GRCh38)
Gene constraint: LOEUF 0.064 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.22 · 21 PDB
Residue 1462: 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-leu1462pro (accessed [today's date]).

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