Is CHRNE p.Pro333Ser (c.997C>T) pathogenic?

CHRNE p.Pro333Ser (c.997C>T) is classified Uncertain significance in CHRNE (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-23). AlphaMissense: likely benign (0.1532); Absent from gnomAD v4.1; Associated with congenital myasthenic syndrome 4A.

What condition is associated with CHRNE p.Pro333Ser (c.997C>T)?

CHRNE p.Pro333Ser (c.997C>T) is associated with congenital myasthenic syndrome 4A (ClinVar).

How common is CHRNE p.Pro333Ser (c.997C>T) in the general population?

CHRNE p.Pro333Ser (c.997C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHRNE p.Pro333Ser (c.997C>T)?

AlphaMissense predicts likely benign (score 0.1532) — an in-silico prediction, not a clinical call.

CHRNE p.Pro333Ser

c.997C>T · VCV3608505

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1532 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myasthenic syndrome 4A

Computational evidence

Protein change
AlphaMissense	0.1532	likely benign
REVEL	0.718	pathogenic-leaning
SaProt	LLR -10.31	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
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 1.15	unconstrained · MANE · 4,324 bp · p 7.4e-05 · regional, not allelic
Overall
CADD	24.7	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

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: CHRNE
Protein: p.Pro333Ser
Coding: c.997C>T
MANE Select: NM_000080
Type: single nucleotide variant
Location: chr17:4899503 (GRCh38)
Gene constraint: LOEUF 1.298 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 25 PDB
Residue 333: a turn

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

Disease context

congenital myasthenic syndrome 4A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHRNE p.Pro333= Likely benign ★ same residue
CHRNE c.1032+1G>A Likely pathogenic ★★ same condition
CHRNE c.1033-1G>C Pathogenic/Likely pathogenic ★★ same condition
CHRNE c.1033-2A>T Pathogenic/Likely pathogenic ★★ same condition
CHRNE c.1219+2T>G Pathogenic ★★ same condition
CHRNE c.1220-1G>C Pathogenic/Likely pathogenic ★★ same condition
CHRNE c.1220-2A>G Pathogenic/Likely pathogenic ★★ same condition
CHRNE c.1326+1G>A Pathogenic/Likely pathogenic ★★ 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/chrne-p-pro333ser (accessed [today's date]).

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