Is CHRNE p.Pro358= (c.1074G>A) pathogenic?

CHRNE p.Pro358= (c.1074G>A) is classified Likely benign in CHRNE (ClinVar, Single submitter, 2 submitters; last evaluated 2024-05-15). Ultra-rare (popmax 0.0233%, afr); Associated with congenital myasthenic syndrome 4A.

What condition is associated with CHRNE p.Pro358= (c.1074G>A)?

CHRNE p.Pro358= (c.1074G>A) is associated with congenital myasthenic syndrome 4A, congenital myasthenic syndrome (ClinVar).

How common is CHRNE p.Pro358= (c.1074G>A) in the general population?

CHRNE p.Pro358= (c.1074G>A) is ultra-rare (popmax 0.0233%, afr) (gnomAD).

CHRNE p.Pro358=

c.1074G>A · rs745744138 · VCV990478

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0233%, afr)

Conditions

congenital myasthenic syndrome 4A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.9	GERP -3.3
Overall
CADD	3.466	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0233% African / African-American · 17/72,986 alleles

Filtering AF 0.0147% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.00149% 23/1,544,476 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0233%	4,293
Admixed American	0.00198%	50,542
European (non-Finnish)	0.000434%	230,301

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: CHRNE
Protein: p.Pro358=
Coding: c.1074G>A
MANE Select: NM_000080
dbSNP: rs745744138
Type: single nucleotide variant
Location: chr17:4899343 (GRCh38)
Gene constraint: LOEUF 1.298 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 25 PDB

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

Also linked: congenital myasthenic syndrome

Similar variants

CHRNE p.Pro358Leu Uncertain significance ★★ ⚠ same residue
CHRNE p.Pro358fs Pathogenic ★ same residue
CHRNE p.Pro358Gln Uncertain significance ★ ⚠ 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

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-pro358 (accessed [today's date]).

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