Is CHRNE p.Arg352= (c.1056C>T) pathogenic?

CHRNE p.Arg352= (c.1056C>T) is classified Likely benign in CHRNE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-06). Ultra-rare (popmax 0.0393%, mid); Associated with congenital myasthenic syndrome 4A.

What condition is associated with CHRNE p.Arg352= (c.1056C>T)?

CHRNE p.Arg352= (c.1056C>T) is associated with congenital myasthenic syndrome 4A (ClinVar).

How common is CHRNE p.Arg352= (c.1056C>T) in the general population?

CHRNE p.Arg352= (c.1056C>T) is ultra-rare (popmax 0.0393%, mid) (gnomAD).

CHRNE p.Arg352=

c.1056C>T · rs558633663 · VCV1089763

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0393%, mid)

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 -0.6	GERP -3.5
Overall
CADD	2.774	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0393% Middle Eastern · 2/5,086 alleles

Filtering AF 0.00911% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00723%

Overall 0.00208% 32/1,535,776 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0393%	2,543
South Asian	0.0155%	6,462
Remaining individualsnot grpmax-eligible	0.00168%	59,616
African / African-American	0.00137%	72,894
European (non-Finnish)	0.00131%	76,446

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.Arg352=
Coding: c.1056C>T
MANE Select: NM_000080
dbSNP: rs558633663
Type: single nucleotide variant
Location: chr17:4899361 (GRCh38)
Gene constraint: LOEUF 1.298 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 25 PDB
Residue 352: an α-helix

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.Arg352His Uncertain significance ★ ⚠ same residue
CHRNE p.Arg352Ser 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
CHRNE c.1220-2A>G 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-arg352 (accessed [today's date]).

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