Is CHRNE p.Arg331= (c.991C>A) pathogenic?

CHRNE p.Arg331= (c.991C>A) is classified Likely benign in CHRNE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-01). Ultra-rare (popmax 0.034%, amr); Associated with congenital myasthenic syndrome 4A.

What condition is associated with CHRNE p.Arg331= (c.991C>A)?

CHRNE p.Arg331= (c.991C>A) is associated with congenital myasthenic syndrome 4A (ClinVar).

How common is CHRNE p.Arg331= (c.991C>A) in the general population?

CHRNE p.Arg331= (c.991C>A) is ultra-rare (popmax 0.034%, amr) (gnomAD).

CHRNE p.Arg331=

c.991C>A · rs121909515 · VCV534260

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.034%, amr)

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 3.5	GERP -1.5, phastCons 1
Overall
CADD	6.758	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.034% Admixed American · 20/58,750 alleles

Filtering AF 0.0225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0188%

Overall 0.00224% 36/1,603,576 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.034%	2,937
Remaining individualsnot grpmax-eligible	0.00322%	31,055
European (non-Finnish)	0.00119%	84,027

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.Arg331=
Coding: c.991C>A
MANE Select: NM_000080
dbSNP: rs121909515
Type: single nucleotide variant
Location: chr17:4899509 (GRCh38)
Gene constraint: LOEUF 1.298 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 25 PDB
Residue 331: a UniProt-annotated variant site (in cms4c; shortens burst duration 2-fold by slowing the rate of channel opening and speeding the rate of ach dissociation; has a mild fast-channel kinetic effect on the achr by shortening the long burst and increasing the decay of the endplate current)

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.Arg331Gln Pathogenic/Likely pathogenic ★★ ⚠ same residue
CHRNE p.Arg331Trp Pathogenic/Likely pathogenic ★★ ⚠ 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-arg331 (accessed [today's date]).

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