Is CHRNE p.Arg331Trp (c.991C>T) pathogenic?

CHRNE p.Arg331Trp (c.991C>T) is classified Pathogenic/Likely pathogenic in CHRNE (ClinVar, Multiple submitters, 10 submitters; last evaluated 2025-12-29). AlphaMissense: ambiguous (0.4897); Very rare (popmax 0.00133%, afr); Associated with CHRNE-related disorder.

What condition is associated with CHRNE p.Arg331Trp (c.991C>T)?

CHRNE p.Arg331Trp (c.991C>T) is associated with CHRNE-related disorder, congenital myasthenic syndrome 4A, congenital myasthenic syndrome 4C (ClinVar).

How common is CHRNE p.Arg331Trp (c.991C>T) in the general population?

CHRNE p.Arg331Trp (c.991C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CHRNE p.Arg331Trp (c.991C>T)?

AlphaMissense predicts ambiguous (score 0.4897) — an in-silico prediction, not a clinical call.

CHRNE p.Arg331Trp

c.991C>T · rs121909515 · VCV18358

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

ambiguous

0.4897 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

CHRNE-related disorder

Computational evidence

Protein change
AlphaMissense	0.4897	ambiguous
REVEL	0.733	pathogenic-leaning
SaProt	LLR -13.57	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP -1.5, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 4,324 bp · p 7.4e-05 · regional, not allelic
Overall
CADD	21.6	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

Grpmax group 0.00133% African / African-American · 1/74,956 alleles

Filtering AF 0.000617% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000475%

Overall 0.000965% 14/1,451,402 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,956
European (non-Finnish)	0.00111%	90,490

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.Arg331Trp
Coding: c.991C>T
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

CHRNE-related disorder

Also linked: congenital myasthenic syndrome 4A congenital myasthenic syndrome 4C congenital myasthenic syndrome 4B congenital myasthenic syndrome

Similar variants

CHRNE p.Arg331Gln Pathogenic/Likely pathogenic ★★ ⚠ same residue
CHRNE p.Arg331= 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

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-arg331trp (accessed [today's date]).

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