Is CHRNE p.Arg449Ser (c.1345C>A) pathogenic?

CHRNE p.Arg449Ser (c.1345C>A) is classified Uncertain significance in CHRNE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-05-19). AlphaMissense: likely benign (0.2285); Very rare (popmax 0.00115%, sas); Associated with congenital myasthenic syndrome 4A.

What condition is associated with CHRNE p.Arg449Ser (c.1345C>A)?

CHRNE p.Arg449Ser (c.1345C>A) is associated with congenital myasthenic syndrome 4A, congenital myasthenic syndrome (ClinVar).

How common is CHRNE p.Arg449Ser (c.1345C>A) in the general population?

CHRNE p.Arg449Ser (c.1345C>A) is very rare (popmax 0.00115%, sas) (gnomAD).

What do computational predictors say about CHRNE p.Arg449Ser (c.1345C>A)?

AlphaMissense predicts likely benign (score 0.2285) — an in-silico prediction, not a clinical call.

CHRNE p.Arg449Ser

c.1345C>A · rs149083639 · VCV959504

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2285 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00115%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital myasthenic syndrome 4A

Computational evidence

Protein change
AlphaMissense	0.2285	likely benign
REVEL	0.356	indeterminate
SaProt	LLR -8.64	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.20	acceptor loss · deltas
Pangolin	Δ0.20	gain · loss 0.13 · SpliceAI calls loss · independent
Constraint at this position
Conservation	phyloP 7.5	GERP 0.65, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 4,324 bp · p 7.4e-05 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00115% South Asian · 1/87,000 alleles

Overall 6.99e-05% 1/1,430,516 alleles · very rare

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.Arg449Ser
Coding: c.1345C>A
MANE Select: NM_000080
dbSNP: rs149083639
Type: single nucleotide variant
Location: chr17:4898873 (GRCh38)
Gene constraint: LOEUF 1.298 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 25 PDB
Residue 449: 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

Also linked: congenital myasthenic syndrome

Similar variants

CHRNE p.Arg449Cys Uncertain significance ★★ ⚠ same residue
CHRNE p.Arg449His 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-arg449ser (accessed [today's date]).

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