Is CHRNE p.Pro340Arg (c.1019C>G) pathogenic?

CHRNE p.Pro340Arg (c.1019C>G) is classified Uncertain significance in CHRNE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-29). AlphaMissense: likely benign (0.0748); Very rare (popmax 0.00835%, nfe); Associated with congenital myasthenic syndrome 4A.

What condition is associated with CHRNE p.Pro340Arg (c.1019C>G)?

CHRNE p.Pro340Arg (c.1019C>G) is associated with congenital myasthenic syndrome 4A, congenital myasthenic syndrome (ClinVar).

How common is CHRNE p.Pro340Arg (c.1019C>G) in the general population?

CHRNE p.Pro340Arg (c.1019C>G) is very rare (popmax 0.00835%, nfe) (gnomAD).

What do computational predictors say about CHRNE p.Pro340Arg (c.1019C>G)?

AlphaMissense predicts likely benign (score 0.0748) — an in-silico prediction, not a clinical call.

CHRNE p.Pro340Arg

c.1019C>G · rs139922367 · VCV970144

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0748 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00835%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital myasthenic syndrome 4A

Computational evidence

Protein change
AlphaMissense	0.0748	likely benign
REVEL	0.296	indeterminate
SaProt	LLR -7.79	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -4.1, phastCons 0.9
Regional constraint	o/e 1.15	unconstrained · MANE · 4,324 bp · p 7.4e-05 · regional, not allelic
Overall
CADD	8.909	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 0.00835% European (non-Finnish) · 98/1,173,664 alleles

Filtering AF 0.00701% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00644%

Overall 0.00651% 104/1,597,416 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00835%	11,976
South Asian	0.00455%	21,997
East Asian	0.00226%	44,268
Remaining individualsnot grpmax-eligible	0.00162%	61,822

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.Pro340Arg
Coding: c.1019C>G
MANE Select: NM_000080
dbSNP: rs139922367
Type: single nucleotide variant
Location: chr17:4899481 (GRCh38)
Gene constraint: LOEUF 1.298 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 25 PDB
Residue 340: 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.Pro340Gln Uncertain significance ★★ ⚠ same residue
CHRNE p.Pro340Ser Uncertain significance ★★ ⚠ same residue
CHRNE p.Pro340Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CHRNE p.Pro340= 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

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-pro340arg (accessed [today's date]).

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