Is CHRNE p.Leu289fs (c.866del) pathogenic?

CHRNE p.Leu289fs (c.866del) is classified Pathogenic/Likely pathogenic in CHRNE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-25). Ultra-rare (popmax 0.0117%, amr); Associated with congenital myasthenic syndrome 4A.

What condition is associated with CHRNE p.Leu289fs (c.866del)?

CHRNE p.Leu289fs (c.866del) is associated with congenital myasthenic syndrome 4A (ClinVar).

How common is CHRNE p.Leu289fs (c.866del) in the general population?

CHRNE p.Leu289fs (c.866del) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

CHRNE p.Leu289fs

c.866del · rs1451776623 · VCV2079328

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Conditions

congenital myasthenic syndrome 4A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -2.7	GERP -4.1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% Admixed American · 7/60,014 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000434% 7/1,614,088 alleles · ultra-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.Leu289fs
Coding: c.866del
MANE Select: NM_001145536 · reported on NM_000080
dbSNP: rs1451776623
Type: Deletion
Location: chr17:4900844 (GRCh38)

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

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-leu289fs (accessed [today's date]).

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