Is CHRNE p.Leu289Phe (c.865C>T) pathogenic?

CHRNE p.Leu289Phe (c.865C>T) is classified Pathogenic/Likely pathogenic in CHRNE (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-01-25). AlphaMissense: likely pathogenic (0.7639); Absent from gnomAD v4.1; Associated with CHRNE-related disorder.

What condition is associated with CHRNE p.Leu289Phe (c.865C>T)?

CHRNE p.Leu289Phe (c.865C>T) is associated with CHRNE-related disorder, congenital myasthenic syndrome 4A (ClinVar).

How common is CHRNE p.Leu289Phe (c.865C>T) in the general population?

CHRNE p.Leu289Phe (c.865C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHRNE p.Leu289Phe (c.865C>T)?

AlphaMissense predicts likely pathogenic (score 0.7639) — an in-silico prediction, not a clinical call.

CHRNE p.Leu289Phe

c.865C>T · rs121909511 · VCV18344

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7639 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CHRNE-related disorder

Computational evidence

Protein change
AlphaMissense	0.7639	likely pathogenic ✓ concordant with ClinVar
REVEL	0.917	moderately pathogenic-leaning
SaProt	LLR -9.38	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 8.5	GERP 2.1, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 4,324 bp · p 7.4e-05 · regional, not allelic
Overall
CADD	28.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CHRNE
Protein: p.Leu289Phe
Coding: c.865C>T
MANE Select: NM_001145536 · reported on NM_000080
dbSNP: rs121909511
Type: single nucleotide variant
Location: chr17:4900845 (GRCh38)

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

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-leu289phe (accessed [today's date]).

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