Is CHRNE p.Ala415= (c.1245C>T) pathogenic?

CHRNE p.Ala415= (c.1245C>T) is classified Conflicting classifications of pathogenicity in CHRNE (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-05-01). Ultra-rare (popmax 0.0837%, nfe); Associated with congenital myasthenic syndrome 4A.

What condition is associated with CHRNE p.Ala415= (c.1245C>T)?

CHRNE p.Ala415= (c.1245C>T) is associated with congenital myasthenic syndrome 4A, congenital myasthenic syndrome (ClinVar).

How common is CHRNE p.Ala415= (c.1245C>T) in the general population?

CHRNE p.Ala415= (c.1245C>T) is ultra-rare (popmax 0.0837%, nfe) (gnomAD).

CHRNE p.Ala415=

c.1245C>T · rs202051373 · VCV465858

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0837%, nfe)

Conditions

congenital myasthenic syndrome 4A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.3	GERP -3.5
Overall
CADD	7.005	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0837% European (non-Finnish) · 987/1,179,446 alleles

Filtering AF 0.0793% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0775%

Overall 0.0643% 1,035/1,610,888 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0837%	1,195
Remaining individualsnot grpmax-eligible	0.0529%	1,889
African / African-American	0.00933%	10,719
Admixed American	0.00668%	14,962
Finnishnot grpmax-eligible	0.00482%	20,727
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,542

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.Ala415=
Coding: c.1245C>T
MANE Select: NM_000080
dbSNP: rs202051373
Type: single nucleotide variant
Location: chr17:4899082 (GRCh38)
Gene constraint: LOEUF 1.298 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 25 PDB

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.Ala415fs Pathogenic ★ same residue
CHRNE p.Ala415Thr 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-ala415 (accessed [today's date]).

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