Is CHRNE p.Cys322= (c.966C>T) pathogenic?

CHRNE p.Cys322= (c.966C>T) is classified Benign in CHRNE (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). Common (popmax 5.19%, sas) — too common for a highly-penetrant pathogenic allele; Associated with congenital myasthenic syndrome.

What condition is associated with CHRNE p.Cys322= (c.966C>T)?

CHRNE p.Cys322= (c.966C>T) is associated with congenital myasthenic syndrome, congenital myasthenic syndrome 4A (ClinVar).

How is Congenital myasthenic syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

CHRNE p.Cys322=

Q: How common is CHRNE p.Cys322= (c.966C>T) in the general population?

CHRNE p.Cys322= (c.966C>T) is common (popmax 5.19%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.966C>T · rs56377005 · VCV254904

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 5.19%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

congenital myasthenic syndrome

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 1.9	GERP -1.5, phastCons 1
Overall
CADD	14.42	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.19% South Asian · 4,596/88,622 alleles

Filtering AF 5.06% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.01%

Overall 1.45% 23,261/1,603,594 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	5.19%	19
Middle Eastern	5.17%	19
Ashkenazi Jewishnot grpmax-eligible	3.8%	26
Remaining individualsnot grpmax-eligible	1.81%	55
European (non-Finnish)	1.27%	79
Admixed American	1.15%	87
Finnishnot grpmax-eligible	0.61%	164
African / African-American	0.207%	484
East Asian	0.018%	5,570

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.Cys322=
Coding: c.966C>T
MANE Select: NM_000080
dbSNP: rs56377005
Type: single nucleotide variant
Location: chr17:4899534 (GRCh38)
Gene constraint: LOEUF 1.298 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 25 PDB
Residue 322: an α-helix

Full CHRNE gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital myasthenic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital myasthenic syndrome 4A

For Congenital myasthenic syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

CHRNE p.Cys322Ter Pathogenic/Likely pathogenic ★★ same residue
CHRNE p.Cys322Tyr 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-cys322 (accessed [today's date]).

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