Is CHAT p.Arg117fs (c.349del) pathogenic?

CHAT p.Arg117fs (c.349del) is classified Conflicting classifications of pathogenicity in CHAT (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-07-24). Very rare (popmax 8.48e-05%, nfe); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Arg117fs (c.349del)?

CHAT p.Arg117fs (c.349del) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Arg117fs (c.349del) in the general population?

CHAT p.Arg117fs (c.349del) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

CHAT p.Arg117fs

c.349del · rs1198717023 · VCV817424

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -4.2	GERP -4.3

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,424 alleles

Overall 6.2e-05% 1/1,612,804 alleles · very rare exomes 1/1,460,804 · genomes 0/152,000 · joint denominator

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: CHAT
Protein: p.Arg117fs
Coding: c.349del
MANE Select: NM_020549
dbSNP: rs1198717023
Type: Deletion
Location: chr10:49616560 (GRCh38)
Gene constraint: LOEUF 0.973 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 84.73 · 8 PDB

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

Disease context

congenital myasthenic syndrome 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHAT p.Arg117His Conflicting classifications of pathogenicity ★ ⚠ same residue
CHAT p.Arg117Cys Likely benign ★ same residue
CHAT p.Asp328fs Pathogenic/Likely pathogenic ★★ same condition
CHAT p.Cys453_Glu455delinsTer Pathogenic/Likely pathogenic ★★ same condition
CHAT p.Gln223fs Pathogenic ★★ same condition
CHAT p.Gly617fs Pathogenic/Likely pathogenic ★★ same condition
CHAT p.Pro138fs Likely pathogenic ★★ same condition
CHAT p.Gly2_Leu3insTer Uncertain significance ★★ 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/chat-p-arg117fs (accessed [today's date]).

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