Is CHAT p.Leu541fs (c.1620dup) pathogenic?

CHAT p.Leu541fs (c.1620dup) is classified Pathogenic in CHAT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-30). Very rare (popmax 0.00133%, afr); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Leu541fs (c.1620dup)?

CHAT p.Leu541fs (c.1620dup) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Leu541fs (c.1620dup) in the general population?

CHAT p.Leu541fs (c.1620dup) is very rare (popmax 0.00133%, afr) (gnomAD).

CHAT p.Leu541fs

c.1620dup · rs2132820703 · VCV1451989

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

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 11 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,074 alleles

Overall 6.84e-05% 1/1,461,886 alleles · very 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: CHAT
Protein: p.Leu541fs
Coding: c.1620dup
MANE Select: NM_020549
dbSNP: rs2132820703
Type: Duplication
Location: chr10:49651991 (GRCh38)
Gene constraint: LOEUF 0.973 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 84.73 · 8 PDB
Residue 541: an α-helix

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.Ala593fs Pathogenic/Likely pathogenic ★★ same condition
CHAT p.Arg481fs Pathogenic/Likely pathogenic ★★ same condition
CHAT p.Arg482fs Pathogenic ★ same condition
CHAT p.Glu156delinsAlaThrLeuGlyValTer Likely pathogenic ★ same condition
CHAT p.Glu91fs Likely pathogenic ★ same condition
CHAT p.Leu175fs Pathogenic ★ same condition
CHAT p.Leu249fs Pathogenic ★ same condition
CHAT p.Ser355fs 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/chat-p-leu541fs (accessed [today's date]).

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