Is CHAT p.Arg481fs (c.1441dup) pathogenic?

CHAT p.Arg481fs (c.1441dup) is classified Pathogenic/Likely pathogenic in CHAT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-06). Very rare (popmax 0.00133%, afr); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Arg481fs (c.1441dup)?

CHAT p.Arg481fs (c.1441dup) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Arg481fs (c.1441dup) in the general population?

CHAT p.Arg481fs (c.1441dup) is very rare (popmax 0.00133%, afr) (gnomAD).

CHAT p.Arg481fs

c.1441dup · rs773268576 · VCV2680729

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

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 10 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.8	GERP -1.4, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

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 · 1/74,922 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000558% 9/1,613,670 alleles · very rare exomes 8/1,461,490 · genomes 1/152,180 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00786%	12,730
Remaining individualsnot grpmax-eligible	0.0016%	62,488
African / African-Americangrpmax	0.00133%	74,922
European (non-Finnish)	0.000169%	590,012

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg481fs
Coding: c.1441dup
MANE Select: NM_020549
dbSNP: rs773268576
Type: Duplication
Location: chr10:49649560 (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.Arg481Trp Uncertain significance ★★ ⚠ same residue
CHAT p.Arg481= Likely benign ★ same residue
CHAT p.Ala593fs 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

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-arg481fs (accessed [today's date]).

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