Is CHAT p.Arg504Ter (c.1510C>T) pathogenic?

CHAT p.Arg504Ter (c.1510C>T) is classified Pathogenic/Likely pathogenic in CHAT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-07). Very rare (popmax 0.00167%, amr); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Arg504Ter (c.1510C>T)?

CHAT p.Arg504Ter (c.1510C>T) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Arg504Ter (c.1510C>T) in the general population?

CHAT p.Arg504Ter (c.1510C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

CHAT p.Arg504Ter

c.1510C>T · rs371470622 · VCV1452196

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 10 of 15
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.17	GERP -2.7, phastCons 0.002
Overall
CADD	39.0	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 0.00167% Admixed American · 1/60,014 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,613,612 alleles · very rare exomes 5/1,461,438 · genomes 1/152,174 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,014
European (non-Finnish)	0.000424%	236,006

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.Arg504Ter
Coding: c.1510C>T
MANE Select: NM_020549
dbSNP: rs371470622
Type: single nucleotide variant
Location: chr10:49649635 (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 504: 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.Arg504Gln Uncertain significance ★★ ⚠ same residue
SLC18A3 p.Val504Leu Uncertain significance ★★ ⚠ same residue
SLC18A3 p.Val504Met Uncertain significance ★ ⚠ same residue
CHAT c.1282-2A>T Likely pathogenic ★★ same condition
CHAT c.1840-9A>G Pathogenic/Likely pathogenic ★★ same condition
CHAT c.698+1G>T Likely pathogenic ★★ same condition
CHAT c.698+2T>C Likely pathogenic ★★ same condition
CHAT p.Ala557Thr 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/chat-p-arg504ter (accessed [today's date]).

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