Is CHAT p.Arg561Gln (c.1682G>A) pathogenic?

CHAT p.Arg561Gln (c.1682G>A) is classified Benign/Likely benign in CHAT (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-03-01). AlphaMissense: ambiguous (0.3795); Low-frequency (popmax 1.17%, amr); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Arg561Gln (c.1682G>A)?

CHAT p.Arg561Gln (c.1682G>A) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Arg561Gln (c.1682G>A) in the general population?

CHAT p.Arg561Gln (c.1682G>A) is low-frequency (popmax 1.17%, amr) (gnomAD).

What do computational predictors say about CHAT p.Arg561Gln (c.1682G>A)?

AlphaMissense predicts ambiguous (score 0.3795) — an in-silico prediction, not a clinical call.

CHAT p.Arg561Gln

c.1682G>A · rs80097077 · VCV128721

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

ambiguous

0.3795 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.17%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
AlphaMissense	0.3795	ambiguous
REVEL	0.706	pathogenic-leaning
SaProt	LLR -7.87	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 16 kb · p 0.024 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.17% Admixed American · 702/60,012 alleles

Filtering AF 1.11% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1%

Overall 0.96% 15,499/1,614,060 alleles · low-frequency

Ancestry group	Frequency	1 in
Admixed Americangrpmax	1.17%	85
European (non-Finnish)	1.13%	89
Ashkenazi Jewishnot grpmax-eligible	0.851%	117
Remaining individualsnot grpmax-eligible	0.811%	123
Finnishnot grpmax-eligible	0.8%	125
Middle Eastern	0.66%	152
Amishnot grpmax-eligible	0.219%	456
African / African-American	0.215%	466
South Asian	0.0373%	2,678
East Asian	0.00446%	22,442

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.Arg561Gln
Coding: c.1682G>A
MANE Select: NM_020549
dbSNP: rs80097077
Type: single nucleotide variant
Location: chr10:49655142 (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.Arg561Ter Pathogenic/Likely pathogenic ★★ 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
CHAT p.Arg151Ter Pathogenic/Likely pathogenic ★★ same condition
CHAT p.Arg207Gly 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-arg561gln (accessed [today's date]).

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