Is CHAT p.Arg222Gln (c.665G>A) pathogenic?

CHAT p.Arg222Gln (c.665G>A) is classified Likely benign in CHAT (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0779); Ultra-rare (popmax 0.0923%, sas); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Arg222Gln (c.665G>A)?

CHAT p.Arg222Gln (c.665G>A) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Arg222Gln (c.665G>A) in the general population?

CHAT p.Arg222Gln (c.665G>A) is ultra-rare (popmax 0.0923%, sas) (gnomAD).

What do computational predictors say about CHAT p.Arg222Gln (c.665G>A)?

AlphaMissense predicts likely benign (score 0.0779) — an in-silico prediction, not a clinical call.

CHAT p.Arg222Gln

c.665G>A · rs8178989 · VCV843376

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0779 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0923%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
AlphaMissense	0.0779	likely benign
REVEL	0.134	moderately benign-leaning
SaProt	LLR -6.80	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4	GERP -4.8
Regional constraint	o/e 1.06	unconstrained · MANE · 32 kb · p 0.16 · regional, not allelic
Overall
CADD	13.42	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 0.0923% South Asian · 84/91,056 alleles

Filtering AF 0.0763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0704%

Overall 0.00812% 131/1,613,610 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0923%	1,084
Middle Eastern	0.0495%	2,020
Remaining individualsnot grpmax-eligible	0.0048%	20,823
European (non-Finnish)	0.00339%	29,492
African / African-American	0.00133%	75,002

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.Arg222Gln
Coding: c.665G>A
MANE Select: NM_020549
dbSNP: rs8178989
Type: single nucleotide variant
Location: chr10:49620580 (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 222: a UniProt-annotated variant site (in); 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.Arg222Pro Conflicting classifications of pathogenicity ★ ⚠ 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-arg222gln (accessed [today's date]).

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