Is CHAT p.Thr366= (c.1098G>A) pathogenic?

CHAT p.Thr366= (c.1098G>A) is classified Likely benign in CHAT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-16). Ultra-rare (popmax 0.0166%, mid); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Thr366= (c.1098G>A)?

CHAT p.Thr366= (c.1098G>A) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Thr366= (c.1098G>A) in the general population?

CHAT p.Thr366= (c.1098G>A) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

CHAT p.Thr366=

c.1098G>A · rs780860401 · VCV461446

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.6	GERP -4.6
Overall
CADD	0.318	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,034 alleles

Filtering AF 0.00454% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00417%

Overall 0.00452% 73/1,613,612 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,034
European (non-Finnish)	0.00568%	17,610
East Asian	0.00446%	22,444
Remaining individualsnot grpmax-eligible	0.0032%	31,232
South Asian	0.0011%	91,066

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.Thr366=
Coding: c.1098G>A
MANE Select: NM_020549
dbSNP: rs780860401
Type: single nucleotide variant
Location: chr10:49627772 (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 366: 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.Thr366Lys Uncertain significance ★★ ⚠ same residue
CHAT p.Thr366Met 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
CHAT p.Arg151Ter 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-thr366 (accessed [today's date]).

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