Is CHAT p.Thr289= (c.867G>A) pathogenic?

CHAT p.Thr289= (c.867G>A) is classified Conflicting classifications of pathogenicity in CHAT (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-04-01). Ultra-rare (popmax 0.0307%, afr); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Thr289= (c.867G>A)?

CHAT p.Thr289= (c.867G>A) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Thr289= (c.867G>A) in the general population?

CHAT p.Thr289= (c.867G>A) is ultra-rare (popmax 0.0307%, afr) (gnomAD).

CHAT p.Thr289=

c.867G>A · rs574542737 · VCV198239

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0307%, afr)

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 -6.9	GERP -4.3
Overall
CADD	0.07	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0307% African / African-American · 23/74,946 alleles

Filtering AF 0.021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0178%

Overall 0.00249% 40/1,608,676 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0307%	3,259
Middle Eastern	0.0165%	6,056
Admixed American	0.0101%	9,880
South Asian	0.00223%	44,922
Remaining individualsnot grpmax-eligible	0.0016%	62,312
European (non-Finnish)	0.000594%	168,211

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.Thr289=
Coding: c.867G>A
MANE Select: NM_020549
dbSNP: rs574542737
Type: single nucleotide variant
Location: chr10:49625587 (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 289: a β-strand

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.Thr289Met Uncertain significance ★★ ⚠ same residue
SLC18A3 p.Pro289His Uncertain significance ★ ⚠ same residue
SLC18A3 p.Pro289= Likely benign ★ 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-thr289 (accessed [today's date]).

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