Is CHAT p.Thr228= (c.684C>T) pathogenic?

CHAT p.Thr228= (c.684C>T) is classified Likely benign in CHAT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-02). Ultra-rare (popmax 0.0514%, eas); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Thr228= (c.684C>T)?

CHAT p.Thr228= (c.684C>T) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Thr228= (c.684C>T) in the general population?

CHAT p.Thr228= (c.684C>T) is ultra-rare (popmax 0.0514%, eas) (gnomAD).

CHAT p.Thr228=

c.684C>T · rs79030468 · VCV2696951

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0514%, eas)

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.22	GERP -1.9, phastCons 0.17
Overall
CADD	4.276	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0514% East Asian · 23/44,768 alleles

Filtering AF 0.0351% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0297%

Overall 0.00601% 97/1,612,740 alleles · ultra-rare exomes 95/1,460,482 · genomes 2/152,258 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0514%	1,946
South Asian	0.0143%	7,004
European (non-Finnish)	0.005%	19,982
Admixed American	0.00167%	59,998
African / African-American	0.00133%	75,018

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.Thr228=
Coding: c.684C>T
MANE Select: NM_020549
dbSNP: rs79030468
Type: single nucleotide variant
Location: chr10:49620599 (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 228: 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

SLC18A3 p.Ala228Ser 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
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-thr228 (accessed [today's date]).

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