Is CHAT p.Thr664= (c.1992G>A) pathogenic?

CHAT p.Thr664= (c.1992G>A) is classified Likely benign in CHAT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-03). Very rare (popmax 0.005%, amr); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Thr664= (c.1992G>A)?

CHAT p.Thr664= (c.1992G>A) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Thr664= (c.1992G>A) in the general population?

CHAT p.Thr664= (c.1992G>A) is very rare (popmax 0.005%, amr) (gnomAD).

CHAT p.Thr664=

c.1992G>A · rs767717703 · VCV1370540

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

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 8.6	GERP 1.2, phastCons 1
Overall
CADD	14.03	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,004 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.00124% 20/1,614,080 alleles · very rare exomes 17/1,461,892 · genomes 3/152,188 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,001
African / African-American	0.004%	24,974
Remaining individualsnot grpmax-eligible	0.0032%	31,244
European (non-Finnish)	0.00102%	98,337

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.Thr664=
Coding: c.1992G>A
MANE Select: NM_020549
dbSNP: rs767717703
Type: single nucleotide variant
Location: chr10:49664791 (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 664: 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.Thr664Met 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
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-thr664 (accessed [today's date]).

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