Is CHAT p.Ile689= (c.2067C>T) pathogenic?

CHAT p.Ile689= (c.2067C>T) is classified Benign in CHAT (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). Common (popmax 32.2%, eas) — too common for a highly-penetrant pathogenic allele; Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Ile689= (c.2067C>T)?

CHAT p.Ile689= (c.2067C>T) is associated with congenital myasthenic syndrome 6 (ClinVar).

CHAT p.Ile689=

Q: How common is CHAT p.Ile689= (c.2067C>T) in the general population?

CHAT p.Ile689= (c.2067C>T) is common (popmax 32.2%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2067C>T · rs3793801 · VCV128722

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 32.2%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.21	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 0.41	GERP -1, phastCons 0.52
Overall
CADD	15.09	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 32.2% East Asian · 14,461/44,874 alleles

Filtering AF 31.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 31.6%

Overall 1.46% 23,549/1,614,196 alleles · common exomes 21,210/1,461,890 · genomes 2,339/152,306 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	32.2%	3
South Asian	5.31%	19
Remaining individualsnot grpmax-eligible	2.12%	47
Finnishnot grpmax-eligible	1.29%	78
Middle Eastern	1.06%	95
Ashkenazi Jewishnot grpmax-eligible	0.909%	110
Admixed American	0.212%	473
African / African-American	0.172%	582
European (non-Finnish)	0.128%	783

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.Ile689=
Coding: c.2067C>T
MANE Select: NM_020549
dbSNP: rs3793801
Type: single nucleotide variant
Location: chr10:49664866 (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 689: 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 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
CHAT p.Arg207His 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-ile689 (accessed [today's date]).

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