Is CHAT p.Leu70fs (c.208del) pathogenic?

CHAT p.Leu70fs (c.208del) is classified Uncertain significance in CHAT (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-14). Very rare (popmax 0.000266%, nfe); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Leu70fs (c.208del)?

CHAT p.Leu70fs (c.208del) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Leu70fs (c.208del) in the general population?

CHAT p.Leu70fs (c.208del) is very rare (popmax 0.000266%, nfe) (gnomAD).

CHAT p.Leu70fs

c.208del · rs1838400244 · VCV954911

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000266%, nfe)

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.14	GERP -2.3

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000266% European (non-Finnish) · 3/1,126,494 alleles

Filtering AF 7.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2e-05%

Overall 0.000219% 3/1,372,794 alleles · very rare

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.Leu70fs
Coding: c.208del
MANE Select: NM_020549
dbSNP: rs1838400244
Type: Deletion
Location: chr10:49614394 (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 70: the 'disordered' region

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.Leu70= Likely benign ★ same residue
CHAT p.Asp328fs Pathogenic/Likely pathogenic ★★ same condition
CHAT p.Cys453_Glu455delinsTer Pathogenic/Likely pathogenic ★★ same condition
CHAT p.Gln223fs Pathogenic ★★ same condition
CHAT p.Gly617fs Pathogenic/Likely pathogenic ★★ same condition
CHAT p.Pro138fs Likely pathogenic ★★ same condition
CHAT p.Gly2_Leu3insTer Uncertain significance ★★ same condition
CHAT c.1977+1_1977+9del 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-leu70fs (accessed [today's date]).

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