Is CHAT p.Lys16fs (c.45del) pathogenic?

CHAT p.Lys16fs (c.45del) is classified Uncertain significance in CHAT (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-18). Very rare (popmax 0.000431%, nfe); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Lys16fs (c.45del)?

CHAT p.Lys16fs (c.45del) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Lys16fs (c.45del) in the general population?

CHAT p.Lys16fs (c.45del) is very rare (popmax 0.000431%, nfe) (gnomAD).

CHAT p.Lys16fs

c.45del · rs1838387913 · VCV949501

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 0.000431%, 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 0.54	GERP -3.4, phastCons 0.93
Region caveats
Repeat context	tandem	G-rich low complexity · ambiguous alignment · confidence, not pathogenicity

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000431% European (non-Finnish) · 3/696,184 alleles

Filtering AF 0.000115% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.2e-05%

Overall 0.000561% 5/890,894 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00515%	19,420
European (non-Finnish)grpmax	0.000431%	232,061

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Lys16fs
Coding: c.45del
MANE Select: NM_020549
dbSNP: rs1838387913
Type: Deletion
Location: chr10:49614229 (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 16: 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.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
SLC18A3 p.Lys16Glu Uncertain significance ★★ ⚠ same residue
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-lys16fs (accessed [today's date]).

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