Is CHAT p.Glu343Lys (c.1027G>A) pathogenic?

CHAT p.Glu343Lys (c.1027G>A) is classified Uncertain significance in CHAT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-10). AlphaMissense: likely benign (0.1249); Very rare (popmax 0.00668%, eas); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Glu343Lys (c.1027G>A)?

CHAT p.Glu343Lys (c.1027G>A) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Glu343Lys (c.1027G>A) in the general population?

CHAT p.Glu343Lys (c.1027G>A) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about CHAT p.Glu343Lys (c.1027G>A)?

AlphaMissense predicts likely benign (score 0.1249) — an in-silico prediction, not a clinical call.

CHAT p.Glu343Lys

c.1027G>A · rs778837182 · VCV1010345

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1249 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
AlphaMissense	0.1249	likely benign
REVEL	0.447	indeterminate
SaProt	LLR -7.55	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 32 kb · p 0.16 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00668% East Asian · 3/44,904 alleles

Filtering AF 0.00342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.00347% 56/1,614,018 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,968
European (non-Finnish)	0.00441%	22,692
Admixed American	0.00167%	60,002

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.Glu343Lys
Coding: c.1027G>A
MANE Select: NM_020549
dbSNP: rs778837182
Type: single nucleotide variant
Location: chr10:49627701 (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 343: 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

CHAT p.Glu343Ter Pathogenic/Likely pathogenic ★★ 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-glu343lys (accessed [today's date]).

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