Is CHAT p.Glu441Lys (c.1321G>A) pathogenic?

CHAT p.Glu441Lys (c.1321G>A) is classified Pathogenic/Likely pathogenic in CHAT (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-04-06). AlphaMissense: likely pathogenic (0.9889); Very rare (popmax 0.00223%, eas); Associated with congenital myasthenic syndrome.

What condition is associated with CHAT p.Glu441Lys (c.1321G>A)?

CHAT p.Glu441Lys (c.1321G>A) is associated with congenital myasthenic syndrome, congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Glu441Lys (c.1321G>A) in the general population?

CHAT p.Glu441Lys (c.1321G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Congenital myasthenic syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CHAT p.Glu441Lys (c.1321G>A)?

AlphaMissense predicts likely pathogenic (score 0.9889) — an in-silico prediction, not a clinical call.

CHAT p.Glu441Lys

c.1321G>A · rs121912816 · VCV17507

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9889 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myasthenic syndrome

Computational evidence

Protein change
AlphaMissense	0.9889	likely pathogenic ✓ concordant with ClinVar · top 3% in CHAT
REVEL	0.885	moderately pathogenic-leaning
SaProt	LLR -12.96	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 1,990 bp · p 0.0015 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,886 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000558% 9/1,613,860 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,886
African / African-American	0.00134%	74,892
European (non-Finnish)	0.000593%	168,565

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.Glu441Lys
Coding: c.1321G>A
MANE Select: NM_020549
dbSNP: rs121912816
Type: single nucleotide variant
Location: chr10:49648546 (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 441: a UniProt-annotated variant site (in cms6; completely lack activity)

Full CHAT gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital myasthenic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital myasthenic syndrome 6

For Congenital myasthenic syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

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-glu441lys (accessed [today's date]).

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