Is CHAT p.Asp423Asn (c.1267G>A) pathogenic?

CHAT p.Asp423Asn (c.1267G>A) is classified Uncertain significance in CHAT (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-30). AlphaMissense: likely pathogenic (0.9729); Ultra-rare (popmax 0.0173%, mid); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Asp423Asn (c.1267G>A)?

CHAT p.Asp423Asn (c.1267G>A) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Asp423Asn (c.1267G>A) in the general population?

CHAT p.Asp423Asn (c.1267G>A) is ultra-rare (popmax 0.0173%, mid) (gnomAD).

What do computational predictors say about CHAT p.Asp423Asn (c.1267G>A)?

AlphaMissense predicts likely pathogenic (score 0.9729) — an in-silico prediction, not a clinical call.

CHAT p.Asp423Asn

c.1267G>A · rs759707536 · VCV961538

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9729 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0173%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
AlphaMissense	0.9729	likely pathogenic · top 7% in CHAT
REVEL	0.869	moderately pathogenic-leaning
SaProt	LLR -12.48	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 2.2, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 1,990 bp · p 0.0015 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0173% Middle Eastern · 1/5,770 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000744% 12/1,613,672 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0173%	5,770
East Asian	0.00223%	44,886
Admixed American	0.00167%	60,010
European (non-Finnish)	0.000763%	131,114

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.Asp423Asn
Coding: c.1267G>A
MANE Select: NM_020549
dbSNP: rs759707536
Type: single nucleotide variant
Location: chr10:49646660 (GRCh38)
Gene constraint: LOEUF 0.973 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 84.73 · 8 PDB

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.Asp423= Likely benign ★ same residue
SLC18A3 p.Ile423Met Uncertain significance ★ ⚠ 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

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-asp423asn (accessed [today's date]).

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