Is CHAT p.Cys487Ser (c.1459T>A) pathogenic?

CHAT p.Cys487Ser (c.1459T>A) is classified Uncertain significance in CHAT (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-04). AlphaMissense: ambiguous (0.4898); Very rare (popmax 8.47e-05%, nfe); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Cys487Ser (c.1459T>A)?

CHAT p.Cys487Ser (c.1459T>A) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Cys487Ser (c.1459T>A) in the general population?

CHAT p.Cys487Ser (c.1459T>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CHAT p.Cys487Ser (c.1459T>A)?

AlphaMissense predicts ambiguous (score 0.4898) — an in-silico prediction, not a clinical call.

CHAT p.Cys487Ser

c.1459T>A · rs375424189 · VCV1943100

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4898 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
AlphaMissense	0.4898	ambiguous
REVEL	0.456	indeterminate
SaProt	LLR -4.85	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 16 kb · p 0.024 · regional, not allelic
Overall
CADD	23.4	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 8.47e-05% European (non-Finnish) · 1/1,180,024 alleles

Overall 6.84e-05% 1/1,461,558 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.Cys487Ser
Coding: c.1459T>A
MANE Select: NM_020549
dbSNP: rs375424189
Type: single nucleotide variant
Location: chr10:49649584 (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.Cys487Phe 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
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-cys487ser (accessed [today's date]).

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