Is CHAT p.Ser558= (c.1674C>T) pathogenic?

CHAT p.Ser558= (c.1674C>T) is classified Benign in CHAT (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). Common (popmax 7.21%, afr) — too common for a highly-penetrant pathogenic allele; Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Ser558= (c.1674C>T)?

CHAT p.Ser558= (c.1674C>T) is associated with congenital myasthenic syndrome 6 (ClinVar).

CHAT p.Ser558=

Q: How common is CHAT p.Ser558= (c.1674C>T) in the general population?

CHAT p.Ser558= (c.1674C>T) is common (popmax 7.21%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1674C>T · rs7073028 · VCV128720

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 7.21%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.44	GERP 1.2, phastCons 0.99
Overall
CADD	8.414	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.21% African / African-American · 5,410/75,026 alleles

Filtering AF 7.05% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.98%

Overall 0.397% 6,413/1,614,088 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.21%	14
Remaining individualsnot grpmax-eligible	0.582%	172
Admixed American	0.55%	182
Middle Eastern	0.247%	404
European (non-Finnish)	0.0236%	4,245
South Asian	0.0176%	5,692

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.Ser558=
Coding: c.1674C>T
MANE Select: NM_020549
dbSNP: rs7073028
Type: single nucleotide variant
Location: chr10:49655134 (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 558: a binding site; a β-strand

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 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-ser558 (accessed [today's date]).

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