Is CHAT p.Ser475Cys (c.1423A>T) pathogenic?

CHAT p.Ser475Cys (c.1423A>T) is classified Uncertain significance in CHAT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-01). AlphaMissense: likely benign (0.1261); Very rare (popmax 0.00856%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CHAT p.Ser475Cys (c.1423A>T)?

CHAT p.Ser475Cys (c.1423A>T) is associated with Inborn genetic diseases, congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Ser475Cys (c.1423A>T) in the general population?

CHAT p.Ser475Cys (c.1423A>T) is very rare (popmax 0.00856%, nfe) (gnomAD).

What do computational predictors say about CHAT p.Ser475Cys (c.1423A>T)?

AlphaMissense predicts likely benign (score 0.1261) — an in-silico prediction, not a clinical call.

CHAT p.Ser475Cys

c.1423A>T · rs765549293 · VCV664793

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1261 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00856%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1261	likely benign
REVEL	0.423	indeterminate
SaProt	LLR -7.85	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 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	20.1	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 0.00856% European (non-Finnish) · 101/1,180,052 alleles

Filtering AF 0.00716% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00668%

Overall 0.00651% 105/1,613,804 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00856%	11,684
African / African-American	0.00267%	37,477
Admixed American	0.00167%	60,012
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Ser475Cys
Coding: c.1423A>T
MANE Select: NM_020549
dbSNP: rs765549293
Type: single nucleotide variant
Location: chr10:49649548 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital myasthenic syndrome 6

Similar variants

CHAT p.Ser475Arg Uncertain significance ★ ⚠ same residue
CHAT p.Ser475= Likely benign ★ 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-ser475cys (accessed [today's date]).

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