Is CHAT p.Ser464Asn (c.1391G>A) pathogenic?

CHAT p.Ser464Asn (c.1391G>A) is classified Conflicting classifications of pathogenicity in CHAT (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-24). AlphaMissense: likely benign (0.1023); Rare (popmax 0.494%, afr); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Ser464Asn (c.1391G>A)?

CHAT p.Ser464Asn (c.1391G>A) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Ser464Asn (c.1391G>A) in the general population?

CHAT p.Ser464Asn (c.1391G>A) is rare (popmax 0.494%, afr) (gnomAD).

What do computational predictors say about CHAT p.Ser464Asn (c.1391G>A)?

AlphaMissense predicts likely benign (score 0.1023) — an in-silico prediction, not a clinical call.

CHAT p.Ser464Asn

c.1391G>A · rs148525631 · VCV705007

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1023 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.494%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
AlphaMissense	0.1023	likely benign
REVEL	0.271	benign-leaning
SaProt	LLR -6.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -1.4, phastCons 0.16
Regional constraint	o/e 0.89	unconstrained · MANE · 16 kb · p 0.024 · regional, not allelic
Overall
CADD	17.69	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 0.494% African / African-American · 371/75,076 alleles

Filtering AF 0.453% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.436%

Overall 0.0247% 399/1,613,844 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.494%	202
Remaining individualsnot grpmax-eligible	0.024%	4,167
Admixed American	0.0167%	6,003
Middle Eastern	0.0165%	6,060
South Asian	0.0011%	91,082
European (non-Finnish)	8.47e-05%	1,180,054

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.Ser464Asn
Coding: c.1391G>A
MANE Select: NM_020549
dbSNP: rs148525631
Type: single nucleotide variant
Location: chr10:49649516 (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

SLC18A3 p.Pro464= 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
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-ser464asn (accessed [today's date]).

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