Is CHAT p.Val396Met (c.1186G>A) pathogenic?

CHAT p.Val396Met (c.1186G>A) is classified Uncertain significance in CHAT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-26). AlphaMissense: likely benign (0.0802); Very rare (popmax 0.00333%, amr); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Val396Met (c.1186G>A)?

CHAT p.Val396Met (c.1186G>A) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Val396Met (c.1186G>A) in the general population?

CHAT p.Val396Met (c.1186G>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CHAT p.Val396Met (c.1186G>A)?

AlphaMissense predicts likely benign (score 0.0802) — an in-silico prediction, not a clinical call.

CHAT p.Val396Met

c.1186G>A · rs536359684 · VCV1064329

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0802 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
AlphaMissense	0.0802	likely benign
REVEL	0.11	moderately benign-leaning
SaProt	LLR -5.96	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 -1.2	GERP -4.1
Regional constraint	o/e 0.64	unconstrained · MANE · 1,990 bp · p 0.0015 · regional, not allelic
Overall
CADD	6.52	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 0.00333% Admixed American · 2/60,038 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00161% 26/1,614,234 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,019
European (non-Finnish)	0.00195%	51,305
South Asian	0.0011%	91,084

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.Val396Met
Coding: c.1186G>A
MANE Select: NM_020549
dbSNP: rs536359684
Type: single nucleotide variant
Location: chr10:49646579 (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.Val396= Likely benign ★ same residue
CHAT p.Val396_Glu397del Likely pathogenic ★ 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-val396met (accessed [today's date]).

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