Is CHAT p.Val461Thr (c.1381_1382inv) pathogenic?

CHAT p.Val461Thr (c.13811382inv) is classified Uncertain significance in CHAT (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-17). Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Val461Thr (c.1381_1382inv)?

CHAT p.Val461Thr (c.1381_1382inv) is associated with congenital myasthenic syndrome 6 (ClinVar).

CHAT p.Val461Thr

c.1381_1382inv · VCV1043354

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

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 · substitutions only
Constraint at this position
Conservation	phyloP 4.6	GERP -0.21, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 16 kb · p 0.024 · regional, not allelic

Variant & gene context

Gene: CHAT
Protein: p.Val461Thr
Coding: c.1381_1382inv
MANE Select: NM_020549
Type: Inversion
Location: chr10:49648606 (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 461: a UniProt-annotated variant site (in); an α-helix

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.Val461Met Benign ★★ same residue
CHAT p.Val461= Uncertain significance ★ same residue
CHAT p.Val461Leu Uncertain significance ★ ⚠ same residue
CHAT p.Val461Ala 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

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-val461thr (accessed [today's date]).

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