Is CHAT p.Val461Met (c.1381G>A) pathogenic?

CHAT p.Val461Met (c.1381G>A) is classified Benign in CHAT (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0754); Common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele; Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Val461Met (c.1381G>A)?

CHAT p.Val461Met (c.1381G>A) is associated with congenital myasthenic syndrome 6 (ClinVar).

What do computational predictors say about CHAT p.Val461Met (c.1381G>A)?

AlphaMissense predicts likely benign (score 0.0754) — an in-silico prediction, not a clinical call.

CHAT p.Val461Met

Q: How common is CHAT p.Val461Met (c.1381G>A) in the general population?

CHAT p.Val461Met (c.1381G>A) is common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1381G>A · rs4838544 · VCV199157

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0754 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
AlphaMissense	0.0754	likely benign
REVEL	0.264	benign-leaning
SaProt	LLR -9.30	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 4.6	GERP -0.21, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 16 kb · p 0.024 · regional, not allelic
Overall
CADD	15.12	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 100% East Asian · 44,834/44,834 alleles

Filtering AF 99.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 99.7%

Overall 99.4% 1,599,730/1,609,818 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	100%	1
Amishnot grpmax-eligible	100%	1
Finnishnot grpmax-eligible	100%	1
South Asian	100%	1
European (non-Finnish)	100%	1
Ashkenazi Jewishnot grpmax-eligible	99.9%	1
Admixed American	99.2%	1
Remaining individualsnot grpmax-eligible	99.2%	1
Middle Eastern	99.2%	1
African / African-American	88.5%	1

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.Val461Met
Coding: c.1381G>A
MANE Select: NM_020549
dbSNP: rs4838544
Type: single nucleotide variant
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.Val461= Uncertain significance ★ same residue
CHAT p.Val461Leu Uncertain significance ★ ⚠ same residue
CHAT p.Val461Ala Uncertain significance ⚠ same residue
CHAT p.Val461Thr 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-val461met (accessed [today's date]).

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