Is CHAT p.Arg281Trp (c.841C>T) pathogenic?

CHAT p.Arg281Trp (c.841C>T) is classified Likely pathogenic in CHAT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-19). AlphaMissense: likely pathogenic (0.9699); Very rare (popmax 0.00501%, amr); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Arg281Trp (c.841C>T)?

CHAT p.Arg281Trp (c.841C>T) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Arg281Trp (c.841C>T) in the general population?

CHAT p.Arg281Trp (c.841C>T) is very rare (popmax 0.00501%, amr) (gnomAD).

What do computational predictors say about CHAT p.Arg281Trp (c.841C>T)?

AlphaMissense predicts likely pathogenic (score 0.9699) — an in-silico prediction, not a clinical call.

CHAT p.Arg281Trp

c.841C>T · rs747108035 · VCV1370459

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9699 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00501%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
AlphaMissense	0.9699	likely pathogenic ✓ concordant with ClinVar · top 8% in CHAT
REVEL	0.909	moderately pathogenic-leaning
SaProt	LLR -14.37	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.99 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 32 kb · p 0.16 · regional, not allelic
Overall
CADD	32.0	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 0.00501% Admixed American · 3/59,886 alleles

Filtering AF 0.00208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00236% 38/1,612,768 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00501%	19,962
European (non-Finnish)	0.00288%	34,694
South Asian	0.0011%	90,608

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.Arg281Trp
Coding: c.841C>T
MANE Select: NM_020549
dbSNP: rs747108035
Type: single nucleotide variant
Location: chr10:49625561 (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 281: a β-strand

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.Arg281= Likely benign ★ same residue
SLC18A3 p.Pro281Ala Uncertain significance ★★ ⚠ same residue
SLC18A3 p.Pro281= Likely benign ★ same residue
SLC18A3 p.Pro281Leu 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-arg281trp (accessed [today's date]).

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