Is CHAT p.Arg375Trp (c.1123C>T) pathogenic?

CHAT p.Arg375Trp (c.1123C>T) is classified Benign in CHAT (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-18). AlphaMissense: likely pathogenic (0.659); Ultra-rare (popmax 0.015%, amr); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Arg375Trp (c.1123C>T)?

CHAT p.Arg375Trp (c.1123C>T) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Arg375Trp (c.1123C>T) in the general population?

CHAT p.Arg375Trp (c.1123C>T) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about CHAT p.Arg375Trp (c.1123C>T)?

AlphaMissense predicts likely pathogenic (score 0.659) — an in-silico prediction, not a clinical call.

CHAT p.Arg375Trp

c.1123C>T · rs141794970 · VCV702782

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.659 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
AlphaMissense	0.659	likely pathogenic
REVEL	0.858	moderately pathogenic-leaning
SaProt	LLR -12.01	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 0.96, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 32 kb · p 0.16 · regional, not allelic
Overall
CADD	31.0	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 0.015% Admixed American · 9/60,006 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00578%

Overall 0.0251% 405/1,614,062 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.98%	102
Remaining individualsnot grpmax-eligible	0.0672%	1,488
Admixed Americangrpmax	0.015%	6,667
European (non-Finnish)	0.00517%	19,345
African / African-American	0.00267%	37,472
South Asian	0.0011%	91,086

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg375Trp
Coding: c.1123C>T
MANE Select: NM_020549
dbSNP: rs141794970
Type: single nucleotide variant
Location: chr10:49646516 (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 375: 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.Arg375Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
CHAT p.Arg375= 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

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-arg375trp (accessed [today's date]).

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