Is CHAT p.Arg375= (c.1123C>A) pathogenic?

CHAT p.Arg375= (c.1123C>A) is classified Likely benign in CHAT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-14). Ultra-rare (popmax 0.0692%, sas); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Arg375= (c.1123C>A)?

CHAT p.Arg375= (c.1123C>A) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Arg375= (c.1123C>A) in the general population?

CHAT p.Arg375= (c.1123C>A) is ultra-rare (popmax 0.0692%, sas) (gnomAD).

CHAT p.Arg375=

c.1123C>A · rs141794970 · VCV1404644

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0692%, sas)

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 · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 0.96, phastCons 1
Overall
CADD	12.26	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0692% South Asian · 63/91,082 alleles

Filtering AF 0.0554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0505%

Overall 0.00415% 67/1,614,180 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0692%	1,446
Remaining individualsnot grpmax-eligible	0.0032%	31,254
European (non-Finnish)	0.000169%	590,012

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.Arg375=
Coding: c.1123C>A
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.Arg375Trp Benign ★★ same residue
CHAT p.Arg375Gln Conflicting classifications of pathogenicity ★ ⚠ 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-arg375 (accessed [today's date]).

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