Is CHAT p.Arg375Gln (c.1124G>A) pathogenic?

CHAT p.Arg375Gln (c.1124G>A) is classified Conflicting classifications of pathogenicity in CHAT (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-17). AlphaMissense: likely benign (0.3204); Rare (popmax 0.138%, sas); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Arg375Gln (c.1124G>A)?

CHAT p.Arg375Gln (c.1124G>A) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Arg375Gln (c.1124G>A) in the general population?

CHAT p.Arg375Gln (c.1124G>A) is rare (popmax 0.138%, sas) (gnomAD).

What do computational predictors say about CHAT p.Arg375Gln (c.1124G>A)?

AlphaMissense predicts likely benign (score 0.3204) — an in-silico prediction, not a clinical call.

CHAT p.Arg375Gln

c.1124G>A · rs201616704 · VCV654080

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3204 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.138%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
AlphaMissense	0.3204	likely benign
REVEL	0.726	pathogenic-leaning
SaProt	LLR -8.10	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 32 kb · p 0.16 · regional, not allelic
Overall
CADD	33.0	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 0.138% South Asian · 126/91,090 alleles

Filtering AF 0.119% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.111%

Overall 0.0178% 287/1,614,196 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.138%	723
Ashkenazi Jewishnot grpmax-eligible	0.105%	955
Remaining individualsnot grpmax-eligible	0.0208%	4,808
Admixed American	0.0167%	6,003
European (non-Finnish)	0.0089%	11,238
Finnishnot grpmax-eligible	0.00156%	64,006
African / African-American	0.00133%	75,062

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.Arg375Gln
Coding: c.1124G>A
MANE Select: NM_020549
dbSNP: rs201616704
Type: single nucleotide variant
Location: chr10:49646517 (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.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-arg375gln (accessed [today's date]).

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