Is CHAT p.Arg323His (c.968G>A) pathogenic?

CHAT p.Arg323His (c.968G>A) is classified Conflicting classifications of pathogenicity in CHAT (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-24). AlphaMissense: likely benign (0.1263); Ultra-rare (popmax 0.015%, nfe); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Arg323His (c.968G>A)?

CHAT p.Arg323His (c.968G>A) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Arg323His (c.968G>A) in the general population?

CHAT p.Arg323His (c.968G>A) is ultra-rare (popmax 0.015%, nfe) (gnomAD).

What do computational predictors say about CHAT p.Arg323His (c.968G>A)?

AlphaMissense predicts likely benign (score 0.1263) — an in-silico prediction, not a clinical call.

CHAT p.Arg323His

c.968G>A · rs200176236 · VCV582744

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1263 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
AlphaMissense	0.1263	likely benign
REVEL	0.741	pathogenic-leaning
SaProt	LLR -8.54	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.6	GERP 1.3, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 32 kb · p 0.16 · regional, not allelic
Overall
CADD	28.6	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% European (non-Finnish) · 177/1,179,992 alleles

Filtering AF 0.0132% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.013% 210/1,614,108 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.015%	6,667
African / African-American	0.0133%	7,504
Remaining individualsnot grpmax-eligible	0.0128%	7,812
Finnishnot grpmax-eligible	0.0109%	9,147
East Asian	0.00891%	11,220
South Asian	0.00329%	30,361
Admixed American	0.00167%	60,020

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.Arg323His
Coding: c.968G>A
MANE Select: NM_020549
dbSNP: rs200176236
Type: single nucleotide variant
Location: chr10:49627642 (GRCh38)
Gene constraint: LOEUF 0.973 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 84.73 · 8 PDB

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.Arg323Cys 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
CHAT p.Ala557Thr Pathogenic/Likely pathogenic ★★ same condition
CHAT p.Arg151Ter Pathogenic/Likely pathogenic ★★ same condition
CHAT p.Arg207Gly 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-arg323his (accessed [today's date]).

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