Is CHAT p.Arg322Cys (c.964C>T) pathogenic?

CHAT p.Arg322Cys (c.964C>T) is classified Conflicting classifications of pathogenicity in CHAT (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-10-17). AlphaMissense: likely benign (0.2176); Ultra-rare (popmax 0.033%, mid); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Arg322Cys (c.964C>T)?

CHAT p.Arg322Cys (c.964C>T) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Arg322Cys (c.964C>T) in the general population?

CHAT p.Arg322Cys (c.964C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about CHAT p.Arg322Cys (c.964C>T)?

AlphaMissense predicts likely benign (score 0.2176) — an in-silico prediction, not a clinical call.

CHAT p.Arg322Cys

c.964C>T · rs147815999 · VCV1592820

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2176 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
AlphaMissense	0.2176	likely benign
REVEL	0.591	indeterminate
SaProt	LLR -8.43	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.64 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.9	GERP 1.3, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 32 kb · p 0.16 · regional, not allelic
Overall
CADD	26.5	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 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00638% 103/1,614,144 alleles · ultra-rare exomes 90/1,461,812 · genomes 13/152,332 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0906%	1,104
Middle Easterngrpmax	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.0256%	3,906
East Asian	0.00446%	22,443
South Asian	0.0022%	45,538
European (non-Finnish)	0.00195%	51,304

Finnish 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.Arg322Cys
Coding: c.964C>T
MANE Select: NM_020549
dbSNP: rs147815999
Type: single nucleotide variant
Location: chr10:49627638 (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.Arg322His Uncertain significance ★ ⚠ same residue
CHAT p.Arg322= 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-arg322cys (accessed [today's date]).

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