Is CASQ2 p.Cys53Phe (c.158G>T) pathogenic?

CASQ2 p.Cys53Phe (c.158G>T) is classified Uncertain significance in CASQ2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-01-03). AlphaMissense: ambiguous (0.5581); Very rare (popmax 0.00424%, nfe); Associated with catecholaminergic polymorphic ventricular tachycardia 1.

What condition is associated with CASQ2 p.Cys53Phe (c.158G>T)?

CASQ2 p.Cys53Phe (c.158G>T) is associated with catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia 2 (ClinVar).

How common is CASQ2 p.Cys53Phe (c.158G>T) in the general population?

CASQ2 p.Cys53Phe (c.158G>T) is very rare (popmax 0.00424%, nfe) (gnomAD).

What do computational predictors say about CASQ2 p.Cys53Phe (c.158G>T)?

AlphaMissense predicts ambiguous (score 0.5581) — an in-silico prediction, not a clinical call.

CASQ2 p.Cys53Phe

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.158G>T · rs151168851 · VCV838554

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.5581 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00424%, nfe)

Conditions

catecholaminergic polymorphic ventricular tachycardia 1

Computational evidence

Protein change
AlphaMissense	0.5581	ambiguous
REVEL	0.412	indeterminate
SaProt	LLR -5.93	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 67 kb · p 0.83 · regional, not allelic
Overall
CADD	27.4	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 0.00424% European (non-Finnish) · 50/1,179,922 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00294%

Overall 0.0031% 50/1,613,878 alleles · very rare

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: CASQ2
Protein: p.Cys53Phe
Coding: c.158G>T
MANE Select: NM_001232
dbSNP: rs151168851
Type: single nucleotide variant
Location: chr1:115768384 (GRCh38)
Gene constraint: LOEUF 1.322 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.63 · 4 PDB
Residue 53: a β-strand

Full CASQ2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

catecholaminergic polymorphic ventricular tachycardia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: catecholaminergic polymorphic ventricular tachycardia 2

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

CASQ2 p.Cys53Tyr Uncertain significance ★ ⚠ same residue
CASQ2 c.235-2A>G Likely pathogenic ★★ same condition
CASQ2 c.319+2T>G Likely pathogenic ★★ same condition
CASQ2 c.320-2A>G Pathogenic ★★ same condition
CASQ2 c.420+1G>A Likely pathogenic ★★ same condition
CASQ2 c.532+1G>A Pathogenic/Likely pathogenic ★★ same condition
CASQ2 c.533-2A>G Likely pathogenic ★★ same condition
CASQ2 c.606+1G>C 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/casq2-p-cys53phe (accessed [today's date]).

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