Is CASQ2 p.Pro254= (c.762A>G) pathogenic?

CASQ2 p.Pro254= (c.762A>G) is classified Likely benign in CASQ2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-03). Ultra-rare (popmax 0.0111%, sas); Associated with catecholaminergic polymorphic ventricular tachycardia 1.

What condition is associated with CASQ2 p.Pro254= (c.762A>G)?

CASQ2 p.Pro254= (c.762A>G) is associated with catecholaminergic polymorphic ventricular tachycardia 1 (ClinVar).

How common is CASQ2 p.Pro254= (c.762A>G) in the general population?

CASQ2 p.Pro254= (c.762A>G) is ultra-rare (popmax 0.0111%, sas) (gnomAD).

CASQ2 p.Pro254=

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.762A>G · rs753016201 · VCV1591485

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, sas)

Conditions

catecholaminergic polymorphic ventricular tachycardia 1

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 -0.83	GERP -2.2, phastCons 0.016
Overall
CADD	8.669	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0111% South Asian · 10/90,072 alleles

Filtering AF 0.006% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00458%

Overall 0.000699% 10/1,430,108 alleles · ultra-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.Pro254=
Coding: c.762A>G
MANE Select: NM_001232
dbSNP: rs753016201
Type: single nucleotide variant
Location: chr1:115725529 (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 254: a turn

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

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

CASQ2 p.Pro254Ser 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.606+1G>C Pathogenic/Likely pathogenic ★★ same condition
CASQ2 c.606+2T>A Likely pathogenic ★★ same condition
CASQ2 c.737+1G>A 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-pro254 (accessed [today's date]).

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