Is CASQ2 p.Pro247Ser (c.739C>T) pathogenic?

CASQ2 p.Pro247Ser (c.739C>T) is classified Uncertain significance in CASQ2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-15). AlphaMissense: likely benign (0.1696); Very rare (popmax 0.00119%, sas); Associated with catecholaminergic polymorphic ventricular tachycardia 1.

What condition is associated with CASQ2 p.Pro247Ser (c.739C>T)?

CASQ2 p.Pro247Ser (c.739C>T) is associated with catecholaminergic polymorphic ventricular tachycardia 1 (ClinVar).

How common is CASQ2 p.Pro247Ser (c.739C>T) in the general population?

CASQ2 p.Pro247Ser (c.739C>T) is very rare (popmax 0.00119%, sas) (gnomAD).

What do computational predictors say about CASQ2 p.Pro247Ser (c.739C>T)?

AlphaMissense predicts likely benign (score 0.1696) — an in-silico prediction, not a clinical call.

CASQ2 p.Pro247Ser

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.739C>T · rs747600202 · VCV2318759

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1696 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

catecholaminergic polymorphic ventricular tachycardia 1

Computational evidence

Protein change
AlphaMissense	0.1696	likely benign
REVEL	0.621	indeterminate
SaProt	LLR -7.27	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP 2.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 67 kb · p 0.83 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00119% South Asian · 1/84,302 alleles

Filtering AF 0.000571% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000451%

Overall 0.000865% 13/1,503,492 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00119%	84,302
European (non-Finnish)	0.00107%	93,315

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.Pro247Ser
Coding: c.739C>T
MANE Select: NM_001232
dbSNP: rs747600202
Type: single nucleotide variant
Location: chr1:115725552 (GRCh38)
Gene constraint: LOEUF 1.322 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.63 · 4 PDB

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.Pro247Arg Uncertain significance ★★ ⚠ same residue
CASQ2 p.Pro247= Likely benign ★ 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

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-pro247ser (accessed [today's date]).

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