Is CASQ2 p.Pro59= (c.177G>A) pathogenic?

CASQ2 p.Pro59= (c.177G>A) is classified Likely benign in CASQ2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-29). Ultra-rare (popmax 0.032%, afr); Associated with Cardiovascular phenotype.

How common is CASQ2 p.Pro59= (c.177G>A) in the general population?

CASQ2 p.Pro59= (c.177G>A) is ultra-rare (popmax 0.032%, afr) (gnomAD).

CASQ2 p.Pro59=

Q: What condition is associated with CASQ2 p.Pro59= (c.177G>A)?

CASQ2 p.Pro59= (c.177G>A) is associated with Cardiovascular phenotype, catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia 2 (ClinVar).

c.177G>A · rs371260149 · VCV162822

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.032%, afr)

Conditions

Cardiovascular phenotype

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 -9.3	GERP -3.8
Overall
CADD	1.121	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.032% African / African-American · 24/75,004 alleles

Filtering AF 0.022% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0187%

Overall 0.00508% 82/1,613,988 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.032%	3,125
East Asian	0.00669%	14,957
Remaining individualsnot grpmax-eligible	0.0048%	20,835
European (non-Finnish)	0.00398%	25,105
Admixed American	0.00333%	29,992
South Asian	0.0022%	45,530
Finnishnot grpmax-eligible	0.00156%	64,032

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.Pro59=
Coding: c.177G>A
MANE Select: NM_001232
dbSNP: rs371260149
Type: single nucleotide variant
Location: chr1:115768365 (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 59: an α-helix

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: catecholaminergic polymorphic ventricular tachycardia 1 catecholaminergic polymorphic ventricular tachycardia 2

Similar variants

CASQ2 p.Pro59Leu Uncertain significance ★★ ⚠ same residue
CASQ2 p.Pro59Ser Uncertain significance ★★ ⚠ same residue
CASQ2 p.Pro59Thr 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

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-pro59 (accessed [today's date]).

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