Is CASQ2 p.Ala339Pro (c.1015G>C) pathogenic?

CASQ2 p.Ala339Pro (c.1015G>C) is classified Uncertain significance in CASQ2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-17). AlphaMissense: likely pathogenic (0.9696); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with CASQ2 p.Ala339Pro (c.1015G>C)?

CASQ2 p.Ala339Pro (c.1015G>C) is associated with Cardiovascular phenotype (ClinVar).

How common is CASQ2 p.Ala339Pro (c.1015G>C) in the general population?

CASQ2 p.Ala339Pro (c.1015G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CASQ2 p.Ala339Pro (c.1015G>C)?

AlphaMissense predicts likely pathogenic (score 0.9696) — an in-silico prediction, not a clinical call.

CASQ2 p.Ala339Pro

c.1015G>C · VCV3485298

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9696 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9696	likely pathogenic · top 5% in CASQ2
REVEL	0.713	pathogenic-leaning
SaProt	LLR -10.11	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 67 kb · p 0.83 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CASQ2
Protein: p.Ala339Pro
Coding: c.1015G>C
MANE Select: NM_001232
Type: single nucleotide variant
Location: chr1:115701426 (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

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

Similar variants

CASQ2 c.319+2T>G Likely pathogenic ★★ same condition
CASQ2 c.420+1G>A Likely pathogenic ★★ same condition
CASQ2 c.533-2A>G Likely pathogenic ★★ same condition
CASQ2 c.939+1G>T Pathogenic/Likely pathogenic ★★ same condition
CASQ2 p.Arg33Ter Pathogenic/Likely pathogenic ★★ same condition
CASQ2 p.Gln67Ter Pathogenic ★★ same condition
CASQ2 p.Trp343Ter Pathogenic ★★ same condition
CASQ2 p.Tyr55Cys 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-ala339pro (accessed [today's date]).

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