Is CASQ2 p.Pro329Ser (c.985C>T) pathogenic?

CASQ2 p.Pro329Ser (c.985C>T) is classified Conflicting classifications of pathogenicity in CASQ2 (ClinVar, Conflicting submitters, 15 submitters; last evaluated 2026-02-04). AlphaMissense: likely pathogenic (0.9489); Ultra-rare (popmax 0.0253%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with CASQ2 p.Pro329Ser (c.985C>T)?

CASQ2 p.Pro329Ser (c.985C>T) is associated with Cardiovascular phenotype, cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1 (ClinVar).

How common is CASQ2 p.Pro329Ser (c.985C>T) in the general population?

CASQ2 p.Pro329Ser (c.985C>T) is ultra-rare (popmax 0.0253%, nfe) (gnomAD).

What do computational predictors say about CASQ2 p.Pro329Ser (c.985C>T)?

AlphaMissense predicts likely pathogenic (score 0.9489) — an in-silico prediction, not a clinical call.

CASQ2 p.Pro329Ser

c.985C>T · rs28730713 · VCV190747

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 15 submitters

AlphaMissense

likely pathogenic

0.9489 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0253%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9489	likely pathogenic · top 7% in CASQ2
REVEL	0.741	pathogenic-leaning
SaProt	LLR -8.57	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 67 kb · p 0.83 · regional, not allelic
Overall
CADD	32.0	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 0.0253% European (non-Finnish) · 298/1,179,832 alleles

Filtering AF 0.0229% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0219%

Overall 0.0224% 361/1,613,686 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0781%	1,280
European (non-Finnish)grpmax	0.0253%	3,959
Remaining individualsnot grpmax-eligible	0.0112%	8,927
African / African-American	0.00666%	15,006
Admixed American	0.00167%	59,952

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro329Ser
Coding: c.985C>T
MANE Select: NM_001232
dbSNP: rs28730713
Type: single nucleotide variant
Location: chr1:115702950 (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

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

Similar variants

CASQ2 p.Pro329= Likely benign ★★ same residue
CASQ2 p.Pro329Thr 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

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-pro329ser (accessed [today's date]).

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