Is CASQ1 p.Ala172Val (c.515C>T) pathogenic?

CASQ1 p.Ala172Val (c.515C>T) is classified Uncertain significance in CASQ1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-25). AlphaMissense: likely pathogenic (0.6828); Very rare (popmax 0.00669%, eas); Associated with myopathy due to calsequestrin and SERCA1 protein overload.

What condition is associated with CASQ1 p.Ala172Val (c.515C>T)?

CASQ1 p.Ala172Val (c.515C>T) is associated with myopathy due to calsequestrin and SERCA1 protein overload (ClinVar).

How common is CASQ1 p.Ala172Val (c.515C>T) in the general population?

CASQ1 p.Ala172Val (c.515C>T) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about CASQ1 p.Ala172Val (c.515C>T)?

AlphaMissense predicts likely pathogenic (score 0.6828) — an in-silico prediction, not a clinical call.

CASQ1 p.Ala172Val

Q: How is Vacuolar myopathy with sarcoplasmic reticulum protein aggregates inherited?

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

c.515C>T · rs190698081 · VCV2162707

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6828 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

myopathy due to calsequestrin and SERCA1 protein overload

Computational evidence

Protein change
AlphaMissense	0.6828	likely pathogenic
REVEL	0.492	indeterminate
SaProt	LLR -7.06	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 11 kb · p 0.42 · regional, not allelic
Overall
CADD	28.4	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 0.00669% East Asian · 3/44,860 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000892%

Overall 0.00124% 20/1,613,202 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,953
Admixed American	0.00167%	59,918
Remaining individualsnot grpmax-eligible	0.0016%	62,456
European (non-Finnish)	0.00127%	78,634

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: CASQ1
Protein: p.Ala172Val
Coding: c.515C>T
MANE Select: NM_001231
dbSNP: rs190698081
Type: single nucleotide variant
Location: chr1:160195061 (GRCh38)
Gene constraint: LOEUF 0.965 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.51 · 6 PDB
Residue 172: an α-helix

Full CASQ1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

myopathy due to calsequestrin and SERCA1 protein overload — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Vacuolar myopathy with sarcoplasmic reticulum protein aggregates (Orphanet):

Inheritance: Autosomal dominant, Unknown
Onset: Adult

Similar variants

CASQ1 p.Ala172Pro Uncertain significance ★★ ⚠ same residue
CASQ1 p.Ala172= Benign/Likely benign ★★ same residue
CASQ1 p.Ala172Glu Uncertain significance ★ ⚠ same residue
CASQ1 p.Asp244Gly Pathogenic ★★ ⚠ same condition
CASQ1 c.984+2T>G Uncertain significance ★★ same condition
CASQ1 p.Ala289Thr Uncertain significance ★★ ⚠ same condition
CASQ1 p.Arg48His Uncertain significance ★★ ⚠ same condition
CASQ1 p.Asp159Gly Uncertain significance ★★ ⚠ 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/casq1-p-ala172val (accessed [today's date]).

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