Is CAPN15 p.Ala559= (c.1677G>A) pathogenic?

CAPN15 p.Ala559= (c.1677G>A) is classified Likely benign in CAPN15 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-06-07). Ultra-rare (popmax 0.0367%, mid); Associated with CAPN15-related disorder.

What condition is associated with CAPN15 p.Ala559= (c.1677G>A)?

CAPN15 p.Ala559= (c.1677G>A) is associated with CAPN15-related disorder (ClinVar).

How common is CAPN15 p.Ala559= (c.1677G>A) in the general population?

CAPN15 p.Ala559= (c.1677G>A) is ultra-rare (popmax 0.0367%, mid) (gnomAD).

CAPN15 p.Ala559=

c.1677G>A · rs1176553372 · VCV3044481

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0367%, mid)

Conditions

CAPN15-related disorder

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 -6	GERP -2.5
Overall
CADD	1.101	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0367% Middle Eastern · 2/5,454 alleles

Filtering AF 0.00642% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00264%

Overall 0.00145% 23/1,591,256 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0367%	2,727
Admixed American	0.00508%	19,698
East Asian	0.00225%	44,350
Remaining individualsnot grpmax-eligible	0.00162%	61,836
European (non-Finnish)	0.00128%	78,381
South Asian	0.00112%	89,474

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: CAPN15
Protein: p.Ala559=
Coding: c.1677G>A
MANE Select: NM_005632
dbSNP: rs1176553372
Type: single nucleotide variant
Location: chr16:549306 (GRCh38)
Gene constraint: LOEUF 0.974 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.65
Residue 559: the calpain catalytic domain

Full CAPN15 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CAPN15-related disorder

Similar variants

CAPN15 p.Ala559Val Uncertain significance ★ ⚠ same residue
CAPN15 p.Pro494Ser Uncertain significance ★ ⚠ same condition
CAPN15 p.Ser613Leu Conflicting classifications of pathogenicity ★ ⚠ same condition
CAPN15 p.Thr950Ala Uncertain significance ⚠ same condition
CAPN15 p.Ala817= Likely benign same condition
CAPN15 p.Arg428Gln Likely benign same condition
CAPN15 p.Asn745= Likely benign same condition
CAPN15 p.Asp590= Benign 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/capn15-p-ala559 (accessed [today's date]).

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