Is CAPN15 p.Pro494Ser (c.1480C>T) pathogenic?

CAPN15 p.Pro494Ser (c.1480C>T) is classified Uncertain significance in CAPN15 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-03). AlphaMissense: ambiguous (0.5412); Absent from gnomAD v4.1; Associated with CAPN15-related disorder.

What condition is associated with CAPN15 p.Pro494Ser (c.1480C>T)?

CAPN15 p.Pro494Ser (c.1480C>T) is associated with CAPN15-related disorder (ClinVar).

How common is CAPN15 p.Pro494Ser (c.1480C>T) in the general population?

CAPN15 p.Pro494Ser (c.1480C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CAPN15 p.Pro494Ser (c.1480C>T)?

AlphaMissense predicts ambiguous (score 0.5412) — an in-silico prediction, not a clinical call.

CAPN15 p.Pro494Ser

c.1480C>T · rs2505842019 · VCV2630204

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5412 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

CAPN15-related disorder

Computational evidence

Protein change
AlphaMissense	0.5412	ambiguous
REVEL	0.808	moderately pathogenic-leaning
SaProt	LLR -11.80	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.2, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 2,296 bp · p 0.00013 · regional, not allelic
Overall
CADD	25.8	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

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: CAPN15
Protein: p.Pro494Ser
Coding: c.1480C>T
MANE Select: NM_005632
dbSNP: rs2505842019
Type: single nucleotide variant
Location: chr16:549023 (GRCh38)
Gene constraint: LOEUF 0.974 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.65
Residue 494: 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.Ser613Leu Conflicting classifications of pathogenicity ★ ⚠ same condition
CAPN15 p.Thr950Ala Uncertain significance ⚠ same condition
CAPN15 p.Ala559= Likely benign 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
CAPN15 p.Cys64= Likely 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-pro494ser (accessed [today's date]).

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