Is CAPN15 p.Cys588Arg (c.1762T>C) pathogenic?

CAPN15 p.Cys588Arg (c.1762T>C) is classified Uncertain significance in CAPN15 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-08-19). AlphaMissense: likely pathogenic (0.9984); Very rare (popmax 0.000509%, nfe).

How common is CAPN15 p.Cys588Arg (c.1762T>C) in the general population?

CAPN15 p.Cys588Arg (c.1762T>C) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about CAPN15 p.Cys588Arg (c.1762T>C)?

AlphaMissense predicts likely pathogenic (score 0.9984) — an in-silico prediction, not a clinical call.

CAPN15 p.Cys588Arg

c.1762T>C · VCV3781203

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9984 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9984	likely pathogenic · top 4% in CAPN15
REVEL	0.61	indeterminate
SaProt	LLR -13.71	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.2, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 321 bp · p 5e-06 · regional, not allelic
Overall
CADD	28.9	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

Grpmax group 0.000509% European (non-Finnish) · 6/1,178,612 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000375% 6/1,598,546 alleles · very rare

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.Cys588Arg
Coding: c.1762T>C
MANE Select: NM_005632
Type: single nucleotide variant
Location: chr16:549391 (GRCh38)
Gene constraint: LOEUF 0.974 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.65
Residue 588: the calpain catalytic domain

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

Similar variants

CAPN15 c.2192+8C>T Uncertain significance ★★ same type
CAPN15 p.Arg428Trp Uncertain significance ★★ ⚠ same type
CAPN15 p.Arg867Cys Uncertain significance ★★ ⚠ same type
CAPN15 p.Arg867His Uncertain significance ★★ ⚠ same type
CAPN15 p.Cys363Arg Uncertain significance ★★ ⚠ same type
CAPN15 p.Glu776Ala Uncertain significance ★★ ⚠ same type
CAPN15 p.Val489Met Uncertain significance ★★ ⚠ same type
CAPN15 p.Val841Met Uncertain significance ★★ ⚠ same type

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-cys588arg (accessed [today's date]).

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