Is CAPN9 p.Arg524Pro (c.1571G>C) pathogenic?

CAPN9 p.Arg524Pro (c.1571G>C) is classified Uncertain significance in CAPN9 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-21). AlphaMissense: likely pathogenic (0.9533); Absent from gnomAD v4.1.

How common is CAPN9 p.Arg524Pro (c.1571G>C) in the general population?

CAPN9 p.Arg524Pro (c.1571G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CAPN9 p.Arg524Pro (c.1571G>C)?

AlphaMissense predicts likely pathogenic (score 0.9533) — an in-silico prediction, not a clinical call.

CAPN9 p.Arg524Pro

c.1571G>C · rs780593179 · VCV2619907

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9533 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9533	likely pathogenic · top 8% in CAPN9
REVEL	0.745	pathogenic-leaning
SaProt	LLR -18.34	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP 0.9, phastCons 0.12
Regional constraint	o/e 0.98	unconstrained · MANE · 54 kb · p 0.54 · regional, not allelic
Overall
CADD	22.4	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

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: CAPN9
Protein: p.Arg524Pro
Coding: c.1571G>C
MANE Select: NM_006615
dbSNP: rs780593179
Type: single nucleotide variant
Location: chr1:230787574 (GRCh38)
Gene constraint: LOEUF 1.036 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.14 · 2 PDB
Residue 524: the ef-hand 1 domain; the 'domain iv' region

Full CAPN9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPN9 p.Arg524Gln Uncertain significance ★ ⚠ same residue
CAPN9 p.Arg524Trp Uncertain significance ★ ⚠ same residue
CAPN9 p.Ala101= Likely benign ★★ same type
CAPN9 c.1657+2T>G Uncertain significance ★ same type
CAPN9 p.Ala255Thr Uncertain significance ★ ⚠ same type
CAPN9 p.Ala345Val Uncertain significance ★ ⚠ same type
CAPN9 p.Ala525Asp Uncertain significance ★ ⚠ same type
CAPN9 p.Ala531Thr 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/capn9-p-arg524pro (accessed [today's date]).

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