Is CAPN9 p.Ala525Asp (c.1574C>A) pathogenic?

CAPN9 p.Ala525Asp (c.1574C>A) is classified Uncertain significance in CAPN9 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-06). AlphaMissense: likely benign (0.125); Rare (popmax 0.121%, afr).

How common is CAPN9 p.Ala525Asp (c.1574C>A) in the general population?

CAPN9 p.Ala525Asp (c.1574C>A) is rare (popmax 0.121%, afr) (gnomAD).

What do computational predictors say about CAPN9 p.Ala525Asp (c.1574C>A)?

AlphaMissense predicts likely benign (score 0.125) — an in-silico prediction, not a clinical call.

CAPN9 p.Ala525Asp

c.1574C>A · rs142552467 · VCV2208652

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.125 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.121%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.125	likely benign
REVEL	0.275	benign-leaning
SaProt	LLR -8.54	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.27	GERP -1.3
Regional constraint	o/e 0.98	unconstrained · MANE · 54 kb · p 0.54 · regional, not allelic
Overall
CADD	11.48	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.121% African / African-American · 91/75,036 alleles

Filtering AF 0.101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0936%

Overall 0.00682% 110/1,614,050 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.121%	825
Admixed American	0.0233%	4,287
Middle Eastern	0.0165%	6,054
Remaining individualsnot grpmax-eligible	0.0064%	15,624

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: CAPN9
Protein: p.Ala525Asp
Coding: c.1574C>A
MANE Select: NM_006615
dbSNP: rs142552467
Type: single nucleotide variant
Location: chr1:230787577 (GRCh38)
Gene constraint: LOEUF 1.036 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.14 · 2 PDB
Residue 525: 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.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.Ala531Thr Uncertain significance ★ ⚠ same type
CAPN9 p.Ala605Thr Uncertain significance ★ ⚠ same type
CAPN9 p.Arg115Gly Uncertain significance ★ ⚠ same type
CAPN9 p.Arg149His 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-ala525asp (accessed [today's date]).

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