Is CAPN3 p.Pro458fs (c.1373del) pathogenic?

CAPN3 p.Pro458fs (c.1373del) is classified Pathogenic in CAPN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2016-04-20). Very rare (popmax 0.000763%, nfe).

How common is CAPN3 p.Pro458fs (c.1373del) in the general population?

CAPN3 p.Pro458fs (c.1373del) is very rare (popmax 0.000763%, nfe) (gnomAD).

CAPN3 p.Pro458fs

c.1373del · rs886043705 · VCV287712

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 11 of 24
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000763% European (non-Finnish) · 9/1,180,020 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000616% 9/1,461,864 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: CAPN3
Protein: p.Pro458fs
Coding: c.1373del
MANE Select: NM_000070
dbSNP: rs886043705
Type: Deletion
Location: chr15:42401657 (GRCh38)
Gene constraint: LOEUF 0.896 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 79.18 · 5 PDB
Residue 458: the 'domain iii' region

Full CAPN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPN3 c.1194-2del Pathogenic ★★★ same type
CAPN3 p.Asp764fs Pathogenic ★★★ same type
CAPN3 p.Gln660_Ile661insTer Pathogenic ★★★ same type
CAPN3 p.Glu582fs Pathogenic ★★★ same type
CAPN3 p.Gly441fs Pathogenic ★★★ same type
CAPN3 p.Leu74fs Likely pathogenic ★★★ same type
CAPN3 p.Lys613fs Pathogenic ★★★ same type
CAPN3 p.Phe200_Leu204del Pathogenic ★★★ 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/capn3-p-pro458fs (accessed [today's date]).

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