Is CAPN3 p.Val433fs (c.1298_1299del) pathogenic?

CAPN3 p.Val433fs (c.12981299del) is classified Pathogenic in CAPN3 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-02-25). Very rare (popmax 0.00439%, sas); Associated with muscular dystrophy, limb-girdle, autosomal dominant 4.

What condition is associated with CAPN3 p.Val433fs (c.1298_1299del)?

CAPN3 p.Val433fs (c.1298_1299del) is associated with muscular dystrophy, limb-girdle, autosomal dominant 4, autosomal recessive limb-girdle muscular dystrophy type 2A (ClinVar).

How common is CAPN3 p.Val433fs (c.1298_1299del) in the general population?

CAPN3 p.Val433fs (c.1298_1299del) is very rare (popmax 0.00439%, sas) (gnomAD).

CAPN3 p.Val433fs

Q: How is Calpain-3-related limb-girdle muscular dystrophy D4 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1298_1299del · rs1293496023 · VCV557732

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Conditions

muscular dystrophy, limb-girdle, autosomal dominant 4

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 10 of 24
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	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 0.00439% South Asian · 4/91,058 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000274% 4/1,461,694 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.Val433fs
Coding: c.1298_1299del
MANE Select: NM_000070
dbSNP: rs1293496023
Type: Microsatellite
Location: chr15:42399594 (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 433: the 'domain iii' region

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

Disease context

muscular dystrophy, limb-girdle, autosomal dominant 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive limb-girdle muscular dystrophy type 2A

For Calpain-3-related limb-girdle muscular dystrophy D4 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

CAPN3 p.Glu467del Pathogenic ★★★ same condition
CAPN3 p.Lys254del Pathogenic ★★★ same condition
CAPN3 p.His690fs Pathogenic ★★ same condition
CAPN3 p.Ser581fs Pathogenic/Likely pathogenic ★★ same condition
CAPN3 p.Thr679fs Pathogenic ★★ same condition
CAPN3 p.Thr736fs Pathogenic/Likely pathogenic ★★ same condition
CAPN3 c.2440-10CTT[3] Benign/Likely benign ★★ same condition
CAPN3 c.2117_2120del Likely pathogenic ★ 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/capn3-p-val433fs (accessed [today's date]).

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