Is CAPN3 p.Glu467del (c.1395GGA[2]) pathogenic?

CAPN3 p.Glu467del (c.1395GGA[2]) is classified Pathogenic in CAPN3 (ClinVar, Expert panel, 8 submitters; last evaluated 2025-06-24). Very rare (popmax 0.00195%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy.

What condition is associated with CAPN3 p.Glu467del (c.1395GGA[2])?

CAPN3 p.Glu467del (c.1395GGA[2]) is associated with autosomal recessive limb-girdle muscular dystrophy, autosomal recessive limb-girdle muscular dystrophy type 2A, muscular dystrophy, limb-girdle, autosomal dominant 4 (ClinVar).

How common is CAPN3 p.Glu467del (c.1395GGA[2]) in the general population?

CAPN3 p.Glu467del (c.1395GGA[2]) is very rare (popmax 0.00195%, nfe) (gnomAD).

CAPN3 p.Glu467del

c.1395GGA[2] · rs746075428 · VCV553852

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00195%, nfe)

Conditions

autosomal recessive limb-girdle muscular dystrophy

ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP

Pathogenic for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):

PP4_Moderate PM2_Supporting PM3_VeryStrong PM4

Curation rationale (ClinGen, verbatim)

The NM_000070.3: c.1401_1403del variant in CAPN3 is expected to cause an in-frame deletion of one amino acid, p.(Glu467del) (PM4). This variant has been identified in at least 8 individuals with features consistent with LGMD (PMID: 16141003, 17994539, 16650086, 31555977, 18854869, 38391941, LOVD CAPN3_000200), including in a homozygous state without reported consanguinity in at least one patient (0.5 pts, PMID: 17994539, LOVD Individual # 00214553), confirmed in trans with a likely pathogenic or pathogenic variant in two patients (c.2148G>T p.(Glu716Asp), 1.0 pt, PMID: 37526466; c.967G>T (p.Glu323Ter), 1.0 pt, PMID: 38391941), and in unknown phase with a pathogenic variant in three patients (c.2242C>T p.(Arg748Ter), 0.5 pts x2 = 1.0 pt, PMID: 16141003, 18854869, LOVD Individuals 00214012, 00214187; c.1865_1866del p.(Glu622GlyfsTer9), 0.5 pts, PMID: 16650086, LOVD Individual #00214391) (PM3_Very Strong). At least one patient with this variant and a second presumed diagnostic variant in CAPN3 displayed progressive limb girdle muscle weakness and significantly reduced expression of calpain-3 protein in skeletal muscle, which is specific for CAPN3-related LGMD (PMID: 18854869; PP4_Moderate). The filtering allele frequency of this variant in gnomAD v4.1.0 exomes is 0.000027195 (the upper threshold of the 95% CI of 21/1111998 European (non-Finnish) chromosomes) , which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 06/24/2025): PM3_Very Strong, PP4_Moderate, PM2_Supporting, PM4.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.1	GERP 0.48, phastCons 1
Overall
CADD	20.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00195% European (non-Finnish) · 23/1,180,036 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00142% 23/1,614,050 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.Glu467del
Coding: c.1395GGA[2]
MANE Select: NM_000070
dbSNP: rs746075428
Type: Microsatellite
Location: chr15:42401681 (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 467: the 'domain iii' region

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

Disease context

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

Also linked: autosomal recessive limb-girdle muscular dystrophy type 2A muscular dystrophy, limb-girdle, autosomal dominant 4

Similar variants

CAPN3 p.Glu467= Likely benign ★ same residue
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 p.Val433fs Pathogenic ★★ same condition
CAPN3 c.2440-10CTT[3] Benign/Likely benign ★★ 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-glu467del (accessed [today's date]).

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