# NM_000070.3(CAPN3):c.717del (p.Phe239fs)

https://sugi.bio/variant/capn3-p-phe239fs

## Summary

**CAPN3 p.Phe239fs (c.717del)** is classified **Pathogenic** in CAPN3 (ClinVar, Expert panel, 8 submitters; last evaluated 2026-04-29). Very rare (popmax 0.0011%, sas); Associated with autosomal recessive limb-girdle muscular dystrophy.

**At a glance:** Pathogenic · review: Expert panel · rsID rs776059672 · 8 submitters · 2 linked conditions · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the CAPN3 gene that is considered disease-causing, submitted by 8 submitters, and is linked to autosomal recessive limb-girdle muscular dystrophy.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019825/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CAPN3](https://sugi.bio/atlas/gene/CAPN3/) |
| Protein change (HGVS p.) | p.Phe239fs |
| Coding change (HGVS c.) | c.717del |
| MANE Select transcript | [NM_000070](https://www.ncbi.nlm.nih.gov/nuccore/NM_000070) |
| dbSNP | [rs776059672](https://www.ncbi.nlm.nih.gov/snp/rs776059672/) |
| Variant type | Deletion |
| Location | chr15:42389007-42389007 (GRCh38) |
| ClinVar | [VCV284807](https://www.ncbi.nlm.nih.gov/clinvar/variation/284807/) |

**All HGVS expressions:** `LRG_849:g.45910del`, `LRG_849t1:c.717del`, `NC_000015.10:g.42389012del`, `NC_000015.9:g.42681210del`, `NG_008660.1:g.45910del`, `NM_000070.3:c.717del`, `NM_000070.3:c.717delT`, `NM_024344.2:c.717del`, `NM_173087.2:c.717del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 1.45, GERP -2.17, phastCons 1 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.896, pLI 5.2262e-19. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 5 of 24**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (sas) · FAF95 0.000183% · FAF99 0.00012% · 1/91,080 in the highest group · 7/1,614,126 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0011% | 91,080 |
| European (non-Finnish) | 0.000508% | 196,668 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CAPN3** population constraint: LOEUF 0.896, pLI 5.2262e-19, missense-Z 0.86012; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **muscular dystrophy, limb-girdle, autosomal dominant** — Definitive (AD)
- **autosomal recessive limb-girdle muscular dystrophy** — Definitive (AR)

## Protein context {#protein}

Residue **239** lies in the calpain catalytic domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 79.18, 44% of residues very-high.

**5 experimental structure(s)** (PDB): [4OKH](https://www.rcsb.org/structure/4OKH), [6BDT](https://www.rcsb.org/structure/6BDT), [6BGP](https://www.rcsb.org/structure/6BGP), [6BJD](https://www.rcsb.org/structure/6BJD), [6BKJ](https://www.rcsb.org/structure/6BKJ) — incl. mutant structure 6BDT.

## What this gene does {#gene-function}

*Describes the biological roles of CAPN3 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CAPN3's established molecular role includes catalytic activity. p.Phe239fs falls in the calpain catalytic domain.


### Pathways affected {#pathways}

CAPN3 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Degradation of the extracellular matrix](https://reactome.org/content/detail/R-HSA-1474228) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** catalytic activity, peptidase activity, cysteine-type peptidase activity, titin binding, identical protein binding.

**Biological process:** proteolysis, protein catabolic process, protein destabilization, negative regulation of protein sumoylation, negative regulation of apoptotic process, regulation of canonical NF-kappaB signal transduction.

## Clinical significance {#significance}

**Pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2026-04-29.

**Submitter consensus:** conflicting (7 Pathogenic, 1 Likely pathogenic).

**Submission history:** 8 submissions (2015–2026); classifications have differed over time.

**ClinGen expert panel:** Pathogenic — Limb Girdle Muscular Dystrophy VCEP (autosomal recessive limb-girdle muscular dystrophy). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PVS1`, `PM2_Supporting`, `PP4_Strong`, `PM3`.
*Considered but not met:* `PS4`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_000070.3: c.717del (p.Phe239LeufsTer14) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 5/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in a homozygous state in six patients with signs of LGMD (1.0 pt; PMID: 10330340, 18073330, 17236769; PM3). At least one of the patients had a clinical diagnosis of LGMD and absent calpain-3 protein expression, which is highly specific for CAPN3-related LGMD (PMID: 17236769; PP4_Strong). The upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.1 is 0.00001 (6/1180006 European (non-Finnish) chromosomes), which is lower than the ClinGen LGMD VCEP threshold (<0.0001) for PM2_Supporting, and therefore meets this criterion (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 (specifications v2.0.0; 04/29/2026): PVS1, PM3, PP4_Strong, PM2_Supporting.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50061 · approved 2026-04-29 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/27330316-f60e-491c-8a82-8a1f1bde9ac8).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Eurofins Ntd Llc (ga) | Pathogenic | criteria provided, single submitter | clinical testing | 2015-11-13 |
| Counsyl | Likely pathogenic | no assertion criteria provided | clinical testing | 2017-10-06 |
| Kariminejad - Najmabadi Pathology & Genetics Center | Pathogenic | criteria provided, single submitter | clinical testing | 2021-07-10 |
| MGZ Medical Genetics Center | Pathogenic | criteria provided, single submitter | clinical testing | 2022-08-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-02-24 |
| First Genomix Gene Laboratory, Genetic Diagnostics Department | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-20 |
| ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen | Pathogenic | reviewed by expert panel | curation | 2026-04-29 |
| Institute of Human Genetics, Heidelberg University | Pathogenic | criteria provided, single submitter | clinical testing | 2026-02-27 |

## Associated conditions {#conditions}

[autosomal recessive limb-girdle muscular dystrophy](https://sugi.bio/atlas/disease/autosomal-recessive-limb-girdle-muscular-dystrophy/), [autosomal recessive limb-girdle muscular dystrophy type 2A](https://sugi.bio/atlas/disease/autosomal-recessive-limb-girdle-muscular-dystrophy-type-2a/).

**Reported phenotype names (ClinVar):** Autosomal recessive limb-girdle muscular dystrophy, Autosomal recessive limb-girdle muscular dystrophy type 2A, not provided, Abnormality of the musculature, none provided, Calpainopathy, Muscular dystrophy, limb-girdle, type 2A, Amish, LEYDEN-MOEBIUS MUSCULAR DYSTROPHY, MUSCULAR DYSTROPHY, PELVOFEMORAL, Limb-girdle muscular dystrophy, type 2A.

## Similar variants {#similar}

Related CAPN3 variant pages (same residue, condition, or type): [CAPN3 c.1194-2del](/variant/capn3-c-1194-minus-2del), [CAPN3 p.Asp764fs](/variant/capn3-p-asp764fs), [CAPN3 p.Gln660_Ile661insTer](/variant/capn3-p-gln660-ile661inster), [CAPN3 p.Glu582fs](/variant/capn3-p-glu582fs), [CAPN3 p.Gly441fs](/variant/capn3-p-gly441fs), [CAPN3 p.Leu74fs](/variant/capn3-p-leu74fs), [CAPN3 p.Lys613fs](/variant/capn3-p-lys613fs), [CAPN3 p.Phe200_Leu204del](/variant/capn3-p-phe200-leu204del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 284807). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*