# NM_000070.3(CAPN3):c.689del (p.Asp230fs)

https://sugi.bio/variant/capn3-p-asp230fs

## Summary

**CAPN3 p.Asp230fs (c.689del)** is classified **Likely pathogenic** in CAPN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-10). No gnomAD frequency available for this variant; Associated with Abnormality of the musculature.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2141167797 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CAPN3 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to Abnormality of the musculature.

*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:** [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.Asp230fs |
| Coding change (HGVS c.) | c.689del |
| MANE Select transcript | [NM_000070](https://www.ncbi.nlm.nih.gov/nuccore/NM_000070) |
| dbSNP | [rs2141167797](https://www.ncbi.nlm.nih.gov/snp/rs2141167797/) |
| Variant type | Deletion |
| Location | chr15:42388984-42388984 (GRCh38) |
| ClinVar | [VCV1180794](https://www.ncbi.nlm.nih.gov/clinvar/variation/1180794/) |

**All HGVS expressions:** `LRG_849:g.45882del`, `LRG_849t1:c.689del`, `NC_000015.10:g.42388984del`, `NC_000015.9:g.42681182del`, `NG_008660.1:g.45882del`, `NM_000070.3:c.689del`, `NM_000070.3:c.689delA`, `NM_024344.2:c.689del`, `NM_173087.2:c.689del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 11.743, GERP 2.82, phastCons 1 — highly conserved position (PP3-type support)
- 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: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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 30, triplosensitivity 0 (0–3 scale). *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 **230** lies in the calpain catalytic domain; an α-helix.

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.Asp230fs 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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-07-10.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Kariminejad - Najmabadi Pathology & Genetics Center | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-07-10 |

## Associated conditions {#conditions}

[Abnormality of the musculature](https://sugi.bio/atlas/disease/abnormality-of-the-musculature/).

**Reported phenotype names (ClinVar):** Abnormality of the musculature.

## Similar variants {#similar}

Related CAPN3 variant pages (same residue, condition, or type): [CAPN3 p.Gln545fs](/variant/capn3-p-gln545fs), [CAPN3 p.Asp230Gly](/variant/capn3-p-asp230gly), [CAPN3 p.Asp230His](/variant/capn3-p-asp230his), [CAPN3 p.Asp230=](/variant/capn3-p-asp230), [CAPN3 p.Gly221Cys](/variant/capn3-p-gly221cys), [CAPN3 p.Ala483Thr](/variant/capn3-p-ala483thr), [CAPN3 p.Ser337Pro](/variant/capn3-p-ser337pro), [CAPN3 p.Ser432fs](/variant/capn3-p-ser432fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 1180794). 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.*