# NM_000070.3(CAPN3):c.483del (p.Ile162fs)

https://sugi.bio/variant/capn3-p-ile162fs

## Summary

**CAPN3 p.Ile162fs (c.483del)** is classified **Pathogenic** in CAPN3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-10-20). No gnomAD frequency available for this variant; Associated with muscular dystrophy, limb-girdle, autosomal dominant 4.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs863224963 · 4 submitters · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CAPN3 gene that is considered disease-causing, submitted by 4 submitters, and is linked to muscular dystrophy, limb-girdle, autosomal dominant 4.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adult |
| Prevalence | <1 / 1 000 000 (Worldwide) |
| Diagnostic panels | CAPN3 is a diagnostic-grade gene on 3 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0022272/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.Ile162fs |
| Coding change (HGVS c.) | c.483del |
| MANE Select transcript | [NM_000070](https://www.ncbi.nlm.nih.gov/nuccore/NM_000070) |
| dbSNP | [rs863224963](https://www.ncbi.nlm.nih.gov/snp/rs863224963/) |
| Variant type | Deletion |
| Location | chr15:42386268-42386268 (GRCh38) |
| ClinVar | [VCV217156](https://www.ncbi.nlm.nih.gov/clinvar/variation/217156/) |

**All HGVS expressions:** `LRG_849:g.43168del`, `LRG_849t1:c.483del`, `NC_000015.10:g.42386270del`, `NC_000015.9:g.42678468del`, `NG_008660.1:g.43168del`, `NM_000070.3:c.483del`, `NM_024344.2:c.483del`, `NM_173087.2:c.483del`

## 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 -7.024, GERP -5.65 — fast-evolving / accelerated 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 3 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 **162** lies in the calpain catalytic domain; a β-strand; a UniProt-annotated variant site (in lgmdr1).

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.Ile162fs 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-10-20.

**Submitter consensus:** unanimous (4/4 Pathogenic).

**Submission history:** 4 submissions (2018–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Athena Diagnostics | Pathogenic | criteria provided, single submitter | clinical testing | 2018-08-27 |
| Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Pathogenic | criteria provided, single submitter | research | 2018-12-03 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-10-20 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-06-19 |

## Associated conditions {#conditions}

[muscular dystrophy, limb-girdle, autosomal dominant 4](https://sugi.bio/atlas/disease/muscular-dystrophy-limb-girdle-autosomal-dominant-4/), [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):** Muscular dystrophy, limb-girdle, autosomal dominant 4, not provided, Autosomal recessive limb-girdle muscular dystrophy type 2A, Calpain-3-related limb-girdle muscular dystrophy D4, MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1I, none provided, Limb-girdle muscular dystrophy, type 2A, Calpainopathy, LEYDEN-MOEBIUS MUSCULAR DYSTROPHY, MUSCULAR DYSTROPHY, PELVOFEMORAL.

## Similar variants {#similar}

Related CAPN3 variant pages (same residue, condition, or type): [CAPN3 p.Ile162Phe](/variant/capn3-p-ile162phe), [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).

### 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 217156). 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.*