# NM_000070.3(CAPN3):c.328C>T (p.Arg110Ter)

https://sugi.bio/variant/capn3-p-arg110ter

## Summary

**CAPN3 p.Arg110Ter (c.328C>T)** is classified **Pathogenic** in CAPN3 (ClinVar, Expert panel, 12 submitters; last evaluated 2025-01-07). Very rare (popmax 0.000424%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy.

**At a glance:** Pathogenic · review: Expert panel · rsID rs121434545 · 12 submitters · 3 linked conditions · very rare (popmax 0.000424%, nfe)

## For patients & families {#patients}

This is a change in the CAPN3 gene that is considered disease-causing, submitted by 12 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.Arg110Ter |
| Coding change (HGVS c.) | c.328C>T |
| MANE Select transcript | [NM_000070](https://www.ncbi.nlm.nih.gov/nuccore/NM_000070) |
| dbSNP | [rs121434545](https://www.ncbi.nlm.nih.gov/snp/rs121434545/) |
| Variant type | single nucleotide variant |
| Location | chr15:42384501-42384501 (GRCh38) |
| ClinVar | [VCV17615](https://www.ncbi.nlm.nih.gov/clinvar/variation/17615/) |

**All HGVS expressions:** `LRG_849:g.41399C>T`, `LRG_849t1:c.328C>T`, `NC_000015.10:g.42384501C>T`, `NC_000015.9:g.42676699C>T`, `NG_008660.1:g.41399C>T`, `NM_000070.3:c.328C>T`, `NM_024344.2:c.328C>T`, `NM_173087.2:c.328C>T`

## 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 1.439, GERP -2.55, phastCons 0.395 — weakly conserved position
- Molecular consequence: **nonsense (stop-gain)** — 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 2 of 24**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 38.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000424%** (nfe) · FAF95 0.000124% · FAF99 9e-05% · 5/1,179,674 in the highest group · 5/1,461,486 alleles overall — very rare (popmax 0.000424%, nfe).

*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 **110** lies in the calpain catalytic domain.

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.Arg110Ter 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 2025-01-07.

**Submitter consensus:** unanimous (12/12 Pathogenic).

**Submission history:** 12 submissions (1995–2025); classifications have been stable.

**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`, `PP4_Moderate`, `PM2_Supporting`, `PP1`.
*Considered but not met:* `PM6`, `PS1`, `PS2`, `PS3`, `PS4`, `PM1`, `PP2`, `PP3`, `BS2`, `PM3`, `BS1`, `BS4`, `BS3`, `BP5`, `BP7`, `PM5`, `BP4`, `BP3`, `BP1`, `BP2`, `BA1`, `PM4`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_000070.3: c.328C>T p.(Arg110Ter) variant in CAPN3 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 2/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in trans with a second CAPN3 variant in at least three unrelated individuals with LGMD (PMID: 26677118, 18854869). At least one patient with this variant displayed progressive limb girdle muscle weakness and reduced calpain-3 protein expression, which is specific for CAPN3-related LGMD (PP4_Moderate; PMID: 18854869). The variant has also been reported to co-segregate with the disease in one affected family member (PP1; PMID: 26677118). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008793 (1/113722 exome alleles) in the European (non-Finnish) population, which is less than the 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; 01/07/2025): PVS1, PP4_Moderate, PP1, PM2_Supporting.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50061 · approved 2025-01-07 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/042a61fa-0733-4208-9bcf-82ea00d74c79).*
*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 |
| --- | --- | --- | --- | --- |
| Mendelics | Pathogenic | criteria provided, single submitter | clinical testing | 2019-05-28 |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-03-06 |
| Revvity Omics, Revvity | Pathogenic | criteria provided, single submitter | clinical testing | 2024-06-20 |
| Natera, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-12 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1995-04-07 |
| Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Pathogenic | criteria provided, single submitter | research | 2018-12-03 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-03-04 |
| ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen | Pathogenic | reviewed by expert panel | curation | 2025-01-07 |
| Dasa | Pathogenic | criteria provided, single submitter | clinical testing | 2022-01-05 |
| Counsyl | Pathogenic | no assertion criteria provided | clinical testing | 2017-03-21 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-10-15 |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-26 |

## 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/), [muscular dystrophy, limb-girdle, autosomal dominant 4](https://sugi.bio/atlas/disease/muscular-dystrophy-limb-girdle-autosomal-dominant-4/).

**Reported phenotype names (ClinVar):** Autosomal recessive limb-girdle muscular dystrophy, Autosomal recessive limb-girdle muscular dystrophy type 2A, Muscular dystrophy, limb-girdle, autosomal dominant 4, not provided, Calpain-3-related limb-girdle muscular dystrophy D4, MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1I, Calpainopathy, Muscular dystrophy, limb-girdle, type 2A, Amish, LEYDEN-MOEBIUS MUSCULAR DYSTROPHY, MUSCULAR DYSTROPHY, PELVOFEMORAL.

## Same-residue context {#hotspot}

Residue **110** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CAPN3 p.Arg110fs](/variant/capn3-p-arg110fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CAPN3 variant pages (same residue, condition, or type): [CAPN3 p.Arg110Gln](/variant/capn3-p-arg110gln), [CAPN3 p.Arg110fs](/variant/capn3-p-arg110fs), [CAPN3 c.1115+5G>C](/variant/capn3-c-1115-plus-5g-c), [CAPN3 c.1194-2A>G](/variant/capn3-c-1194-minus-2a-g), [CAPN3 c.1194-9A>G](/variant/capn3-c-1194-minus-9a-g), [CAPN3 c.1746-20C>G](/variant/capn3-c-1746-minus-20c-g), [CAPN3 c.1993-1G>A](/variant/capn3-c-1993-minus-1g-a), [CAPN3 c.499-1G>A](/variant/capn3-c-499-minus-1g-a).

### 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 17615). 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.*