# NM_000070.3(CAPN3):c.1076C>T (p.Pro359Leu)

https://sugi.bio/variant/capn3-p-pro359leu

## Summary

**CAPN3 p.Pro359Leu (c.1076C>T)** is classified **Likely pathogenic** in CAPN3 (ClinVar, Expert panel, 7 submitters; last evaluated 2026-04-28). AlphaMissense: likely pathogenic (0.9836); Very rare (popmax 8.67e-05%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy.

**At a glance:** Likely pathogenic · review: Expert panel · rsID rs794727895 · 7 submitters · 3 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 8.67e-05%, nfe)

## For patients & families {#patients}

This is a change in the CAPN3 gene that is considered likely disease-causing, submitted by 7 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.Pro359Leu |
| Coding change (HGVS c.) | c.1076C>T |
| MANE Select transcript | [NM_000070](https://www.ncbi.nlm.nih.gov/nuccore/NM_000070) |
| dbSNP | [rs794727895](https://www.ncbi.nlm.nih.gov/snp/rs794727895/) |
| Variant type | single nucleotide variant |
| Location | chr15:42394302-42394302 (GRCh38) |
| ClinVar | [VCV198690](https://www.ncbi.nlm.nih.gov/clinvar/variation/198690/) |

**All HGVS expressions:** `LRG_849:g.51200C>T`, `LRG_849t1:c.1076C>T`, `NC_000015.10:g.42394302C>T`, `NC_000015.9:g.42686500C>T`, `NG_008660.1:g.51200C>T`, `NM_000070.3:c.1076C>T`, `NM_024344.2:c.1076C>T`, `NM_173087.2:c.932C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9836) — concordant with the pathogenic call
- REVEL 0.955 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.326 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.602, GERP 2.82, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 33.0**. 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.*
- Regional missense constraint: **o/e 0.96** across the covering region of the MANE Select transcript (42,359,806–42,411,770), spanning 51,964 bp. Chi-square p 0.21. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **8.67e-05%** (nfe) · 1/1,153,474 in the highest group · 2/1,411,530 alleles overall — very rare (popmax 8.67e-05%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00165% | 60,664 |
| European (non-Finnish) (grpmax) | 8.67e-05% | 1,153,474 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **359** 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.Pro359Leu 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 Expert panel *(reviewed by expert panel)*, last evaluated 2026-04-28.

**Submitter consensus:** conflicting (4 Likely pathogenic, 2 Pathogenic, 1 Likely Pathogenic, 1 Uncertain significance).

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

**ClinGen expert panel:** Likely 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):** `PM2_Supporting`, `PP4_Strong`, `PP3`, `PM3`.
*Considered but not met:* `PM5`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_000070.3: c.1076C>T variant in CAPN3 is a missense variant predicted to cause substitution of proline by leucine at amino acid 359 (p.Pro359Leu). This variant has been reported in at least 8 patients with clinical signs of LGMD, including in a homozygous state in at least 6 individuals (1.0 pt; PMID: 22926650, 17596655, 30564623; ClinVar SCV001524377.1, SCV001544778.3 internal data communication; LOVD CAPN3_000128) and in unconfirmed phase with a likely pathogenic variant in at least one individual (c.1256A>G p.(Asp419Gly), 0.25 pts, PMID: 30564623, LOVD Individual #00220445, GRASP-LGMD Consortium internal data communication) (PM3). At least one patient homozygous for this variant displayed progressive limb girdle muscle weakness and absent expression of calpain-3 in skeletal muscle, which is highly specific for CAPN3-related LGMD (PMID: 17596655; PP4_Strong). The highest population minor allele frequency in gnomAD v4.1.1 is 0.00001648 (1/60664 alleles) in the Remaining population, which is lower than the ClinGen LGMD VCEP threshold (<0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.955, which is above the threshold of 0.70, evidence that correlates with impact to CAPN3 function (PP3). In summary, this variant meets the criteria to be classified as Likely 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; 04/28/2026): PM3, PP4_Strong, PM2_Supporting, PP3.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50061 · approved 2026-04-28 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/71dae65f-5eda-48c7-b87f-d1a68c7de555).*
*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 |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2019-10-30 |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-10-16 |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-01-16 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-04-05 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-11-18 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-01-01 |
| ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen | Likely Pathogenic | reviewed by expert panel | curation | 2026-04-28 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2015-11-04 |

## 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, not provided, Autosomal recessive limb-girdle muscular dystrophy type 2A, Muscular dystrophy, limb-girdle, autosomal dominant 4, Calpain-3-related limb-girdle muscular dystrophy D4, MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1I, none provided, MUSCULAR DYSTROPHY, PELVOFEMORAL, Muscular dystrophy, limb-girdle, type 2A, Amish, LEYDEN-MOEBIUS MUSCULAR DYSTROPHY.

## Similar variants {#similar}

Related CAPN3 variant pages (same residue, condition, or type): [CAPN3 p.Pro359=](/variant/capn3-p-pro359), [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), [CAPN3 p.Ala702Val](/variant/capn3-p-ala702val).

### 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 198690). 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.*