# NM_000070.3(CAPN3):c.2338G>C (p.Asp780His)

https://sugi.bio/variant/capn3-p-asp780his

## Summary

**CAPN3 p.Asp780His (c.2338G>C)** is classified **Pathogenic** in CAPN3 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-01-13). AlphaMissense: likely pathogenic (0.9523); Very rare (popmax 0.00549%, sas); Associated with autosomal recessive limb-girdle muscular dystrophy type 2A.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs778768583 · 13 submitters · 2 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00549%, sas)

## For patients & families {#patients}

This is a change in the CAPN3 gene that is considered disease-causing, submitted by 13 submitters, and is linked to autosomal recessive limb-girdle muscular dystrophy type 2A.

*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 recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 5 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CAPN3 is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of Calpain-3-related limb-girdle muscular dystrophy R1** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Generalized muscle weakness — Very frequent (99-80%)
- Flexion contracture — Frequent (79-30%)
- Elbow flexion contracture — Frequent (79-30%)
- Hamstring contractures — Frequent (79-30%)
- Elevated circulating creatine kinase concentration — Frequent (79-30%)
- Spinal rigidity — Frequent (79-30%)
- Hyperlordosis — Frequent (79-30%)
- Muscular dystrophy — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0001057/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.Asp780His |
| Coding change (HGVS c.) | c.2338G>C |
| MANE Select transcript | [NM_000070](https://www.ncbi.nlm.nih.gov/nuccore/NM_000070) |
| dbSNP | [rs778768583](https://www.ncbi.nlm.nih.gov/snp/rs778768583/) |
| Variant type | single nucleotide variant |
| Location | chr15:42410958-42410958 (GRCh38) |
| ClinVar | [VCV195641](https://www.ncbi.nlm.nih.gov/clinvar/variation/195641/) |

**All HGVS expressions:** `LRG_849:g.67856G>C`, `LRG_849t1:c.2338G>C`, `NC_000015.10:g.42410958G>C`, `NC_000015.9:g.42703156G>C`, `NG_008660.1:g.67856G>C`, `NM_000070.3:c.2338G>C`, `NM_000070.3:c.[2338G>C]`, `NM_024344.2:c.2320G>C`, `NM_173087.2:c.2062G>C`, `NM_173088.2:c.802G>C`, `NM_173089.2:c.343G>C`, `NM_173090.2:c.343G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9523) — concordant with the pathogenic call
- REVEL 0.955 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.423 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.792, GERP 2.92, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 32.0**. 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 **0.00549%** (sas) · FAF95 0.0021% · FAF99 0.00136% · 5/91,080 in the highest group · 6/1,461,844 alleles overall — very rare (popmax 0.00549%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00549% | 18,216 |
| European (non-Finnish) | 8.47e-05% | 1,180,012 |

*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 **780** lies in the 'domain iv' region; 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.Asp780His falls in the domain iv region.


### 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 2026-01-13.

**Submitter consensus:** conflicting (11 Pathogenic, 1 not provided, 1 Likely pathogenic).

**Submission history:** 13 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Eurofins Ntd Llc (ga) | Pathogenic | criteria provided, single submitter | clinical testing | 2016-09-02 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-13 |
| Athena Diagnostics | Pathogenic | criteria provided, single submitter | clinical testing | 2017-04-17 |
| Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Pathogenic | criteria provided, single submitter | research | 2018-12-03 |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-04-05 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-03-07 |
| Revvity Omics, Revvity | Pathogenic | criteria provided, single submitter | clinical testing | 2025-05-27 |
| Natera, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-26 |
| GeneReviews | not provided | no classification provided | literature only |  |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2023-12-18 |
| Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Pathogenic | no assertion criteria provided | clinical testing | 2018-09-18 |
| Neuberg Centre For Genomic Medicine, NCGM | Pathogenic | criteria provided, single submitter | clinical testing | 2024-02-01 |
| Counsyl | Likely pathogenic | no assertion criteria provided | clinical testing | 2017-02-08 |

## Associated conditions {#conditions}

[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 type 2A, not provided, Muscular dystrophy, limb-girdle, autosomal dominant 4, none provided, Muscular dystrophy, limb-girdle, type 2A, Amish, MUSCULAR DYSTROPHY, PELVOFEMORAL, Calpainopathy, Limb-girdle muscular dystrophy, type 2A, LEYDEN-MOEBIUS MUSCULAR DYSTROPHY, Calpain-3-related limb-girdle muscular dystrophy D4.

## Same-residue context {#hotspot}

Residue **780** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [CAPN3 p.Asp780fs](/variant/capn3-p-asp780fs), [CAPN3 p.Asp780Ter](/variant/capn3-p-asp780ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CAPN3 variant pages (same residue, condition, or type): [CAPN3 p.Asp780=](/variant/capn3-p-asp780), [CAPN3 p.Asp780fs](/variant/capn3-p-asp780fs), [CAPN3 p.Asp780Ter](/variant/capn3-p-asp780ter), [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).

### 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 195641). 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.*