# NM_000070.3(CAPN3):c.1812C>T (p.Phe604=)

https://sugi.bio/variant/capn3-p-phe604

## Summary

**CAPN3 p.Phe604= (c.1812C>T)** is classified **Likely benign** in CAPN3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-20). Ultra-rare (popmax 0.0183%, amr); Associated with autosomal recessive limb-girdle muscular dystrophy type 2A.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs144383704 · 3 submitters · 1 linked condition · ultra-rare (popmax 0.0183%, amr)

## For patients & families {#patients}

This is a change in the CAPN3 gene that is classified as likely benign — not considered disease-causing, submitted by 3 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.Phe604= |
| Coding change (HGVS c.) | c.1812C>T |
| MANE Select transcript | [NM_000070](https://www.ncbi.nlm.nih.gov/nuccore/NM_000070) |
| dbSNP | [rs144383704](https://www.ncbi.nlm.nih.gov/snp/rs144383704/) |
| Variant type | single nucleotide variant |
| Location | chr15:42408222-42408222 (GRCh38) |
| ClinVar | [VCV743177](https://www.ncbi.nlm.nih.gov/clinvar/variation/743177/) |

**All HGVS expressions:** `LRG_849:g.65120C>T`, `LRG_849t1:c.1812C>T`, `NC_000015.10:g.42408222C>T`, `NC_000015.9:g.42700420C>T`, `NG_008660.1:g.65120C>T`, `NM_000070.3:c.1812C>T`, `NM_024344.2:c.1794C>T`, `NM_173087.2:c.1639-1081C>T`, `NM_173088.2:c.276C>T`, `NM_173089.2:c.-81-1081C>T`, `NM_173090.2:c.-81-1081C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.27) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 2.701, GERP 1.63, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 15.8**. 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 deltas (raw): acceptor loss **0.27**, donor loss **0.02**, acceptor gain **0.06**, donor gain **0.00**. Largest is acceptor loss, 11 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.06**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.28** (loss), gain 0.05 / loss 0.28. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0183%** (amr) · FAF95 0.0102% · FAF99 0.00786% · 11/59,960 in the highest group · 39/1,612,686 alleles overall — ultra-rare (popmax 0.0183%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0183% | 5,451 |
| East Asian | 0.0134% | 7,477 |
| African / African-American | 0.00401% | 24,960 |
| South Asian | 0.0022% | 45,509 |
| European (non-Finnish) | 0.00144% | 69,365 |

*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 gene assoc. with recessive phenotype, triplosensitivity 0/3. *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 **604** lies in the 'linker' region.

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.Phe604= falls in the linker 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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-20.

**Submitter consensus:** conflicting (2 Likely benign, 1 Uncertain significance).

**Submission history:** 3 submissions (2020–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-02-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-20 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-01 |

## Associated conditions {#conditions}

[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):** Autosomal recessive limb-girdle muscular dystrophy type 2A, not specified, AllHighlyPenetrant, MUSCULAR DYSTROPHY, PELVOFEMORAL, Limb-girdle muscular dystrophy, type 2A, Calpainopathy, LEYDEN-MOEBIUS MUSCULAR DYSTROPHY, Muscular dystrophy, limb-girdle, type 2A, Amish.

## Same-residue context {#hotspot}

Residue **604** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CAPN3 p.Phe604fs](/variant/capn3-p-phe604fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CAPN3 variant pages (same residue, condition, or type): [CAPN3 p.Phe604del](/variant/capn3-p-phe604del), [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 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 743177). 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.*