# NM_005186.4(CAPN1):c.188C>T (p.Pro63Leu)

https://sugi.bio/variant/capn1-p-pro63leu

## Summary

**CAPN1 p.Pro63Leu (c.188C>T)** is classified **Uncertain significance** in CAPN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-11-10). AlphaMissense: ambiguous (0.4429); No allele count reported in gnomAD v4.1 (AN 1,605,984); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1184269173 · 2 submitters · 1 linked condition · AlphaMissense ambiguous · no allele count reported in gnomAD v4.1 (AN 1,605,984)

## For patients & families {#patients}

This is a change in the CAPN1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to Inborn genetic diseases.

*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:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CAPN1](https://sugi.bio/atlas/gene/CAPN1/) |
| Protein change (HGVS p.) | p.Pro63Leu |
| Coding change (HGVS c.) | c.188C>T |
| MANE Select transcript | [NM_005186](https://www.ncbi.nlm.nih.gov/nuccore/NM_005186) |
| dbSNP | [rs1184269173](https://www.ncbi.nlm.nih.gov/snp/rs1184269173/) |
| Variant type | single nucleotide variant |
| Location | chr11:65182889-65182889 (GRCh38) |
| ClinVar | [VCV1899664](https://www.ncbi.nlm.nih.gov/clinvar/variation/1899664/) |

**All HGVS expressions:** `NC_000011.10:g.65182889C>T`, `NC_000011.9:g.64950360C>T`, `NG_052817.1:g.6675C>T`, `NG_079323.2:g.1375C>T`, `NM_001198868.2:c.188C>T`, `NM_001198869.2:c.188C>T`, `NM_001198870.1:c.97C>T`, `NM_005186.4:c.188C>T`, `NR_040008.2:n.275C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.4429) — no call either way
- REVEL 0.479 (indeterminate)
- SaProt LLR -8.921 (tolerated)
- Conservation: phyloP 7.654, GERP 2.39, phastCons 1 — highly conserved
- CADD: **PHRED 28.2**. 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 0.85** across the covering region of the MANE Select transcript (65,182,702–65,211,283), spanning 28,581 bp. Chi-square p 4.3e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.34 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,605,984)** — 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}

**CAPN1** population constraint: LOEUF 0.977, pLI 2.8441e-20, missense-Z 1.606. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **63** lies in the calpain catalytic domain.

AlphaFold model confidence (whole protein): pLDDT 90.03, 68% of residues very-high.

**5 experimental structure(s)** (PDB): [1ZCM](https://www.rcsb.org/structure/1ZCM), [2ARY](https://www.rcsb.org/structure/2ARY), [7W7O](https://www.rcsb.org/structure/7W7O), [7X79](https://www.rcsb.org/structure/7X79), [8GX3](https://www.rcsb.org/structure/8GX3).

## What this gene does {#gene-function}

*Describes the biological roles of CAPN1 (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:** CAPN1's established molecular role includes calcium-dependent cysteine-type endopeptidase activity. p.Pro63Leu falls in the calpain catalytic domain. In Reactome, CAPN1 is annotated in disease pathway(s) including **Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models**.

**Disease mechanism (Reactome):** CAPN1 loss or alteration is curated in [Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models](https://reactome.org/content/detail/R-HSA-8862803).

### Pathways affected {#pathways}

CAPN1 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models](https://reactome.org/content/detail/R-HSA-8862803) | electronic |
| [Formation of the cornified envelope](https://reactome.org/content/detail/R-HSA-6809371) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Degradation of the extracellular matrix](https://reactome.org/content/detail/R-HSA-1474228) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** calcium-dependent cysteine-type endopeptidase activity, calcium ion binding, peptidase activity.

**Biological process:** proteolysis, regulation of catalytic activity, self proteolysis.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-11-10.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-05-12 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-11-10 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related CAPN1 variant pages (same residue, condition, or type): [CAPN1 p.Pro63=](/variant/capn1-p-pro63), [CAPN1 p.Arg104His](/variant/capn1-p-arg104his), [CAPN1 p.Arg293Gln](/variant/capn1-p-arg293gln), [CAPN1 p.Arg293Trp](/variant/capn1-p-arg293trp), [CAPN1 p.Arg347Cys](/variant/capn1-p-arg347cys), [CAPN1 p.Arg347His](/variant/capn1-p-arg347his), [CAPN1 p.Arg48Gln](/variant/capn1-p-arg48gln), [CAPN1 p.Arg581Gln](/variant/capn1-p-arg581gln).

### 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 1899664). 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.*