# NM_005186.4(CAPN1):c.616_620del (p.Ser206fs)

https://sugi.bio/variant/capn1-p-ser206fs

## Summary

**CAPN1 p.Ser206fs (c.616_620del)** is classified **Pathogenic** in CAPN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-10-23). No gnomAD frequency available for this variant.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1948630635 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CAPN1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter.

*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.Ser206fs |
| Coding change (HGVS c.) | c.616_620del |
| MANE Select transcript | [NM_005186](https://www.ncbi.nlm.nih.gov/nuccore/NM_005186) |
| dbSNP | [rs1948630635](https://www.ncbi.nlm.nih.gov/snp/rs1948630635/) |
| Variant type | Deletion |
| Location | chr11:65186194-65186198 (GRCh38) |
| ClinVar | [VCV987360](https://www.ncbi.nlm.nih.gov/clinvar/variation/987360/) |

**All HGVS expressions:** `NC_000011.10:g.65186195_65186199del`, `NC_000011.9:g.64953666_64953670del`, `NG_052817.1:g.9981_9985del`, `NM_001198868.2:c.616_620del`, `NM_001198869.2:c.616_620del`, `NM_005186.4:c.616_620del`, `NR_040008.2:n.633_637del`

## Computational & population evidence {#evidence}

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

- **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 7.844, GERP 2.39, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.977, pLI 2.8441e-20. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 6 of 22**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — 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 **206** 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.Ser206fs 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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-10-23.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Pathogenic | criteria provided, single submitter | clinical testing | 2020-10-23 |

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

## Similar variants {#similar}

Related CAPN1 variant pages (same residue, condition, or type): [CAPN1 p.Arg377fs](/variant/capn1-p-arg377fs), [CAPN1 p.Gly208fs](/variant/capn1-p-gly208fs), [CAPN1 c.843+114del](/variant/capn1-c-843-plus-114del), [CAPN1 p.Asp673fs](/variant/capn1-p-asp673fs), [CAPN1 p.Pro136fs](/variant/capn1-p-pro136fs), [CAPN1 p.Glu431_Arg433del](/variant/capn1-p-glu431-arg433del), [CAPN1 p.Val178_Phe186del](/variant/capn1-p-val178-phe186del), [CAPN1 c.456+18del](/variant/capn1-c-456-plus-18del).

### 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 987360). 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.*