# NM_005632.3(CAPN15):c.2352C>T (p.Phe784=)

https://sugi.bio/variant/capn15-p-phe784

## Summary

**CAPN15 p.Phe784= (c.2352C>T)** is classified **Likely benign** in CAPN15 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-06-01). Rare (popmax 0.124%, nfe).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs147299088 · 3 submitters · rare (popmax 0.124%, nfe)

## For patients & families {#patients}

This is a change in the CAPN15 gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters.

*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 | [CAPN15](https://sugi.bio/atlas/gene/CAPN15/) |
| Protein change (HGVS p.) | p.Phe784= |
| Coding change (HGVS c.) | c.2352C>T |
| MANE Select transcript | [NM_005632](https://www.ncbi.nlm.nih.gov/nuccore/NM_005632) |
| dbSNP | [rs147299088](https://www.ncbi.nlm.nih.gov/snp/rs147299088/) |
| Variant type | single nucleotide variant |
| Location | chr16:552057-552057 (GRCh38) |
| ClinVar | [VCV2645811](https://www.ncbi.nlm.nih.gov/clinvar/variation/2645811/) |

**All HGVS expressions:** `NC_000016.10:g.552057C>T`, `NC_000016.9:g.602057C>T`, `NM_005632.2:c.2352C>T`, `NM_005632.3:c.2352C>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 (below), not from a missing predictor score.
- Conservation: phyloP -10.386, GERP -3.04 — fast-evolving / accelerated position
- CADD: **PHRED 4.501**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.21 acceptor 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 (gnomAD v4.1): grpmax **0.124%** (nfe) · FAF95 0.118% · FAF99 0.116% · 1,419/1,146,668 in the highest group · 1,618/1,548,520 alleles overall — rare (popmax 0.124%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.124% | 808 |
| Finnish (not grpmax-eligible) | 0.0803% | 1,246 |
| Remaining individuals (not grpmax-eligible) | 0.0784% | 1,275 |
| Admixed American | 0.0687% | 1,457 |
| South Asian | 0.0548% | 1,826 |
| Middle Eastern | 0.0415% | 2,409 |
| African / African-American | 0.0233% | 4,301 |
| East Asian | 0.0122% | 8,187 |

*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}

**CAPN15** population constraint: LOEUF 0.974, pLI 1.819e-14, missense-Z -2.1004. *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 **784** lies in the calpain catalytic domain.

AlphaFold model confidence (whole protein): pLDDT 71.65, 41% of residues very-high.

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

*Describes the biological roles of CAPN15 (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.*


### Pathways affected {#pathways}

CAPN15 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Degradation of the extracellular matrix](https://reactome.org/content/detail/R-HSA-1474228) | curated |

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-06-01.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2019–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-10-28 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-06-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-04 |

**Reported phenotype names (ClinVar):** not provided, CAPN15-related disorder, not specified, AllHighlyPenetrant, CAPN15-related condition, none provided.

## Similar variants {#similar}

Related CAPN15 variant pages (same residue, condition, or type): [CAPN15 c.2192+8C>T](/variant/capn15-c-2192-plus-8c-t), [CAPN15 p.Arg428Trp](/variant/capn15-p-arg428trp), [CAPN15 p.Arg867Cys](/variant/capn15-p-arg867cys), [CAPN15 p.Arg867His](/variant/capn15-p-arg867his), [CAPN15 p.Cys363Arg](/variant/capn15-p-cys363arg), [CAPN15 p.Glu776Ala](/variant/capn15-p-glu776ala), [CAPN15 p.Val489Met](/variant/capn15-p-val489met), [CAPN15 p.Val841Met](/variant/capn15-p-val841met).

### 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 2645811). 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.*