# NM_001748.5(CAPN2):c.1843G>A (p.Asp615Asn)

https://sugi.bio/variant/capn2-p-asp615asn

## Summary

**CAPN2 p.Asp615Asn (c.1843G>A)** is classified **Uncertain significance** in CAPN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: likely pathogenic (0.9846); Ultra-rare (popmax 0.0547%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0547%, afr)

## For patients & families {#patients}

This is a change in the CAPN2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [CAPN2](https://sugi.bio/atlas/gene/CAPN2/) |
| Protein change (HGVS p.) | p.Asp615Asn |
| Coding change (HGVS c.) | c.1843G>A |
| MANE Select transcript | [NM_001748](https://www.ncbi.nlm.nih.gov/nuccore/NM_001748) |
| Variant type | single nucleotide variant |
| Location | chr1:223770465-223770465 (GRCh38) |
| ClinVar | [VCV4218878](https://www.ncbi.nlm.nih.gov/clinvar/variation/4218878/) |

**All HGVS expressions:** `NC_000001.10:g.223958167G>A`, `NC_000001.11:g.223770465G>A`, `NM_001146068.2:c.1609G>A`, `NM_001748.5:c.1843G>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9846)
- REVEL 0.691 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -11.085 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.766, GERP 2.02, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 33.0**. 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 0.88** across the covering region of the MANE Select transcript (223,712,641–223,774,854), spanning 62,213 bp. Chi-square p 0.00029. 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 (G>T, Δ0.35 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 **0.0547%** (afr) · FAF95 0.0414% · FAF99 0.0368% · 41/74,936 in the highest group · 51/1,613,520 alleles overall — ultra-rare (popmax 0.0547%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0547% | 1,828 |
| Admixed American | 0.00334% | 29,973 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,243 |
| South Asian | 0.0011% | 91,008 |
| European (non-Finnish) | 0.000424% | 235,945 |

*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}

**CAPN2** population constraint: LOEUF 1.026, pLI 2.3939e-17, missense-Z 1.1953. *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 **615** lies in a binding site; the ef-hand 2 domain; the 'domain iv' region.

AlphaFold model confidence (whole protein): pLDDT 89.48, 60% of residues very-high.

**3 experimental structure(s)** (PDB): [1KFU](https://www.rcsb.org/structure/1KFU), [1KFX](https://www.rcsb.org/structure/1KFX), [2NQA](https://www.rcsb.org/structure/2NQA).

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

*Describes the biological roles of CAPN2 (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:** CAPN2's established molecular role includes calcium-dependent cysteine-type endopeptidase activity. p.Asp615Asn falls in the ef-hand 2 domain. In Reactome, CAPN2 is annotated in disease pathway(s) including **Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models**.

**Disease mechanism (Reactome):** CAPN2 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}

CAPN2 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 |
| [Degradation of the extracellular matrix](https://reactome.org/content/detail/R-HSA-1474228) | curated |
| [Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells](https://reactome.org/content/detail/R-HSA-9860927) | curated |
| [High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells](https://reactome.org/content/detail/R-HSA-9856530) | electronic |

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

**Molecular function:** calcium-dependent cysteine-type endopeptidase activity.

**Biological process:** obsolete proteolysis involved in protein catabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-07.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-07 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CAPN2 variant pages (same residue, condition, or type): [CAPN2 p.Ala248Thr](/variant/capn2-p-ala248thr), [CAPN2 p.Gly72Asp](/variant/capn2-p-gly72asp), [CAPN2 p.Asp48=](/variant/capn2-p-asp48), [CAPN2 p.Lys677Gln](/variant/capn2-p-lys677gln), [CAPN2 p.Ala101Pro](/variant/capn2-p-ala101pro), [CAPN2 p.Ala171Asp](/variant/capn2-p-ala171asp), [CAPN2 p.Ala194Ser](/variant/capn2-p-ala194ser), [CAPN2 p.Ala247Pro](/variant/capn2-p-ala247pro).

### 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 4218878). 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.*