# NM_001748.5(CAPN2):c.1810A>T (p.Ile604Phe)

https://sugi.bio/variant/capn2-p-ile604phe

## Summary

**CAPN2 p.Ile604Phe (c.1810A>T)** is classified **Uncertain significance** in CAPN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-12). AlphaMissense: likely pathogenic (0.8215); Very rare (popmax 0.000255%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2464826977 · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.000255%, nfe)

## 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.Ile604Phe |
| Coding change (HGVS c.) | c.1810A>T |
| MANE Select transcript | [NM_001748](https://www.ncbi.nlm.nih.gov/nuccore/NM_001748) |
| dbSNP | [rs2464826977](https://www.ncbi.nlm.nih.gov/snp/rs2464826977/) |
| Variant type | single nucleotide variant |
| Location | chr1:223769895-223769895 (GRCh38) |
| ClinVar | [VCV3137148](https://www.ncbi.nlm.nih.gov/clinvar/variation/3137148/) |

**All HGVS expressions:** `NC_000001.10:g.223957597A>T`, `NC_000001.11:g.223769895A>T`, `NM_001146068.2:c.1576A>T`, `NM_001748.5:c.1810A>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8215)
- REVEL 0.368 (indeterminate)
- SaProt LLR -12.862 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 11.092, GERP 2.18, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 28.1**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000255%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,174,602 in the highest group · 3/1,451,106 alleles overall — very rare (popmax 0.000255%, nfe).

*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 **604** lies in an α-helix; the ef-hand 1 domain; 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.Ile604Phe falls in the ef-hand 1 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 2023-12-12.

**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 | 2023-12-12 |

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

## Similar variants {#similar}

Related CAPN2 variant pages (same residue, condition, or type): [CAPN2 p.Ile604Thr](/variant/capn2-p-ile604thr), [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).

### 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 3137148). 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.*