# NM_004055.5(CAPN5):c.897G>A (p.Ser299=)

https://sugi.bio/variant/capn5-p-ser299

## Summary

**CAPN5 p.Ser299= (c.897G>A)** is classified **Likely benign** in CAPN5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-09). Ultra-rare (popmax 0.0165%, mid).

**At a glance:** Likely benign · review: Single submitter · rsID rs545510595 · 1 submitter · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the CAPN5 gene that is classified as likely benign — not considered disease-causing, 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 | [CAPN5](https://sugi.bio/atlas/gene/CAPN5/) |
| Protein change (HGVS p.) | p.Ser299= |
| Coding change (HGVS c.) | c.897G>A |
| MANE Select transcript | [NM_004055](https://www.ncbi.nlm.nih.gov/nuccore/NM_004055) |
| dbSNP | [rs545510595](https://www.ncbi.nlm.nih.gov/snp/rs545510595/) |
| Variant type | single nucleotide variant |
| Location | chr11:77116229-77116229 (GRCh38) |
| ClinVar | [VCV1583595](https://www.ncbi.nlm.nih.gov/clinvar/variation/1583595/) |

**All HGVS expressions:** `NC_000011.10:g.77116229G>A`, `NC_000011.9:g.76827275G>A`, `NG_033002.1:g.54284G>A`, `NM_004055.5:c.897G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.67) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -1.195, GERP -3.24 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 20.2**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.67**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.67**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0165%** (mid) · FAF95 0.00172% · FAF99 0.00149% · 1/6,054 in the highest group · 37/1,611,944 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,054 |
| African / African-American | 0.004% | 25,007 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,207 |
| European (non-Finnish) | 0.00246% | 40,661 |
| Admixed American | 0.00167% | 59,780 |
| South Asian | 0.00111% | 90,332 |

*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}

**CAPN5** population constraint: LOEUF 0.928, pLI 5.467e-14, missense-Z 1.2087; ClinGen dosage — haploinsufficiency 0, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **CAPN5-related vitreoretinopathy** — Definitive (AD)

## Protein context {#protein}

Residue **299** lies in the calpain catalytic domain.

AlphaFold model confidence (whole protein): pLDDT 91.71, 77% of residues very-high.

**1 experimental structure(s)** (PDB): [6P3Q](https://www.rcsb.org/structure/6P3Q).

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

*Describes the biological roles of CAPN5 (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}

CAPN5 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 Single submitter *(criteria provided, single submitter)*, last evaluated 2025-07-09.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-09 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related CAPN5 variant pages (same residue, condition, or type): [CAPN5 p.Ser299Leu](/variant/capn5-p-ser299leu), [CAPN5 p.Arg243Leu](/variant/capn5-p-arg243leu), [CAPN5 p.Arg289Trp](/variant/capn5-p-arg289trp), [CAPN5 p.Ala118Val](/variant/capn5-p-ala118val), [CAPN5 p.Ala183Ser](/variant/capn5-p-ala183ser), [CAPN5 p.Ala185Val](/variant/capn5-p-ala185val), [CAPN5 p.Ala237Val](/variant/capn5-p-ala237val), [CAPN5 p.Ala245Val](/variant/capn5-p-ala245val).

### 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 1583595). 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.*