# NM_006366.3(CAP2):c.870del (p.Ser291fs)

https://sugi.bio/variant/cap2-p-ser291fs

## Summary

**CAP2 p.Ser291fs (c.870del)** is classified **Likely pathogenic** in CAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-11). Associated with cardiomyopathy, dilated, 2I.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the CAP2 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to cardiomyopathy, dilated, 2I.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0026864/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CAP2](https://sugi.bio/atlas/gene/CAP2/) |
| Protein change (HGVS p.) | p.Ser291fs |
| Coding change (HGVS c.) | c.870del |
| MANE Select transcript | [NM_006366](https://www.ncbi.nlm.nih.gov/nuccore/NM_006366) |
| Variant type | Deletion |
| Location | chr6:17541014-17541014 (GRCh38) |
| ClinVar | [VCV4845338](https://www.ncbi.nlm.nih.gov/clinvar/variation/4845338/) |

**All HGVS expressions:** `NC_000006.11:g.17541247del`, `NC_000006.12:g.17541016del`, `NM_001363533.2:c.534del`, `NM_001363534.2:c.792del`, `NM_006366.3:c.870del`

## 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 0.045, GERP -4.07, phastCons 0.954 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. For a truncating variant the loss-of-function impact is position-dependent — C-terminal / last-exon truncations may escape nonsense-mediated decay. *Descriptive; not an applied PVS1 code.*
- 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.

*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.*

## Protein context {#protein}

Residue **291** lies in the peptidase s1 domain.

AlphaFold model confidence (whole protein): pLDDT 88.01, 67% of residues very-high.

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

*Describes the biological roles of CAP2 (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:** CAP2's established molecular role includes serine-type peptidase activity. p.Ser291fs falls in the peptidase s1 domain.


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

**Molecular function:** serine-type peptidase activity.

**Biological process:** proteolysis, regulation of gene expression, protein processing, negative regulation of growth rate, positive regulation of viral entry into host cell.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-03-11.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-03-11 |

## Associated conditions {#conditions}

[cardiomyopathy, dilated, 2I](https://sugi.bio/atlas/disease/cardiomyopathy-dilated-2i/).

**Reported phenotype names (ClinVar):** Cardiomyopathy, dilated, 2I.

## Similar variants {#similar}

Related CAP2 variant pages (same residue, condition, or type): [CAP2 p.Cys430fs](/variant/cap2-p-cys430fs), [CAP2 p.Arg17His](/variant/cap2-p-arg17his), [CAP2 p.Arg13Gln](/variant/cap2-p-arg13gln), [CAP2 p.Met1Thr](/variant/cap2-p-met1thr), [CAP2 c.636+1G>A](/variant/cap2-c-636-plus-1g-a), [CAP2 p.Tyr316Ter](/variant/cap2-p-tyr316ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 4845338). 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.*