# NM_001005242.3(PKP2):c.308_309del (p.Pro103fs)

https://sugi.bio/variant/pkp2-p-pro103fs

## Summary

**PKP2 p.Pro103fs (c.308_309del)** is classified **Pathogenic** in PKP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-06). No gnomAD frequency available for this variant; Associated with arrhythmogenic right ventricular dysplasia 9.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1956960817 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the PKP2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to arrhythmogenic right ventricular dysplasia 9.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | No data available |
| Diagnostic panels | PKP2 is a diagnostic-grade gene on 5 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024852/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PKP2](https://sugi.bio/atlas/gene/PKP2/) |
| Protein change (HGVS p.) | p.Pro103fs |
| Coding change (HGVS c.) | c.308_309del |
| MANE Select transcript | [NM_001005242](https://www.ncbi.nlm.nih.gov/nuccore/NM_001005242) |
| dbSNP | [rs1956960817](https://www.ncbi.nlm.nih.gov/snp/rs1956960817/) |
| Variant type | Deletion |
| Location | chr12:32878947-32878948 (GRCh38) |
| ClinVar | [VCV2131491](https://www.ncbi.nlm.nih.gov/clinvar/variation/2131491/) |

**All HGVS expressions:** `LRG_398:g.22899_22900del`, `LRG_398t1:c.308_309del`, `NC_000012.11:g.33031881_33031882del`, `NC_000012.12:g.32878947_32878948del`, `NG_009000.1:g.22899_22900del`, `NM_001005242.3:c.308_309del`, `NM_001407155.1:c.308_309delCT`, `NM_001407156.1:c.308_309delCT`, `NM_001407157.1:c.308_309delCT`, `NM_001407158.1:c.-20_-19delCT`, `NM_001407159.1:c.-20_-19delCT`, `NM_001407160.1:c.-20_-19delCT`, `NM_001407161.1:c.308_309delCT`, `NM_001407162.1:c.-20_-19delCT`, `NM_004572.4:c.308_309del`

## 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 0.36 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 13**, so the transcript is predicted to undergo NMD.
- 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.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**PKP2** population constraint: LOEUF 1.105, pLI 1.2177e-19, missense-Z 0.99086; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **catecholaminergic polymorphic ventricular tachycardia** — Disputed (AD)
- **dilated cardiomyopathy** — Disputed (AD)
- **arrhythmogenic right ventricular cardiomyopathy** — Definitive (AD)
- **Brugada syndrome 1** — Disputed (AD)

## Protein context {#protein}

Residue **103** lies in the 'required for interaction with influenza a virus rna polymerase subunit pb1' region; a UniProt-annotated variant site (in arvd9; uncertain significance); the 'required for binding to single-stranded dna' region.

AlphaFold model confidence (whole protein): pLDDT 64.32, 42% of residues very-high.

**1 experimental structure(s)** (PDB): [3TT9](https://www.rcsb.org/structure/3TT9) — incl. mutant structure 3TT9.

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

*Describes the biological roles of PKP2 (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:** PKP2's established molecular role includes DNA binding. p.Pro103fs falls in the required for interaction with influenza a virus rna polymerase subunit pb1 region.


### Pathways affected {#pathways}

PKP2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Formation of the cornified envelope](https://reactome.org/content/detail/R-HSA-6809371) | curated |
| [Keratinization](https://reactome.org/content/detail/R-HSA-6805567) | curated |

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

**Molecular function:** DNA binding, protein kinase C binding, intermediate filament binding, alpha-catenin binding, cadherin binding, molecular adaptor activity.

**Biological process:** desmosome assembly, cell-cell signaling, regulation of cell-substrate adhesion, intermediate filament bundle assembly, maintenance of animal organ identity, ventricular cardiac muscle tissue morphogenesis.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-09-06.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-09-06 |

## Associated conditions {#conditions}

[arrhythmogenic right ventricular dysplasia 9](https://sugi.bio/atlas/disease/arrhythmogenic-right-ventricular-dysplasia-9/).

**Reported phenotype names (ClinVar):** Arrhythmogenic right ventricular dysplasia 9, Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy 9, ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 9.

## Similar variants {#similar}

Related PKP2 variant pages (same residue, condition, or type): [PKP2 p.Pro103Ser](/variant/pkp2-p-pro103ser), [PKP2 p.Pro103Ala](/variant/pkp2-p-pro103ala), [PKP2 p.Pro103Thr](/variant/pkp2-p-pro103thr), [PKP2 p.Pro103=](/variant/pkp2-p-pro103), [PKP2 c.224-1639_274del](/variant/pkp2-c-224-minus-1639-274del), [PKP2 c.2437_2445+41del](/variant/pkp2-c-2437-2445-plus-41del), [PKP2 p.Ala418fs](/variant/pkp2-p-ala418fs), [PKP2 p.Ala657fs](/variant/pkp2-p-ala657fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2131491). 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.*