# NM_001005242.3(PKP2):c.307C>T (p.Pro103Ser)

https://sugi.bio/variant/pkp2-p-pro103ser

## Summary

**PKP2 p.Pro103Ser (c.307C>T)** is classified **Uncertain significance** in PKP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-25). AlphaMissense: likely benign (0.0789); Absent from gnomAD v4.1; Associated with arrhythmogenic right ventricular dysplasia 9.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs139215336 · 2 submitters · 1 linked condition · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the PKP2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, 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.Pro103Ser |
| Coding change (HGVS c.) | c.307C>T |
| MANE Select transcript | [NM_001005242](https://www.ncbi.nlm.nih.gov/nuccore/NM_001005242) |
| dbSNP | [rs139215336](https://www.ncbi.nlm.nih.gov/snp/rs139215336/) |
| Variant type | single nucleotide variant |
| Location | chr12:32878949-32878949 (GRCh38) |
| ClinVar | [VCV1485413](https://www.ncbi.nlm.nih.gov/clinvar/variation/1485413/) |

**All HGVS expressions:** `LRG_398:g.22898C>T`, `LRG_398t1:c.307C>T`, `NC_000012.11:g.33031883G>A`, `NC_000012.12:g.32878949G>A`, `NG_009000.1:g.22898C>T`, `NM_001005242.3:c.307C>T`, `NM_004572.3:c.307C>T`, `NM_004572.4:c.307C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0789)
- REVEL 0.048 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.013 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 3.195, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 16.95**. 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 0.91** across the covering region of the MANE Select transcript (32,792,427–32,896,731), spanning 104,304 bp. Chi-square p 0.0023. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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.Pro103Ser 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-02-25.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2023–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-06-05 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-02-25 |

## 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, Cardiovascular phenotype, Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy 9, ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 9.

## Same-residue context {#hotspot}

Residue **103** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [PKP2 p.Pro103fs](/variant/pkp2-p-pro103fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PKP2 variant pages (same residue, condition, or type): [PKP2 p.Pro103Ala](/variant/pkp2-p-pro103ala), [PKP2 p.Pro103Thr](/variant/pkp2-p-pro103thr), [PKP2 p.Pro103=](/variant/pkp2-p-pro103), [PKP2 p.Pro103fs](/variant/pkp2-p-pro103fs), [PKP2 c.1034+1G>C](/variant/pkp2-c-1034-plus-1g-c), [PKP2 c.1034+1G>T](/variant/pkp2-c-1034-plus-1g-t), [PKP2 c.1035-2A>G](/variant/pkp2-c-1035-minus-2a-g), [PKP2 c.1170+1G>A](/variant/pkp2-c-1170-plus-1g-a).

### 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 1485413). 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.*