# NM_000551.4(VHL):c.305dup (p.Pro103fs)

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

## Summary

**VHL p.Pro103fs (c.305dup)** is classified **Pathogenic** in VHL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-19). No gnomAD frequency available for this variant; Associated with Chuvash polycythemia.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1559426145 · 1 submitter · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the VHL gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Chuvash polycythemia.

*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 recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | VHL is a diagnostic-grade gene on 23 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017176/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [VHL](https://sugi.bio/atlas/gene/VHL/) |
| Protein change (HGVS p.) | p.Pro103fs |
| Coding change (HGVS c.) | c.305dup |
| MANE Select transcript | [NM_000551](https://www.ncbi.nlm.nih.gov/nuccore/NM_000551) |
| dbSNP | [rs1559426145](https://www.ncbi.nlm.nih.gov/snp/rs1559426145/) |
| Variant type | Duplication |
| Location | chr3:10142150-10142151 (GRCh38) |
| ClinVar | [VCV2943402](https://www.ncbi.nlm.nih.gov/clinvar/variation/2943402/) |

**All HGVS expressions:** `LRG_322:g.5518dup`, `LRG_322t1:c.305dup`, `NC_000003.11:g.10183836dup`, `NC_000003.12:g.10142152dup`, `NG_008212.3:g.5518dup`, `NM_000551.4:c.305dup`, `NM_001354723.2:c.305dup`, `NM_198156.3:c.305dup`, `NR_176335.1:n.375dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 3.904, GERP 0.444, phastCons 1 — highly conserved position (PP3-type support)
- 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 1 of 3**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication 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}

**VHL** population constraint: LOEUF 0.987, pLI 0.0019543, missense-Z -1.1373; 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):

- **von Hippel-Lindau disease** — Definitive (AD)

## Protein context {#protein}

Residue **103** lies in the 'involved in binding to cct complex' region.

AlphaFold model confidence (whole protein): pLDDT 85.45, 72% of residues very-high.

**143 experimental structure(s)** (PDB): [1LM8](https://www.rcsb.org/structure/1LM8), [1LQB](https://www.rcsb.org/structure/1LQB), [1VCB](https://www.rcsb.org/structure/1VCB), [3ZRC](https://www.rcsb.org/structure/3ZRC), [3ZRF](https://www.rcsb.org/structure/3ZRF), [3ZTC](https://www.rcsb.org/structure/3ZTC).

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

*Describes the biological roles of VHL (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:** VHL's established molecular role includes transcription elongation factor activity. p.Pro103fs falls in the involved in binding to cct complex region. In Reactome, VHL is annotated in disease pathway(s) including **Replication of the SARS-CoV-1 genome**, **Replication of the SARS-CoV-2 genome**.

**Disease mechanism (Reactome):** VHL loss or alteration is curated in [Replication of the SARS-CoV-1 genome](https://reactome.org/content/detail/R-HSA-9682706), [Replication of the SARS-CoV-2 genome](https://reactome.org/content/detail/R-HSA-9694686).

### Pathways affected {#pathways}

VHL participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Replication of the SARS-CoV-1 genome](https://reactome.org/content/detail/R-HSA-9682706) | curated |
| ⚕ [Replication of the SARS-CoV-2 genome](https://reactome.org/content/detail/R-HSA-9694686) | electronic |
| [Antigen processing: Ubiquitination & Proteasome degradation](https://reactome.org/content/detail/R-HSA-983168) | curated |
| [Neddylation](https://reactome.org/content/detail/R-HSA-8951664) | curated |
| [RHOBTB3 ATPase cycle](https://reactome.org/content/detail/R-HSA-9706019) | curated |
| [SUMOylation of ubiquitinylation proteins](https://reactome.org/content/detail/R-HSA-3232142) | curated |
| [Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha](https://reactome.org/content/detail/R-HSA-1234176) | electronic |

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

**Molecular function:** transcription elongation factor activity, transcription corepressor activity, enzyme binding, molecular adaptor activity, protein serine/threonine kinase binding, DNA-binding transcription factor binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, regulation of DNA-templated transcription, negative regulation of cell population proliferation, negative regulation of signal transduction, regulation of gene expression, negative regulation of autophagy.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-01-19.

**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 | 2023-01-19 |

## Associated conditions {#conditions}

[Chuvash polycythemia](https://sugi.bio/atlas/disease/chuvash-polycythemia/), [von Hippel-Lindau disease](https://sugi.bio/atlas/disease/von-hippel-lindau-disease/).

**Reported phenotype names (ClinVar):** Chuvash polycythemia, Von Hippel-Lindau syndrome, POLYCYTHEMIA, VHL-DEPENDENT, von Hippel–Lindau syndrome, VHL syndrome, Von Hippel-Lindau.

## Similar variants {#similar}

Related VHL variant pages (same residue, condition, or type): [VHL p.Pro103=](/variant/vhl-p-pro103), [VHL p.Pro103Ala](/variant/vhl-p-pro103ala), [VHL p.Pro103Leu](/variant/vhl-p-pro103leu), [VHL p.Pro103Ser](/variant/vhl-p-pro103ser), [VHL p.Arg60fs](/variant/vhl-p-arg60fs), [VHL p.Arg64fs](/variant/vhl-p-arg64fs), [VHL p.Arg69fs](/variant/vhl-p-arg69fs), [VHL p.Glu55fs](/variant/vhl-p-glu55fs).

### 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 2943402). 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.*