# NM_000551.4(VHL):c.135G>C (p.Pro45=)

https://sugi.bio/variant/vhl-p-pro45

## Summary

**VHL p.Pro45= (c.135G>C)** is classified **Likely benign** in VHL (ClinVar, Single submitter, 1 submitter; last evaluated 2019-09-19). Very rare (popmax 0.00117%, sas); Associated with Chuvash polycythemia.

**At a glance:** Likely benign · review: Single submitter · rsID rs773519476 · 1 submitter · 2 linked conditions · very rare (popmax 0.00117%, sas)

## For patients & families {#patients}

This is a change in the VHL gene that is classified as likely benign — not considered disease-causing, 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.Pro45= |
| Coding change (HGVS c.) | c.135G>C |
| MANE Select transcript | [NM_000551](https://www.ncbi.nlm.nih.gov/nuccore/NM_000551) |
| dbSNP | [rs773519476](https://www.ncbi.nlm.nih.gov/snp/rs773519476/) |
| Variant type | single nucleotide variant |
| Location | chr3:10141982-10141982 (GRCh38) |
| ClinVar | [VCV1123711](https://www.ncbi.nlm.nih.gov/clinvar/variation/1123711/) |

**All HGVS expressions:** `LRG_322:g.5348G>C`, `NC_000003.11:g.10183666G>C`, `NC_000003.12:g.10141982G>C`, `NG_008212.3:g.5348G>C`, `NM_000551.4:c.135G>C`, `NM_001354723.2:c.135G>C`, `NM_198156.3:c.135G>C`

## 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 -3.405, GERP -3.24 — fast-evolving / accelerated position
- CADD: **PHRED 2.515**. 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: **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 (gnomAD v4.1): grpmax **0.00117%** (sas) · 1/85,756 in the highest group · 2/1,567,378 alleles overall — very rare (popmax 0.00117%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00117% | 85,756 |
| European (non-Finnish) | 8.64e-05% | 1,157,732 |

*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 **45** lies in the '8 x 5 aa tandem repeats of g-[pavg]-e-e-[daysle]' region; the 'disordered' 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.Pro45= falls in the 8 x 5 aa tandem repeats of g-[pavg]-e-e-[daysle] 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-09-19.

**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 | 2019-09-19 |

## 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, von Hippel–Lindau syndrome, VHL syndrome.

## Similar variants {#similar}

Related VHL variant pages (same residue, condition, or type): [VHL p.Pro45Ala](/variant/vhl-p-pro45ala), [VHL p.Pro45Arg](/variant/vhl-p-pro45arg), [VHL p.Pro45Leu](/variant/vhl-p-pro45leu), [VHL p.Pro45Ser](/variant/vhl-p-pro45ser), [VHL p.Arg64Pro](/variant/vhl-p-arg64pro), [VHL p.Asn78Ser](/variant/vhl-p-asn78ser), [VHL p.Glu70Ter](/variant/vhl-p-glu70ter), [VHL p.Pro86Leu](/variant/vhl-p-pro86leu).

### 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 1123711). 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.*