Is VHL p.Pro61= (c.183C>G) pathogenic?

VHL p.Pro61= (c.183C>G) is classified Benign in VHL (ClinVar, Expert panel, 16 submitters; last evaluated 2024-06-25). Rare (popmax 0.232%, mid); Associated with von Hippel-Lindau disease.

What condition is associated with VHL p.Pro61= (c.183C>G)?

VHL p.Pro61= (c.183C>G) is associated with von Hippel-Lindau disease, nonpapillary renal cell carcinoma, pheochromocytoma (ClinVar).

How common is VHL p.Pro61= (c.183C>G) in the general population?

VHL p.Pro61= (c.183C>G) is rare (popmax 0.232%, mid) (gnomAD).

How is Von Hippel-Lindau disease inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

VHL p.Pro61=

c.183C>G · rs63650860 · VCV135951

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 16 submitters

gnomAD v4.1

Rare

rare (popmax 0.232%, mid)

Conditions

von Hippel-Lindau disease

ClinGen expert panel — VHL VCEP

Benign for von Hippel-Lindau disease. Applied ACMG criteria (verbatim):

BA1

Curation rationale (ClinGen, verbatim)

The variant NM_000551.3(VHL):c.183C>G (p.Pro61=) is a silent variant in the first exon of VHL. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.001902 (192/89258 from South Asian Population). This is higher than the ClinGen VHL VCEP threshold of >=0.000156 (0.0156%) threshold expected for VHL disease (BA1) and is classified as Benign for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.4	GERP -3.4
Overall
CADD	3.899	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.232% Middle Eastern · 14/6,024 alleles

Filtering AF 0.19% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.181%

Overall 0.0994% 1,589/1,598,720 alleles · rare exomes 1,473/1,446,364 · genomes 116/152,356 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.232%	430
South Asian	0.215%	465
Admixed American	0.141%	709
European (non-Finnish)	0.104%	959
Remaining individualsnot grpmax-eligible	0.0856%	1,168
African / African-American	0.0147%	6,799
Ashkenazi Jewishnot grpmax-eligible	0.0137%	7,322
East Asian	0.00907%	11,031
Finnishnot grpmax-eligible	0.00668%	14,961

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: VHL
Protein: p.Pro61=
Coding: c.183C>G
MANE Select: NM_000551
dbSNP: rs63650860
Type: single nucleotide variant
Location: chr3:10142030 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 143 PDB
Residue 61: an α-helix; the 'disordered' region

Full VHL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

von Hippel-Lindau disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nonpapillary renal cell carcinoma pheochromocytoma Chuvash polycythemia hereditary neoplastic syndrome

For Von Hippel-Lindau disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 100 000 (United Kingdom)

Similar variants

VHL p.Pro61Leu Uncertain significance ★★ ⚠ same residue
VHL p.Pro61Ser Uncertain significance ★★ same residue
VHL p.Pro61Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
VHL p.Pro61Arg Uncertain significance ★ ⚠ same residue
VHL p.Pro61_Val62insArgPro Uncertain significance ★★ same residue
VHL p.Pro61fs Pathogenic ★ same residue
VHL p.Arg64Pro Pathogenic ★★★ same condition
VHL p.Asn78Ser Pathogenic ★★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/vhl-p-pro61 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown