Is VHL p.Ser65Pro (c.193T>C) pathogenic?

VHL p.Ser65Pro (c.193T>C) is classified Pathogenic in VHL (ClinVar, Single submitter, 2 submitters; last evaluated 2016-11-01). AlphaMissense: likely pathogenic (0.9858); Absent from gnomAD v4.1; Associated with von Hippel-Lindau disease.

What condition is associated with VHL p.Ser65Pro (c.193T>C)?

VHL p.Ser65Pro (c.193T>C) is associated with von Hippel-Lindau disease (ClinVar).

How common is VHL p.Ser65Pro (c.193T>C) in the general population?

VHL p.Ser65Pro (c.193T>C) is absent from gnomAD v4.1 (gnomAD).

How is Von Hippel-Lindau disease inherited?

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

What do computational predictors say about VHL p.Ser65Pro (c.193T>C)?

AlphaMissense predicts likely pathogenic (score 0.9858) — an in-silico prediction, not a clinical call.

VHL p.Ser65Pro

c.193T>C · rs869025616 · VCV547829

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9858 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

von Hippel-Lindau disease

Computational evidence

Protein change
AlphaMissense	0.9858	likely pathogenic ✓ concordant with ClinVar · top 9% in VHL
REVEL	0.845	moderately pathogenic-leaning
SaProt	LLR -13.86	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 8,114 bp · p 0.039 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Cancer therapy — CIViC

Disease	Level	Significance
Von Hippel-Lindau Disease	C	Predisposition
Von Hippel-Lindau Disease	C	Predisposition
Von Hippel-Lindau Disease	C	Predisposition
Clear Cell Renal Cell Carcinoma	C	Oncogenicity
Von Hippel-Lindau Disease	C
Von Hippel-Lindau Disease	C

Variant & gene context

Gene: VHL
Protein: p.Ser65Pro
Coding: c.193T>C
MANE Select: NM_000551
dbSNP: rs869025616
Type: single nucleotide variant
Location: chr3:10142040 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 143 PDB
Residue 65: a UniProt-annotated variant site (in pcc); a UniProt-annotated variant site (in vhld; type i); 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

For Von Hippel-Lindau disease (Orphanet):

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

Similar variants

VHL p.Ser65Trp Pathogenic ★★★ same residue
VHL p.Ser65Leu Pathogenic ★★ same residue
VHL p.Ser65Ter Pathogenic ★★ same residue
VHL p.Ser65= Benign/Likely benign ★★ same residue
VHL p.Ser65Thr Pathogenic ★ same residue
VHL p.Ser65Ala Likely pathogenic same residue
VHL p.Ser65fs Pathogenic ★★ same residue
VHL p.Arg64Pro 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-ser65pro (accessed [today's date]).

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