Is VHL p.Arg161Pro (c.482G>C) pathogenic?

VHL p.Arg161Pro (c.482G>C) is classified Pathogenic in VHL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-06). AlphaMissense: likely pathogenic (0.997); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with VHL p.Arg161Pro (c.482G>C)?

VHL p.Arg161Pro (c.482G>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is VHL p.Arg161Pro (c.482G>C) in the general population?

VHL p.Arg161Pro (c.482G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about VHL p.Arg161Pro (c.482G>C)?

AlphaMissense predicts likely pathogenic (score 0.997) — an in-silico prediction, not a clinical call.

VHL p.Arg161Pro

c.482G>C · rs730882035 · VCV1743417

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.997 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.997	likely pathogenic ✓ concordant with ClinVar · top 2% in VHL
REVEL	0.852	moderately pathogenic-leaning
SaProt	LLR -15.99	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 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 8,114 bp · p 0.039 · regional, not allelic
Overall
CADD	32.0	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.

Variant & gene context

Gene: VHL
Protein: p.Arg161Pro
Coding: c.482G>C
MANE Select: NM_000551
dbSNP: rs730882035
Type: single nucleotide variant
Location: chr3:10149805 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 143 PDB
Residue 161: a UniProt-annotated variant site (in vhld; type ii); a UniProt-annotated variant site (in pcc and vhld; type i); a UniProt-annotated variant site (in pcc and vhld; type ii); the 'interaction with elongin bc complex' region; an α-helix

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

VHL p.Arg64Pro Pathogenic ★★★ same condition
VHL p.Asn78Ser Pathogenic ★★★ ⚠ same condition
VHL p.Glu70Ter Pathogenic ★★★ same condition
VHL p.Pro86Leu Pathogenic ★★★ same condition
VHL p.Ser65Trp Pathogenic ★★★ same condition
VHL p.Trp88Cys Likely pathogenic ★★★ same condition
VHL p.Trp88Ter Pathogenic ★★★ same condition
VHL p.Phe91Leu Uncertain significance ★★★ ⚠ 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-arg161pro (accessed [today's date]).

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