Is VHL p.Arg113Pro (c.338G>C) pathogenic?

VHL p.Arg113Pro (c.338G>C) is classified Uncertain significance in VHL (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-21). AlphaMissense: likely pathogenic (0.9253); Very rare (popmax 0.000848%, nfe); Associated with von Hippel-Lindau disease.

What condition is associated with VHL p.Arg113Pro (c.338G>C)?

VHL p.Arg113Pro (c.338G>C) is associated with von Hippel-Lindau disease, Chuvash polycythemia, hereditary neoplastic syndrome (ClinVar).

How common is VHL p.Arg113Pro (c.338G>C) in the general population?

VHL p.Arg113Pro (c.338G>C) is very rare (popmax 0.000848%, nfe) (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.Arg113Pro (c.338G>C)?

AlphaMissense predicts likely pathogenic (score 0.9253) — an in-silico prediction, not a clinical call.

VHL p.Arg113Pro

c.338G>C · rs767062290 · VCV411987

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9253 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000848%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

von Hippel-Lindau disease

Computational evidence

Protein change
AlphaMissense	0.9253	likely pathogenic
REVEL	0.624	indeterminate
SaProt	LLR -8.09	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 0.45, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 8,114 bp · p 0.039 · regional, not allelic
Overall
CADD	23.9	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

Grpmax group 0.000848% European (non-Finnish) · 10/1,179,318 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000688% 11/1,597,698 alleles · very rare exomes 9/1,445,562 · genomes 2/152,136 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	62,270
European (non-Finnish)grpmax	0.000848%	117,932

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg113Pro
Coding: c.338G>C
MANE Select: NM_000551
dbSNP: rs767062290
Type: single nucleotide variant
Location: chr3:10142185 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 143 PDB
Residue 113: the 'involved in binding to cct complex' 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: 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.Arg113Ter Pathogenic ★★ same residue
VHL p.Arg113= Uncertain significance ★ same residue
VHL p.Arg113Gly Uncertain significance ★ ⚠ same residue
VHL p.Arg113Gln Likely benign ★ same residue
VHL p.Arg64Pro Pathogenic ★★★ same condition
VHL p.Asn78Ser Pathogenic ★★★ ⚠ same condition
VHL p.Glu70Ter Pathogenic ★★★ same condition
VHL p.Pro86Leu 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-arg113pro (accessed [today's date]).

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