Is VHL p.Arg82= (c.246C>T) pathogenic?

VHL p.Arg82= (c.246C>T) is classified Benign in VHL (ClinVar, Expert panel, 13 submitters; last evaluated 2024-06-25). Ultra-rare (popmax 0.0309%, nfe); Associated with von Hippel-Lindau disease.

What condition is associated with VHL p.Arg82= (c.246C>T)?

VHL p.Arg82= (c.246C>T) is associated with von Hippel-Lindau disease, Chuvash polycythemia, hereditary neoplastic syndrome (ClinVar).

How common is VHL p.Arg82= (c.246C>T) in the general population?

VHL p.Arg82= (c.246C>T) is ultra-rare (popmax 0.0309%, nfe) (gnomAD).

How is Von Hippel-Lindau disease inherited?

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

VHL p.Arg82=

c.246C>T · rs587780993 · VCV137905

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 13 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0309%, nfe)

Conditions

von Hippel-Lindau disease

ClinGen expert panel — VHL VCEP

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

BP4 BA1

Curation rationale (ClinGen, verbatim)

The variant NM_000551.4(VHL):c.246C>T (p.Arg82=) is a synonymous (silent) variant that does not display splicing impact according to SpliceAI and VarSeak (BP4). The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.0002832 (365/1179692 from European, Non-Finnish Population). This is higher than the ClinGen VHL VCEP threshold of >=0.000156 (0.0156%) threshold expected for VHL disease (BA1). In summary, this variant meets the criteria to be classified as Benign for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) 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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.1	GERP -0.37, phastCons 1
Overall
CADD	13.58	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0309% European (non-Finnish) · 365/1,179,692 alleles

Filtering AF 0.0283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0273%

Overall 0.0246% 395/1,604,406 alleles · ultra-rare exomes 375/1,452,208 · genomes 20/152,198 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0353%	2,835
European (non-Finnish)grpmax	0.0309%	3,232
African / African-American	0.0107%	9,365

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.Arg82=
Coding: c.246C>T
MANE Select: NM_000551
dbSNP: rs587780993
Type: single nucleotide variant
Location: chr3:10142093 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 143 PDB
Residue 82: a β-strand; a UniProt-annotated variant site (in vhld); a UniProt-annotated variant site (in vhld; type i)

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.Arg82Leu Pathogenic/Likely pathogenic ★★ same residue
VHL p.Arg82Pro Pathogenic ★★ same residue
VHL p.Arg82Cys Uncertain significance ★★ ⚠ same residue
VHL p.Arg82Gly Pathogenic ★ same residue
VHL p.Arg82His Conflicting classifications of pathogenicity ★ ⚠ same residue
VHL p.Arg82fs 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-arg82 (accessed [today's date]).

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