Is VHL p.Asp92= (c.276C>T) pathogenic?

VHL p.Asp92= (c.276C>T) is classified Benign/Likely benign in VHL (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-21). Very rare (popmax 0.0011%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with VHL p.Asp92= (c.276C>T)?

VHL p.Asp92= (c.276C>T) is associated with hereditary neoplastic syndrome, von Hippel-Lindau disease, Chuvash polycythemia (ClinVar).

How common is VHL p.Asp92= (c.276C>T) in the general population?

VHL p.Asp92= (c.276C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

VHL p.Asp92=

c.276C>T · rs1442093467 · VCV486708

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

hereditary neoplastic syndrome

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 -0.85	GERP -0.49, phastCons 0.006
Overall
CADD	12.52	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,040 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00025% 4/1,600,754 alleles · very rare exomes 4/1,448,462 · genomes 0/152,292 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	62,272
South Asiangrpmax	0.0011%	91,040
European (non-Finnish)	0.00017%	589,807

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.Asp92=
Coding: c.276C>T
MANE Select: NM_000551
dbSNP: rs1442093467
Type: single nucleotide variant
Location: chr3:10142123 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 143 PDB
Residue 92: a β-strand; 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

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

Also linked: von Hippel-Lindau disease Chuvash polycythemia

Similar variants

VHL p.Asp92Ala Uncertain significance ★ ⚠ same residue
VHL p.Asp92Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
VHL p.Asp92Glu Uncertain significance ★ ⚠ same residue
VHL p.Asp92Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
VHL p.Asp92Val Conflicting classifications of pathogenicity ★ ⚠ same residue
VHL p.Asp92His Benign ★ 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-asp92 (accessed [today's date]).

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