Is VHL p.Phe91Val (c.271T>G) pathogenic?

VHL p.Phe91Val (c.271T>G) is classified Likely benign in VHL (ClinVar, Single submitter, 1 submitter; last evaluated 2018-08-01). AlphaMissense: likely pathogenic (0.9741); Very rare (popmax 0.00223%, eas); Associated with von Hippel-Lindau disease.

What condition is associated with VHL p.Phe91Val (c.271T>G)?

VHL p.Phe91Val (c.271T>G) is associated with von Hippel-Lindau disease (ClinVar).

How common is VHL p.Phe91Val (c.271T>G) in the general population?

VHL p.Phe91Val (c.271T>G) is very rare (popmax 0.00223%, eas) (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.Phe91Val (c.271T>G)?

AlphaMissense predicts likely pathogenic (score 0.9741) — an in-silico prediction, not a clinical call.

VHL p.Phe91Val

c.271T>G · rs1559426039 · VCV625231

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9741 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

von Hippel-Lindau disease

Computational evidence

Protein change
AlphaMissense	0.9741	likely pathogenic
REVEL	0.892	moderately pathogenic-leaning
SaProt	LLR -12.37	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 7.3	GERP 1.5, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 8,114 bp · p 0.039 · regional, not allelic
Overall
CADD	25.4	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 0.00223% East Asian · 1/44,832 alleles

Overall 6.24e-05% 1/1,601,516 alleles · very rare exomes 1/1,449,268 · genomes 0/152,248 · joint denominator

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.Phe91Val
Coding: c.271T>G
MANE Select: NM_000551
dbSNP: rs1559426039
Type: single nucleotide variant
Location: chr3:10142118 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 143 PDB
Residue 91: a β-strand; a UniProt-annotated variant site (in cerebellar hemangioblastoma; uncertain significance)

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.Phe91Leu Uncertain significance ★★★ ⚠ same residue
VHL p.Phe91= Benign/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
VHL p.Ser65Trp Pathogenic ★★★ same condition
VHL p.Trp88Cys Likely 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-phe91val (accessed [today's date]).

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