Is VHL p.Ser38= (c.114C>T) pathogenic?

VHL p.Ser38= (c.114C>T) is classified Benign/Likely benign in VHL (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-01-30). Rare (popmax 0.193%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with VHL p.Ser38= (c.114C>T)?

VHL p.Ser38= (c.114C>T) is associated with hereditary neoplastic syndrome, von Hippel-Lindau disease, Chuvash polycythemia (ClinVar).

How common is VHL p.Ser38= (c.114C>T) in the general population?

VHL p.Ser38= (c.114C>T) is rare (popmax 0.193%, mid) (gnomAD).

VHL p.Ser38=

c.114C>T · rs417164 · VCV220918

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Rare

rare (popmax 0.193%, mid)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.3	GERP -3.2
Overall
CADD	2.047	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.193% Middle Eastern · 10/5,188 alleles

Filtering AF 0.105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0795%

Overall 0.00426% 66/1,549,742 alleles · rare exomes 60/1,397,604 · genomes 6/152,138 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.193%	519
African / African-American	0.00685%	14,590
European (non-Finnish)	0.00427%	23,410
Remaining individualsnot grpmax-eligible	0.00334%	29,978

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.Ser38=
Coding: c.114C>T
MANE Select: NM_000551
dbSNP: rs417164
Type: single nucleotide variant
Location: chr3:10141961 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 143 PDB
Residue 38: the '8 x 5 aa tandem repeats of g-[pavg]-e-e-[daysle]' region; a UniProt-annotated variant site (in vhld; type ii); the 'disordered' region

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.Ser38Phe Uncertain significance ★★ ⚠ same residue
VHL p.Ser38Ala Uncertain significance ★ ⚠ same residue
VHL p.Ser38Tyr Uncertain significance ★ ⚠ same residue
VHL p.Ser38_Glu52del Uncertain significance ★★ same residue
VHL p.Ser38_Glu52dup Uncertain significance ★★ same residue
VHL p.Ser38_Glu47del Uncertain significance ★ 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-ser38 (accessed [today's date]).

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