chr3-10142088-C-A

Variant names:

• chr3-10142088-C-A
• rs104893829
• NM_000551.4:c.241C>A
• VHL p.Pro81Thr

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+5 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 5 classification points (ACGS-UK Somatic Oncogenicity v2025). O1_SupportingO3_ModerateO5_SupportingO7_Supporting

The NM_000551.4(VHL):c.241C>A (p.Pro81Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene VHL is a tumor suppressor gene (CancerMine: 345 TSG, 114 oncogene, 46 driver citations). The gene VHL is a known oncogene (CancerMine: 345 TSG, 114 oncogene, 46 driver citations). The gene VHL is a cancer driver gene (CancerMine: 345 TSG, 114 oncogene, 46 driver citations). The variant allele was found at a cumulative frequency of 0.000000688 (AC=1) in the gnomAD database across 1,453,020 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000009. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (no review stars). A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.P81L: Pathogenic/Likely_pathogenic (ClinVar VariationId 36899, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.P81A: Uncertain_significance (ClinVar VariationId 1068142, 1 star); p.P81= (synonymous): Benign/Likely_benign (ClinVar VariationId 3468038, 2 stars); p.P81= (synonymous): Benign/Likely_benign (ClinVar VariationId 2927601, 2 stars); p.P81= (synonymous): Benign (ClinVar VariationId 4071324, 1 star); p.P81S: Benign (ClinVar VariationId 2233, 3 stars)

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 1.47
• Publications: 25 publications found

Genes affected

VHL (HGNC:12687): (von Hippel-Lindau tumor suppressor) This gene encodes a component of a ubiquitination complex. The encoded protein is involved in the ubiquitination and degradation of hypoxia-inducible-factor (HIF), which is a transcription factor that plays a central role in the regulation of gene expression by oxygen. In addition to oxygen-related gene expression, this protein plays a role in many other cellular processes including cilia formation, cytokine signaling, regulation of senescence, and formation of the extracellular matrix. Variants of this gene are associated with von Hippel-Lindau syndrome, pheochromocytoma, erythrocytosis, renal cell carcinoma, and cerebellar hemangioblastoma. [provided by RefSeq, Jun 2022]

VHL Gene-Disease associations (from GenCC):

• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• von Hippel-Lindau disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Genomics England PanelApp
• renal cell carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal recessive secondary polycythemia not associated with VHL gene

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• Chuvash polycythemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for VHL are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O1Established oncogenic variant		TSG gene: ClinVar germline P/LP (single/no review) — Supporting (O1); O1 contributing sources (1.0 pts): ClinVar germline P/LP in TSG
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = 0.000001, AC = 1 — absent/extremely rare (O3 moderate [+2])
	O5Same location/impact as known oncogenic		Different AA at same residue with oncogenic evidence (or germline P/LP in TSG), or same AA change SCI Tier II Potential — Supporting (O5); ClinVar same-AA oncogenic/T1: false | ClinVar same-AA SCI tier: — | CGI same-AA oncogenic: false | TSG: true | ClinVar same-AA germline P/LP: false | CIViC LOF: false | ClinVar diff-AA oncogenic: false | ClinVar diff-AA germline P/LP: true
	O7Mutational hotspot or critical domain		Supporting: cancerhotspots.org hit, critical domain, or missense neighbourhood hotspot; No cancerhotspots.org hit at this position; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 39 pathogenic, 6 benign (OR vs. background: 30.4); Variant does not impact splicing — splice-hotspot path not applicable

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000551.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	VHL NM_000551.4	MANE Select	c.241C>A p.Pro81Thr	missense	Exon 1 of 3	Prot: NP_000542.1 UniProt:
	VHL NM_001354723.2		c.241C>A p.Pro81Thr	missense	Exon 1 of 3	Prot: NP_001341652.1 UniProt:
	VHL NM_198156.3		c.241C>A p.Pro81Thr	missense	Exon 1 of 2	Prot: NP_937799.1 UniProt:

VHL NM_000551.4

MANE Select

HGVSc / HGVSpc.241C>Ap.Pro81Thr

Exon rankExon 1 of 3

missense

Prot: NP_000542.1UniProt: A0A024R2F2P40337-1

VHL NM_001354723.2

HGVSc / HGVSpc.241C>Ap.Pro81Thr

Exon rankExon 1 of 3

missense

Prot: NP_001341652.1UniProt: A0A8Q3WL21

VHL NM_198156.3

HGVSc / HGVSpc.241C>Ap.Pro81Thr

Exon rankExon 1 of 2

missense

Prot: NP_937799.1UniProt: P40337-2A0A0S2Z4K1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	VHL ENST00000256474.3	TSL:1MANE Select	c.241C>A p.Pro81Thr	missense	Exon 1 of 3	Prot: ENSP00000256474.3 UniProt:
	VHL ENST00000345392.3	TSL:1	c.241C>A p.Pro81Thr	missense	Exon 1 of 2	Prot: ENSP00000344757.2 UniProt:
	VHL ENST00000477538.2	TSL:1	n.287C>A	non_coding_transcript_exon	Exon 1 of 3	Prot:

VHL ENST00000256474.3

TSL:1MANE Select

HGVSc / HGVSpc.241C>Ap.Pro81Thr

Exon rankExon 1 of 3

missense

Prot: ENSP00000256474.3UniProt: P40337-1

VHL ENST00000345392.3

TSL:1

HGVSc / HGVSpc.241C>Ap.Pro81Thr

Exon rankExon 1 of 2

missense

Prot: ENSP00000344757.2UniProt: P40337-2

VHL ENST00000477538.2

TSL:1

HGVSc / HGVSpn.287C>A

Exon rankExon 1 of 3

non_coding_transcript_exon

Prot:

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF: 6.88e-7	AC:1	Hom:0	AN:1453020	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	24
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D
Eigen	Benign	-0.042
Eigen_PC	Benign	0.090
FATHMM_MKL	Uncertain	0.88	D
FuncVEP CTI	Pathogenic	0.54
GPN-Star LLR	N/A	-8.0
GPN-Star score	N/A	8.0
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Pathogenic	0.95	D
Mutation Taster	N/A	11/89	disease causing
MutationAssessor	Benign	1.1	L
PhyloP100	Benign	1.5
popEVE	Benign	-3.2
PrimateAI	Pathogenic	0.90	D
PromoterAI	N/A	-0.033	Neutral
PROVEAN	Uncertain	-3.0	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Uncertain	0.50
Sift	Benign	0.072	T
Sift4G	Benign	0.59	T
Varity_R	N/A	0.84
VESM-3B	Benign	-7.1

Showing 31 of 31 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs104893829;

hg19: chr3-10183772;

COSMIC: COSV56562473;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar