VHLL

Summary

VHLL (VHL like, HGNC:30666) is a protein-coding gene on chromosome 1q22, encoding von Hippel-Lindau-like protein (Q6RSH7). Functions as a dominant-negative VHL to serve as a protector of HIFalpha.

Von Hippel-Lindau (VHL) tumor suppressor protein is a component of an E3 ubiquitin ligase complex that selectively ubiquitinates the alpha subunit of the hypoxia-inducible factor (HIF) transcription factor for proteasome-mediated degradation. Inactivation of VHL causes VHL disease and sporadic kidney cancer. This gene encodes a VHL homolog that lacks one of two key domains necessary for VHL function. This gene may contribute to the regulation of oxygen homeostasis and neovascularization during placenta development. This gene is intronless, and can also be interpreted as a retrotransposed pseudogene of the VHL locus located on chromosome 3. However, the protein is represented in this RefSeq due to evidence in PMID:14757845 that strongly suggests it is translated. The same publication also indicates that this protein binds HIF alpha but fails to recruit the E3 ubiquitin ligase complex, and it therefore functions as a dominant-negative VHL protein and a protector of HIF alpha.

Source: NCBI Gene 391104 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 26 total
• MANE Select transcript: NM_001004319

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30666
Approved symbol	VHLL
Name	VHL like
Location	1q22
Locus type	gene with protein product
Status	Approved
Aliases	VLP
Ensembl gene	ENSG00000189030
Ensembl biotype	protein_coding
OMIM	619650
Entrez	391104

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000339922

RefSeq mRNA: 1 — MANE Select: NM_001004319 NM_001004319

Canonical transcript exons

ENST00000339922 — 1 exons

Exon	Start	End
ENSE00001372006	156298624	156299307

Expression profiles

Bgee: expression breadth broad, 42 present calls, max score 50.40.

Top tissues by expression

97 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	50.40	gold quality
granulocyte	CL:0000094	49.26	silver quality
cerebellum	UBERON:0002037	47.37	gold quality
cerebellar cortex	UBERON:0002129	47.02	gold quality
cerebellar hemisphere	UBERON:0002245	47.00	gold quality
lower esophagus mucosa	UBERON:0035834	45.21	silver quality
skeletal muscle tissue	UBERON:0001134	44.02	silver quality
right hemisphere of cerebellum	UBERON:0014890	43.76	gold quality
colonic epithelium	UBERON:0000397	42.30	gold quality
muscle tissue	UBERON:0002385	40.33	silver quality
muscle of leg	UBERON:0001383	40.10	gold quality
gastrocnemius	UBERON:0001388	39.65	gold quality
sural nerve	UBERON:0015488	36.88	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
bone marrow cell	CL:0002092	36.16	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
mucosa of stomach	UBERON:0001199	35.41	gold quality
liver	UBERON:0002107	34.84	silver quality
bone marrow	UBERON:0002371	31.74	gold quality
calcaneal tendon	UBERON:0003701	31.54	gold quality
prefrontal cortex	UBERON:0000451	31.05	gold quality
tonsil	UBERON:0002372	30.76	gold quality
corpus callosum	UBERON:0002336	30.55	gold quality
lymph node	UBERON:0000029	30.34	gold quality
Brodmann (1909) area 9	UBERON:0013540	30.34	silver quality
gall bladder	UBERON:0002110	30.29	gold quality
brain	UBERON:0000955	30.25	gold quality
nucleus accumbens	UBERON:0001882	30.20	silver quality
stromal cell of endometrium	CL:0002255	29.87	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.98

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

12 targeting VHLL, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-141-5P	99.57	67.86	897
HSA-MIR-5004-3P	99.54	68.27	1371
HSA-MIR-488-5P	99.28	68.12	821
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-4705	99.10	69.10	1091
HSA-MIR-6830-3P	98.62	68.07	1760
HSA-MIR-219B-5P	97.91	65.80	531
HSA-MIR-490-3P	97.79	65.54	606
HSA-MIR-635	96.00	65.54	687
HSA-MIR-6774-5P	95.94	65.18	722
HSA-MIR-5586-3P	95.51	67.00	805

Literature-anchored findings (GeneRIF, showing 1)

• von Hippel-Lindau-like protein (VLP) is conserved in upper mammals and specifically expressed in brain and testis. Structural analysis and molecular dynamics simulations show VLP to be similar to von Hippel-Lindau tumor suppressor protein (pVHL) three-dimensional organization and binding dynamics. Conservation of elements at the protein interfaces suggests VLP to be a functional pVHL homolog possessing multiple functions. (PMID:31485743)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	vhl	ENSDARG00000070617
rattus_norvegicus		ENSRNOG00000088614
drosophila_melanogaster	Vhl	FBGN0041174

Paralogs (1): VHL (ENSG00000134086)

Protein

Protein identifiers

von Hippel-Lindau-like protein — Q6RSH7 (reviewed: Q6RSH7)

All UniProt accessions (1): Q6RSH7

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a dominant-negative VHL to serve as a protector of HIFalpha.

Subunit / interactions. Interacts via the beta domain with the ODD domain of HIF1A. This interaction is independent of prolyl hydroxylation of HIF1A.

Tissue specificity. Abundantly expressed in the placenta.

Miscellaneous. Has little or no E3 ubiquitin ligase activity as it lacks the alpha domain required for nucleating the multiprotein E3 ubiquitin ligase complex.

Similarity. Belongs to the VHL family.

RefSeq proteins (1): NP_001004319* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR022772	VHL_tumour_suppress_b/a_dom	Domain
IPR024053	VHL_beta_dom	Domain
IPR036208	VHL_sf	Homologous_superfamily
IPR037140	VHL_beta_dom_sf	Homologous_superfamily

Pfam: PF01847

UniProt features (4 total): region of interest 2, chain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6RSH7-F1	77.42	0.43

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (1):

Position	Phenotype
93–96	preferentially binds to a hydroxylated odd peptide.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 6 (showing top): chr1q22, CTCTATG_MIR368, ZNF362_TARGET_GENES, MIR4705, BLANCO_MELO_MERS_COV_INFECTION_MCR5_CELLS_UP, TCTATGA_MIR376A_MIR376B

GO Biological Process (0):

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	1

Protein interactions and networks

STRING

341 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VHLL	ELOC	Q15369	516
VHLL	CUL2	Q13617	487
VHLL	RBX1	P62877	414
VHLL	EGLN3	Q9H6Z9	414
VHLL	HIF1A	Q16665	374
VHLL	EGLN1	Q9GZT9	369
VHLL	EPAS1	Q99814	364
VHLL	EGLN2	Q96KS0	346
VHLL	ELOB	Q15370	345
VHLL	PAQR6	Q6TCH4	328
VHLL	NBPF12	Q5TAG4	321
VHLL	BPGM	P07738	318
VHLL	ZER1	Q7Z7L7	311
VHLL	HIF3A	Q9Y2N7	301
VHLL	PAQR5	Q9NXK6	287

IntAct

21 interactions, top by confidence:

A	B	Type	Score
VHLL	DAZAP2	psi-mi:“MI:0915”(physical association)	0.720
DAZAP2	VHLL	psi-mi:“MI:0915”(physical association)	0.720
RBPMS	VHLL	psi-mi:“MI:0915”(physical association)	0.560
VHLL	RBPMS	psi-mi:“MI:0915”(physical association)	0.560
VAC14	VHLL	psi-mi:“MI:0915”(physical association)	0.560
VENTX	VHLL	psi-mi:“MI:0915”(physical association)	0.560
VHLL	RBPMS	psi-mi:“MI:0915”(physical association)	0.000
VHLL	DAZAP2	psi-mi:“MI:0915”(physical association)	0.000
VHLL	VAC14	psi-mi:“MI:0915”(physical association)	0.000
VENTX	VHLL	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (8): VHLL (Two-hybrid), VHLL (Two-hybrid), VHLL (Two-hybrid), VHLL (Two-hybrid), VHLL (Two-hybrid), VHLL (Two-hybrid), VHLL (Reconstituted Complex), HIF1A (Affinity Capture-Western)

ESM2 similar proteins: A2BD94, A2RRT3, B2RYN2, C3VD30, E1BP92, E1CHH8, F5HF68, O43900, O75333, O94966, O95238, P0C2N6, P98153, P98154, Q0D2D2, Q19213, Q2KHT9, Q2T9Z2, Q3SYK4, Q3TQF0, Q3U2C5, Q3UTB7, Q4R6Y5, Q4R739, Q5EA48, Q5R7P6, Q5SPX3, Q5VZI3, Q5XUX0, Q62600, Q6DGF9, Q6NZK8, Q6Q783, Q6QN11, Q6RSH7, Q80U38, Q80WB0, Q810F8, Q8N9V6, Q8NC06

Diamond homologs: P40337, P40338, Q5Q9Z2, Q64259, Q6RSH7, Q9V3C1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

26 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	26
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

173 predictions. Top by Δscore:

Variant	Effect	Δscore
1:156298867:T:C	donor_gain	0.8200
1:156298874:T:TA	donor_gain	0.7500
1:156299247:T:TA	donor_gain	0.7100
1:156298879:G:A	donor_gain	0.7000
1:156298782:C:CC	acceptor_gain	0.6900
1:156299005:C:CC	acceptor_gain	0.6500
1:156298866:AT:A	donor_gain	0.6400
1:156298965:G:A	donor_gain	0.6400
1:156298780:CA:C	acceptor_gain	0.6200
1:156298866:A:AC	donor_gain	0.6100
1:156298792:A:C	acceptor_gain	0.6000
1:156298822:T:TC	acceptor_gain	0.6000
1:156299011:T:TC	acceptor_gain	0.6000
1:156298928:C:A	donor_gain	0.5800
1:156298905:T:TA	donor_gain	0.5700
1:156298821:A:C	acceptor_gain	0.5600
1:156298792:A:AC	acceptor_gain	0.5400
1:156298778:TACA:T	acceptor_gain	0.5300
1:156298787:G:GC	acceptor_gain	0.5300
1:156298750:A:AT	donor_gain	0.5200
1:156298795:T:C	acceptor_gain	0.5200
1:156298814:C:CT	acceptor_gain	0.5100
1:156298820:CAT:C	acceptor_gain	0.5100
1:156299248:C:A	donor_gain	0.5100
1:156298854:A:T	donor_gain	0.4900
1:156298627:CTGTG:C	donor_gain	0.4800
1:156299014:C:CT	acceptor_gain	0.4800
1:156298822:T:C	acceptor_gain	0.4700
1:156298789:G:C	acceptor_gain	0.4600
1:156298749:C:CT	donor_gain	0.4500

AlphaMissense

894 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:156298887:G:C	F101L	0.839
1:156298887:G:T	F101L	0.839
1:156298889:A:G	F101L	0.839
1:156298836:A:C	F118L	0.819
1:156298836:A:T	F118L	0.819
1:156298838:A:G	F118L	0.819
1:156298908:G:C	F94L	0.772
1:156298908:G:T	F94L	0.772
1:156298910:A:G	F94L	0.772
1:156298800:A:C	F130L	0.738
1:156298800:A:T	F130L	0.738
1:156298802:A:G	F130L	0.738
1:156299004:G:C	S62R	0.697
1:156299004:G:T	S62R	0.697
1:156299006:T:G	S62R	0.697
1:156298923:G:C	F89L	0.634
1:156298923:G:T	F89L	0.634
1:156298925:A:G	F89L	0.634
1:156299010:A:C	N60K	0.583
1:156299010:A:T	N60K	0.583
1:156298895:A:G	W99R	0.565
1:156298895:A:T	W99R	0.565

dbSNP variants (sampled 300 via entrez): RS1000290695 (1:156298677 C>G,T), RS1000588829 (1:156298418 C>T), RS1000595212 (1:156298424 C>T), RS1000768571 (1:156298691 T>A,C), RS1001594585 (1:156299051 A>G), RS1002032550 (1:156299281 G>A,C), RS1002974719 (1:156300170 G>A), RS1003089038 (1:156300330 TAAAAA>T,TAAAA,TAAAAAA), RS1003301031 (1:156300764 G>A), RS1003978177 (1:156298814 C>T), RS1004729894 (1:156300889 T>C), RS1004760995 (1:156301183 C>G,T), RS1006673451 (1:156298660 A>C,G), RS1008095957 (1:156299686 G>A,C), RS1008407772 (1:156299351 T>A)

Disease associations

OMIM: gene MIM:619650 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST000582_7	Mean corpuscular hemoglobin concentration	3.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004509	hemoglobin measurement
EFO:0004528	mean corpuscular hemoglobin concentration

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

3 total (human), top 3 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
Benzo(a)pyrene	affects methylation	1
Tobacco Smoke Pollution	increases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.