HIF3A

Summary

HIF3A (hypoxia inducible factor 3 subunit alpha, HGNC:15825) is a protein-coding gene on chromosome 19q13.32, encoding Hypoxia-inducible factor 3-alpha (Q9Y2N7). Acts as a transcriptional regulator in adaptive response to low oxygen tension.

The protein encoded by this gene is the alpha-3 subunit of one of several alpha/beta-subunit heterodimeric transcription factors that regulate many adaptive responses to low oxygen tension (hypoxia). The alpha-3 subunit lacks the transactivation domain found in factors containing either the alpha-1 or alpha-2 subunits. It is thought that factors containing the alpha-3 subunit are negative regulators of hypoxia-inducible gene expression. Multiple alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 64344 — RefSeq curated summary.

At a glance

• GWAS associations: 220
• Clinical variants (ClinVar): 168 total
• MANE Select transcript: NM_152795

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15825
Approved symbol	HIF3A
Name	hypoxia inducible factor 3 subunit alpha
Location	19q13.32
Locus type	gene with protein product
Status	Approved
Aliases	IPAS, MOP7, PASD7, bHLHe17
Ensembl gene	ENSG00000124440
Ensembl biotype	protein_coding
OMIM	609976
Entrez	64344

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 7 retained_intron, 6 protein_coding, 5 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000244302, ENST00000244303, ENST00000291300, ENST00000300862, ENST00000377670, ENST00000472815, ENST00000475432, ENST00000524533, ENST00000525854, ENST00000526506, ENST00000528563, ENST00000529205, ENST00000529542, ENST00000531043, ENST00000533145, ENST00000533789, ENST00000600236, ENST00000600383, ENST00000600879

RefSeq mRNA: 4 — MANE Select: NM_152795 NM_022462, NM_152794, NM_152795, NM_152796

CCDS: CCDS12681, CCDS12682, CCDS42580

Canonical transcript exons

ENST00000377670 — 15 exons

Exon	Start	End
ENSE00002241186	46339525	46343433
ENSE00002280073	46334905	46334986
ENSE00002301675	46331156	46331273
ENSE00003474147	46303898	46304088
ENSE00003509970	46329207	46329478
ENSE00003517407	46308663	46308775
ENSE00003541450	46321776	46321966
ENSE00003555639	46308221	46308305
ENSE00003556410	46305245	46305390
ENSE00003569240	46320443	46320561
ENSE00003623228	46325535	46325639
ENSE00003634090	46312506	46312653
ENSE00003653476	46312161	46312267
ENSE00003653498	46309151	46309359
ENSE00003909450	46297042	46297102

Expression profiles

Bgee: expression breadth ubiquitous, 223 present calls, max score 98.72.

FANTOM5 (CAGE): breadth broad, TPM avg 11.9425 / max 751.4776, expressed in 716 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
176541	7.4752	517
176539	3.9672	447
176543	0.3267	96
176548	0.0847	31
176540	0.0492	13
176544	0.0275	13
176545	0.0119	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of stomach	UBERON:0001199	98.72	gold quality
apex of heart	UBERON:0002098	97.34	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.69	gold quality
right lung	UBERON:0002167	96.64	gold quality
lower esophagus	UBERON:0013473	96.61	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.36	gold quality
left uterine tube	UBERON:0001303	95.56	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.24	gold quality
right atrium auricular region	UBERON:0006631	95.00	gold quality
sural nerve	UBERON:0015488	94.99	gold quality
heart left ventricle	UBERON:0002084	94.21	gold quality
popliteal artery	UBERON:0002250	94.02	gold quality
tibial artery	UBERON:0007610	93.99	gold quality
cardiac atrium	UBERON:0002081	93.83	gold quality
artery	UBERON:0001637	93.80	gold quality
right coronary artery	UBERON:0001625	93.53	gold quality
cardiac ventricle	UBERON:0002082	93.49	gold quality
left coronary artery	UBERON:0001626	93.29	gold quality
right ovary	UBERON:0002118	93.25	gold quality
adrenal tissue	UBERON:0018303	93.08	gold quality
aorta	UBERON:0000947	92.91	gold quality
coronary artery	UBERON:0001621	92.50	gold quality
heart	UBERON:0000948	92.28	gold quality
thoracic aorta	UBERON:0001515	91.75	gold quality
body of uterus	UBERON:0009853	91.64	gold quality
ascending aorta	UBERON:0001496	91.62	gold quality
body of stomach	UBERON:0001161	91.37	gold quality
peripheral nervous system	UBERON:0000010	91.27	gold quality
tibial nerve	UBERON:0001323	91.27	gold quality
descending thoracic aorta	UBERON:0002345	90.99	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	76.51
E-HCAD-25	yes	23.72
E-ENAD-20	yes	21.32
E-ENAD-17	no	146.73
E-CURD-97	no	39.45
E-MTAB-9067	no	3.33
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

6 targets.

Target	Regulation
EDN1	Repression
EPAS1	Unknown
GHRHR
HIF1A	Unknown
LOX	Repression
VEGFA	Repression

JASPAR motifs

Motif	Name	Family
MA2674.1	HIF3A	PAS

JASPAR matrix evidence (PMIDs): PMID:31768607

Upstream regulators (CollecTRI, top): EPAS1, HIF1A

miRNA regulators (miRDB)

217 targeting HIF3A, 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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4514	99.99	67.10	1870

Literature-anchored findings (GeneRIF, showing 40)

• multiple splice variants of locus are targets of the von Hippel-Lindau E3 ubiquitin ligase complex (PMID:12538644)
• The splice isoform HIF-3alpha4 inhibits transcription of VEGF and GLUT1 by binding to and inhibiting HIF-1alpha and HIF-1beta. (PMID:16126907)
• IPAS1 and IPAS2 inhibit angiogenesis by binding to and inhibiting HIF-1alpha and HIF-1beta. (PMID:16182248)
• findings suggest that HIF-3alpha, as a member of the HIF system, is complementary rather than redundant to HIF-1alpha induction in protection against hypoxic damage in alveolar epithelial cells. (PMID:16775626)
• The expression of HIF-3alpha4 suppresses the growth of tumor xenografts in SCID mice. (PMID:17998805)
• The findings shed light on a novel aspect of HIF-3alpha as a HIF-1 target gene and point to a possible role as a modulator of hypoxic gene induction. (PMID:19694616)
• Hypoxia upregulated transcription from all three alternative HIF-3alpha promoters. siRNA experiments showed that this induction is mediated specifically by HIF-1 and not by HIF-2. (PMID:20416395)
• HIF3A is regulated by hypoxia in the developing human lung. (PMID:20551700)
• Cell-specific and hypoxia-dependent regulation of human HIF-3alpha. (PMID:21069422)
• It is a negative regulator of tumorigenesis. (review) (PMID:21404626)
• data indicate that the HIF-3alpha variants may have more versatile and specific roles in the regulation of the hypoxia response than previously anticipated (PMID:21479871)
• Were significantly upregulated in the HIF3alpha expressing lungs. (PMID:23451260)
• the transcription of HIF-3alpha4 was silenced by the promoter DNA methylation in meningiomas, and inducible HIF-3alpha4 impaired angiogenesis, proliferation, and metabolism/oxidation in hypervascular meningiomas (PMID:23485455)
• The Inhibitory Per/Arnt/Sim (PAS) domain protein (IPAS) is a splice variant of hypoxia-inducible factor (HIF)-3alpha, and possesses two entirely different functions. The results strongly suggest that IPAS is a nucleocytoplasmic shuttling protein. (PMID:24092767)
• These findings highlight the importance of the hypoxia-sensing pathway and HIFs in clinical hematology. (PMID:24371328)
• Here we provide evidence for the miRNA mediated regulation of HIF3a by hypoxia responsive miRNAs in STS, which may help to tightly regulate and fine-tune the hypoxic response. (PMID:24927770)
• HIF3alpha has a transcriptional regulatory function, which negatively affects gene expression by competing with HIF1alpha and HIF2alpha in binding to transcriptional elements in target genes during hypoxia. (Review) (PMID:25936862)
• A DNA methylation variant in HIF3A was associated with BMI changes through interactions with total or supplemental vitamin B2, vitamin B12, and folate. (PMID:26001398)
• The association between increased DNA methylation at HIF3A and increased adiposity is present in neonates. (PMID:26011824)
• inverse association with hypertrophic markers in chondrogenic cells (PMID:26174816)
• Unsaturated fatty acids are high-affinity ligands of the C-terminal domain from the HIF-3alpha. (PMID:26237540)
• HIF3A DNA Methylation Is Associated with Childhood Obesity and ALT (PMID:26717317)
• Parkin is downregulated under hypoxia and that it interferes with HIF expression based on cellular oxygen tension. (PMID:26742768)
• Results were discordant with those expected if HIF3A methylation has a causal effect on body mass index (BMI) & provided more evidence for causality in the reverse direction (i.e., an effect of BMI on HIF3A methylation); results also show a long-lasting intergenerational influence of maternal BMI on offspring methylation at this locus, which may confound associations between own adiposity & HIF3A methylation. (PMID:26861784)
• miR210 may be a negative regulator of the progression of osteoarthritis, which increases chondrocyte proliferation and prompts extracellular matrix deposition by directly targeting HIF3alpha. (PMID:26861791)
• DNA methylation in HIF3A shares moderate correlation between adipose tissue and blood, and both are associated with BMI. In contrast, methylation in FASN is poorly correlated across tissues, but the DNA methylation in adipose tissue but not blood is highly associated with BMI (PMID:26891033)
• This provides a compelling model for how hypoxia-induced miR-429 regulates the switch between HIF-1 adaptive responses to HIF-3 survival responses by rapidly decreasing HIF1A levels while simultaneously slowing the progression of HIF3A expression until the miR-429 levels drop below normoxic levels. (PMID:26954587)
• TIMP2 suppression, in a hypoxic environment, was induced through a regulatory feedback circuit consisting of hypoxia-inducible factor (HIF) 1 alpha, microRNA-210 (miR-210), and HIF-3alpha. (PMID:27018975)
• Results confirmed a positive association between BMI and HIF3A DNA promoter methylation in the blood. The tissue-specific results of HIF3A gene expression indicate that subcutaneous adipose tissue is the more functional tissue in which a low expression may adversely affect whole-body insulin sensitivity. (PMID:27594926)
• Reduced lifetimes of the donor were partially restored by coexpression of HIF-1alpha or Bcl-xL, binding proteins of IPAS in the nucleus and mitochondria, respectively. (PMID:28003430)
• NAP peptide prevents outer blood retinal barrier breakdown by reducing HIF1alpha/HIF2alpha, VEGF/VEGFRs, and increasing HIF3alpha expression Moreover it is able to reduce the percentage of apoptotic cells by modulating the expression of two death related genes, BAX and Bcl2. (PMID:28436035)
• MicroRNA-300 is a tumor suppressor microRNA in non-small cell lung cancer by downregulating HIF3alpha expression. (PMID:28485161)
• AA can protect cardiomyocytes against hypoxia-induced apoptosis through regulating the miR-1290/HIF3A/HIF-1alpha axis, and miR-1290 may be a potential target in the prevention of myocardial ischemia-reperfusion injury (PMID:28686797)
• HIF3A methylation was found in the association between the HIF3A rs3826795 polymorphism and alanine aminotransferase among obese children. (PMID:28754107)
• Under normoxia, HIF-3alpha overexpression promoted pancreatic cancer cell invasion and migration and stimulated F-actin polymerization. In summary, HIF-3alpha promotes pancreatic cancer cell invasion and metastasis in vivo and promotes pancreatic cancer cell invasion and metastasis by transcriptionally activating the RhoC-ROCK1 signaling pathway. (PMID:28928287)
• Study in human mesenchymal stromal/stem cells revealed robust hypermethylation of histone H3 across HIF3A locus driven by pro-inflammatory cytokines. Experiments in a murine model of arteriotomy highlighted the activation of Hif3alpha expression in infiltrated inflammatory cells, suggesting a new role for Hif3alpha in inflammation in vivo. (PMID:29643458)
• data suggest an important role of miR-210 in sustaining HIF-1alpha activity via the suppression of HIF-3alpha, regulating cell growth and chemotherapeutic drug resistance in cholangiocarcinoma. (PMID:29953500)
• Study mapped the functional nuclear localization signal (NLS) to the unique C-terminal region of Hif-3alpha and identified two clusters of basic residues critical for its nuclear localization. The two NLS motifs are functionally redundant. These results suggest that Hif-3alpha nuclear localization is mediated through two redundant NLS motifs located in its unique C-terminal region. (PMID:30047986)
• Expression level of HIF3A is downregulated in gestational diabetes patients. The methylation status of HIF3A promoter region is highly correlated with gestational diabetes. (PMID:30743315)
• HIF-3alpha showed reduced expression in myofibroblasts from idiopathic pulmonary fibrosis patients. (PMID:31234835)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	hif1al	ENSDARG00000100826
mus_musculus	Hif3a	ENSMUSG00000004328
rattus_norvegicus	Hif3a	ENSRNOG00000017198
drosophila_melanogaster	trh	FBGN0262139
drosophila_melanogaster	sima	FBGN0266411
caenorhabditis_elegans		WBGENE00001851

Paralogs (7): HIF1A (ENSG00000100644), SIM1 (ENSG00000112246), EPAS1 (ENSG00000116016), NPAS1 (ENSG00000130751), NPAS3 (ENSG00000151322), SIM2 (ENSG00000159263), NPAS4 (ENSG00000174576)

Protein

Protein identifiers

Hypoxia-inducible factor 3-alpha — Q9Y2N7 (reviewed: Q9Y2N7)

Alternative names: Basic-helix-loop-helix-PAS protein MOP7, Class E basic helix-loop-helix protein 17, HIF3-alpha-1, Inhibitory PAS domain protein, Member of PAS protein 7, PAS domain-containing protein 7

All UniProt accessions (7): E9PJR0, E9PLC8, E9PNQ7, Q9Y2N7, H0YDZ5, H0YE02, M0R104

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a transcriptional regulator in adaptive response to low oxygen tension. Acts as a regulator of hypoxia-inducible gene expression. Functions as an inhibitor of angiogenesis in hypoxic cells of the cornea. Plays a role in the development of the cardiorespiratory system. May also be involved in apoptosis. Attenuates the ability of transcription factor HIF1A to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation. Also inhibits hypoxia-inducible ARNT-mediated gene expression. Attenuates the ability of transcription factor HIF1A to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation. Attenuates the ability of transcription factor HIF1A and EPAS1/HIF2A to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation. May act as a tumor suppressor and inhibits malignant cell transformation. Attenuates the ability of transcription factor HIF1A to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation.

Subunit / interactions. Isoform 2 interacts (via ODD domain) with VHL (via beta domain). Isoform 4 interacts with HIF1A; the interaction inhibits the binding of HIF1A to hypoxia-responsive element (HRE) and HIF1A/ARNT-dependent transcriptional activation. Isoform 4 interacts with ARNT; the interaction occurs in a HIF1A- and DNA-binding-independent manner and does not induce HIF1A/ARNT-dependent transcriptional activation. Isoform 4 interacts with EPAS1. Interacts with BAD, BCL2L2 and MCL1.

Subcellular location. Nucleus. Cytoplasm. Nucleus speckle. Mitochondrion.

Tissue specificity. Expressed in vascular cells (at protein level). Expressed in kidney. Expressed in lung epithelial cells. Expressed in endothelial cells (venous and arterial cells from umbilical cord and aortic endothelial cells) and in vascular smooth muscle cells (aorta). Strongly expressed in the heart, placenta, and skeletal muscle, whereas a weak expression profile was found in the lung, liver, and kidney. Expressed weakly in cell renal cell carcinoma (CC-RCC) compared to normal renal cells. Expression is down-regulated in numerous kidney tumor cells compared to non tumor kidney tissues. Isoform 2 is expressed in heart, placenta, lung, liver, skeletal muscle and pancreas and in numerous cancer cell lines. Isoform 3 and isoform 4 are weakly expressed in heart, placenta, lung, liver, skeletal muscle and pancreas. Isoform 4 is expressed in fetal tissues, such as heart, brain, thymus, lung, liver, skeletal kidney and spleen. Isoform 3 is weakly expressed in fetal tissues, such as liver and kidney.

Post-translational modifications. In normoxia, hydroxylated on Pro-492 in the oxygen-dependent degradation domain (ODD) by prolyl hydroxylase(s) (PHD). The hydroxylated proline promotes interaction with VHL, initiating rapid ubiquitination and subsequent proteasomal degradation. Ubiquitinated; ubiquitination occurs in a VHL- and oxygen-dependent pathway and subsequently targeted for proteasomal degradation.

Induction. Up-regulated by hypoxia (at protein level). Induced by hypoxia. Isoform 2, isoform 3, isoform 4 and isoform 5 are up-regulated by hypoxia in a HIF1A- and EPAS1/HIF2A-dependent manner. Isoform 4 is down-regulated by hypoxia and up-regulated upon restoring normoxia in embryonic kidney cells.

Miscellaneous. Incomplete sequence. Incomplete sequence.

Isoforms (7)

UniProt ID	Names	Canonical?
Q9Y2N7-1	1	yes
Q9Y2N7-2	2, HIF-3alpha1
Q9Y2N7-3	3, HIF-3alpha2
Q9Y2N7-4	4, HIF-3alpha4
Q9Y2N7-5	5, HIF-3alpha3
Q9Y2N7-6	6, HIF-3alpha6
Q9Y2N7-7	7

RefSeq proteins (4): NP_071907, NP_690007, NP_690008, NP_690009 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000014	PAS	Domain
IPR001610	PAC	Repeat
IPR011598	bHLH_dom	Domain
IPR013767	PAS_fold	Domain
IPR021537	HIF_alpha-like	Domain
IPR035965	PAS-like_dom_sf	Homologous_superfamily
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily

Pfam: PF00989, PF11413, PF14598, PF23171

UniProt features (50 total): region of interest 9, splice variant 8, strand 6, compositionally biased region 5, helix 5, domain 3, mutagenesis site 3, short sequence motif 2, cross-link 2, sequence variant 2, sequence conflict 2, chain 1, modified residue 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4WN5	X-RAY DIFFRACTION	1.15

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y2N7-F1	65.75	0.34

Functional residue map

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

Post-translational modifications (3): 492, 467, 570

Mutagenesis-validated functional residues (3):

Position	Phenotype
467	no loss of ubiquitination. reduced ubiquitination; when associated with r-570.
492	reduced hydroxylation activity. reduced ubiquitination.
570	no loss of ubiquitination. reduced ubiquitination; when associated with r-467.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1234176	Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha
R-HSA-452723	Transcriptional regulation of pluripotent stem cells
R-HSA-8951664	Neddylation
R-HSA-1234158	Regulation of gene expression by Hypoxia-inducible Factor

MSigDB gene sets: 159 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, PAX4_01, GCANCTGNY_MYOD_Q6, MARTINEZ_RB1_TARGETS_UP, YGACNNYACAR_UNKNOWN, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_LEVELS, GOBP_RESPONSE_TO_OXYGEN_LEVELS, GOBP_BLOOD_VESSEL_MORPHOGENESIS, HIF1_Q3, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS, TGGNNNNNNKCCAR_UNKNOWN, VDR_Q3, E12_Q6, MODULE_48, MARTINEZ_RB1_AND_TP53_TARGETS_UP

GO Biological Process (7): angiogenesis (GO:0001525), response to hypoxia (GO:0001666), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), apoptotic process (GO:0006915), intracellular oxygen homeostasis (GO:0032364), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (6): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), protein dimerization activity (GO:0046983), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700)

GO Cellular Component (9): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), mitochondrion (GO:0005739), cytosol (GO:0005829), plasma membrane (GO:0005886), nuclear speck (GO:0016607), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Cellular response to hypoxia	2
Developmental Biology	1
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
regulation of DNA-templated transcription	2
DNA-templated transcription	2
transcription cis-regulatory region binding	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
intracellular membrane-bounded organelle	2
cytoplasm	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
response to stress	1
response to decreased oxygen levels	1
transcription by RNA polymerase II	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
intracellular chemical homeostasis	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
protein binding	1
nucleic acid binding	1
transcription regulator activity	1
chromosome	1
nuclear lumen	1
protein-containing complex	1
membrane	1
cell periphery	1
nuclear ribonucleoprotein granule	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1574 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HIF3A	ARNT	P27540	991
HIF3A	EPAS1	Q99814	984
HIF3A	HIF1A	Q16665	984
HIF3A	ARNT2	Q9HBZ2	958
HIF3A	EGLN1	Q9GZT9	841
HIF3A	VHL	P40337	753
HIF3A	EGLN2	Q96KS0	734
HIF3A	EPO	P01588	724
HIF3A	EGLN3	Q9H6Z9	709
HIF3A	EIF5B	O60841	701
HIF3A	P4HA1	P13674	685
HIF3A	SLC2A1	P11166	681
HIF3A	SESN2	P58004	668
HIF3A	CREB3	O43889	622
HIF3A	EPOR	P19235	608

IntAct

0 interactions, top by confidence:

BioGRID (11): EPAS1 (Affinity Capture-Western), HIF3A (Affinity Capture-Western), HIF3A (Affinity Capture-Western), ARNT (Affinity Capture-Western), HIF3A (Affinity Capture-Western), ARNT (Affinity Capture-Western), HIF1A (Affinity Capture-Western), HIF3A (FRET), HIF3A (Reconstituted Complex), VHL (Affinity Capture-Western), HIF3A (Reconstituted Complex)

ESM2 similar proteins: A5PK23, A5PKW4, E7FFX1, E9Q0S6, F1MUS9, O14512, O14559, O15055, O15534, O35973, O54943, O70361, O70405, O94983, O95402, O95886, P12813, P22736, P22829, P46062, P51666, P56645, P97838, Q00322, Q01094, Q02346, Q03484, Q09019, Q0V8F0, Q0VBL6, Q1ECW2, Q5DTT2, Q63HR2, Q69ZH9, Q6PFD5, Q80VC9, Q80Y50, Q80YF9, Q8CGB6, Q8CHI5

Diamond homologs: A1YFY6, A2T6X9, A9YTQ3, O09000, O35800, P05709, P81133, P97459, P97481, Q0PGG7, Q0VBL6, Q14190, Q16665, Q24119, Q24167, Q309Z6, Q61045, Q61079, Q61221, Q8IXF0, Q98SJ5, Q98SW2, Q99742, Q99814, Q9I8A9, Q9JHS1, Q9JHS2, Q9QZQ0, Q9XTA5, Q9Y2N7, Q9YIB9, E7FFX1, O02747, O44712, O57539, O61734, P30561, P35869, P41738, P70365

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
HIF3A	“down-regulates quantity by repression”	HIF1A	“transcriptional regulation”
HIF3A	“down-regulates quantity by repression”	EPAS1	“transcriptional regulation”
PRKN	“down-regulates quantity by destabilization”	HIF3A	ubiquitination
PINK1	“down-regulates activity”	HIF3A	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	124
Likely benign	13
Benign	9

Top pathogenic / likely-pathogenic (0)

SpliceAI

2650 predictions. Top by Δscore:

Variant	Effect	Δscore
19:46304086:CAGG:C	donor_loss	1.0000
19:46304089:GTGA:G	donor_loss	1.0000
19:46304090:T:G	donor_loss	1.0000
19:46308304:GA:G	donor_gain	1.0000
19:46308773:A:T	donor_gain	1.0000
19:46308773:AAGG:A	donor_loss	1.0000
19:46308774:AGGT:A	donor_loss	1.0000
19:46308775:GGTG:G	donor_loss	1.0000
19:46308776:GTGC:G	donor_loss	1.0000
19:46309336:G:GT	donor_gain	1.0000
19:46309359:GGTG:G	donor_loss	1.0000
19:46309360:G:T	donor_loss	1.0000
19:46312159:A:AG	acceptor_gain	1.0000
19:46312159:AG:A	acceptor_gain	1.0000
19:46312160:G:GG	acceptor_gain	1.0000
19:46312160:GG:G	acceptor_gain	1.0000
19:46312268:G:GG	donor_gain	1.0000
19:46325530:CACA:C	acceptor_loss	1.0000
19:46325533:A:AG	acceptor_gain	1.0000
19:46325533:AGGCT:A	acceptor_gain	1.0000
19:46325534:G:GA	acceptor_loss	1.0000
19:46325534:G:GG	acceptor_gain	1.0000
19:46325534:GGCT:G	acceptor_gain	1.0000
19:46325534:GGCTG:G	acceptor_gain	1.0000
19:46325636:TCAGG:T	donor_loss	1.0000
19:46325637:CAGGT:C	donor_loss	1.0000
19:46325638:AGG:A	donor_loss	1.0000
19:46325640:G:GC	donor_loss	1.0000
19:46325641:T:G	donor_loss	1.0000
19:46329205:AG:A	acceptor_gain	1.0000

AlphaMissense

4308 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:46303939:C:A	A23D	1.000
19:46304026:A:T	D52V	1.000
19:46304030:G:C	K53N	1.000
19:46304030:G:T	K53N	1.000
19:46303941:C:A	R24S	0.999
19:46303950:C:A	R27S	0.999
19:46303981:T:C	L37P	0.999
19:46304025:G:C	D52H	0.999
19:46304026:A:C	D52A	0.999
19:46304028:A:C	K53Q	0.999
19:46304028:A:G	K53E	0.999
19:46304029:A:T	K53M	0.999
19:46304047:T:C	L59P	0.999
19:46308228:T:C	L124P	0.999
19:46308234:G:A	G126E	0.999
19:46308721:G:C	K169N	0.999
19:46308721:G:T	K169N	0.999
19:46309316:A:C	S243R	0.999
19:46309318:C:A	S243R	0.999
19:46309318:C:G	S243R	0.999
19:46309341:T:C	F251S	0.999
19:46303948:G:C	R26P	0.998
19:46303951:G:C	R27P	0.998
19:46303961:G:C	E30D	0.998
19:46303961:G:T	E30D	0.998
19:46304025:G:T	D52Y	0.998
19:46304026:A:G	D52G	0.998
19:46304027:C:A	D52E	0.998
19:46304027:C:G	D52E	0.998
19:46304034:T:C	S55P	0.998

dbSNP variants (sampled 300 via entrez): RS1000045656 (19:46341269 G>A), RS1000051118 (19:46322705 T>C), RS1000147284 (19:46300037 G>A), RS1000198527 (19:46299676 C>T), RS1000208159 (19:46298175 G>A,C,T), RS1000232569 (19:46332299 C>T), RS1000288492 (19:46343821 G>A), RS1000300563 (19:46311215 C>G), RS1000343132 (19:46317650 A>G,T), RS1000450407 (19:46311774 T>C), RS1000540675 (19:46299433 G>A,C), RS1000563191 (19:46339319 G>A), RS1000571939 (19:46299683 C>T), RS1000585438 (19:46338285 T>C), RS1000647829 (19:46339795 A>C,G)

Disease associations

OMIM: gene MIM:609976 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

220 associations (top):

Study	Trait	p-value
GCST002366_8	Response to anti-retroviral therapy (ddI/d4T) in HIV-1 infection (Grade 1 peripheral neuropathy)	3.000000e-06
GCST005449_10	Total triglycerides levels	1.000000e-08
GCST005449_11	Total triglycerides levels	1.000000e-08
GCST005449_12	Total triglycerides levels	1.000000e-08
GCST005449_13	Total triglycerides levels	1.000000e-08
GCST005449_14	Total triglycerides levels	1.000000e-08
GCST005449_15	Total triglycerides levels	1.000000e-08
GCST005449_16	Total triglycerides levels	1.000000e-08
GCST005449_17	Total triglycerides levels	1.000000e-08
GCST005449_18	Total triglycerides levels	1.000000e-08
GCST005449_19	Total triglycerides levels	1.000000e-08
GCST005449_20	Total triglycerides levels	1.000000e-08
GCST005449_21	Total triglycerides levels	1.000000e-08
GCST005449_22	Total triglycerides levels	1.000000e-08
GCST005449_23	Total triglycerides levels	1.000000e-08
GCST005449_24	Total triglycerides levels	1.000000e-08
GCST005449_6	Total triglycerides levels	5.000000e-08
GCST005449_7	Total triglycerides levels	1.000000e-08
GCST005449_8	Total triglycerides levels	1.000000e-08
GCST005449_9	Total triglycerides levels	1.000000e-08
GCST005453_10	Very large VLDL particle concentration	3.000000e-08
GCST005453_11	Very large VLDL particle concentration	3.000000e-08
GCST005453_12	Very large VLDL particle concentration	3.000000e-08
GCST005453_13	Very large VLDL particle concentration	3.000000e-08
GCST005453_14	Very large VLDL particle concentration	3.000000e-08
GCST005453_15	Very large VLDL particle concentration	3.000000e-08
GCST005453_16	Very large VLDL particle concentration	3.000000e-08
GCST005453_17	Very large VLDL particle concentration	3.000000e-08
GCST005453_18	Very large VLDL particle concentration	3.000000e-08
GCST005453_19	Very large VLDL particle concentration	3.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0000180	HIV-1 infection
EFO:0004530	triglyceride measurement
EFO:0008591	free cholesterol measurement
EFO:0004338	body weight

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

43 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases methylation	7
trichostatin A	affects cotreatment, decreases expression	3
Tobacco Smoke Pollution	decreases expression, increases expression	3
cobaltous chloride	decreases expression, increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	2
Doxorubicin	decreases expression	2
Nickel	decreases expression	2
Oxygen	affects binding, increases reaction, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
dicrotophos	increases expression	1
bisphenol A	affects cotreatment, increases expression	1
delphinidin	decreases reaction, increases expression	1
1,10-phenanthroline	decreases expression	1
cobalt sulfate	decreases expression	1
mercuric bromide	affects cotreatment, decreases expression	1
dinophysistoxin 1	affects expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Vorinostat	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Deferoxamine	increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Estradiol	affects cotreatment, decreases expression	1
Hydrogen Peroxide	decreases reaction, increases expression	1
Indomethacin	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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