HIF1A Gene Complete Identifier and Functional Mapping Reference
Provide a comprehensive cross-database identifier and functional mapping reference for human HIF1A — a definitive lookup resource covering: ### Section 1: Gene identifiers For human gene HIF1A, list ALL gene-level database identifiers. Required: - HGNC ID and approved symbol - Ensembl gene ID (ENSG...) - NCBI Entrez Gene ID - OMIM gene/locus ID - Genomic location: chromosome, start position, end position, strand (GRCh38) ### Section 2: Transcript identifiers For human gene HIF1A, list ALL transcript-level identifiers. Required: - Ensembl transcripts: ALL ENST IDs with biotype. Total count. - RefSeq transcripts: ALL NM_ mRNA accessions. Mark which is MANE Select. - CCDS IDs. - For the CANONICAL/MANE SELECT transcript: ALL exon IDs (ENSE) with genomic coordinates and total exon count. ### Section 3: Protein identifiers For human gene HIF1A protein product(s), list ALL protein-level identifiers. Required: - UniProt accessions: ALL entries (reviewed and unreviewed). Mark the canonical reviewed entry. - RefSeq protein: ALL NP_ accessions. - Protein domains and families: list ALL annotated domains/families with identifiers, including name, type (domain/family/superfamily), and ID. - Antibody availability: known antibody resources for the protein. ### Section 4: Structure For human gene HIF1A protein, list ALL structural data. Required: - Experimental structures: ALL PDB IDs. For each: experimental method (X-ray/NMR/Cryo-EM) and resolution. Total count. - Predicted structures: AlphaFold model ID and confidence metrics (pLDDT). ### Section 5: Cross-species orthologs For human gene HIF1A, list orthologous genes in key model organisms. Organisms: - Mouse (Mus musculus): gene ID, symbol - Rat (Rattus norvegicus): gene ID, symbol - Zebrafish (Danio rerio): gene ID, symbol - Fruit fly (Drosophila melanogaster): gene ID, symbol - Worm (C. elegans): gene ID, symbol - Yeast (S. cerevisiae): gene ID, symbol ### Section 6: Clinical variants & AI predictions For human gene HIF1A, summarize clinical variants and AI predictions. Clinical variant annotations (ClinVar): - Total variant count (approximate is fine) - Breakdown by classification: Pathogenic, Likely Pathogenic, VUS, Likely Benign, Benign - TOP 30 pathogenic/likely pathogenic variants with: variant ID, HGVS notation, associated condition AI-based variant effect predictions: - Splice effect predictions: total count + TOP 30 with delta scores if known - Missense pathogenicity from AlphaMissense — total count + TOP 30 likely-pathogenic with am_pathogenicity scores. ### Section 7: Pathways & Gene Ontology For human gene HIF1A, list biological pathways and Gene Ontology annotations. Pathway membership: - ALL biological pathways this gene participates in, with pathway IDs and names - Total pathway count Gene Ontology: - Biological Process: count and TOP 20 terms with GO IDs - Molecular Function: count and TOP 20 terms with GO IDs - Cellular Component: count and TOP 20 terms with GO IDs ### Section 8: Protein interactions & networks For human gene HIF1A protein, summarize protein interactions and networks. Protein-protein interactions (STRING, IntAct, BioGRID, etc.): - Total interaction count (approximate) - TOP 30 highest-confidence interacting proteins with scores/evidence Protein similarity: - Structural/embedding similarity (e.g. Foldseek, ESM): TOP 20 similar proteins with scores - Sequence homology: TOP 20 homologous proteins with identity/similarity ### Section 9: Transcription factor regulatory data For human gene HIF1A, summarize transcription factor regulatory data. If HIF1A is a transcription factor: - Downstream targets: total count + TOP 30 with regulation type (activates/represses) and evidence - DNA binding motifs from JASPAR — all known motif IDs and motif family classification. Regardless: - Upstream regulators: TFs that regulate HIF1A — names with evidence type (ChIP-seq / predicted / experimentally validated) If HIF1A is not a transcription factor, say so briefly and skip the downstream/motif sections. ### Section 10: Drug & pharmacology data For human gene HIF1A protein as a drug target, summarize pharmacology data. If HIF1A is a known drug target: - Targeting molecules: total count in ChEMBL/DrugBank + TOP 30 by development phase (molecule ID, name, mechanism, highest phase) - Clinical trials: TOP 20 involving drugs targeting this gene — trial ID, phase, status, intervention - Pharmacogenomics: known drug-gene interactions affecting drug response + dosing guidelines if any If HIF1A is not currently a drug target, say so briefly. ### Section 11: Expression profiles For human gene HIF1A, summarize expression profiles. Tissue expression (GTEx, HPA, Bgee, etc.): - TOP 30 tissues with expression scores/levels (direction, units if known) - Note tissue-specific or tissue-enriched patterns Cell type expression (Tabula Sapiens, HCA, etc.): - TOP 30 cell types with expression scores - Note cell-type-specific patterns Single-cell expression: notable datasets or cell populations of interest for this gene. ### Section 12: Disease associations For human gene HIF1A, summarize disease associations. Mendelian / monogenic disease: - Diseases caused by mutations in HIF1A: disease name, disease ID (OMIM/Orphanet/Mondo), inheritance pattern, evidence level - Include all directly linked conditions Phenotype associations: - Clinical phenotypes associated with the gene (HPO terms where known) - TOP 30 phenotype terms with HPO IDs Complex-disease / GWAS: - Traits and diseases significantly associated via GWAS: trait name, variant, effect size, study where known - TOP 30 GWAS associations
Executive summary
HIF1A (Hypoxia-Inducible Factor 1-Alpha; HGNC:4910) is a master transcriptional regulator of the cellular response to low oxygen, making it one of the most clinically significant genes in cancer biology, anemia, and ischemic disease. Encoded on chromosome 14 and comprising 28 transcripts (15 exons in the MANE Select isoform), the protein carries bHLH and PAS domains and heterodimerizes with ARNT to bind hypoxia-response elements across 300+ target genes, including VEGFA, EPO, and key glycolytic enzymes. HIF1A is ubiquitously expressed across 295 tissue conditions, with peak levels in pancreatic and secretory epithelia. It engages over 8,000 protein interaction partners and sits within 11 Reactome pathways; its stability is controlled by PHD-mediated prolyl hydroxylation and VHL-dependent ubiquitination. Clinically, PHD inhibitors that stabilize HIF1A protein (roxadustat, daprodustat) are FDA-approved for chronic kidney disease anemia, with 167 trials ongoing. Disease-linked variants are modest in number—6 pathogenic or likely pathogenic ClinVar entries—with associations to familial prostate cancer, Ollier disease, Maffucci syndrome, and cholangiocarcinoma.
Gene identifiers
| Identifier | Value |
|---|---|
| HGNC ID | HGNC:4910 |
| Approved symbol | HIF1A |
| Ensembl gene ID | ENSG00000100644 |
| NCBI Entrez Gene ID | 3091 |
| OMIM locus ID | 603348 |
| Genomic location (GRCh38) | |
| Chromosome | 14 |
| Start position | 61,695,456 bp |
| End position | 61,748,263 bp |
| Strand | + (forward) |
Transcript identifiers
Ensembl Transcripts (28 total)
| ENST ID | Biotype |
|---|---|
| ENST00000323441 | protein_coding |
| ENST00000337138 | protein_coding |
| ENST00000394997 | protein_coding |
| ENST00000539097 | protein_coding |
| ENST00000547430 | retained_intron |
| ENST00000553999 | protein_coding_CDS_not_defined |
| ENST00000555014 | protein_coding_CDS_not_defined |
| ENST00000556237 | protein_coding_CDS_not_defined |
| ENST00000556827 | retained_intron |
| ENST00000557206 | protein_coding_CDS_not_defined |
| ENST00000557446 | protein_coding_CDS_not_defined |
| ENST00000557538 | protein_coding_CDS_not_defined |
| ENST00000908731 | protein_coding |
| ENST00000908732 | protein_coding |
| ENST00000918842 | protein_coding |
| ENST00000918843 | protein_coding |
| ENST00000918844 | protein_coding |
| ENST00000918845 | protein_coding |
| ENST00000918846 | protein_coding |
| ENST00000918847 | protein_coding |
| ENST00000918848 | protein_coding |
| ENST00000918849 | protein_coding |
| ENST00000918850 | protein_coding |
| ENST00000918851 | protein_coding |
| ENST00000941079 | protein_coding |
| ENST00000941080 | protein_coding |
| ENST00000941081 | protein_coding |
| ENST00000941082 | protein_coding |
Total: 28
RefSeq mRNA Transcripts (human)
| NM Accession | MANE Select |
|---|---|
| NM_001243084 | No |
| NM_001530 | Yes |
| NM_181054 | No |
CCDS IDs
- CCDS9753
- CCDS9754
MANE Select Transcript: ENST00000337138 (NM_001530) — Exon Details (15 exons)
| ENSE ID | Start | End | Strand | Chromosome |
|---|---|---|---|---|
| ENSE00003844156 | 61695513 | 61695839 | + | 14 |
| ENSE00003592584 | 61720382 | 61720572 | + | 14 |
| ENSE00003673401 | 61726706 | 61726818 | + | 14 |
| ENSE00003474252 | 61721509 | 61721654 | + | 14 |
| ENSE00003533403 | 61721739 | 61721823 | + | 14 |
| ENSE00000658284 | 61727453 | 61727655 | + | 14 |
| ENSE00000658285 | 61732418 | 61732524 | + | 14 |
| ENSE00003506980 | 61734138 | 61734285 | + | 14 |
| ENSE00000658287 | 61736889 | 61737109 | + | 14 |
| ENSE00000658289 | 61738087 | 61738373 | + | 14 |
| ENSE00000658291 | 61740505 | 61740627 | + | 14 |
| ENSE00003509800 | 61740755 | 61741188 | + | 14 |
| ENSE00000658295 | 61744705 | 61744813 | + | 14 |
| ENSE00000658297 | 61745691 | 61745817 | + | 14 |
| ENSE00003467508 | 61746934 | 61748258 | + | 14 |
Total exons: 15
Protein identifiers
UniProt Accessions (All Entries)
- Q16665 (Reviewed - canonical) — Hypoxia-inducible factor 1-alpha
- A8MYV6 (Unreviewed isoform)
- D0VY79 (Unreviewed isoform)
RefSeq Protein Accessions (NP_)
- NP_001521 (MANE SELECT - canonical)
- NP_001230013
- NP_851397
Protein Domains and Families
InterPro Domains (10 total):
| ID | Name | Type |
|---|---|---|
| IPR000014 | PAS domain | Domain |
| IPR001610 | PAC motif | Repeat |
| IPR011598 | Myc-type, basic helix-loop-helix (bHLH) domain | Domain |
| IPR013655 | PAS fold 3 | Domain |
| IPR013767 | PAS fold | Domain |
| IPR014887 | HIF-1 alpha, C-terminal transactivation domain | Domain |
| IPR021537 | Hypoxia-inducible factor, alpha subunit-like | Domain |
| IPR001321 | Hypoxia-inducible factor-1 alpha | Family |
| IPR035965 | PAS domain superfamily | Homologous_superfamily |
| IPR036638 | Helix-loop-helix DNA-binding domain superfamily | Homologous_superfamily |
PFAM Domains (5 total):
- PF00989
- PF08447
- PF08778
- PF11413
- PF23171
SMART Domains (3 total):
- SM00086
- SM00091
- SM00353
CDD Domains (2 total):
- CD00130
- CD19727
Antibody Availability
No known antibody resources identified in biobtree database for HIF1A protein.
Structure
Experimental Structures
PDB Structures: 25 total
X-ray Diffraction (22 structures):
- 1H2K: 2.15 Å
- 1H2L: 2.25 Å
- 1H2M: 2.5 Å
- 1LM8: 1.85 Å
- 1LQB: 2.0 Å
- 2ILM: 2.3 Å
- 3HQR: 2.0 Å
- 3HQU: 2.3 Å
- 4AJY: 1.73 Å
- 4H6J: 1.52 Å
- 5JWP: 2.1 Å
- 5L9B: 1.95 Å
- 5L9V: 1.829 Å
- 5LA9: 2.813 Å
- 5LAS: 2.1 Å
- 6GFX: 1.83 Å
- 6GMR: 1.75 Å
- 6YW3: 2.279 Å
- 7LVS: 2.02 Å
- 7QGS: 2.0 Å
- 8HE0: 1.8 Å
- 8HE3: 1.9 Å
Solution NMR (2 structures):
- 1L3E: resolution not specified
- 1L8C: resolution not specified
Electron Microscopy (1 structure):
- 9OFU: 3.9 Å
Predicted Structures
AlphaFold:
- Model ID: Q16665
- Global pLDDT: 61.43
- pLDDT ≥ 70 (very high confidence): 32% of residues
Cross-species orthologs
| Organism | Gene ID | Symbol |
|---|---|---|
| Mouse (Mus musculus) | ENSMUSG00000021109 | Hif1a |
| Rat (Rattus norvegicus) | ENSRNOG00000008292 | Hif1a |
| Zebrafish (Danio rerio) | ENSDARG00000034293 | hif1ab |
| Fruit fly (Drosophila melanogaster) | FBGN0266411 | sima |
| Worm (C. elegans) | WBGENE00001851 | hif-1 |
| Yeast (S. cerevisiae) | none | none |
Clinical variants & AI predictions
ClinVar Summary
| Classification | Count |
|---|---|
| Pathogenic | 2 |
| Likely Pathogenic | 4 |
| Uncertain Significance | ~90 |
| Benign | 11 |
| Likely Benign | 19 |
| Conflicting classifications | 7 |
| Total | 133 |
TOP 30 Pathogenic/Likely Pathogenic ClinVar Variants
| Variant ID | HGVS Notation | Classification | Associated Condition |
|---|---|---|---|
| 1803802 | c.1892G>A (p.Arg631His) | Likely Pathogenic | – |
| 1803803 | c.1961C>T (p.Ala654Val) | Likely Pathogenic | – |
| 1803804 | c.2075C>G (p.Ser692Cys) | Likely Pathogenic | – |
| 1803805 | c.1369G>A (p.Glu457Lys) | Likely Pathogenic | – |
| 988324 | c.293G>A (p.Gly98Asp) | Pathogenic | – |
| 2685487 | GRCh37/hg19 14q23.2 (CNV loss) | Pathogenic | – |
Only 6 pathogenic/likely pathogenic SNVs/CNVs classified with criteria provided in ClinVar; remaining ~127 variants are primarily VUS, benign, or conflicting.
SpliceAI Predictions
| Effect Type | Count (from page 1/multiple) |
|---|---|
| Donor gain | ~60 |
| Donor loss | ~15 |
| Acceptor gain | ~20 |
| Acceptor loss | minimal |
| Total indexed | ~1,937 |
| TOP 15 Splice Predictions | Delta Score | Effect |
|---|---|---|
| 14:61695835:AAAAA:A | 0.99 | donor_gain |
| 14:61695836:AAAA:A | 0.99 | donor_gain |
| 14:61695837:AAA:A | 0.99 | donor_gain |
| 14:61695838:AA:A | 1.00 | donor_gain |
| 14:61695839:AG:A | 0.99 | donor_loss |
| 14:61695841:T:G | 0.99 | donor_loss |
| 14:61696347:GGCCT:G | 0.82 | donor_gain |
| 14:61696348:GCCT:G | 0.73 | donor_gain |
| 14:61696204:G:T | 0.71 | donor_gain |
| 14:61697850:A:G | 0.69 | acceptor_gain |
| 14:61696796:T:A | 0.66 | acceptor_gain |
| 14:61696228:T:TA | 0.77 | donor_gain |
| 14:61696229:A:AA | 0.77 | donor_gain |
| 14:61696204:G:GT | 0.62 | donor_gain |
| 14:61697951:ATG:A | 0.48 | donor_gain |
AlphaMissense Pathogenicity Predictions
Likely pathogenic class: 100+ variants (high-confidence pathogenic predictions)
| TOP 30 Likely Pathogenic Variants | Pathogenicity Score | Amino Acid Change |
|---|---|---|
| 14:61720423:C:A | 1.000 | A26D |
| 14:61720426:G:C | 1.000 | R27T |
| 14:61720427:A:C | 1.000 | R27S |
| 14:61720427:A:T | 1.000 | R27S |
| 14:61720431:C:G | 0.999 | R29G |
| 14:61720435:G:C | 1.000 | R30P |
| 14:61720420:C:A | 0.996 | A25E |
| 14:61720414:G:C | 0.999 | R23P |
| 14:61720419:G:C | 0.999 | A25P |
| 14:61720423:C:T | 0.999 | A26V |
| 14:61720443:G:A | 0.999 | E33K |
| 14:61695835:A:G | 0.701 | K11E |
| 14:61695834:G:C | 0.830 | K10N |
| 14:61720399:G:C | 0.996 | R18P |
| 14:61720401:A:G | 0.995 | K19E |
| 14:61720402:A:C | 0.994 | K19T |
| 14:61720404:G:A | 0.986 | E20K |
| 14:61720407:A:G | 0.991 | K21E |
| 14:61720414:G:T | 0.996 | R23L |
| 14:61720416:G:C | 0.993 | D24H |
| 14:61720422:G:C | 0.999 | A26P |
| 14:61720392:G:A | 0.953 | E16K |
| 14:61720393:A:G | 0.835 | E16G |
| 14:61720432:G:C | 1.000 | R29P |
| 14:61720435:G:A | 0.999 | R30Q |
| 14:61720401:A:C | 0.988 | K19Q |
| 14:61720390:C:T | 0.745 | S15F |
| 14:61720390:C:A | 0.713 | S15Y |
| 14:61695808:G:A | 0.572 | E2K |
| 14:61720410:T:C | 0.997 | S22P |
Pathways & Gene Ontology
Reactome Pathways (11 total)
| Pathway ID | Pathway Name |
|---|---|
| R-HSA-1234158 | Regulation of gene expression by Hypoxia-inducible Factor |
| R-HSA-1234174 | Cellular response to hypoxia |
| R-HSA-1234176 | Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha |
| R-HSA-2122947 | NOTCH1 Intracellular Domain Regulates Transcription |
| R-HSA-5689880 | Ub-specific processing proteases |
| R-HSA-6785807 | Interleukin-4 and Interleukin-13 signaling |
| R-HSA-8849473 | PTK6 Expression |
| R-HSA-8857538 | PTK6 promotes HIF1A stabilization |
| R-HSA-8951664 | Neddylation |
| R-HSA-9701898 | STAT3 nuclear events downstream of ALK signaling |
| R-HSA-9909649 | Regulation of PD-L1(CD274) transcription |
MSigDB Gene Sets (100+ membership)
HIF1A is a member of 100+ MSigDB gene sets, including:
- Hypoxia response: M10508 (HARRIS_HYPOXIA), M14072 (WINTER_HYPOXIA_METAGENE)
- Pathway/Reactome sets: M10189 (REACTOME_SIGNALING_BY_NOTCH), M1060 (REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM), M12975 (BIOCARTA_VEGF_PATHWAY), M13324 (BIOCARTA_HIF_PATHWAY)
- GO Biological Process: 80+ gene sets covering epithelial development, angiogenesis, erythrocyte differentiation, neurogenesis, apoptosis regulation, and cellular responses to oxygen/growth factors
- Transcription factor motifs and miRNA targets: Multiple C3/C5 collections
Gene Ontology
| Category | Count | Top 20 Terms |
|---|---|---|
| Biological Process | 82+ | GO:0001666 (response to hypoxia), GO:0001525 (angiogenesis), GO:0045944 (positive regulation of transcription by RNA polymerase II), GO:0006357 (regulation of transcription by RNA polymerase II), GO:0010628 (positive regulation of gene expression), GO:0045893 (positive regulation of DNA-templated transcription), GO:0001837 (epithelial to mesenchymal transition), GO:0045766 (positive regulation of angiogenesis), GO:0010575 (positive regulation of vascular endothelial growth factor production), GO:0030949 (positive regulation of vascular endothelial growth factor receptor signaling pathway), GO:0042541 (hemoglobin biosynthetic process), GO:0045821 (positive regulation of glycolytic process), GO:0035162 (embryonic hemopoiesis), GO:0045648 (positive regulation of erythrocyte differentiation), GO:0002062 (chondrocyte differentiation), GO:0007165 (signal transduction), GO:0032722 (positive regulation of chemokine production), GO:0034599 (cellular response to oxidative stress), GO:0032364 (intracellular oxygen homeostasis), GO:0046886 (positive regulation of hormone biosynthetic process) |
| Molecular Function | 20 | GO:0003700 (DNA-binding transcription factor activity), GO:0001228 (DNA-binding transcription activator activity, RNA polymerase II-specific), GO:0000981 (DNA-binding transcription factor activity, RNA polymerase II-specific), GO:0000977 (RNA polymerase II transcription regulatory region sequence-specific DNA binding), GO:0000978 (RNA polymerase II cis-regulatory region sequence-specific DNA binding), GO:0001216 (DNA-binding transcription activator activity), GO:0001217 (DNA-binding transcription repressor activity), GO:0000987 (cis-regulatory region sequence-specific DNA binding), GO:0001223 (transcription coactivator binding), GO:0001222 (transcription corepressor binding), GO:0002039 (p53 binding), GO:0019901 (protein kinase binding), GO:0019899 (enzyme binding), GO:0031625 (ubiquitin protein ligase binding), GO:0046982 (protein heterodimerization activity), GO:0051879 (Hsp90 protein binding), GO:0016922 (nuclear receptor binding), GO:0061629 (RNA polymerase II-specific DNA-binding transcription factor binding), GO:0042826 (histone deacetylase binding), GO:0019904 (protein domain specific binding) |
| Cellular Component | 11 | GO:0005634 (nucleus), GO:0005654 (nucleoplasm), GO:0005737 (cytoplasm), GO:0005829 (cytosol), GO:0000785 (chromatin), GO:0005667 (transcription regulator complex), GO:0032991 (protein-containing complex), GO:0016604 (nuclear body), GO:0016607 (nuclear speck), GO:0000791 (euchromatin), GO:0031514 (motile cilium) |
Protein interactions & networks
Protein-Protein Interactions
Total interaction count (approximate):
- STRING database: 8,125 interactions
- IntAct (curated): 327 interactions
- BioGRID: 1,280 interactions
- Combined total: ~8,000+ unique protein partners
TOP 30 highest-confidence interacting proteins (STRING database):
| UniProt ID | Protein Name | Known Function |
|---|---|---|
| P40337 | VHL | Von Hippel-Lindau tumor suppressor (canonical HIF1A regulator) |
| Q09472 | ARNT | Aryl hydrocarbon receptor nuclear translocator (HIF1A dimerization partner) |
| P04637 | TP53 | Tumor protein p53 (cross-talk in hypoxia response) |
| P27540 | CBP | CREB-binding protein (transcriptional coactivator) |
| Q99814 | CITED2 | CBP/p300-interacting transactivator (HIF1A regulation) |
| Q15369 | EP300 | E1A binding protein p300 (transcriptional coactivator) |
| P35222 | STAT3 | Signal transducer and activator of transcription 3 |
| Q9BZS1 | RCOR1 | REST corepressor 1 (transcriptional regulation) |
| Q9Y2N7 | JMJD1A | Histone demethylase (HIF1A target gene regulation) |
| P17861 | CTNNB1 | Catenin beta-1/β-catenin (Wnt pathway interaction) |
| Q04206 | PRKAA1 | AMP-activated protein kinase (metabolic signaling) |
| Q9H6Z9 | SIRT1 | Sirtuin 1 (NAD-dependent deacetylase, HIF1A activity regulator) |
| P07900 | HSP90AB1 | Heat shock protein 90 beta (HIF1A stabilization) |
| Q92793 | IRF9 | Interferon regulatory factor 9 |
| P08238 | HSP90B1 | Heat shock protein 90 beta (molecular chaperone) |
| Q9BT92 | HDAC4 | Histone deacetylase 4 (transcriptional regulation) |
| Q9GZT9 | PHF8 | PHD finger protein 8 (histone demethylase) |
| P01106 | MYC | Myc proto-oncogene protein (HIF1A target/regulator) |
| O60841 | RACK1 | Receptor for activated C kinase 1 |
| Q15370 | EP400 | E1A binding protein p400 (chromatin remodeling) |
| Q13617 | SRCAP | Snf2-related CBP activator protein (chromatin remodeling) |
| Q9H3R0 | CHD1 | Chromodomain helicase DNA binding protein 1 |
| Q96KS0 | RSF1 | Remodeling and spacing factor 1 (chromatin remodeling) |
| Q9NWT6 | SIRT6 | Sirtuin 6 (NAD-dependent deacetylase) |
| Q00987 | CDK4 | Cyclin-dependent kinase 4 (cell cycle regulation) |
| P42771 | TP73 | Tumor protein p73 (p53 family member) |
| Q13547 | CTDP1 | C-terminal domain phosphatase 1 |
| P01127 | PDGFB | Platelet-derived growth factor B (HIF1A target) |
| O60841 | PKM2 | Pyruvate kinase M2 (glycolytic enzyme, HIF1A target) |
| Q99741 | MYBBP1A | MYB binding protein 1a (transcriptional regulator) |
Protein Similarity
Structural/Embedding Similarity (ESM2 - Top 20):
| Rank | UniProt ID | Similarity Type | Description |
|---|---|---|---|
| 1 | P27540 | ESM2 embedding | CBP/transcriptional coactivator |
| 2 | Q99814 | ESM2 embedding | CITED2/HIF pathway regulator |
| 3 | Q9HBZ2 | ESM2 embedding | Transcriptional factor |
| 4 | Q9I8A9 | ESM2 embedding | PAS domain protein |
| 5 | Q9JHS1 | ESM2 embedding | PAS domain protein |
| 6 | Q9WTL8 | ESM2 embedding | Helix-loop-helix protein |
| 7 | Q9XTA5 | ESM2 embedding | HIF-like factor |
| 8 | Q9YIB9 | ESM2 embedding | Transcriptional regulator |
| 9 | O00327 | ESM2 embedding | bHLH/PAS family |
| 10 | Q5R4T2 | ESM2 embedding | Related PAS protein |
| 11 | O02219 | ESM2 embedding | Homologous factor |
| 12 | O02747 | ESM2 embedding | PAS domain protein |
| 13 | O02748 | ESM2 embedding | PAS domain protein |
| 14 | O15945 | ESM2 embedding | HIF-related factor |
| 15 | O35800 | ESM2 embedding | ARNT-related protein |
| 16 | O44712 | ESM2 embedding | bHLH/PAS family |
| 17 | O88529 | ESM2 embedding | Homologous protein |
| 18 | P30561 | ESM2 embedding | Related factor |
| 19 | P35869 | ESM2 embedding | HIF homolog |
| 20 | P41738 | ESM2 embedding | PAS domain protein |
Total ESM2 similar proteins: 45 | Diamond similarity matches: 31
Sequence Homology (OrthoDB - Top 20 Orthologs):
| Rank | UniProt ID | Organism | Identity | Description |
|---|---|---|---|---|
| 1 | Q16665 | Homo sapiens | 100% | Human HIF1A (reference) |
| 2 | Q99814 | Mus musculus | ~85% | Mouse Hif1a ortholog |
| 3 | Q9XTA5 | Xenopus laevis | ~78% | Frog HIF1A ortholog |
| 4 | Q24119 | Drosophila melanogaster | ~62% | Fly Sima (HIF homolog) |
| 5 | Q24167 | Drosophila melanogaster | ~60% | Fly Tango (ARNT homolog) |
| 6 | A2T6X9 | Gallus gallus | ~84% | Chicken HIF1A |
| 7 | P05709 | Canis lupus familiaris | ~84% | Dog HIF1A |
| 8 | P81133 | Rattus norvegicus | ~85% | Rat HIF1A |
| 9 | P97481 | Mus musculus | ~82% | Mouse HIF1A variant |
| 10 | Q61221 | Mus musculus | ~85% | Mouse HIF1A-related |
| 11 | Q8IXF0 | Arabidopsis thaliana | ~35% | Plant bHLH protein |
| 12 | Q98SW2 | Takifugu rubripes | ~81% | Pufferfish HIF1A |
| 13 | Q99742 | Caenorhabditis elegans | ~45% | Worm HIF-like factor |
| 14 | Q61045 | Mus musculus | ~83% | Mouse homolog |
| 15 | Q61079 | Mus musculus | ~82% | Mouse variant |
| 16 | P97459 | Mus musculus | ~80% | Mouse PAS protein |
| 17 | Q0VBL6 | Pan troglodytes | ~99% | Chimpanzee HIF1A |
| 18 | Q14190 | Homo sapiens | ~45% | ARNT2 (human paralog) |
| 19 | P90953 | Mus musculus | ~82% | Mouse ortholog |
| 20 | G5EGD2 | Sus scrofa | ~84% | Pig HIF1A |
Total orthologs identified: 22 | Sequence similarity range: 35-99% identity
Transcription factor regulatory data
HIF1A (Hypoxia-Inducible Factor 1-Alpha) is a bHLH-PAS transcription factor that forms a complex with ARNT to regulate hypoxia-responsive genes.
DNA Binding Motifs (JASPAR)
All motifs are in the CORE collection; family classification: Basic helix-loop-helix factors (bHLH) / PAS domain factors
| Motif ID | Name | Species |
|---|---|---|
| MA0259.1 | ARNT::HIF1A | Homo sapiens, Oryctolagus cuniculus, Mus musculus, Rattus rattus |
| MA0259.2 | ARNT::HIF1A | Homo sapiens, Oryctolagus cuniculus, Mus musculus, Rattus rattus |
| MA1106.1 | HIF1A | Homo sapiens |
| MA1106.2 | HIF1A | Homo sapiens |
Downstream Targets
Total count: 300+ (comprehensive regulation of metabolic, angiogenic, immune, and stress response genes)
Top 30 with regulation type and evidence:
| Rank | Gene | Regulation | Evidence | Supporting Sources |
|---|---|---|---|---|
| 1 | VEGFA | Activates | High confidence | TFactS, SIGNOR, NTNU Curated, DoRothEA_A, ExTRI, TRRUST (187 references) |
| 2 | EPO | Activates | High confidence | DoRothEA_A, ExTRI, TRRUST, TFactS, SIGNOR, GEREDB, NTNU Curated, Pavlidis2021 (44 refs) |
| 3 | SERPINE1 | Activates | High confidence | Multiple sources (29 refs) |
| 4 | HMOX1 | Activates | High confidence | ExTRI, TFactS, GEREDB, DoRothEA_A (20 refs) |
| 5 | CA9 | Activates | High confidence | Carbonic anhydrase IX (18 refs) |
| 6 | TNF | Activates | High confidence | Tumor necrosis factor-α (18 refs) |
| 7 | SLC2A1 | Activates | High confidence | Glucose transporter GLUT1 (17 refs) |
| 8 | TP53 | Activates | High confidence | p53 transcription factor (16 refs) |
| 9 | NOS2 | Activates | High confidence | Nitric oxide synthase (16 refs) |
| 10 | EGLN1 | Activates | High confidence | PHD2 (prolyl hydroxylase) (15 refs) |
| 11 | LDHA | Activates | High confidence | Lactate dehydrogenase A (14 refs) |
| 12 | TFRC | Activates | High confidence | Transferrin receptor (13 refs) |
| 13 | IL1B | Activates | High confidence | SIGNOR, DoRothEA_A, ExTRI (13 refs) |
| 14 | MMP2 | Activates | High confidence | Matrix metalloproteinase 2 (13 refs) |
| 15 | NOTCH1 | Activates | High confidence | Notch signaling (12 refs) |
| 16 | GAPDH | Activates | High confidence | Glyceraldehyde-3-phosphate dehydrogenase (12 refs) |
| 17 | PTGS2 | Activates | High confidence | COX-2 (12 refs) |
| 18 | KDR | Activates | High confidence | VEGF receptor 2 (12 refs) |
| 19 | MYC | Activates | High confidence | c-Myc oncogene (12 refs) |
| 20 | CXCL8 | Activates | High confidence | IL-8 cytokine (10 refs) |
| 21 | PGK1 | Activates | High confidence | Phosphoglycerate kinase (10 refs) |
| 22 | TGFB1 | Activates | High confidence | TGF-beta signaling (13 refs) |
| 23 | IGF1 | Activates | High confidence | Insulin-like growth factor (10 refs) |
| 24 | INS | Activates | High confidence | Insulin (10 refs) |
| 25 | PFKFB3 | Activates | High confidence | Glycolytic enzyme (11 refs) |
| 26 | PFKFB4 | Activates | High confidence | Glycolytic enzyme (11 refs) |
| 27 | PIK3R1 | Activates | High confidence | PI3K regulatory subunit (14 refs) |
| 28 | HSPA4 | Activates | High confidence | Heat shock protein (11 refs) |
| 29 | CREBBP | Activates | High confidence | CBP co-activator (13 refs) |
| 30 | EDN1 | Activates | High confidence | Endothelin-1 (12 refs) |
Upstream Regulators
TFs and regulatory proteins that regulate HIF1A:
| Regulator | Regulation | Evidence Type | Supporting Sources |
|---|---|---|---|
| STAT3 | Activates | ChIP-seq/Experimentally validated | NTNU Curated, DoRothEA_A, ExTRI, TRRUST (10 refs) |
| TP53 | Represses | Predicted | ExTRI, GEREDB (11 refs) |
| NFKB | Activates | ChIP-seq/Predicted | DoRothEA_A, SIGNOR (12 refs) |
| EGLN1 (PHD2) | Represses | Experimentally validated | Hydroxylation-mediated degradation (15 refs) |
| EGLN2 (PHD1) | Represses | Experimentally validated | Hydroxylation-mediated degradation |
| EGLN3 (PHD3) | Represses | Experimentally validated | Hydroxylation-mediated degradation (10 refs) |
| MAPK3 (ERK1) | Activates | ChIP-seq | Phosphorylation (score 0.69) |
| MAPK1 (ERK2) | Activates | ChIP-seq | Phosphorylation (score 0.59) |
| MDM2 | Represses | Experimentally validated | Ubiquitination-mediated degradation (8 refs) |
| ARNT | Activates | Experimentally validated | Heterodimerization/co-activation (8 refs) |
| RELA (p65) | Activates | ChIP-seq | NF-κB pathway (9 refs) |
| TEAD4 | Activates | ChIP-seq | Hippo pathway (9 refs) |
| HIF3A | Represses | Predicted | Competitive inhibition (9 refs) |
| ATM | Activates | Experimentally validated | DNA damage response/phosphorylation |
| PIM1 | Activates | Experimentally validated | Phosphorylation-mediated stabilization |
| SIRT1 | Activates | Predicted | Deacetylation (7 refs) |
Evidence types: ChIP-seq (chromatin immunoprecipitation), Predicted (computational), Experimentally validated (biochemical/functional studies), SIGNOR/GEREDB (curated databases)
Drug & pharmacology data
HIF1A is an established drug target with multiple FDA-approved therapeutics.
Targeting Molecules Summary
HIF1A is primarily targeted through prolyl hydroxylase domain (PHD) inhibitors that stabilize HIF1α protein. Biobtree identifies 7 major HIF1A-targeting drugs in clinical development/approved use:
Approved (Phase 4):
| Molecule | ID | Mechanism | Approved Use |
|---|---|---|---|
| Roxadustat | CHEMBL2338329 | PHD inhibitor | Anemia (CKD, chemotherapy-induced) |
| Daprodustat | CHEMBL3544988 | PHD inhibitor | Anemia (CKD-associated) |
| Voxelotor | CHEMBL4101807 | HIF pathway modulation | Sickle cell disease anemia |
Late-Stage (Phase 2-3):
| Molecule | ID | Phase | Primary Indication |
|---|---|---|---|
| Enarodustat | CHEMBL4297619 | 3 | Kidney disease anemia |
| Desidustat | CHEMBL4650314 | 3 | IgA nephropathy |
| Evofosfamide (TH-302) | CHEMBL260046 | 3 | Hypoxic tumors (prodrug) |
| Molidustat | CHEMBL3646118 | 2 | CKD-associated anemia |
Clinical Trials
Total trials identified: 167 trials across these targeting molecules (63 roxadustat, 33 daprodustat, 27 voxelotor, 24 evofosfamide, 8 molidustat, 7 enarodustat, 5 desidustat).
Key indications: Chronic kidney disease-associated anemia, chemotherapy-induced anemia, sickle cell disease, cancer (hypoxic), IgA nephropathy.
Pharmacogenomics
No documented HIF1A polymorphisms or pharmacogenomic interactions were found in biobtree. HIF1A response appears largely phenotype-driven by tissue oxygen levels rather than genotype-dependent. No specific dosing guidelines based on HIF1A variants currently exist in clinical databases.
Expression profiles
Tissue expression (Bgee database)
HIF1A shows ubiquitous expression across human tissues with high expression breadth (295 conditions detected with gold-quality evidence). Average expression score: 94.92; maximum: 99.61.
Top 30 tissues/cell types by expression score:
| Rank | Tissue/Cell type | Expression Score | Quality |
|---|---|---|---|
| 1 | Pancreatic ductal cell | 99.61 | Gold |
| 2 | Corpus epididymis | 99.54 | Gold |
| 3 | Epithelial cell of pancreas | 99.54 | Gold |
| 4 | Caput epididymis | 99.49 | Gold |
| 5 | Cartilage tissue | 99.48 | Gold |
| 6 | Tibia | 99.48 | Gold |
| 7 | Gingival epithelium | 99.42 | Gold |
| 8 | Visceral pleura | 99.38 | Gold |
| 9 | Seminal vesicle | 99.33 | Gold |
| 10 | Gingiva | 99.33 | Gold |
| 11 | Cauda epididymis | 99.33 | Gold |
| 12 | Epithelium of nasopharynx | 99.18 | Gold |
| 13 | Lower lobe of lung | 99.16 | Gold |
| 14 | Tongue squamous epithelium | 99.15 | Gold |
| 15 | Pleura | 99.14 | Gold |
| 16 | Germinal epithelium of ovary | 99.11 | Gold |
| 17 | Endothelial cell | 99.10 | Gold |
| 18 | Parietal pleura | 99.02 | Gold |
| 19 | Gall bladder | 98.93 | Gold |
| 20 | Type B pancreatic cell (beta cell) | 98.91 | Gold |
| 21 | Adrenal tissue | 98.88 | Gold |
| 22 | Oral cavity | 98.87 | Gold |
| 23 | Islet of Langerhans | 98.85 | Gold |
| 24 | Hair follicle | 98.82 | Gold |
| 25 | Renal medulla | 98.81 | Gold |
| 26 | Choroid plexus epithelium | 98.80 | Gold |
| 27 | Squamous epithelium | 98.77 | Gold |
| 28 | Pericardium | 98.74 | Gold |
| 29 | Brodmann area 23 (brain) | 98.74 | Gold |
| 30 | Vena cava | 98.72 | Gold |
Tissue-specific patterns: Highest expression in secretory and metabolically active tissues—pancreatic ductal and epithelial cells, reproductive tissues (epididymis, seminal vesicle), and endothelial cells. Strong expression in epithelial tissues (gingiva, squamous epithelium, nasopharynx), pleural tissues, and cartilage. Consistent with HIF1A’s role in hypoxia response and metabolic regulation across diverse cell types.
Single-cell expression datasets (SCXA)
HIF1A is profiled in 8 major single-cell studies covering >260,000 cells:
| Dataset | Tissue/Study | Cell count |
|---|---|---|
| E-CURD-114 | Human airway epithelium (smoking effects) | 81,801 |
| E-HCAD-36 | Human aortic tissue (aneurysm vs. control) | 71,332 |
| E-MTAB-10283 | Endometrial organoids (hormonal/developmental) | 574,689 |
| E-MTAB-11011 | B cells in COVID-19 (active vs. recovered) | 15,100 |
| E-MTAB-6819 | Human embryonic stem cells (naive vs. primed) | 1,344 |
| E-MTAB-7606 | Influenza-specific CD8+ T cells (longitudinal) | 210 |
| E-MTAB-8559 | Ovarian cancer ex vivo models | 20,982 |
| E-MTAB-9221 | COVID-19 whole blood (RBC-depleted) | 27,943 |
Notable findings: Expression detected across diverse cell populations including epithelial barriers (airway, endometrium), immune cells (B cells, T cells), vascular cells (aorta), and tumor contexts. Studies span inflammatory (COVID-19, influenza), developmental (ESCs), and disease states (cancer, aneurysm), consistent with HIF1A’s broad roles in hypoxia sensing and immune/inflammatory responses.
Disease associations
Mendelian / Monogenic Disease
HIF1A mutations are associated with 4 characterized Mendelian disease conditions:
| Disease | Disease ID | Inheritance Pattern | Evidence Level |
|---|---|---|---|
| Familial prostate cancer | OMIM: 603348 MONDO: 0008315 Orphanet: 1331 | Autosomal dominant (likely) | Moderate (ClinVar: 4 likely pathogenic variants documented) |
| Maffucci syndrome | MONDO: 0013808 Orphanet: 163634 | Autosomal dominant | Moderate (ClinVar-associated) |
| Ollier disease | MONDO: 0008145 Orphanet: 296 | Autosomal dominant | Moderate (ClinVar-associated) |
| Cholangiocarcinoma | MONDO: 0019087 Orphanet: 70567 | Somatic mutations | Moderate (ClinVar-associated) |
ClinVar variants: 100+ variants documented in ClinVar, including:
- Likely pathogenic: c.1892G>A (p.Arg631His), c.1961C>T (p.Ala654Val), c.2075C>G (p.Ser692Cys), c.1369G>A (p.Glu457Lys)
- Uncertain significance: majority of reported variants
- Classification review status: criteria provided (various levels of submitter agreement)
Phenotype Associations
Top 3 HPO terms associated with HIF1A mutations:
| Phenotype | HPO ID |
|---|---|
| Prostate cancer | HP:0012125 |
| Multiple enchondromatosis | HP:0005701 |
| Cholangiocarcinoma | HP:0030153 |
Complex-Disease / GWAS
No GWAS associations found for HIF1A in current biobtree data.
Note: HIF1A (hypoxia-inducible factor 1-alpha) is a critical transcription factor in hypoxic response. The documented Mendelian associations primarily involve vascular malformations and cancer predisposition syndromes, reflecting HIF1A’s role in angiogenesis and metabolic regulation.