HBB Gene Complete Identifier and Functional Mapping Reference
Provide a comprehensive cross-database identifier and functional mapping reference for human HBB — a definitive lookup resource covering: ### Section 1: Gene identifiers For human gene HBB, 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 HBB, 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 HBB 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 HBB 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 HBB, 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 HBB, 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 HBB, 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 HBB 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 HBB, summarize transcription factor regulatory data. If HBB 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 HBB — names with evidence type (ChIP-seq / predicted / experimentally validated) If HBB is not a transcription factor, say so briefly and skip the downstream/motif sections. ### Section 10: Drug & pharmacology data For human gene HBB protein as a drug target, summarize pharmacology data. If HBB 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 HBB is not currently a drug target, say so briefly. ### Section 11: Expression profiles For human gene HBB, 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 HBB, summarize disease associations. Mendelian / monogenic disease: - Diseases caused by mutations in HBB: 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
HBB (Beta-Globin, HGNC:4827) encodes the beta subunit of adult hemoglobin, the principal oxygen-carrying protein in red blood cells, and is one of the most clinically significant genes in medicine. Its primary interacting partner is HBA1 (alpha-globin), and together they form the functional hemoglobin tetramer responsible for oxygen and carbon dioxide transport. HBB harbors over 1,700 catalogued variants in ClinVar, with 230+ classified as pathogenic or likely pathogenic, causing a spectrum of hemoglobinopathies including beta-thalassemia (primarily deletions and splice mutations) and sickle cell disease (missense variants); these conditions together drive 967 and 214 active clinical trials respectively, with emerging gene therapy approaches such as CTX001 in late-stage development. GWAS data reveal that HBB variants confer extraordinarily strong protection against severe malaria (p < 10⁻⁵⁵), reflecting one of the most powerful known examples of natural selection. The gene is regulated by 71 transcription factors, prominently KLF1 and GATA1, and is expressed at near-maximum levels across blood-forming and immune tissues, serving as a lineage-defining marker across 46 single-cell atlas experiments.
Gene identifiers
HBB (Beta-Globin)
| Identifier | ID |
|---|---|
| HGNC ID | HGNC:4827 |
| Approved Symbol | HBB |
| Ensembl Gene ID | ENSG00000244734 |
| NCBI Entrez Gene ID | 3043 |
| OMIM Gene/Locus ID | 141900 |
Genomic Location (GRCh38/hg38)
- Chromosome: 11
- Start: 5,225,464
- End: 5,229,395
- Strand: − (minus/reverse)
Transcript identifiers
Ensembl transcripts (7 total)
| ENST ID | Biotype |
|---|---|
| ENST00000335295 | protein_coding |
| ENST00000380315 | protein_coding |
| ENST00000475226 | retained_intron |
| ENST00000485743 | protein_coding |
| ENST00000633227 | nonsense_mediated_decay |
| ENST00000647020 | protein_coding |
| ENST00000883533 | protein_coding |
RefSeq transcripts
| NM accession | Status | MANE Select |
|---|---|---|
| NM_000518 | REVIEWED | ✓ |
| NM_033234 | PROVISIONAL |
CCDS
- CCDS7753
Canonical/MANE Select transcript exons (ENST00000335295)
Total exons: 3
| Exon ID | Start | End | Chromosome |
|---|---|---|---|
| ENSE00001600613 | 5225464 | 5225726 | 11 |
| ENSE00001057381 | 5226577 | 5226799 | 11 |
| ENSE00001829867 | 5226930 | 5227071 | 11 |
Protein identifiers
UniProt Accessions
- P68871 (reviewed/canonical) - Hemoglobin subunit beta
- A0A0J9YWK4 (unreviewed isoform)
- A0A2R8Y7R2 (unreviewed isoform)
- D9YZU5 (unreviewed isoform)
- F8W6P5 (unreviewed isoform)
RefSeq Protein Identifiers
- NP_000509 (REVIEWED, MANE Select)
Protein Domains and Families
InterPro:
- IPR000971 | Globin | Domain
- IPR002337 | Hemoglobin, beta-type | Family
- IPR009050 | Globin-like superfamily | Homologous_superfamily
- IPR012292 | Globin/Protoglobin | Homologous_superfamily
- IPR050056 | Hemoglobin and related oxygen transporters | Family
Pfam:
- PF00042 | Globin | Domain
PANTHER:
- PTHR11442 | Hemoglobin beta globins | Family
- PTHR11442:SF42 | Hemoglobin beta-1 | Subfamily
CDD (Conserved Domain Database):
- CD08925 | Globin/related proteins | Domain
CATHGENE3D:
- 1.10.490.10 | Globin domain | Superfamily
Antibody Availability
No antibody resources identified in biobtree for HBB protein.
Structure
Experimental Structures
Total PDB Entries: 100 unique structures
X-ray Crystallography
Most structures (majority of the 100 entries). Resolution range: 1.07 Å to 4.5 Å. Notable entries include:
- 2W72: 1.07 Å (highest resolution)
- 2DN1, 2DN2, 2DN3, 1IRD: 1.25 Å
- 7DY4: 1.3 Å
- 7DY3: 1.4 Å
- Multiple structures with 1.5-1.9 Å resolutions
- Various mutants and complexes at 2.0-3.3 Å
Key wild-type entries:
- 1HHB, 2HHB, 3HHB, 4HHB: Deoxyhemoglobin (1.74 Å)
- 1HHO: Oxyhemoglobin (2.1 Å)
- 2HCO, 1HCO: Carbonmonoxyhemoglobin (2.7 Å)
Cryo-EM / Electron Microscopy
- 5NI1: 3.2 Å
- 6NBC, 6NBD: 2.8-3.2 Å (methemoglobin states)
- 8WJ0, 8WJ1, 8WJ2: 2.24-2.35 Å (carbonmonoxy, oxy, deoxy forms)
- 9CQM-9CQW: 2.37-3.01 Å (multiple states)
- 7VDE, 7XGY: 3.5-3.6 Å
- 9VIB, 9VIC: 2.26-2.45 Å (R2 and R states)
- Higher resolution complexes: 7PCH (2.89 Å), 8XMP (3.11 Å)
Neutron Diffraction
- 2DXM: 2.1 Å (deoxyhemoglobin)
- 3KMF: 2.0 Å (room temperature TOF)
Solution NMR
- 2H35: Solution structure (no resolution listed)
- 2M6Z: Refined solution structure, carbonmonoxy form (no resolution listed)
Predicted Structures
AlphaFold Model:
- Model ID: P68871
- pLDDT (per-residue confidence): 97.09 (global metric)
- Confidence distribution: 97% of residues with very high confidence (pLDDT > 70)
- Predicted to be highly reliable across the full structure
Cross-species orthologs
| Organism | Gene ID | Symbol |
|---|---|---|
| Mouse (Mus musculus) | ENSMUSG00000052305 | Hbb-bs |
| Rat (Rattus norvegicus) | ENSRNOG00000081310 | Hbb |
| Zebrafish (Danio rerio) | ENSDARG00000045142 | hbae5 |
| Fruit fly (Drosophila melanogaster) | FBGN0027657 | glob1 |
| Worm (C. elegans) | WBGENE00008996 | glb-14 |
| Yeast (S. cerevisiae) | — | none |
Clinical variants & AI predictions
ClinVar Overview
| Classification | Count |
|---|---|
| Pathogenic | ~150 |
| Likely Pathogenic | ~80 |
| Uncertain Significance | ~100 |
| Conflicting | ~30 |
| Likely Benign | ~1,200 |
| Benign | ~150 |
| Total | ~1,706 |
Top Pathogenic/Likely Pathogenic ClinVar Variants
| ClinVar ID | HGVS Notation | Classification | Associated Condition |
|---|---|---|---|
| 1048666 | NC_000011.10:g.5224303_5227790del | Pathogenic | β-Thalassemia |
| 1074556 | NC_000011.9:g.(?_5247393)_5248785del | Pathogenic | β-Thalassemia |
| 1074558 | NC_000011.9:g.(?_5247493)_5248852del | Pathogenic | β-Thalassemia |
| 1074559 | NC_000011.9:g.(?_5239576)_5247294del | Pathogenic | β-Thalassemia |
| 1074561 | NC_000011.9:g.(?_5246696)_5247105del | Pathogenic | β-Thalassemia |
| 1076533 | NC_000011.10:g.5226755_5227283del | Pathogenic | β-Thalassemia |
| 1065151 | NM_000518.5(HBB):c.233_234del (p.His78fs) | Likely Pathogenic | β-Thalassemia |
| 1098798 | NM_000518.5(HBB):c.126dup (p.Phe43fs) | Likely Pathogenic | Sickle Cell Disease |
Note: Additional ~140 pathogenic/likely pathogenic variants exist; most are splice site mutations and deletions associated with β-thalassemia and sickle cell disease phenotypes.
AlphaMissense Predictions
| Metric | Count |
|---|---|
| Total Predictions | 145 |
| Likely Pathogenic | ~85 |
Top 30 AlphaMissense Likely-Pathogenic Variants
| Protein Variant | Pathogenicity Score | Predicted Effect |
|---|---|---|
| Y146H | 0.998 | Likely Pathogenic |
| Y146D | 0.985 | Likely Pathogenic |
| A139D | 0.985 | Likely Pathogenic |
| A141P | 0.990 | Likely Pathogenic |
| L142P | 0.990 | Likely Pathogenic |
| H147D | 0.971 | Likely Pathogenic |
| Y146G | 0.976 | Likely Pathogenic |
| Y146N | 0.978 | Likely Pathogenic |
| K133I | 0.979 | Likely Pathogenic |
| A139P | 0.985 | Likely Pathogenic |
| A143D | 0.981 | Likely Pathogenic |
| V138E | 0.973 | Likely Pathogenic |
| V134E | 0.975 | Likely Pathogenic |
| K133N | 0.975 | Likely Pathogenic |
| K133E | 0.965 | Likely Pathogenic |
| A143P | 0.984 | Likely Pathogenic |
| H147N | 0.898 | Likely Pathogenic |
| L142Q | 0.989 | Likely Pathogenic |
| L142R | 0.974 | Likely Pathogenic |
| A141V | 0.928 | Likely Pathogenic |
| K145N | 0.924 | Likely Pathogenic |
| A141D | 0.986 | Likely Pathogenic |
| H147R | 0.874 | Likely Pathogenic |
| H147L | 0.874 | Likely Pathogenic |
| H147Q | 0.941 | Likely Pathogenic |
| A139V | 0.833 | Likely Pathogenic |
| L142V | 0.767 | Likely Pathogenic |
| K145E | 0.762 | Likely Pathogenic |
| V135L | 0.754 | Likely Pathogenic |
| V135M | 0.623 | Likely Pathogenic |
SpliceAI Predictions
| Metric | Count |
|---|---|
| Total Predictions | ~260 |
| High-Confidence Splice Effects | ~80+ |
Top Splice-Altering Variants (SpliceAI Score ≥0.8)
| Variant | Effect | Score |
|---|---|---|
| 11:5226576:CCCTG:C | Donor Gain | 1.00 |
| 11:5226575:A:AC | Donor Gain | 1.00 |
| 11:5226575:AC:A | Donor Gain | 1.00 |
| 11:5226575:ACC:A | Donor Gain | 1.00 |
| 11:5226576:CCCT:C | Donor Gain | 1.00 |
| 11:5226576:CCC:C | Donor Gain | 1.00 |
| 11:5226576:C:CC | Donor Gain | 1.00 |
| 11:5226576:C:CA | Donor Gain | 1.00 |
| 11:5226573:TCAC:T | Donor Loss | 1.00 |
| 11:5226574:CA:C | Donor Loss | 1.00 |
| 11:5226572:CTCA:C | Donor Gain | 0.92 |
| 11:5226571:ACTC:A | Donor Loss | 0.92 |
| 11:5226800:C:CC | Acceptor Gain | 0.99 |
| 11:5226806:G:C | Acceptor Gain | 0.99 |
| 11:5226798:GC:G | Acceptor Gain | 0.97 |
| 11:5226795:GCAGC:G | Acceptor Gain | 0.97 |
| 11:5226796:CAGC:C | Acceptor Gain | 0.98 |
| 11:5226723:GGAGC:G | Acceptor Loss | 0.98 |
| 11:5226725:AGCT:A | Acceptor Loss | 0.98 |
| 11:5226726:GCTG:G | Acceptor Loss | 0.98 |
| 11:5226728:T:A | Acceptor Loss | 0.98 |
| 11:5226564:C:A | Donor Gain | 0.88 |
| 11:5226569:AGACT:A | Donor Gain | 0.79 |
| 11:5226722:GGAG:G | Acceptor Gain | 0.97 |
| 11:5226723:GGAG:G | Acceptor Gain | 0.97 |
| 11:5226912:TGTA:T | Donor Gain | 0.98 |
| 11:5226563:T:TA | Donor Gain | 0.75 |
| 11:5226799:CC:C | Acceptor Gain | 0.97 |
| 11:5226814:A:C | Acceptor Gain | 0.92 |
| 11:5225723:GGAG:G | Acceptor Gain | 0.97 |
Summary: HBB contains ~1,700 catalogued variants with 230+ classified as pathogenic/likely pathogenic. AlphaMissense predicts ~85 likely-pathogenic missense variants, predominantly at C-terminus residues (Y146, H147, A139-A143, K133-K145). SpliceAI identifies 260 splice-affecting variants, with 80+ high-confidence predictions (score ≥0.8), concentrated in intron 2 and exon 3 boundaries. Variant burden reflects known disease associations: β-thalassemia (primarily deletions & splice mutations) and sickle cell disease (missense variants in coding sequence).
Pathways & Gene Ontology
Reactome Pathways (10 total)
| Pathway ID | Pathway Name |
|---|---|
| R-HSA-1237044 | Erythrocytes take up carbon dioxide and release oxygen |
| R-HSA-1247673 | Erythrocytes take up oxygen and release carbon dioxide |
| R-HSA-2168880 | Scavenging of heme from plasma |
| R-HSA-6798695 | Neutrophil degranulation |
| R-HSA-9613829 | Chaperone Mediated Autophagy |
| R-HSA-9615710 | Late endosomal microautophagy |
| R-HSA-9707564 | Cytoprotection by HMOX1 |
| R-HSA-9707616 | Heme signaling |
| R-HSA-983231 | Factors involved in megakaryocyte development and platelet production |
| R-HSA-9927020 | Heme assimilation |
MSigDB Gene Sets (100 total)
100 gene sets in Molecular Signatures Database including Reactome pathways (CP), Gene Ontology terms (GO:BP, MF, CC), canonical pathways, and human phenotype terms.
Notable sets include:
- M17493 | GOCC_HEMOGLOBIN_COMPLEX (12 genes)
- M26254 | GOMF_OXYGEN_CARRIER_ACTIVITY (14 genes)
- M26516 | GOMF_HEMOGLOBIN_BINDING (9 genes)
- M19553 | BIOCARTA_AHSP_PATHWAY - Hemoglobin’s Chaperone (13 genes)
Gene Ontology: Biological Process (13 terms)
| GO ID | Term |
|---|---|
| GO:0015671 | oxygen transport |
| GO:0015670 | carbon dioxide transport |
| GO:0048821 | erythrocyte development |
| GO:0008217 | regulation of blood pressure |
| GO:0030185 | nitric oxide transport |
| GO:0006954 | inflammatory response |
| GO:0045429 | positive regulation of nitric oxide biosynthetic process |
| GO:0070527 | platelet aggregation |
| GO:0098869 | cellular oxidant detoxification |
| GO:0042542 | response to hydrogen peroxide |
| GO:0042744 | hydrogen peroxide catabolic process |
| GO:0097746 | blood vessel diameter maintenance |
| GO:0070293 | renal absorption |
Gene Ontology: Molecular Function (6 terms)
| GO ID | Term |
|---|---|
| GO:0005344 | oxygen carrier activity |
| GO:0019825 | oxygen binding |
| GO:0020037 | heme binding |
| GO:0046872 | metal ion binding |
| GO:0030492 | hemoglobin binding |
| GO:0031721 | hemoglobin alpha binding |
Gene Ontology: Cellular Component (10 terms)
| GO ID | Term |
|---|---|
| GO:0005833 | hemoglobin complex |
| GO:0005576 | extracellular region |
| GO:0005615 | extracellular space |
| GO:0005829 | cytosol |
| GO:0031838 | haptoglobin-hemoglobin complex |
| GO:0070062 | extracellular exosome |
| GO:0072562 | blood microparticle |
| GO:0071682 | endocytic vesicle lumen |
| GO:1904724 | tertiary granule lumen |
| GO:1904813 | ficolin-1-rich granule lumen |
Protein interactions & networks
Total Interaction Count:
- BioGRID: ~236 interactions
- IntAct: ~215 interactions
- STRING: Not available
- Combined: ~450+ protein-protein interactions
TOP 30 Highest-Confidence Interacting Proteins (IntAct):
| Rank | Partner Protein | Interaction Type | Confidence Score |
|---|---|---|---|
| 1 | HBA1 (Hemoglobin alpha 1) | Direct interaction | 0.970 |
| 2 | HBA1 | Direct interaction | 0.970 |
| 3 | HBA1 | Direct interaction | 0.970 |
| 4 | HBA1 | Direct interaction | 0.970 |
| 5 | HBA1 | Direct interaction | 0.970 |
| 6 | HBA1 | Direct interaction | 0.970 |
| 7 | HBA1 | Direct interaction | 0.970 |
| 8 | HBA1 | Direct interaction | 0.970 |
| 9 | HBA1 | Direct interaction | 0.970 |
| 10 | HBA1 | Direct interaction | 0.970 |
| 11 | HBA1 | Direct interaction | 0.970 |
| 12 | HBA1 | Direct interaction | 0.970 |
| 13 | HBA1 | Direct interaction | 0.970 |
| 14 | HBA1 | Direct interaction | 0.970 |
| 15 | HBA1 | Direct interaction | 0.970 |
| 16 | HBA1 | Direct interaction | 0.970 |
| 17 | HBA1 | Direct interaction | 0.970 |
| 18 | HBA1 | Direct interaction | 0.970 |
| 19 | HBZ (Hemoglobin zeta) | Physical association | 0.860 |
| 20 | HBZ | Physical association | 0.860 |
| 21 | HBZ | Physical association | 0.860 |
| 22 | HBZ | Physical association | 0.860 |
| 23 | HBM (Hemoglobin M) | Physical association | 0.560 |
| 24 | HBM | Physical association | 0.560 |
| 25 | HBM | Physical association | 0.560 |
| 26 | HBQ1 (Hemoglobin theta 1) | Physical association | 0.560 |
| 27 | HBQ1 | Physical association | 0.560 |
| 28 | HBQ1 | Physical association | 0.560 |
| 29 | MAPK6 | Association | 0.840 |
| 30 | MED4 | Association | 0.900 |
Structural/Embedding Similarity (ESM2) – TOP 20:
| Rank | Protein ID | Top Similarity | Avg Similarity |
|---|---|---|---|
| 1-10 | P68872, P68873, P68232-P68234, P68224-P68225, P68054-P68055 | 1.0000 | 0.9992-0.9994 |
| 11-20 | P61772-P61775, P67819-P67824 | 1.0000 | 0.9986-0.9993 |
Note: Top 20 ESM2 matches are hemoglobin variants with near-perfect similarity (0.9986-1.0000), indicating nearly identical embedding representations.
Sequence Homology (DIAMOND) – TOP 20:
| Rank | Protein ID | Identity (%) | Bitscore |
|---|---|---|---|
| 1 | D0VX08 | 100.0 | 298 |
| 2 | P02030 | 100.0 | 302 |
| 3 | P02084 | 100.0 | 298 |
| 4 | P02085 | 100.0 | 298 |
| 5 | P07415 | 100.0 | 301 |
| 6 | P14391 | 100.0 | 298 |
| 7 | P02029 | 99.3 | 301 |
| 8 | P02026 | 99.3 | 302 |
| 9 | P02035 | 99.3 | 300 |
| 10 | P02040 | 99.3 | 300 |
| 11 | P02042 | 99.3 | 301 |
| 12 | P10893 | 99.3 | 300 |
| 13 | P15449 | 99.3 | 300 |
| 14 | P14392 | 99.3 | 296 |
| 15 | P02024 | 99.3 | 303 |
| 16 | P04244 | 98.0 | 293 |
| 17 | P02025 | 98.6 | 299 |
| 18 | P02028 | 98.6 | 298 |
| 19 | P02031 | 98.6 | 300 |
| 20 | P02032 | 98.6 | 299 |
Note: Top homologous matches are other hemoglobin variants with 98.6-100% sequence identity, representing orthologs and variants across species.
Transcription factor regulatory data
HBB is not a transcription factor. HBB (hemoglobin subunit beta) is a structural protein component of hemoglobin, not a DNA-binding transcription factor. Skipping downstream targets and DNA binding motifs.
Upstream regulators: Transcription factors regulating HBB
Total identified regulators: 71 (from CollecTRI database)
Top regulators by evidence support:
| Rank | TF | Evidence Type | Regulation | Sources |
|---|---|---|---|---|
| 1 | KLF1 | Experimentally validated | Unknown | ExTRI, TRRUST, SIGNOR, GEREDB, NTNU Curated |
| 2 | GATA1 | Experimentally validated | Unknown | ExTRI, HTRI, TRRUST, NTNU Curated, DoRothEA_A |
| 3 | NFE2 | Experimentally validated | Activation | ExTRI, SIGNOR, GEREDB, NTNU Curated |
| 4 | BACH1 | Experimentally validated | Activation | ExTRI, GOA, GEREDB, NTNU Curated |
| 5 | DLX4 | Experimentally validated | Unknown | ExTRI, HTRI |
| 6 | USF1 | Experimentally validated | Unknown | ExTRI, NTNU Curated |
| 7 | MAFK | Experimentally validated | Unknown | ExTRI |
| 8 | NFE2L2 | Experimentally validated | Unknown | ExTRI, TRRUST |
| 9 | MYC | Experimentally validated | Unknown | ExTRI, GEREDB, HTRI, NTNU Curated |
| 10 | GTF2I | Experimentally validated | Unknown | ExTRI |
| 11 | TBP | Experimentally validated | Unknown | ExTRI, GEREDB |
| 12 | KLF2 | Experimentally validated | Activation | ExTRI, GEREDB |
| 13 | STAT5A | Experimentally validated | Activation | SIGNOR |
| 14 | POU2F2 | Predicted/inferred | Unknown | ExTRI, TRRUST, GEREDB |
| 15 | ESR1 | Predicted/inferred | Unknown | ExTRI |
Additional regulators (16-71): AP1, AR, BACH2, BCL11A, CEBPB, CEBPD, CEBPG, CTCF, EGF, EHMT2, EIF2AK1, EPAS1, EPO, ESR2, ETV6, FGF2, FLI1, GLI3, HMGA1, HIF1A, HLTF, HOXC13, JUN, KLF8, KLF11, LMO2, MAPK11, MAPK14, MIB, MYB, NFE2L1, NFE2L3, NR1I2, NR2F2, NFYA, NFYB, NFYC, PAX1, POU2F1, RBPJ, SMARCdA1, SP1, SP2, SPI1, SUZ12, TGFB1, TFAP2A, TFCP2, TPA2, TP53, USF2, ZNF354C, ZNF362, ZFPM1
Drug & pharmacology data
HBB protein status as therapeutic target: HBB (beta-globin) is not a traditional “druggable” protein target in the sense of direct inhibitors or activators, but rather is central to hemoglobinopathy treatment where compounds indirectly affect hemoglobin function or compensate for defective beta-globin. Most “HBB-targeting” compounds in ChEMBL (CHEMBL4331) actually refer to in vitro screening hits and compounds tested for effects on hemoglobin, rather than clinical therapeutics specifically designed to modulate HBB.
Molecules with HBB activity: ChEMBL reports 255 molecules with recorded activity against CHEMBL4331 (Hemoglobin subunit beta), though the majority are research compounds with Phase 0 status (in vitro screening only).
Top approved molecules (Phase 4) with recorded HBB activity:
- Azacitidine (CHEMBL1489) — epigenetic modifier for hemoglobinopathies
- Hydroxyurea (reference compound) — fetal hemoglobin inducer
- Mercaptopurine (CHEMBL1425), Thioguanine (CHEMBL727), Azathioprine (CHEMBL1542)
- Fluorouracil (CHEMBL185), Acyclovir (CHEMBL184), Topotecan (CHEMBL1607)
- Others recorded: Phenazopyridine, Menadione, Hydroquinone, Thiotepa, Reserpine
Clinical trials for hemoglobinopathies (sickle cell & beta-thalassemia):
Sickle Cell Disease (MONDO:0011382): 967 clinical trials total, including major Phase 3 programs:
- Voxelotor (GBT440) — Phase 3 completed, mechanism: allosteric hemoglobin modifier
- Crizanlizumab — P-selectin antagonist, Phase 3
- CTX001 — CRISPR gene therapy, Phase 2/3
- Etavopivat (AG-348) — pyruvate kinase activator, Phase 3
- Luspatercept — late-stage erythroid maturation regulator
Beta-Thalassemia (MONDO:0019402): 214 clinical trials, including:
- CTX001 gene therapy — Phase 2/3 ongoing
- Luspatercept — Phase 2/3 trials
- Etavopivat — Phase 2/3 program
- Gene editing approaches (EDIT-301, BB305 lentiviral vectors) — Phase 1/2
Pharmacogenomics: No specific HBB-drug interaction guidelines identified in PharmGKB. However, sickle cell & thalassemia are themselves pharmacogenomic conditions — HBB mutations (>1,700 variants in ClinVar) determine disease manifestation and drug response (e.g., hydroxyurea efficacy correlates with ability to induce fetal hemoglobin). Dosing of iron chelators (deferasirox, deferoxamine) is weight-based without HBB-specific adjustments.
Expression profiles
Tissue Expression
HBB shows ubiquitous expression across 284 of 288 tissue conditions in Bgee, with an average expression score of 93.6 and maximum score of 100. Expression is particularly enriched in blood-forming tissues.
| Rank | Tissue | Expression Score | Quality |
|---|---|---|---|
| 1 | Vena cava | 100.00 | Gold |
| 2 | Periodontal ligament | 100.00 | Gold |
| 3 | Blood | 99.92 | Gold |
| 4 | Bone marrow | 99.99 | Gold |
| 5 | Spleen | 99.81 | Gold |
| 6 | Monocyte (cell type) | 100.00 | Gold |
| 7 | Triceps brachii | 99.98 | Gold |
| 8 | Biceps brachii | 99.96 | Gold |
| 9 | Gluteal muscle | 99.97 | Gold |
| 10 | Trabecular bone tissue | 99.99 | Gold |
| 11 | Skeletal muscle (biceps) | 99.98 | Gold |
| 12 | Rectus abdominis | 99.76 | Gold |
| 13 | Vastus lateralis | 99.67 | Gold |
| 14 | Diaphragm | 99.76 | Gold |
| 15 | Heart apex | 99.75 | Gold |
| 16 | Bronchus | 99.71 | Gold |
| 17 | Bronchial epithelium | 99.71 | Gold |
| 18 | Colonic epithelium | 99.71 | Gold |
| 19 | Stomach cardia | 99.69 | Gold |
| 20 | Placenta | 99.68 | Gold |
| 21 | Mononuclear cell | 99.99 | Gold |
| 22 | Bone marrow cell | 99.98 | Gold |
| 23 | Decidua | 99.90 | Gold |
| 24 | Bronchial epithelial cell | 99.89 | Gold |
| 25 | Trigeminal ganglion | 99.64 | Gold |
| 26 | Superior vestibular nucleus | 99.59 | Gold |
| 27 | Inferior olivary complex | 99.68 | Gold |
| 28 | Metanephros cortex | 99.57 | Gold |
| 29 | Gall bladder | 99.57 | Gold |
| 30 | Adult organism | 99.92 | Gold |
Cell Type Expression
HBB is highly enriched in hematopoietic and immune cells. The gene serves as a marker gene in 46/46 SCXA experiments, with maximum mean expression of 562,006 TPM (transcripts per million), indicating it is a defining feature of blood-cell populations.
Top cell types (from Bgee + SCXA):
- Monocytes (100.0)
- Mononuclear cells (99.99)
- Bone marrow cells (99.98)
- Bronchial epithelial cells (99.89)
- Red blood cells and erythroid progenitors (implied from max expression)
Single-Cell Expression Datasets
HBB is prominently expressed across 15 human single-cell atlases, primarily in hematopoietic tissues and immune populations:
| Dataset ID | Title | Tissue/System | Cell Count |
|---|---|---|---|
| E-HCAD-4 | Census of Immune Cells | Immune system | 791,344 |
| E-MTAB-7407 | Fetal liver, skin, kidney | Multiple tissues | 473,803 |
| E-MTAB-9543 | Human gastrointestinal tract | GI tract | 319,479 |
| E-CURD-122 | Cross-tissue immune cell analysis | Multi-tissue immune | 356,580 |
| E-MTAB-10042 | Emergent haematopoiesis (fetal bone marrow) | Hematopoiesis | 21,485 |
| E-CURD-112 | Emergent haematopoiesis (10X) | Fetal bone marrow | 56,592 |
| E-CURD-98 | Human fetal liver | Fetal hematopoiesis | 197,943 |
| E-HCAD-6 | CD34+ cells (bone marrow) | Hematopoietic stem cells | 34,596 |
| E-CURD-6 | Bone marrow differentiation hierarchy | Hematopoiesis | 1,024 |
| E-MTAB-10553 | Human liver cells | Liver | 24,355 |
| E-MTAB-10662 | Fetal lung with R-SPONDIN inhibition | Lung development | 39,900 |
| E-MTAB-6653 | Lung carcinomas | Lung cancer | 55,719 |
| E-MTAB-8884 | Chronic myelomonocytic leukemia stem cells | Leukemia | 9,386 |
| E-MTAB-9221 | RBC-depleted whole blood (COVID-19) | Peripheral blood | 27,943 |
| E-MTAB-10432 | Post-MI heart failure bone vascular niche | Heart/bone | 8,228 |
Expression Pattern: HBB is a lineage-defining marker for erythroid and myeloid cells, with particularly high expression in mature red blood cells, bone marrow progenitors, and immune cell populations.
Disease associations
Mendelian / Monogenic Diseases
HBB mutations cause multiple autosomal recessive and dominant hemoglobinopathies:
| Disease | Disease ID(s) | Inheritance Pattern | Evidence Level |
|---|---|---|---|
| Beta-thalassemia (HBB/LCRB) | OMIM 613985, MONDO:0013517, Orphanet 231214 | Autosomal recessive | Definitive/Strong |
| Sickle cell disease | OMIM 603903, MONDO:0011382, Orphanet 232 | Autosomal recessive | Strong/Supportive |
| Dominant beta-thalassemia | OMIM 603902, MONDO:0011381, Orphanet 231226 | Autosomal dominant | Strong/Supportive |
| Hemoglobin M disease | OMIM 617971, Orphanet 330041 | Autosomal dominant | Moderate/Supportive |
| Erythrocytosis, familial, 6 | OMIM 617980, MONDO:0054801 | Autosomal dominant | Strong/Supportive |
| Heinz body anemia | OMIM 140700, MONDO:0007705 | Autosomal dominant | Strong/Supportive |
| Hemoglobin C disease | Orphanet 2132 | Autosomal recessive | Supportive |
| Hemoglobin E disease | OMIM 603951, MONDO:0016243, Orphanet 2133 | Autosomal recessive | Supportive |
| Beta-thalassemia major | MONDO:0016486, Orphanet 231214 | Autosomal recessive | Supportive |
| Beta-thalassemia intermedia | MONDO:0016487, Orphanet 231222 | Autosomal recessive | Supportive |
| Delta-beta-thalassemia | MONDO:0016489, Orphanet 231237 | Autosomal recessive | Supportive |
| Hemoglobin C-beta-thalassemia syndrome | Orphanet 231242 | Autosomal recessive | Supportive |
| Hemoglobin E-beta-thalassemia syndrome | MONDO:0016491, Orphanet 231249 | Autosomal recessive | Supportive |
| Sickle cell-beta-thalassemia disease syndrome | Orphanet 251359 | Autosomal recessive | Supportive |
| Sickle cell-hemoglobin C disease syndrome | MONDO:0016669, Orphanet 251365 | Autosomal recessive | Supportive |
| Sickle cell-hemoglobin D disease syndrome | Orphanet 251370 | Autosomal recessive | Supportive |
| Sickle cell-hemoglobin E disease syndrome | Orphanet 251375 | Autosomal recessive | Supportive |
| Hereditary persistence of fetal hemoglobin-sickle cell disease syndrome | MONDO:0020989, Orphanet 251380 | Autosomal recessive | Supportive |
| Hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome | Orphanet 46532 | Autosomal dominant | Supportive |
| Hemoglobin D disease | MONDO:0019537, Orphanet 90039 | Autosomal recessive | Supportive |
Additional broadly associated categories: Hemoglobinopathy (MONDO:0044348), Thalassemia (MONDO:0000984), Hemolytic anemia (MONDO:0003664)
Phenotype Associations
Top 30 HPO terms associated with HBB mutations:
| HPO ID | Phenotype |
|---|---|
| HP:0001878 | Hemolytic anemia |
| HP:0001903 | Anemia |
| HP:0001744 | Splenomegaly |
| HP:0000952 | Jaundice |
| HP:0008282 | Unconjugated hyperbilirubinemia |
| HP:0001433 | Hepatosplenomegaly |
| HP:0001281 | Hepatomegaly |
| HP:0012622 | Chronic kidney disease |
| HP:0003259 | Elevated circulating creatinine concentration |
| HP:0001922 | Fever |
| HP:0000961 | Cyanosis |
| HP:0012418 | Hypoxemia |
| HP:0001297 | Stroke |
| HP:0002140 | Ischemic stroke |
| HP:0001626 | Abnormality of the cardiovascular system |
| HP:0001640 | Cardiomegaly |
| HP:0001644 | Dilated cardiomyopathy |
| HP:0001722 | High-output congestive heart failure |
| HP:0010885 | Avascular necrosis |
| HP:0002754 | Osteomyelitis |
| HP:0001510 | Growth delay |
| HP:0001531 | Failure to thrive in infancy |
| HP:0000823 | Delayed puberty |
| HP:0008346 | Increased red cell sickling tendency |
| HP:0030058 | Sickled erythrocytes |
| HP:0045047 | HbS hemoglobin |
| HP:0011902 | Abnormal hemoglobin |
| HP:0011904 | Persistence of hemoglobin F |
| HP:0011905 | Reduced hemoglobin A |
| HP:0200023 | Priapism |
Complex Disease / GWAS Associations
Top 30 GWAS associations (p < 10⁻⁶):
| Trait | P-value | Study | Notes |
|---|---|---|---|
| Malaria (severe) | 4.0×10⁻⁶⁹ | GCST010725_48 | HBB variant protection; strong effect |
| Malaria (severe) | 2.0×10⁻⁶⁷ | GCST010725_61 | HBB variant protection |
| Malaria | 1.0×10⁻⁵⁵ | GCST010725_1 | Strongest known protective association |
| Glycated hemoglobin (HbA1c) levels | 3.0×10⁻³⁹ | GCST008398_13 | HBB locus |
| Hemoglobin levels | 4.0×10⁻²⁶ | GCST003122_3 | HBD gene |
| Hemoglobin A1c levels | 8.0×10⁻²⁷ | GCST008034_18 | HBB directly implicated |
| Mean corpuscular hemoglobin concentration | 7.0×10⁻²⁴ | GCST004329_2 | HBB locus |
| Total cholesterol levels | 5.0×10⁻²³ | GCST011346_59 | HBB region |
| Low density lipoprotein cholesterol levels | 6.0×10⁻²² | GCST011347_35 | HBB region |
| Mean corpuscular volume | 1.0×10⁻²² | GCST004335_16 | HBB locus |
| Red cell distribution width | 6.0×10⁻¹⁷ | GCST008333_1 | HBB locus |
| Malaria | 6.0×10⁻¹⁴ | GCST001637_1 | HBG2, HBE1, OR51B5 co-associated |
| Mean corpuscular hemoglobin concentration | 1.0×10⁻¹³ | GCST001782_4 | HBG2, HBE1 |
| Hemoglobin levels | 2.0×10⁻¹² | GCST009681_7 | HBB direct effect |
| Urinary albumin-to-creatinine ratio | 8.0×10⁻¹² | GCST003774_2 | HBB locus |
| Hematocrit | 9.0×10⁻¹⁰ | GCST004330_1 | HBB locus |
| Estimated glomerular filtration rate (non-diabetics) | 3.0×10⁻⁸ | GCST008745_92 | HBB region |
| Urinary albumin-to-creatinine ratio | 6.0×10⁻⁸ | GCST008793_1 | HBB locus |
| Hematocrit | 9.0×10⁻¹⁰ | GCST009682_2 | HBB locus |
| Hemolysis of donated blood (osmotic) | 4.0×10⁻¹⁰ | GCST012130_2 | HBB locus |
| Urate levels | 5.0×10⁻¹⁵ | GCST008972_7 | HBB locus |
| Inflammatory biomarkers | 2.0×10⁻⁹ | GCST001385_6 | HBE1, HBG2 co-associated |
| Hematology traits | 5.0×10⁻¹¹ | GCST001779_3 | HBG2, HBE1 |
| HbA2 levels | 1.0×10⁻¹¹ | GCST001710_2 | OR51V1-HBB region |
| Fetal hemoglobin levels | 2.0×10⁻²¹ | GCST000150_1 | HBE1, HBG2 co-associated |
| F-cell distribution | 2.0×10⁻³⁸ | GCST000069_3 | HBB locus |
| Malaria | 4.0×10⁻¹¹ | GCST000410_3 | OR51V1-HBB region |
| Estimated glomerular filtration rate (diabetes) | 7.0×10⁻¹³ | GCST008746_23 | HBB region |
| Blood cell traits (multivariate) | 5.0×10⁻²⁰ | GCST008337_2 | HBB locus |
| Blood cell traits (multivariate) | 1.0×10⁻¹² | GCST008338_4 | HBB locus |
Key findings:
- Malaria resistance: HBB variants (especially sickle allele) show extremely strong protection against severe malaria (p < 10⁻⁵⁵)
- Hematologic traits: HBB is a major QTL for hemoglobin levels, hematocrit, RBC indices, and related blood parameters
- Metabolic/renal: Secondary associations with glycemic traits (HbA1c), lipid levels, and kidney function markers
- Inheritance: All Mendelian HBB disorders show clear autosomal inheritance (recessive for most thalassemias and sickling disorders; dominant for some hemoglobinopathies)