HBB

Summary

HBB (hemoglobin subunit beta, HGNC:4827) is a protein-coding gene on chromosome 11p15.4, encoding Hemoglobin subunit beta (P68871). Involved in oxygen transport from the lung to the various peripheral tissues.

The alpha (HBA) and beta (HBB) loci determine the structure of the 2 types of polypeptide chains in adult hemoglobin, Hb A. The normal adult hemoglobin tetramer consists of two alpha chains and two beta chains. Mutant beta globin causes sickle cell anemia. Absence of beta chain causes beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. The order of the genes in the beta-globin cluster is 5’-epsilon – gamma-G – gamma-A – delta – beta–3'.

Source: NCBI Gene 3043 — RefSeq curated summary.

At a glance

• Gene–disease (curated): beta-thalassemia HBB/LCRB (Definitive, ClinGen) — +22 more curated relationships
• GWAS associations: 40
• Clinical variants (ClinVar): 1,661 total — 271 pathogenic, 58 likely-pathogenic
• Phenotypes (HPO): 139
• Druggable target: yes — 23 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000518

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4827
Approved symbol	HBB
Name	hemoglobin subunit beta
Location	11p15.4
Locus type	gene with protein product
Status	Approved
Aliases	CD113t-C, beta-globin
Ensembl gene	ENSG00000244734
Ensembl biotype	protein_coding
OMIM	141900
Entrez	3043

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000335295, ENST00000380315, ENST00000475226, ENST00000485743, ENST00000633227, ENST00000647020, ENST00000883533

RefSeq mRNA: 1 — MANE Select: NM_000518 NM_000518

CCDS: CCDS7753

Canonical transcript exons

ENST00000335295 — 3 exons

Exon	Start	End
ENSE00001057381	5226577	5226799
ENSE00001600613	5225464	5225726
ENSE00001829867	5226930	5227071

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 100.00.

FANTOM5 (CAGE): breadth broad, TPM avg 6381.9136 / max 2211023.8012, expressed in 360 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
118350	6377.9670	359
118343	2.1194	45
118342	1.6631	43
118341	0.1641	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	100.00	gold quality
trabecular bone tissue	UBERON:0002483	100.00	gold quality
vena cava	UBERON:0004087	100.00	gold quality
periodontal ligament	UBERON:0008266	100.00	gold quality
mononuclear cell	CL:0000842	99.99	gold quality
bone marrow	UBERON:0002371	99.99	gold quality
bone marrow cell	CL:0002092	99.98	gold quality
triceps brachii	UBERON:0001509	99.98	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.98	gold quality
gluteal muscle	UBERON:0002000	99.97	gold quality
biceps brachii	UBERON:0001507	99.96	gold quality
blood	UBERON:0000178	99.92	gold quality
adult organism	UBERON:0007023	99.92	gold quality
decidua	UBERON:0002450	99.90	gold quality
bronchial epithelial cell	CL:0002328	99.89	gold quality
spleen	UBERON:0002106	99.81	gold quality
diaphragm	UBERON:0001103	99.76	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.76	gold quality
apex of heart	UBERON:0002098	99.75	gold quality
colonic epithelium	UBERON:0000397	99.71	gold quality
epithelium of bronchus	UBERON:0002031	99.71	gold quality
bronchus	UBERON:0002185	99.71	gold quality
cardia of stomach	UBERON:0001162	99.69	gold quality
placenta	UBERON:0001987	99.68	gold quality
inferior olivary complex	UBERON:0002127	99.68	gold quality
vastus lateralis	UBERON:0001379	99.67	gold quality
trigeminal ganglion	UBERON:0001675	99.64	gold quality
superior vestibular nucleus	UBERON:0007227	99.59	gold quality
gall bladder	UBERON:0002110	99.57	gold quality
metanephros cortex	UBERON:0010533	99.57	gold quality

Single-cell (SCXA)

Detected in 46 experiment(s), a significant marker in 42.

Experiment	Marker?	Max mean expression
E-HCAD-36	yes	562006.17
E-MTAB-9221	yes	538290.66
E-HCAD-8	yes	532109.96
E-MTAB-8207	yes	478937.09
E-MTAB-6678	yes	443742.86
E-MTAB-6653	yes	419427.96
E-GEOD-139324	yes	402622.88
E-GEOD-150728	yes	395457.14
E-MTAB-8495	yes	372575.14
E-HCAD-9	yes	368244.78
E-CURD-122	yes	365015.71
E-MTAB-9467	yes	364956.80
E-CURD-120	yes	346320.47
E-CURD-55	yes	339223.64
E-GEOD-149689	yes	325256.84

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
TNF	Activation

Upstream regulators (CollecTRI, top): ADNP2, AP1, AR, BACH1, BACH2, BCL11A, CEBPB, CEBPD, CEBPG, CTCF, DLX4, EGF, EHMT2, EIF2AK1, EPAS1, EPO, ESR1, ESR2, ETV6, FGF2, FLI1, GATA1, GLI3, GTF2I, HIF1A, HLTF, HMGA1, HOXC13, JUN, KAT7, KLF11, KLF1, KLF2, KLF8, LMO2, MAFK, MAPK11, MAPK14, MIF, MYB

miRNA regulators (miRDB)

18 targeting HBB, 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-4307	99.82	70.45	3374
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-4520-2-3P	99.14	69.28	1009
HSA-MIR-3922-5P	98.77	66.53	1059
HSA-MIR-4520-3P	98.75	66.55	963
HSA-MIR-9500	98.62	66.54	1845
HSA-MIR-1910-3P	98.44	67.51	1695
HSA-MIR-6511A-5P	98.13	67.47	1770
HSA-MIR-4423-3P	97.98	69.66	912
HSA-MIR-6886-3P	96.96	66.36	844
HSA-MIR-6851-3P	95.73	65.11	688
HSA-MIR-3914	94.91	65.77	643
HSA-MIR-5009-5P	94.82	63.89	775
HSA-MIR-8058	94.76	63.41	632
HSA-MIR-6750-5P	93.94	66.68	797
HSA-MIR-6822-5P	93.94	66.34	812

Literature-anchored findings (GeneRIF, showing 40)

• The 5’-boundary region of the human beta-globin locus control region hypersensitive site-2 was examined in intact cells utilising the DNA damaging agents bleomycin and hedamycin. (PMID:10856700)
• molecular analysis of the beta-globin gene cluster in the Niokholo Mandenka population reveals a recent origin of the beta(S) Senegal mutation (PMID:11741197)
• An erythroid-specific chromatin-opening cis-acting element reorganizes the beta-globin promoter chromatin structure and augments gene expression. (PMID:11778661)
• Sickle hemoglobin polymer stability probed by triple and quadruple mutant hybrids (Hemoglobin S) (PMID:11782463)
• site HS3.5 may play an important role in the regulation of the beta-globin gene cluster (PMID:11800015)
• using differential interference contrast microscopy; spontaneous, thermal fluctuations in fiber shape are measured to obtain bending moduli (kappa) and persistence lengths (lambda(p)) (PMID:11812133)
• genetic interaction between the beta-globin complex and chromosome 8q in the expression of fetal hemoglobin (PMID:11822023)
• Recombination across nine intervals in the human beta-globin gene cluster by single-sperm analysis (PMID:11823440)
• Assembly of human hemoglobin (Hb) beta- and gamma-globin chains expressed in a cell-free system with alpha-globin chains to form Hb A and Hb F. (PMID:11827978)
• study of mutations on severity in beta-thalassemia patients; effects of alpha-thalassemia (PMID:11833853)
• Hb Pyrgos is due to a missense mutation in codon 83 (GGC–>GAC, Gly–>Asp. Its presence in a triple heterozygote for Hb CS and alpha-thalassemia has no effect on the other hemoglobins. (PMID:11843288)
• The 3’ breakpoint of the (deltabeta)(0)-thalassemia deletion in a compound heterozygote lay withing a cluster of L1 repetitive sequences at 4.7 kb 3’ to the beta globin gene. (PMID:11860449)
• The beta-globin locus contains more than 20 single-base restriction fragment length polymorphism (RFLP) sites spanning over 80 kb on chromosome 11. HS (hypersensitive site) region in sickle cell anemia we searched in the AT-rich region using SSCP. (PMID:11869935)
• Successful treatment of murine beta-thalassemia intermedia by transfer of the human beta-globin gene. (PMID:11877258)
• Results show that enzymatic removal of terminal histidine and penultimate tyrosine residues of beta hemoglobin subunits affects their interaction and assembly properties (PMID:11890201)
• BP1, a homeodomain-containing isoform of DLX4, represses the beta-globin gene. (PMID:11909945)
• 31 alleles carrying the betaS mutation, 6 beta-thalassaemic alleles & 17 G6PD alleles, were studied from a group of carriers or affected subjects. Allele frequencies were 3% for haemoglobin S, 1% for beta-thalassaemia trait and 9.5% for G6PD deficiency. (PMID:11920200)
• A nonsense mutation at codon 37 (G–>A) was found. Other mutations were: IVS-I-110 (G–>A), frameshift codon 5 (- CT), IVS-I-1 (G–>A), IVS-II-1 (G–>A), Hb S [beta6(A3)Glu–>Val], frameshift codons 8/9 (+G), codon 39 (C–>T), and -30 (T–>A). (PMID:11939510)
• A novel beta0-thalassemia mutation at codon 55 (-A) and a rare 17 bp deletion at codons 126-131 (PMID:11939511)
• Hb G-San Jose variant levels correlate with alpha-thalassemia genotypes. (PMID:11939513)
• determining if the locus control region is required for globin gene activation (PMID:11971871)
• Conserved CTCF insulator elements flank the mouse and human beta-globin loci. (PMID:11997516)
• Evidence that DNase I hypersensitive site 5 of the human beta-globin locus control region functions as a chromosomal insulator in transgenic mice (PMID:12034837)
• Esterification of the propionate groups promotes alpha/beta hemoglobin chain homogeneity of CN-hemin binding (PMID:12054662)
• examination of the depolymerization of hemoglobin (Hb) S fibers in the presence of CO by using photolysis of COHbS to create and isolate individual fibers, then removing photolysis to induce depolymerization (PMID:12217699)
• genotypes in Albanian patients affected by beta-globin gene disorders (PMID:12217813)
• beta-globin is degraded with an endonuclease with preference for UG dinucleotides (PMID:12242335)
• Allosteric effects of chloride ions at the interfaces between the alphabeta dimers. (PMID:12360531)
• Definition of transcriptional promoters in the human beta globin locus control region (PMID:12419253)
• High-mobility group protein 2 binds specifically to the first AT-rich region flanking the hypersensitive site 2 core sequence of the human beta-globin gene locus control region (PMID:12555809)
• regulatory sequences required for activation and silencing of the beta-globin gene family during ontogeny reside proximally to the genes and immediately 5’ to the gamma- and beta-globin genes (PMID:12629213)
• analyses show, while one common haplotype in a block of high linkage disequilibrium represents a long segment from a single ancestral chromosome, others are mosaics of short segments from multiple ancestors related in genealogies of unsuspected complexity (PMID:12736816)
• Nuclear matrix association of the beta-globin locus. (PMID:12799453)
• developmentally related activation of human beta-like globin genes in human and transgenic mice hematopoietic progenitor cells is preceded by a wave of gene-specific histone H3 hyperacetylation and K4 dimethylation (PMID:12920025)
• HS5 of the beta-globin locus control region is a developmental stage-specific border in erythroid cells. (PMID:12941700)
• nucleosome remodeling and covalent histone modification mediated by the beta-globin locus control region HS2 enhancer at nucleosome-level resolution (PMID:14585970)
• undecamer quasi- palindromic sequence d(TGGGGACCCCA) (HPA11) and its reported polymorphic (SNP) version d(TGG GGGCCCCA) (HPG11) exist in hairpin-duplex equilibria (PMID:14627823)
• beta-globin locus control region HS5 contains enhancer-blocking (insulator) activity that is both CTCF and developmental stage dependent (PMID:14645507)
• Point mutations reported for two new variant associated with erythrocytosis; quaternary protein structures and oxygen binding are discussed (PMID:14649314)
• new variant (Hb Buzen) with point mutation at codon 138 was isolated, sequenced, and characterized. RBC parameters and isopropanol statibility test and oxygen binding were normal. (PMID:14649315)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	hbae5	ENSDARG00000045142
danio_rerio	hbaa2	ENSDARG00000069735
danio_rerio	si:ch211-5k11.8	ENSDARG00000079078
danio_rerio	hbae3	ENSDARG00000079305
danio_rerio	hbae1.2	ENSDARG00000088330
danio_rerio	hbae1.3	ENSDARG00000089124
danio_rerio	hbae1.1	ENSDARG00000089475
danio_rerio	hbaa1	ENSDARG00000097011
drosophila_melanogaster	glob1	FBGN0027657
caenorhabditis_elegans		WBGENE00008996
caenorhabditis_elegans		WBGENE00077763

Paralogs (11): HBQ1 (ENSG00000086506), HBZ (ENSG00000130656), CYGB (ENSG00000161544), HBA2 (ENSG00000188536), HBG2 (ENSG00000196565), MB (ENSG00000198125), HBA1 (ENSG00000206172), HBM (ENSG00000206177), HBE1 (ENSG00000213931), HBG1 (ENSG00000213934), HBD (ENSG00000223609)

Protein

Protein identifiers

Hemoglobin subunit beta — P68871 (reviewed: P68871)

Alternative names: Beta-globin, Hemoglobin beta chain

All UniProt accessions (5): A0A0J9YWK4, A0A2R8Y7R2, D9YZU5, F8W6P5, P68871

UniProt curated annotations — full annotation on UniProt →

Function. Involved in oxygen transport from the lung to the various peripheral tissues. LVV-hemorphin-7 potentiates the activity of bradykinin, causing a decrease in blood pressure. Functions as an endogenous inhibitor of enkephalin-degrading enzymes such as DPP3, and as a selective antagonist of the P2RX3 receptor which is involved in pain signaling, these properties implicate it as a regulator of pain and inflammation.

Subunit / interactions. Heterotetramer of two alpha chains and two beta chains in adult hemoglobin A (HbA). Heterotetramer of two zeta chains and two beta chains in hemoglobin Portland-2, detected in fetuses and neonates with homozygous alpha-thalassemia.

Tissue specificity. Red blood cells.

Post-translational modifications. Glucose reacts non-enzymatically with the N-terminus of the beta chain to form a stable ketoamine linkage. This takes place slowly and continuously throughout the 120-day life span of the red blood cell. The rate of glycation is increased in patients with diabetes mellitus. S-nitrosylated; a nitric oxide group is first bound to Fe(2+) and then transferred to Cys-94 to allow capture of O(2). Acetylated on Lys-60, Lys-83 and Lys-145 upon aspirin exposure.

Disease relevance. Heinz body anemias (HEIBAN) [MIM:140700] Form of non-spherocytic hemolytic anemia of Dacie type 1. After splenectomy, which has little benefit, basophilic inclusions called Heinz bodies are demonstrable in the erythrocytes. Before splenectomy, diffuse or punctate basophilia may be evident. Most of these cases are probably instances of hemoglobinopathy. The hemoglobin demonstrates heat lability. Heinz bodies are observed also with the Ivemark syndrome (asplenia with cardiovascular anomalies) and with glutathione peroxidase deficiency. The disease may be caused by variants affecting the gene represented in this entry. Beta-thalassemia (B-THAL) [MIM:613985] A form of thalassemia. Thalassemias are common monogenic diseases occurring mostly in Mediterranean and Southeast Asian populations. The hallmark of beta-thalassemia is an imbalance in globin-chain production in the adult HbA molecule. Absence of beta chain causes beta(0)-thalassemia, while reduced amounts of detectable beta globin causes beta(+)-thalassemia. In the severe forms of beta-thalassemia, the excess alpha globin chains accumulate in the developing erythroid precursors in the marrow. Their deposition leads to a vast increase in erythroid apoptosis that in turn causes ineffective erythropoiesis and severe microcytic hypochromic anemia. Clinically, beta-thalassemia is divided into thalassemia major which is transfusion dependent, thalassemia intermedia (of intermediate severity), and thalassemia minor that is asymptomatic. The disease is caused by variants affecting the gene represented in this entry. Sickle cell disease (SKCA) [MIM:603903] Characterized by abnormally shaped red cells resulting in chronic anemia and periodic episodes of pain, serious infections and damage to vital organs. Normal red blood cells are round and flexible and flow easily through blood vessels, but in sickle cell anemia, the abnormal hemoglobin (called Hb S) causes red blood cells to become stiff. They are C-shaped and resemble a sickle. These stiffer red blood cells can lead to microvascular occlusion thus cutting off the blood supply to nearby tissues. The disease is caused by variants affecting the gene represented in this entry. Beta-thalassemia, dominant, inclusion body type (B-THALIB) [MIM:603902] An autosomal dominant form of beta thalassemia characterized by moderate anemia, lifelong jaundice, cholelithiasis and splenomegaly, marked morphologic changes in the red cells, erythroid hyperplasia of the bone marrow with increased numbers of multinucleate red cell precursors, and the presence of large inclusion bodies in the normoblasts, both in the marrow and in the peripheral blood after splenectomy. The disease is caused by variants affecting the gene represented in this entry.

Polymorphism. Genetic variations in HBB are involved in resistance to malaria [MIM:611162]. Hemoglobin S (Hb S), which at homozygosity is responsible for sickle cell anemia, is not associated with any clinical abnormality when heterozygous. At heterozygosity, Hb S confers an increase in protection from life-threatening malaria. Additional variants conferring resistance against severe malaria are hemoglobin C (Hb C) and hemoglobin E (Hb E).

Miscellaneous. One molecule of 2,3-bisphosphoglycerate can bind to two beta chains per hemoglobin tetramer.

Similarity. Belongs to the globin family.

RefSeq proteins (1): NP_000509* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000971	Globin	Domain
IPR002337	Hemoglobin_b	Family
IPR009050	Globin-like_sf	Homologous_superfamily
IPR012292	Globin/Proto	Homologous_superfamily
IPR050056	Hemoglobin_oxygen_transport	Family

Pfam: PF00042

UniProt features (325 total): sequence variant 261, site 22, helix 11, modified residue 11, binding site 6, glycosylation site 6, peptide 2, sequence conflict 2, initiator methionine 1, chain 1, turn 1, domain 1

Structure

Experimental structures (PDB)

350 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
2W72	X-RAY DIFFRACTION	1.07
1IRD	X-RAY DIFFRACTION	1.25
2DN1	X-RAY DIFFRACTION	1.25
2DN2	X-RAY DIFFRACTION	1.25
2DN3	X-RAY DIFFRACTION	1.25
7DY4	X-RAY DIFFRACTION	1.3
6KA9	X-RAY DIFFRACTION	1.4
6KAO	X-RAY DIFFRACTION	1.4
6LCW	X-RAY DIFFRACTION	1.4
6LCX	X-RAY DIFFRACTION	1.4
7DY3	X-RAY DIFFRACTION	1.4
3S66	X-RAY DIFFRACTION	1.4
1J40	X-RAY DIFFRACTION	1.45
1J41	X-RAY DIFFRACTION	1.45
2D5Z	X-RAY DIFFRACTION	1.45
6KAE	X-RAY DIFFRACTION	1.45
6KAH	X-RAY DIFFRACTION	1.45
6KAI	X-RAY DIFFRACTION	1.45
6KAP	X-RAY DIFFRACTION	1.45
6L5V	X-RAY DIFFRACTION	1.45
7JY3	X-RAY DIFFRACTION	1.48
1BAB	X-RAY DIFFRACTION	1.5
1BZ0	X-RAY DIFFRACTION	1.5
1THB	X-RAY DIFFRACTION	1.5
1UIW	X-RAY DIFFRACTION	1.5
6KAQ	X-RAY DIFFRACTION	1.5
6L5W	X-RAY DIFFRACTION	1.5
9HBA	X-RAY DIFFRACTION	1.51
5WOG	X-RAY DIFFRACTION	1.54
1J3Y	X-RAY DIFFRACTION	1.55

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P68871-F1	97.09	0.97

Antibody-complex structures (SAbDab): 1 — 8VYL

Functional residue map

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

Catalytic / active sites (22): 8–9 ((microbial infection) cleavage; by n.americanus apr-2); 26–27 ((microbial infection) cleavage; by n.americanus apr-2); 30–31 ((microbial infection) cleavage; by n.americanus apr-2); 36–37 ((microbial infection) cleavage; by n.americanus apr-2); 38–39 ((microbial infection) cleavage; by n.americanus apr-2); 46–47 ((microbial infection) cleavage; by n.americanus apr-2); 53–54 ((microbial infection) cleavage; by n.americanus apr-2); 57–58 ((microbial infection) cleavage; by n.americanus apr-2); 60 (not glycated); 72–73 ((microbial infection) cleavage; by n.americanus apr-2); 75–76 ((microbial infection) cleavage; by n.americanus apr-2); 83 (not glycated) …

Ligand- & substrate-binding residues (6): 144; 2; 3; 64 (distal binding residue); 83; 93 (proximal binding residue)

Post-translational modifications (11): 2, 2, 10, 13, 45, 51, 60, 83, 88, 94, 145

Glycosylation sites (6): 2, 9, 18, 67, 121, 145

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
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: 0 (showing top):

GO Biological Process (13): inflammatory response (GO:0006954), regulation of blood pressure (GO:0008217), carbon dioxide transport (GO:0015670), oxygen transport (GO:0015671), nitric oxide transport (GO:0030185), response to hydrogen peroxide (GO:0042542), hydrogen peroxide catabolic process (GO:0042744), positive regulation of nitric oxide biosynthetic process (GO:0045429), erythrocyte development (GO:0048821), renal absorption (GO:0070293), platelet aggregation (GO:0070527), blood vessel diameter maintenance (GO:0097746), cellular oxidant detoxification (GO:0098869)

GO Molecular Function (9): oxygen carrier activity (GO:0005344), oxygen binding (GO:0019825), heme binding (GO:0020037), hemoglobin binding (GO:0030492), hemoglobin alpha binding (GO:0031721), metal ion binding (GO:0046872), peroxidase activity (GO:0004601), protein binding (GO:0005515), haptoglobin binding (GO:0031720)

GO Cellular Component (10): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytosol (GO:0005829), hemoglobin complex (GO:0005833), haptoglobin-hemoglobin complex (GO:0031838), extracellular exosome (GO:0070062), endocytic vesicle lumen (GO:0071682), blood microparticle (GO:0072562), tertiary granule lumen (GO:1904724), ficolin-1-rich granule lumen (GO:1904813)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
O2/CO2 exchange in erythrocytes	2
Autophagy	2
Binding and Uptake of Ligands by Scavenger Receptors	1
Innate Immune System	1
Cellular response to chemical stress	1
Cellular responses to stress	1
Hemostasis	1
Metal ion assimilation from the host	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
intracellular organelle lumen	3
blood circulation	2
gas transport	2
protein binding	2
protein-containing complex	2
defense response	1
regulation of biological quality	1
one-carbon compound transport	1
nitrogen compound transport	1
response to reactive oxygen species	1
catabolic process	1
hydrogen peroxide metabolic process	1
nitric oxide biosynthetic process	1
positive regulation of biosynthetic process	1
regulation of nitric oxide biosynthetic process	1
erythrocyte differentiation	1
myeloid cell development	1
renal system process	1
platelet activation	1
homotypic cell-cell adhesion	1
vascular process in circulatory system	1
regulation of tube diameter	1
cellular detoxification	1
oxygen transport	1
oxygen binding	1
molecular carrier activity	1
small molecule binding	1
tetrapyrrole binding	1
hemoglobin binding	1
cation binding	1
antioxidant activity	1
oxidoreductase activity, acting on peroxide as acceptor	1
binding	1
cytoplasm	1
cytosol	1
extracellular vesicle	1
endocytic vesicle	1
extracellular region	1
tertiary granule	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

215 interactions, top by confidence:

A	B	Type	Score
HBB	HBA1	psi-mi:“MI:0407”(direct interaction)	0.970
HBA1	HBB	psi-mi:“MI:0407”(direct interaction)	0.970
HBA1	HBB	psi-mi:“MI:2364”(proximity)	0.970
HBA1	HBB	psi-mi:“MI:0915”(physical association)	0.970
HBB	HBA1	psi-mi:“MI:0915”(physical association)	0.970
HBB	HBA1	psi-mi:“MI:2364”(proximity)	0.970
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
HBZ	HBB	psi-mi:“MI:0915”(physical association)	0.860

BioGRID (239): HBB (Affinity Capture-MS), HBB (Affinity Capture-MS), HBB (Affinity Capture-MS), HBB (Affinity Capture-MS), HBB (Affinity Capture-MS), HBB (Affinity Capture-MS), HBB (Affinity Capture-MS), HBB (Affinity Capture-MS), HBB (Affinity Capture-MS), HBB (Affinity Capture-MS), HBB (Affinity Capture-MS), HBB (Affinity Capture-MS), HBB (Affinity Capture-MS), HBB (Affinity Capture-MS), HBB (Affinity Capture-MS)

ESM2 similar proteins: P02024, P02025, P02026, P02028, P02029, P02030, P02031, P02032, P02033, P02035, P02036, P02038, P02040, P02042, P02044, P02051, P08259, P13557, P15449, P18985, P19885, P19886, P23602, P61772, P61773, P61774, P61775, P67821, P67822, P68044, P68046, P68047, P68222, P68223, P68224, P68225, P68232, P68234, P68871, P68872

Diamond homologs: B2KHZ4, B3EWE2, D0VX08, P02024, P02025, P02026, P02028, P02029, P02030, P02032, P02033, P02035, P02036, P02038, P02039, P02040, P02042, P02044, P02047, P02048, P02049, P02051, P02055, P02057, P02058, P02061, P07412, P08259, P08535, P09840, P09909, P10893, P11752, P11754, P11756, P11758, P13557, P13558, P14388, P14391

SIGNOR signaling

30 interactions.

A	Effect	B	Mechanism
HBB	“up-regulates activity”	CD163	binding
HBB	“down-regulates activity”	ADAMTS13
HBB	“down-regulates activity”	AHSP
HBB	“up-regulates quantity by expression”	TNF	“transcriptional regulation”
HBB	“up-regulates quantity by stabilization”	APOB
HBB	“up-regulates activity”	CYP2E1
HBB	“down-regulates activity”	EDN1
ACVR1B	“up-regulates quantity by stabilization”	HBB
ARSA	“up-regulates activity”	HBB	acetylation
EIF2AK1	“down-regulates quantity by repression”	HBB	“transcriptional regulation”
EHMT2	“up-regulates quantity by expression”	HBB	“transcriptional regulation”
KLF1	“up-regulates quantity by expression”	HBB	“transcriptional regulation”
EPAS1	“up-regulates quantity by expression”	HBB	“transcriptional regulation”
ETV6	“up-regulates quantity by expression”	HBB	“transcriptional regulation”
FGF2	“down-regulates quantity by repression”	HBB	“transcriptional regulation”
TGFB1	“up-regulates quantity by expression”	HBB	“transcriptional regulation”
HPX	“down-regulates activity”	HBB
HLTF	“up-regulates quantity by expression”	HBB	“transcriptional regulation”
HP	“down-regulates quantity”	HBB	binding
MIF	“down-regulates quantity by repression”	HBB	“transcriptional regulation”
MAPK11	“up-regulates quantity by expression”	HBB	“transcriptional regulation”
MAPK14	“up-regulates quantity by expression”	HBB	“transcriptional regulation”
NCL	“up-regulates quantity by expression”	HBB	“post transcriptional regulation”
heme	“up-regulates activity”	HBB	“chemical activation”
HBB	“form complex”	Hemoglobin	binding
EGF	“up-regulates quantity by expression”	HBB	“transcriptional regulation”
EPO	“up-regulates quantity by expression”	HBB	“transcriptional regulation”
STAT5A	“up-regulates quantity by expression”	HBB	“transcriptional regulation”
NFE2	“up-regulates quantity by expression”	HBB	“transcriptional regulation”
KLF8	“down-regulates quantity by repression”	HBB	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 218 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Neutrophil degranulation	18	3.0×	9e-03

GO biological processes:

GO term	Partners	Fold	FDR
oxygen transport	6	32.9×	2e-05
erythrocyte development	6	16.5×	8e-04

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

1661 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	271
Likely pathogenic	58
Uncertain significance	245
Likely benign	694
Benign	24

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1048666	NC_000011.10:g.5224303_5227790del	Pathogenic
1074556	NC_000011.9:g.(?_5247393)_5248785del	Pathogenic
1074558	NC_000011.9:g.(?_5247493)_5248852del	Pathogenic
1074559	NC_000011.9:g.(?_5239576)_5247294del	Pathogenic
1074561	NC_000011.9:g.(?_5246696)_5247105del	Pathogenic
1074874	NM_000518.5(HBB):c.196A>T (p.Lys66Ter)	Pathogenic
1076533	NC_000011.10:g.5226755_5227283del	Pathogenic
1189030	NM_000518.5(HBB):c.394_404del (p.Gln132fs)	Pathogenic
1455047	NC_000011.9:g.(?5145468)(5247440_?)del	Pathogenic
1459872	NM_000518.5(HBB):c.380_396del (p.Val127fs)	Pathogenic
15060	NC_000011.10:g.5226638_5234052del	Pathogenic
15061	NC_000011.10:g.5226570_5233984del	Pathogenic
15063	NM_000518.4(HBB):c.-7305_92+16del	Pathogenic
15096	NM_000518.5(HBB):c.435G>C (p.Lys145Asn)	Pathogenic
15161	NM_000518.5(HBB):c.79G>A (p.Glu27Lys)	Pathogenic
15166	NM_000518.5(HBB):c.71_73del (p.Val24del)	Pathogenic
15183	NM_000518.4(HBB):c.86T>C (p.Leu29Pro)	Pathogenic
15190	NM_000518.5(HBB):c.128T>C (p.Phe43Ser)	Pathogenic
15208	NM_000518.5(HBB):c.279C>R (p.His93Gln)	Pathogenic
15230	NM_000518.5(HBB):c.328G>C (p.Val110Leu)	Pathogenic
15234	NM_000518.4(HBB):c.92G>C (p.Arg31Thr)	Pathogenic
15239	NM_000518.5(HBB):c.82G>T (p.Ala28Ser)	Pathogenic
15241	NM_000518.5(HBB):c.295G>A (p.Val99Met)	Pathogenic
15250	Hb Little Rock	Pathogenic
15255	NM_000518.4(HBB):c.277C>T (p.His93Tyr)	Pathogenic
15257	NM_000518.5(HBB):c.346G>C (p.Ala116Pro)	Pathogenic
15258	NM_000518.5(HBB):c.59A>G (p.Asn20Ser)	Pathogenic
15281	NM_000518.4(HBB):c.25A>G (p.Lys9Glu)	Pathogenic
15290	NM_000518.5(HBB):c.404T>A (p.Val135Glu)	Pathogenic
15308	NM_000518.4(HBB):c.98T>C (p.Leu33Pro)	Pathogenic

SpliceAI

260 predictions. Top by Δscore:

Variant	Effect	Δscore
11:5226573:TCAC:T	donor_loss	1.0000
11:5226574:CA:C	donor_loss	1.0000
11:5226575:A:AC	donor_gain	1.0000
11:5226575:A:T	donor_loss	1.0000
11:5226575:AC:A	donor_gain	1.0000
11:5226575:ACC:A	donor_gain	1.0000
11:5226576:C:CA	donor_gain	1.0000
11:5226576:C:CC	donor_gain	1.0000
11:5226576:CCC:C	donor_gain	1.0000
11:5226576:CCCT:C	donor_gain	1.0000
11:5226576:CCCTG:C	donor_gain	1.0000
11:5225727:C:CC	acceptor_gain	0.9900
11:5225940:A:AC	donor_gain	0.9900
11:5226798:GCCT:G	acceptor_loss	0.9900
11:5226799:CCTA:C	acceptor_loss	0.9900
11:5226800:C:CC	acceptor_gain	0.9900
11:5226806:G:C	acceptor_gain	0.9900
11:5226806:G:GC	acceptor_gain	0.9900
11:5226945:C:CT	donor_gain	0.9900
11:5225723:GGAGC:G	acceptor_loss	0.9800
11:5225725:AGCT:A	acceptor_loss	0.9800
11:5225726:GCTG:G	acceptor_loss	0.9800
11:5225727:CT:C	acceptor_loss	0.9800
11:5225728:T:A	acceptor_loss	0.9800
11:5225927:TA:T	donor_gain	0.9800
11:5225928:AA:A	donor_gain	0.9800
11:5225928:AAC:A	donor_gain	0.9800
11:5226796:CAGC:C	acceptor_gain	0.9800
11:5226912:TGTA:T	donor_gain	0.9800
11:5226926:CAAC:C	donor_loss	0.9800

AlphaMissense

957 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:5226580:G:C	F104L	0.999
11:5226580:G:T	F104L	0.999
11:5226582:A:G	F104L	0.999
11:5225606:A:G	Y146H	0.998
11:5226615:G:C	H93D	0.998
11:5226763:A:C	F43L	0.998
11:5226763:A:T	F43L	0.998
11:5226765:A:G	F43L	0.998
11:5226581:A:G	F104S	0.997
11:5226583:G:C	N103K	0.997
11:5226583:G:T	N103K	0.997
11:5226613:G:C	H93Q	0.997
11:5226613:G:T	H93Q	0.997
11:5226754:A:C	F46L	0.997
11:5226754:A:T	F46L	0.997
11:5226756:A:G	F46L	0.997
11:5226615:G:T	H93N	0.996
11:5226698:C:A	G65V	0.996
11:5226698:C:T	G65D	0.996
11:5226702:G:C	H64D	0.996
11:5225719:C:T	G108D	0.995
11:5225720:C:G	G108R	0.995
11:5226581:A:C	F104C	0.995
11:5226582:A:C	F104V	0.995
11:5226766:G:C	F42L	0.995
11:5226766:G:T	F42L	0.995
11:5226768:A:G	F42L	0.995
11:5226593:T:C	D100G	0.994
11:5226602:A:G	L97P	0.994
11:5226617:A:G	L92P	0.994

dbSNP variants (sampled 300 via entrez): RS1000203596 (11:5228181 C>G,T), RS1000257309 (11:5228366 T>A,C,G), RS1001129219 (11:5226223 C>A,T), RS1001725140 (11:5227755 A>C,G), RS1001777596 (11:5227944 A>G), RS1001788972 (11:5228114 A>T), RS1003586 (11:5228140 C>T), RS1003790835 (11:5225840 G>A,T), RS1005042281 (11:5225871 C>A,G,T), RS1006081845 (11:5228710 A>G), RS1006108171 (11:5228932 A>G), RS1007106029 (11:5225124 A>G), RS1007540955 (11:5228387 G>T), RS1007588378 (11:5228614 G>T), RS1007800439 (11:5227196 C>A,T)

Disease associations

OMIM: gene MIM:141900 | disease phenotypes: MIM:613985, MIM:603902, MIM:617980, MIM:140700, MIM:603903, MIM:604131, MIM:611162, MIM:617047

GenCC curated gene-disease

Disease	Classification	Inheritance
beta-thalassemia HBB/LCRB	Definitive	Semidominant
beta thalassemia	Definitive	Autosomal recessive
hemoglobin M disease	Strong	Autosomal dominant
erythrocytosis, familial, 6	Strong	Autosomal dominant
Heinz body anemia	Strong	Autosomal dominant
dominant beta-thalassemia	Strong	Autosomal dominant
sickle cell disease	Strong	Autosomal recessive
delta-beta-thalassemia	Strong	Autosomal dominant
hereditary persistence of fetal hemoglobin	Strong	Autosomal dominant
hemoglobin C disease	Supportive	Autosomal recessive
hemoglobin E disease	Supportive	Autosomal recessive
beta-thalassemia major	Supportive	Autosomal recessive
beta-thalassemia intermedia	Supportive	Autosomal recessive
hemoglobin C-beta-thalassemia syndrome	Supportive	Autosomal recessive
hemoglobin E-beta-thalassemia syndrome	Supportive	Autosomal recessive
sickle cell-beta-thalassemia disease syndrome	Supportive	Autosomal recessive
sickle cell-hemoglobin c disease syndrome	Supportive	Autosomal recessive
sickle cell-hemoglobin d disease syndrome	Supportive	Autosomal recessive
sickle cell-hemoglobin E disease syndrome	Supportive	Autosomal recessive
hereditary persistence of fetal hemoglobin-sickle cell disease syndrome	Supportive	Autosomal recessive
hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (6)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
beta-thalassemia HBB/LCRB	Definitive	AR
hemoglobin M disease	Definitive	AD
obsolete sickle cell disease and related diseases	Definitive	AR
unstable hemoglobin disease	Definitive	AD
dominant beta-thalassemia	Definitive	AD
erythrocytosis, familial, 6	Definitive	AD

Mondo (31): beta thalassemia (MONDO:0019402), beta-thalassemia HBB/LCRB (MONDO:0013517), delta-beta-thalassemia (MONDO:0016489), hemoglobinopathy (MONDO:0044348), dominant beta-thalassemia (MONDO:0011381), thalassemia (MONDO:0000984), erythrocytosis, familial, 6 (MONDO:0054801), Heinz body anemia (MONDO:0007705), sickle cell disease (MONDO:0011382), alpha thalassemia spectrum (MONDO:0011399), hereditary persistence of fetal hemoglobin (MONDO:0020989), malaria, susceptibility to (MONDO:0021024), anemia (MONDO:0002280), congenital anemia (MONDO:0000577), sickle cell-hemoglobin c disease syndrome (MONDO:0016669)

Orphanet (17): Beta-thalassemia (Orphanet:848), Delta-beta-thalassemia (Orphanet:231237), Unstable beta globin chain variant disease (Orphanet:231226), OBSOLETE: Heinz body anemia (Orphanet:178330), Sickle cell anemia (Orphanet:232), Sickle cell disease (Orphanet:275752), Malaria (Orphanet:673), Alpha-thalassemia (Orphanet:846), Sickle cell S-C disease (Orphanet:251365), Hereditary persistence of fetal hemoglobin-sickle cell disease syndrome (Orphanet:251380), Hemoglobinopathy (Orphanet:68364), Hemoglobin D disease (Orphanet:90039), Hemoglobin E disease (Orphanet:2133), Hemoglobin E-beta-thalassemia syndrome (Orphanet:231249), Beta-thalassemia major (Orphanet:231214)

HPO phenotypes

139 total (30 of 139 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000114	Proximal tubulopathy
HP:0000135	Hypogonadism
HP:0000164	Abnormality of the dentition
HP:0000488	Retinopathy
HP:0000582	Upslanted palpebral fissure
HP:0000707	Abnormality of the nervous system
HP:0000737	Irritability
HP:0000790	Hematuria
HP:0000819	Diabetes mellitus
HP:0000821	Hypothyroidism
HP:0000822	Hypertension
HP:0000823	Delayed puberty
HP:0000829	Hypoparathyroidism
HP:0000846	Adrenal insufficiency
HP:0000924	Abnormality of the skeletal system
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0000952	Jaundice
HP:0000953	Hyperpigmentation of the skin
HP:0000961	Cyanosis
HP:0000980	Pallor
HP:0001081	Cholelithiasis
HP:0001297	Stroke
HP:0001392	Abnormality of the liver
HP:0001394	Cirrhosis
HP:0001395	Hepatic fibrosis
HP:0001402	Hepatocellular carcinoma

GWAS associations

40 associations (top):

Study	Trait	p-value
GCST000069_3	F-cell distribution	2.000000e-38
GCST000150_1	Fetal hemoglobin levels	2.000000e-21
GCST000410_3	Malaria	4.000000e-11
GCST001385_6	Inflammatory biomarkers	2.000000e-09
GCST001637_1	Malaria	6.000000e-14
GCST001710_2	HbA2 levels	1.000000e-11
GCST001779_5	Hematology traits	5.000000e-11
GCST001782_4	Mean corpuscular hemoglobin concentration	1.000000e-13
GCST002033_3	Malaria	2.000000e-16
GCST003122_3	Hemoglobin levels	4.000000e-86
GCST003122_7	Hemoglobin levels	1.000000e-25
GCST003774_2	Urinary albumin-to-creatinine ratio	8.000000e-12
GCST003774_3	Urinary albumin-to-creatinine ratio	3.000000e-10
GCST004329_3	Mean corpuscular hemoglobin concentration	7.000000e-24
GCST004330_1	Hematocrit	1.000000e-10
GCST004335_13	Mean corpuscular volume	1.000000e-22
GCST005356_14	Severe malaria	9.000000e-13
GCST007005_5	Logical memory (immediate recall) in normal cognition	3.000000e-06
GCST007006_9	Logical memory (delayed recall) in normal cognition	1.000000e-07
GCST008034_18	Hemoglobin A1c levels	8.000000e-27
GCST008333_1	Red cell distribution width	6.000000e-17
GCST008337_3	Blood cell traits (multivariate analysis)	5.000000e-20
GCST008338_4	Blood cell traits (multivariate analysis)	1.000000e-12
GCST008398_13	Glycated hemoglobin levels	3.000000e-39
GCST008745_79	Estimated glomerular filtration rate in non-diabetics	3.000000e-08
GCST008746_23	Estimated glomerular filtration rate in diabetes	7.000000e-13
GCST008793_1	Urinary albumin-to-creatinine ratio	6.000000e-08
GCST008972_89	Urate levels	5.000000e-15
GCST009681_7	Hemoglobin levels	2.000000e-12
GCST009682_2	Hematocrit	9.000000e-10

EFO canonical traits (20, from GWAS)

EFO ID	Trait name
EFO:0004576	fetal hemoglobin measurement
EFO:0005845	hemoglobin A2 measurement
EFO:0004348	hematocrit
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0004509	hemoglobin measurement
EFO:0007778	urinary albumin to creatinine ratio
EFO:0004874	memory performance
EFO:0004541	HbA1c measurement
EFO:0009188	Red cell distribution width
EFO:0004305	erythrocyte count
EFO:0004309	platelet count
EFO:0004833	neutrophil count
EFO:0004842	eosinophil count
EFO:0005090	basophil count
EFO:0005091	monocyte count
EFO:0004531	urate measurement
EFO:0004574	total cholesterol measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0009473	hemolysis
EFO:0004527	mean corpuscular hemoglobin

MeSH disease descriptors (13)

Descriptor	Name	Tree numbers
D000740	Anemia	C15.378.050
D000743	Anemia, Hemolytic	C15.378.050.141
D000755	Anemia, Sickle Cell	C15.378.050.141.150.150; C15.378.420.155; C16.320.070.150; C16.320.365.155
D006445	Hemoglobin C Disease	C15.378.050.141.150.490; C15.378.420.463; C16.320.070.490; C16.320.365.463
D006453	Hemoglobinopathies	C15.378.420; C16.320.365
D013789	Thalassemia	C15.378.050.141.150.875; C15.378.420.826; C16.320.070.875; C16.320.365.826
D017085	alpha-Thalassemia	C15.378.050.141.150.875.100; C15.378.420.826.100; C16.320.070.875.100; C16.320.365.826.100
D017086	beta-Thalassemia	C15.378.050.141.150.875.150; C15.378.420.826.150; C16.320.070.875.150; C16.320.365.826.150
C565834	Beta Thalassemia, Dominant Inclusion Body Type (supp.)
C562716	Delta-Beta Thalassemia (supp.)
C531699	Hb C disease (supp.)
C563030	Heinz Body Anemias (supp.)
C581942	Hemoglobin M Disease (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2095168 (PROTEIN COMPLEX), CHEMBL4331 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

23 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 2,395,966 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1014	CANDESARTAN CILEXETIL	4	11,194
CHEMBL1201001	MECHLORETHAMINE HYDROCHLORIDE	4	22,478
CHEMBL1201022	PHENAZOPYRIDINE HYDROCHLORIDE	4	6,331
CHEMBL1425	MERCAPTOPURINE ANHYDROUS	4	475,838
CHEMBL1489	AZACITIDINE	4	97,123
CHEMBL1542	AZATHIOPRINE	4	120,036
CHEMBL1607	TOPOTECAN HYDROCHLORIDE	4	56,379
CHEMBL184	ACYCLOVIR	4	97,488
CHEMBL185	FLUOROURACIL	4	299,469
CHEMBL3559672	RAUWOLFIA SERPENTINA	4
CHEMBL537	HYDROQUINONE	4	296,240
CHEMBL590	MENADIONE	4	21,034
CHEMBL671	THIOTEPA	4	117,334
CHEMBL727	THIOGUANINE	4	294,612
CHEMBL772	RESERPINE	4	330,645
CHEMBL140	CURCUMIN	3	93,882
CHEMBL273862	HYDROXYCAMPTOTHECIN	3	11,312
CHEMBL1232461	MOLIBRESIB	2	1,538
CHEMBL31574	FISETIN	2	7,745
CHEMBL453863	TEROXIRONE	2	35,288
CHEMBL54918	5-FLUOROURIDINE	2
CHEMBL6246	ELLAGIC ACID	2
CHEMBL8260	BAICALEIN	2

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

ChEMBL bioactivities

105 potent at pChembl≥5 of 302 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.30	Potency	5	nM	CAMPTOTHECIN
7.80	IC50	16	nM	MOLIBRESIB
7.30	Potency	50.1	nM	CHEMBL1557057
7.00	Potency	100	nM	CHEMBL1493502
7.00	Potency	100	nM	CHEMBL1530331
6.90	Potency	125.9	nM	CHEMBL3197413
6.70	Potency	199.5	nM	CHEMBL1495381
6.50	Potency	316.2	nM	AZATHIOPRINE
6.50	Potency	316.2	nM	CHEMBL1447588
6.50	Potency	316.2	nM	CHEMBL1426049
6.40	Potency	398.1	nM	MERCURIC CHLORIDE
6.30	Potency	501.2	nM	AZATHIOPRINE
6.30	Potency	501.2	nM	CHEMBL1447588
6.10	Potency	794.3	nM	CHEMBL27494
6.10	Potency	794.3	nM	8-AZAGUANINE
6.10	Potency	794.3	nM	2-AMINOANTHRACENE
6.10	Potency	794.3	nM	CHEMBL212242
6.10	Potency	794.3	nM	CHEMBL374632
6.00	Potency	1000	nM	CHEMBL2069121
6.00	Potency	1000	nM	CHEMBL1420829
6.00	Potency	1000	nM	CAMPTOTHECIN
5.95	Potency	1122	nM	THIOGUANINE
5.90	Potency	1259	nM	AZACITIDINE
5.90	Potency	1259	nM	CHEMBL1475361
5.90	Potency	1259	nM	NEBULARINE
5.90	Potency	1259	nM	CHEMBL1434516
5.80	Potency	1585	nM	CHEMBL1495381
5.80	Potency	1585	nM	AZATHIOPRINE
5.80	Potency	1585	nM	CHEMBL1514202
5.75	Potency	1778	nM	THIOINOSINE
5.70	Potency	1995	nM	CHEMBL1357641
5.70	Potency	1995	nM	AZATHIOPRINE
5.70	Potency	1995	nM	CHEMBL1447588
5.60	Potency	2512	nM	EUFLAVINE
5.60	Potency	2512	nM	AZATHIOPRINE
5.60	Potency	2512	nM	8-AZAGUANINE
5.60	Potency	2512	nM	THIOTEPA
5.60	Potency	2512	nM	QUINACRINE DIHYDROCHLORIDE
5.50	Potency	3162	nM	CHEMBL1450895
5.50	Potency	3162	nM	CHEMBL1495381
5.50	Potency	3162	nM	THIOINOSINE
5.50	Potency	3162	nM	MERCAPTOPURINE ANHYDROUS
5.50	Potency	3162	nM	CHEMBL137246
5.50	Potency	3162	nM	CHEMBL515505
5.50	Potency	3162	nM	CHEMBL1420829
5.50	Potency	3162	nM	CHEMBL1317506
5.50	Potency	3162	nM	CHEMBL458765
5.50	Potency	3162	nM	CHEMBL1318140
5.50	Potency	3162	nM	CHEMBL1712181
5.50	Potency	3162	nM	CHEMBL1564313

PubChem BioAssay actives

1 with measured affinity, of 875 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178841: Inhibition of HBB (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.0160	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Hemin	affects cotreatment, increases expression, decreases reaction, increases reaction	5
voxelotor	increases stability, decreases reaction, affects binding, affects folding, increases reaction	4
hydroquinone	decreases reaction, increases expression, affects binding, increases reaction, decreases methylation	3
catechol	increases reaction, decreases methylation, affects cotreatment, increases expression, decreases reaction	3
Cadmium	affects binding, decreases reaction, increases abundance, increases palmitoylation, increases expression	3
Oxygen	affects binding, affects folding, increases reaction, increases stability	3
hydroxyhydroquinone	decreases reaction, increases expression	2
sodium arsenite	increases expression, affects cotreatment, decreases expression	2
Decitabine	decreases reaction, increases expression	2
Air Pollutants	affects expression, increases abundance, increases expression	2
Methyl Methanesulfonate	decreases expression, increases methylation	2
Nickel	decreases expression, affects binding	2
Progesterone	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	decreases expression	2
Valproic Acid	affects cotreatment, decreases expression	2
Phenol	decreases reaction, increases expression, increases methylation	2
bisphenol F	increases expression	1
fluorene-9-bisphenol	decreases expression	1
triphenyl phosphate	affects expression	1
kaempferol	decreases reaction, increases response to substance	1
bisphenol A	decreases expression	1
5-chloro-2-methyl-4-isothiazolin-3-one	increases metabolic processing	1
trichostatin A	decreases reaction, increases expression	1
cinnamaldehyde	increases metabolic processing	1
styrene oxide	affects binding	1
tetrathiomolybdate	increases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	affects response to substance, decreases reaction, increases response to substance	1
di-n-butylphosphoric acid	affects expression	1
corosolic acid	increases expression	1

ChEMBL screening assays

68 unique, capped per target: 50 binding, 18 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3136831	Binding	Binding affinity to Hemoglobin (unknown origin) at 10 mM by circular dichroism spectroscopy	Synthesis of amphiphilic, chalcogen-based redox modulators with in vitro cytotoxic activity against cancer cells, macrophages and microbes — Medchemcomm
CHEMBL810680	Functional	Affinity towards oxygen by hemoglobin after modification by compound	Regioselective covalent modification of hemoglobin in search of antisickling agents. — J Med Chem

Cellosaurus cell lines

142 cell lines: 96 induced pluripotent stem cell, 35 transformed cell line, 8 embryonic stem cell, 3 finite cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_3435	SC-1 [Human Cetus]	Transformed cell line	Male
CVCL_A1BY	HNMUi002-A	Induced pluripotent stem cell	Male
CVCL_A1BZ	HNMUi003-A	Induced pluripotent stem cell	Female
CVCL_A1CA	HNMUi004-A	Induced pluripotent stem cell	Male
CVCL_A1CB	HNMUi005-A	Induced pluripotent stem cell	Male
CVCL_A1CC	HNMUi006-A	Induced pluripotent stem cell	Female
CVCL_A1CD	HNMUi007-A	Induced pluripotent stem cell	Male
CVCL_A1CE	HNMUi008-A	Induced pluripotent stem cell	Male
CVCL_A1CF	HNMUi009-A	Induced pluripotent stem cell	Female
CVCL_A1CG	HNMUi010-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00252122	PHASE4	TERMINATED	Pilot Study on the Effects of Intravenous Ketamine on Acute Pain Crisis in Patients With Sickle Cell Disease
NCT00513864	PHASE4	WITHDRAWN	Assessment of Opioid Analgesia in Sickle Cell
NCT00749515	PHASE4	COMPLETED	Pilot Study for Patients With Poor Response to Deferasirox
NCT00880373	PHASE4	TERMINATED	Ibuprofen and Opioid (Morphine or Diamorphine) for Acute Pain in Sickle Cell Disease - Sickle With Ibuprofen & Morphine
NCT00937144	PHASE4	WITHDRAWN	Endothelial Function in Patients With Sickle Cell Anemia Before and After Sildenafil
NCT02041299	PHASE4	TERMINATED	Efficacy and Safety of Ferriprox® in Patients With Sickle Cell Disease or Other Anemias
NCT02149537	PHASE4	COMPLETED	Risk Clinical Stratification of Sickle Cell Disease in Nigeria, Assessment of Efficacy/Safety of Hydroxyurea Treatment
NCT02222246	PHASE4	COMPLETED	Comparing Acute Pain Management Protocols for Patients With Sickle Cell Disease
NCT02443545	PHASE4	TERMINATED	Long-term Safety and Efficacy of Ferriprox® in Iron Overloaded Patients With Sickle Cell Disease or Other Anemias
NCT02522104	PHASE4	COMPLETED	Evaluation of the Impact of Renal Function on the Pharmacokinetics of SIKLOS ® (DARH)
NCT02594462	PHASE4	COMPLETED	Contraception in Women With Sickle Cell Disease
NCT02731157	PHASE4	COMPLETED	Rejuvesol® Washed RBC in Sickle Cell Patients Requiring Frequent Transfusions
NCT03682211	PHASE4	COMPLETED	Intranasal Fentanyl Versus Intravenous Morphine in the Treatment of Severe Painful Sickle Cell Crises in Children
NCT03903133	PHASE4	COMPLETED	Endothelial Monocyte-activating Polypeptide-II in Egyptian Sickle Patients
NCT04400487	PHASE4	COMPLETED	Actigraphy Improvement With Voxelotor (ActIVe) Study
NCT04581356	PHASE4	COMPLETED	Voxelotor Sickle Cell Exercise Study
NCT04657822	PHASE4	RECRUITING	Rollover Study for Patients With Sickle Cell Disease Who Have Completed a Prior Novartis-Sponsored Crizanlizumab Study
NCT04662931	PHASE4	COMPLETED	An Indian Multi-centric Phase IV Study to Assess the Safety of Crizanlizumab in Sickle Cell Disease Patients
NCT04684381	PHASE4	COMPLETED	Pharmacokinetics and Safety of Endari (L-glutamine) in Sickle Cell Disease Patients
NCT05081349	PHASE4	COMPLETED	Hydoxycarbamide and L-Carnitine Therapy in Sickle Cell Anemia
NCT05228821	PHASE4	WITHDRAWN	Voxelotor Brain Oxygenation and Neurocognitive Study
NCT05371184	PHASE4	COMPLETED	Glutamine Role in Preventing Vaso-occlusive Crisis Among SCD Patients
NCT05730205	PHASE4	RECRUITING	Effects of the Contraceptive Implant in Women With Sickle Cell Disease
NCT05848531	PHASE4	UNKNOWN	Clonidine With Morphine in Patient Controlled Analgesia Pump in Vaso-Occlusive Crisis in Sickle Cell Disease Patient
NCT06526117	PHASE4	RECRUITING	Stroke Prevention in Nigeria 2 Trial
NCT06579703	PHASE4	NOT_YET_RECRUITING	Ketorolac for Acute Vaso-Occlusive Crisis in Pediatric Sickle Cell Disease
NCT06665997	PHASE4	RECRUITING	Clinical and Biomarker Effects of Depot Medroxyprogesterone Acetate in Females With Sickle Cell Disease
NCT06979492	PHASE4	RECRUITING	Prophylactic Transfusion In Pregnant in Women With Sickle Cell Disease
NCT07177300	PHASE4	RECRUITING	Effectiveness of Nontraditional Hydroxyurea Algorithms: Novel and Clinical Evaluations (ENHANCE)
NCT07488520	PHASE4	NOT_YET_RECRUITING	Integrating Point of Care Testing (POCT) For Newborn Screening and Early Care for Sickle Cell Disease in Yopougon, Côte d’Ivoire
NCT00103753	PHASE4	UNKNOWN	Combined Chelation Treatment With Deferiprone and Deferoxamine in Thalassemia Major
NCT00564941	PHASE4	COMPLETED	Evaluating the Efficacy of Deferasirox in Transfusion Dependent Chronic Anaemias (Myelodysplastic Syndrome, Beta-thalassaemia Patients) With Chronic Iron Overload
NCT00733811	PHASE4	COMPLETED	Efficacy Study of the Use of Sequential DFP-DFO Versus DFP
NCT03961828	PHASE4	COMPLETED	Hyalornic Acid Level in β-Thalassemic Children Treated for Hepatitis C Virus
NCT00004408	PHASE3	COMPLETED	Phase III Randomized Study of Poloxamer 188 for Vaso-Occlusive Crisis of Sickle Cell Disease
NCT00072761	PHASE3	COMPLETED	Silent Cerebral Infarct Transfusion Multi-Center Clinical Trial
NCT00102791	PHASE3	TERMINATED	A Stratified Sickle Event Randomized Trial (ASSERT)
NCT00235391	PHASE3	COMPLETED	Expanded Access of Deferasirox to Patients With Congenital Disorders of Red Blood Cells and Chronic Iron Overload
NCT00263562	PHASE3	TERMINATED	Steroid Treatment for Sickle Cell Pain Crisis
NCT00294541	PHASE3	TERMINATED	A Study Evaluating the Long-Term Safety of ICA-17043 in Sickle Cell Disease Patients With or Without Hydroxyurea Therapy