beta-thalassemia HBB/LCRB

Summary

beta-thalassemia HBB/LCRB (MONDO:0013517) is a disease caused by HBB (GenCC Definitive), with 1 cohort gene and 9 clinical trials. Top therapeutic interventions include hydroxyurea and thalidomide.

At a glance

• Causal gene: HBB (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 166
• Clinical trials: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	beta-thalassemia HBB/LCRB
Mondo ID	MONDO:0013517
OMIM	613985
GARD	0024933
Is cancer (heuristic)	no

Also known as: thalassemia, beta · thalassemia, hispanic gamma-delta-beta

Data availability: 166 ClinVar variants · 20 ClinGen variant curations · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inherited hemoglobinopathy › thalassemia › beta thalassemia › beta-thalassemia HBB/LCRB

Related subtypes (2): thalassemia, beta+, silent allele, dominant beta-thalassemia

Subtypes (3): beta-thalassemia major, beta-thalassemia intermedia, thalassemia minor

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

166 retrieved; paginated sample, class counts are floors:

68 pathogenic, 30 pathogenic/likely pathogenic, 25 uncertain significance, 23 conflicting classifications of pathogenicity, 12 likely pathogenic, 5 likely benign, 2 benign/likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3255362	Single allele	A-GAMMA3’E	Pathogenic	no assertion criteria provided
3255365	Single allele	A-GAMMA3’E	Pathogenic	no assertion criteria provided
3255366	Single allele	A-GAMMA3’E	Pathogenic	no assertion criteria provided
15126	NM_000518.4(HBB):c.19G>A (p.Glu7Lys)	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15152	NM_000518.4(HBB):c.364G>C (p.Glu122Gln)	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15161	NM_000518.5(HBB):c.79G>A (p.Glu27Lys)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15234	NM_000518.4(HBB):c.92G>C (p.Arg31Thr)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15239	NM_000518.5(HBB):c.82G>T (p.Ala28Ser)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15292	NM_000518.4(HBB):c.364G>A (p.Glu122Lys)	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15300	NM_000518.5(HBB):c.61G>A (p.Val21Met)	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15333	NM_000518.5(HBB):c.20A>T (p.Glu7Val)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15343	NM_000518.4(HBB):c.266T>C (p.Leu89Pro)	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15352	NM_000518.4(HBB):c.332T>C (p.Leu111Pro)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15356	NM_000518.4(HBB):c.320T>C (p.Leu107Pro)	HBB	Pathogenic	criteria provided, single submitter
15395	NM_000518.4(HBB):c.440A>C (p.His147Pro)	HBB	Pathogenic	criteria provided, single submitter
15401	NM_000518.5(HBB):c.52A>T (p.Lys18Ter)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15402	NM_000518.5(HBB):c.118C>T (p.Gln40Ter)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15404	NM_000518.5(HBB):c.364G>T (p.Glu122Ter)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15407	NM_000518.5(HBB):c.184A>T (p.Lys62Ter)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15408	NM_000518.5(HBB):c.108C>A (p.Tyr36Ter)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15413	NM_000518.5(HBB):c.25_26del (p.Lys9fs)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15414	NM_000518.5(HBB):c.51del (p.Lys18fs)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15415	NM_000518.5(HBB):c.135del (p.Phe46fs)	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15417	NM_000518.5(HBB):c.126_129del (p.Phe42fs)	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15418	NM_000518.5(HBB):c.20del (p.Glu7fs)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15419	NM_000518.5(HBB):c.217dup (p.Ser73fs)	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15422	NM_000518.5(HBB):c.17_18del (p.Pro6fs)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15426	NM_000518.5(HBB):c.45dup (p.Trp16fs)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15431	NM_000518.5(HBB):c.112del (p.Trp38fs)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15432	NM_000518.5(HBB):c.85dup (p.Leu29fs)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 33 · Orphanet: 29 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
HBB	Definitive	Semidominant	beta-thalassemia HBB/LCRB	33

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HBB	Orphanet:2132	Hemoglobin C disease
HBB	Orphanet:2133	Hemoglobin E disease
HBB	Orphanet:231214	Beta-thalassemia major
HBB	Orphanet:231222	Beta-thalassemia intermedia
HBB	Orphanet:231226	Unstable beta globin chain variant disease
HBB	Orphanet:231237	Delta-beta-thalassemia
HBB	Orphanet:231242	Hemoglobin C-beta-thalassemia syndrome
HBB	Orphanet:231249	Hemoglobin E-beta-thalassemia syndrome
HBB	Orphanet:232	Sickle cell anemia
HBB	Orphanet:247511	Autosomal dominant secondary polycythemia
HBB	Orphanet:251365	Sickle cell S-C disease
HBB	Orphanet:251370	Sickle cell S-D Punjab disease
HBB	Orphanet:251375	Sickle cell S-E disease
HBB	Orphanet:251380	Hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
HBB	Orphanet:330041	Hemoglobin M disease
HBB	Orphanet:46532	Hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome
HBB	Orphanet:695140	Sickle cell-beta zero-thalassemia
HBB	Orphanet:695147	Sickle cell-beta plus-thalassemia
HBB	Orphanet:699822	Sickle cell S-Lepore disease
HBB	Orphanet:700090	Sickle cell S-O Arab disease
HBB	Orphanet:700107	Sickle cell S-other specified hemoglobin variant
HBB	Orphanet:700111	Homozygous hemoglobin O Arab disease
HBB	Orphanet:715125	Hemoglobin E-beta-thalassemia intermedia
HBB	Orphanet:715128	Hemoglobin E-beta-thalassemia major
HBB	Orphanet:715135	Hemoglobin Lepore-beta-thalassemia intermedia
HBB	Orphanet:715140	Hemoglobin Lepore-beta-thalassemia major
HBB	Orphanet:715143	Heterozygous beta-thalassemia intermedia with supernumerary alpha-globin gene
HBB	Orphanet:715157	Low oxygen affinity beta chain hemoglobin disease
HBB	Orphanet:90039	Hemoglobin D disease

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HBB	HGNC:4827	ENSG00000244734	P68871	Hemoglobin subunit beta	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HBB	Hemoglobin subunit beta	Involved in oxygen transport from the lung to the various peripheral tissues.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HBB	Other/Unknown	no		Globin, Hemoglobin_b, Globin-like_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
monocyte	1
trabecular bone tissue	1
vena cava	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HBB	284	broad	marker	monocyte, trabecular bone tissue, vena cava

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HBB	454

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HBB	P68871	350

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Heme assimilation	1	3806.7×	0.003	HBB
Erythrocytes take up oxygen and release carbon dioxide	1	1268.9×	0.003	HBB
Erythrocytes take up carbon dioxide and release oxygen	1	878.5×	0.003	HBB
Scavenging of heme from plasma	1	878.5×	0.003	HBB
Chaperone Mediated Autophagy	1	496.5×	0.004	HBB
Late endosomal microautophagy	1	326.3×	0.005	HBB
Heme signaling	1	215.5×	0.007	HBB
Cytoprotection by HMOX1	1	184.2×	0.007	HBB
Factors involved in megakaryocyte development and platelet production	1	66.4×	0.017	HBB
Neutrophil degranulation	1	23.1×	0.043	HBB

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
nitric oxide transport	1	3370.4×	0.002	HBB
cellular oxidant detoxification	1	1872.4×	0.002	HBB
renal absorption	1	1685.2×	0.002	HBB
carbon dioxide transport	1	1296.3×	0.002	HBB
oxygen transport	1	1053.2×	0.002	HBB
hydrogen peroxide catabolic process	1	674.1×	0.003	HBB
blood vessel diameter maintenance	1	624.1×	0.003	HBB
erythrocyte development	1	526.6×	0.003	HBB
response to hydrogen peroxide	1	468.1×	0.003	HBB
positive regulation of nitric oxide biosynthetic process	1	455.5×	0.003	HBB
platelet aggregation	1	337.0×	0.004	HBB
regulation of blood pressure	1	221.7×	0.005	HBB
inflammatory response	1	37.7×	0.027	HBB

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
HBB	CANDESARTAN CILEXETIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HBB	23	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CANDESARTAN CILEXETIL	4	HBB
MECHLORETHAMINE HYDROCHLORIDE	4	HBB
PHENAZOPYRIDINE HYDROCHLORIDE	4	HBB
MERCAPTOPURINE ANHYDROUS	4	HBB
AZACITIDINE	4	HBB
AZATHIOPRINE	4	HBB
TOPOTECAN HYDROCHLORIDE	4	HBB
ACYCLOVIR	4	HBB
FLUOROURACIL	4	HBB
RAUWOLFIA SERPENTINA	4	HBB
HYDROQUINONE	4	HBB
MENADIONE	4	HBB
THIOTEPA	4	HBB
THIOGUANINE	4	HBB
RESERPINE	4	HBB
CURCUMIN	3	HBB
HYDROXYCAMPTOTHECIN	3	HBB
MOLIBRESIB	2	HBB
FISETIN	2	HBB
TEROXIRONE	2	HBB
5-FLUOROURIDINE	2	HBB
ELLAGIC ACID	2	HBB
BAICALEIN	2	HBB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
HBB	68	Binding:50, Functional:18

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

23 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
CANDESARTAN CILEXETIL	4	HBB
MECHLORETHAMINE HYDROCHLORIDE	4	HBB
PHENAZOPYRIDINE HYDROCHLORIDE	4	HBB
MERCAPTOPURINE ANHYDROUS	4	HBB
AZACITIDINE	4	HBB
AZATHIOPRINE	4	HBB
TOPOTECAN HYDROCHLORIDE	4	HBB
ACYCLOVIR	4	HBB
FLUOROURACIL	4	HBB
RAUWOLFIA SERPENTINA	4	HBB
HYDROQUINONE	4	HBB
MENADIONE	4	HBB
THIOTEPA	4	HBB
THIOGUANINE	4	HBB
RESERPINE	4	HBB
CURCUMIN	3	HBB
HYDROXYCAMPTOTHECIN	3	HBB
MOLIBRESIB	2	HBB
FISETIN	2	HBB
TEROXIRONE	2	HBB
5-FLUOROURIDINE	2	HBB
ELLAGIC ACID	2	HBB
BAICALEIN	2	HBB

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	HBB
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 9.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5
PHASE2/PHASE3	2
PHASE2	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05132270	PHASE2/PHASE3	COMPLETED	Clinical Experience of Thalidomide in Thalassemic Patients
NCT06153784	PHASE2/PHASE3	COMPLETED	Thalidomide and Hydroxyurea Combination in β-Thalassemia Patients
NCT05736419	PHASE2	RECRUITING	A Study of Immune Suppression Treatment for People With Sickle Cell Disease or β-Thalassemia Who Are Going to Receive an Allogeneic Hematopoietic Cell Transplantation (HCT)
NCT03183375	PHASE2	UNKNOWN	The Efficacy and Safety of HYDROXYUREA in Management of Beta Thalassemia Patients in Karachi Pakistan
NCT05799118	Not specified	RECRUITING	Study of the Role of Genetic Modifiers in Hemoglobinopathies
NCT06041620	Not specified	RECRUITING	Safety and Efficacy Evaluation of Autologous CRISPR-Cas12b Edited Hematopoietic Stem Cells
NCT06298630	Not specified	NOT_YET_RECRUITING	Long-term Follow-up Study of BRL-101 for TDT
NCT06314529	Not specified	RECRUITING	Long-term Follow-up Study of BHC001 for TDT
NCT07099196	Not specified	COMPLETED	Impact of Virtual Reality on Pain and Anxiety During Intravenous Cannulation Procedures Among Thalassemia Patients in UAE.

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
HYDROXYUREA	4	2
THALIDOMIDE	4	2
CHEMBL426123	0	2