Beta-thalassemia intermedia

Summary

Beta-thalassemia intermedia (MONDO:0016487) is a disease with 1 cohort gene and 6 clinical trials. Top therapeutic interventions include sotatercept, sodium 2,2-dimethylbutyrate, and sapablursen.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 1
• ClinVar variants: 13
• Phenotypes (HPO): 36
• Clinical trials: 6

Clinical features

Signs & symptoms

Clinical features (HPO)

36 HPO clinical features (Orphanet curated; top 36 by frequency):

HPO ID	Term	Frequency
HP:0000939	Osteoporosis	Very frequent (80-99%)
HP:0010972	Anemia of inadequate production	Very frequent (80-99%)
HP:0011904	Persistence of hemoglobin F	Very frequent (80-99%)
HP:0025066	Decreased mean corpuscular volume	Very frequent (80-99%)
HP:0000924	Abnormality of the skeletal system	Frequent (30-79%)
HP:0000952	Jaundice	Frequent (30-79%)
HP:0000980	Pallor	Frequent (30-79%)
HP:0001978	Extramedullary hematopoiesis	Frequent (30-79%)
HP:0002659	Increased susceptibility to fractures	Frequent (30-79%)
HP:0004349	Reduced bone mineral density	Frequent (30-79%)
HP:0011031	Abnormality of iron homeostasis	Frequent (30-79%)
HP:0012132	Erythroid hyperplasia	Frequent (30-79%)
HP:0045048	Increased HbA2 hemoglobin	Frequent (30-79%)
HP:0100724	Hypercoagulability	Frequent (30-79%)
HP:0200042	Skin ulcer	Frequent (30-79%)
HP:0000114	Proximal tubulopathy	Occasional (5-29%)
HP:0000938	Osteopenia	Occasional (5-29%)
HP:0001081	Cholelithiasis	Occasional (5-29%)
HP:0001392	Abnormality of the liver	Occasional (5-29%)
HP:0001410	Decreased liver function	Occasional (5-29%)
HP:0001433	Hepatosplenomegaly	Occasional (5-29%)
HP:0001626	Abnormality of the cardiovascular system	Occasional (5-29%)
HP:0001722	High-output congestive heart failure	Occasional (5-29%)
HP:0001744	Splenomegaly	Occasional (5-29%)
HP:0001974	Leukocytosis	Occasional (5-29%)
HP:0002092	Pulmonary arterial hypertension	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0012465	Elevated hepatic iron concentration	Occasional (5-29%)
HP:0000135	Hypogonadism	Very rare (<1-4%)
HP:0000819	Diabetes mellitus	Very rare (<1-4%)
HP:0000821	Hypothyroidism	Very rare (<1-4%)
HP:0000829	Hypoparathyroidism	Very rare (<1-4%)
HP:0000846	Adrenal insufficiency	Very rare (<1-4%)
HP:0001394	Cirrhosis	Very rare (<1-4%)
HP:0001402	Hepatocellular carcinoma	Very rare (<1-4%)
HP:0002176	Spinal cord compression	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	beta-thalassemia intermedia
Mondo ID	MONDO:0016487
Orphanet	231222
DOID	DOID:0080772
SNOMED CT	191189009
UMLS	C0472767
MedGen	450544
GARD	0017163
MedDRA	10062923
Is cancer (heuristic)	no

Data availability: 13 ClinVar variants · 1 GenCC gene-disease record.

Disease family

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 › beta-thalassemia intermedia

Related subtypes (2): beta-thalassemia major, 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

13 retrieved; paginated sample, class counts are floors:

11 pathogenic/likely pathogenic, 1 pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
15450	NM_000518.5(HBB):c.92+6T>C	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15451	NM_000518.5(HBB):c.316-3C>A	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15462	NM_000518.5(HBB):c.-142C>T	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15464	NM_000518.5(HBB):c.-137C>G	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15483	NM_000518.5(HBB):c.380T>G (p.Val127Gly)	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15513	NM_000518.5(HBB):c.344T>C (p.Leu115Pro)	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
36285	NM_000518.5(HBB):c.-137C>A	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
36287	NM_000518.5(HBB):c.-137C>T	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
36341	NM_000518.5(HBB):c.93-3T>G	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
393707	NM_000518.5(HBB):c.*6C>G	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15466	NM_000518.5(HBB):c.-81A>G	LOC106099062	Pathogenic	criteria provided, multiple submitters, no conflicts
15514	NM_000518.5(HBB):c.-140C>T	LOC106099062	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
496005	NM_000518.5(HBB):c.-77_-76del	HBB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

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: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	4
PHASE1/PHASE2	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04432623	PHASE1/PHASE2	ENROLLING_BY_INVITATION	The BENeFiTS Trial in Beta Thalassemia Intermedia
NCT01571635	PHASE2	TERMINATED	Study to Determine the Safety and Tolerability of Sotatercept (ACE-011) in Adults With Beta( β)- Thalassemia.
NCT01609595	PHASE2	COMPLETED	Study of SDMB (2,2 Dimethylbutyrate, Sodium Salt) in Beta Thalassemia Intermedia in Thailand
NCT01642758	PHASE2	COMPLETED	Trial of HQK-1001 in Beta Thalassemia Intermedia in Lebanon
NCT04059406	PHASE2	TERMINATED	Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Sapablursen (Formerly ISIS 702843, IONIS-TMPRSS6-LRx)
NCT06831799	Not specified	COMPLETED	ERN-EuroBloodNet Registry on Patients With Rare Red Blood Cell Defects and COVID-19

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SOTATERCEPT	4	1
SODIUM 2,2-DIMETHYLBUTYRATE	2	2
SAPABLURSEN	2	1