Heinz body anemia

Summary

Heinz body anemia (MONDO:0007705) is a disease caused by variants in HBA1, HBA2, and HBB, with 3 cohort genes. The dominant Reactome pathway is Heme assimilation (3 cohort genes).

At a glance

• Causal genes: HBA1 (GenCC Strong), HBA2 (GenCC Strong), HBB (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 176

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Heinz body anemia
Mondo ID	MONDO:0007705
MeSH	C563030
OMIM	140700
Orphanet	178330
DOID	DOID:0111363
UMLS	C0700299
MedGen	148583
GARD	0010718
MedDRA	10002058
Is cancer (heuristic)	no

Also known as: Heinz body anemias, alpha-

Data availability: 176 ClinVar variants · 6 GenCC gene-disease records · 1 HPO phenotype.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › normocytic anemia › hemolytic anemia › Heinz body anemia

Related subtypes (10): familial hemolytic anemia, lethal hemolytic anemia-genital anomalies syndrome, hemolytic disease of the newborn with Kell alloimmunization, hereditary elliptocytosis, Shiga toxin-associated hemolytic uremic syndrome, hereditary stomatocytosis, autoimmune hemolytic anemia, 6-phosphogluconate dehydrogenase deficiency, non-autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria

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

176 retrieved; paginated sample, class counts are floors:

57 pathogenic, 45 pathogenic/likely pathogenic, 28 uncertain significance, 22 conflicting classifications of pathogenicity, 17 likely pathogenic, 3 pathogenic; other, 2 benign/likely benign, 1 benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1331033	NM_000558.5(HBA1):c.328del (p.Leu110fs)	HBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15624	NM_000517.4(HBA2):c.427T>C (p.Ter143Gln)	HBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15655	NM_000517.6(HBA2):c.410T>C (p.Leu137Pro)	HBA1	Pathogenic	criteria provided, single submitter
15828	NM_000558.5(HBA1):c.410T>G (p.Leu137Arg)	HBA1	Pathogenic; other	no assertion criteria provided
15849	NM_000558.3(HBA1):c.179G>A (p.Gly60Asp)	HBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
2428550	NM_000558.5(HBA1):c.62_63insT (p.Ala22fs)	HBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2428673	NM_000558.5(HBA1):c.1A>G (p.Met1Val)	HBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
2681961	NM_000558.5(HBA1):c.95+1G>A	HBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
3075902	NM_000558.5(HBA1):c.44G>A (p.Trp15Ter)	HBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3579876	NM_000558.5(HBA1):c.2T>C (p.Met1Thr)	HBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3579878	NM_000558.5(HBA1):c.95+2T>C	HBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
439103	NM_000558.5(HBA1):c.43T>C (p.Trp15Arg)	HBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
618153	NM_000558.5(HBA1):c.187del (p.Val63fs)	HBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
619842	NM_000558.5(HBA1):c.237del (p.Asn79fs)	HBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
801167	NM_000558.5(HBA1):c.94_95del (p.Arg32fs)	HBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
801169	NM_000558.5(HBA1):c.96-1G>A	HBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
811820	NM_000558.5(HBA1):c.45G>A (p.Trp15Ter)	HBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
811900	NM_000558.5(HBA1):c.358C>T (p.Pro120Ser)	HBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
1098491	NM_000517.6(HBA2):c.210_211insT (p.Val71fs)	HBA2	Pathogenic	criteria provided, single submitter
15627	NM_000517.6(HBA2):c.428A>C (p.Ter143Ser)	HBA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15630	NM_000517.6(HBA2):c.377T>C (p.Leu126Pro)	HBA2	Pathogenic	criteria provided, multiple submitters, no conflicts
15636	NM_000517.4(HBA2):c.142G>C (p.Asp48His)	HBA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15656	NM_000517.6(HBA2):c.314G>A (p.Cys105Tyr)	HBA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15679	NM_000517.6(HBA2):c.96-2A>G	HBA2	Pathogenic	criteria provided, multiple submitters, no conflicts
15690	NM_000517.6(HBA2):c.377T>G (p.Leu126Arg)	HBA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15692	NM_000517.6(HBA2):c.2del (p.Met1fs)	HBA2	Pathogenic	criteria provided, multiple submitters, no conflicts
280127	NM_000517.6(HBA2):c.60del (p.His21fs)	HBA2	Pathogenic	criteria provided, multiple submitters, no conflicts
375746	NM_000517.6(HBA2):c.95+2_95+6del	HBA2	Pathogenic	criteria provided, multiple submitters, no conflicts
439123	NM_000517.6(HBA2):c.69del (p.Glu24fs)	HBA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
439772	NM_000517.6(HBA2):c.*93_*94del	HBA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 57 · Orphanet: 44 · 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
HBA1	Strong	Autosomal dominant	Heinz body anemia	13
HBA2	Strong	Autosomal dominant	Heinz body anemia	11
HBB	Strong	Autosomal dominant	Heinz body anemia	33

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HBA1	Orphanet:163596	Hemoglobin Bart’s fetalis syndrome
HBA1	Orphanet:247511	Autosomal dominant secondary polycythemia
HBA1	Orphanet:330041	Hemoglobin M disease
HBA1	Orphanet:707789	Unstable alpha globin chain variant disease
HBA1	Orphanet:715143	Heterozygous beta-thalassemia intermedia with supernumerary alpha-globin gene
HBA1	Orphanet:93616	Hemoglobin H disease
HBA1	Orphanet:98791	Alpha-thalassemia-intellectual disability syndrome linked to chromosome 16
HBA2	Orphanet:163596	Hemoglobin Bart’s fetalis syndrome
HBA2	Orphanet:247511	Autosomal dominant secondary polycythemia
HBA2	Orphanet:330041	Hemoglobin M disease
HBA2	Orphanet:707789	Unstable alpha globin chain variant disease
HBA2	Orphanet:715143	Heterozygous beta-thalassemia intermedia with supernumerary alpha-globin gene
HBA2	Orphanet:715154	Low oxygen affinity alpha chain hemoglobin disease
HBA2	Orphanet:93616	Hemoglobin H disease
HBA2	Orphanet:98791	Alpha-thalassemia-intellectual disability syndrome linked to chromosome 16
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

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HBA1	HGNC:4823	ENSG00000206172	P69905	Hemoglobin subunit alpha	gencc,clinvar
HBA2	HGNC:4824	ENSG00000188536	P69905	Hemoglobin subunit alpha	gencc,clinvar
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)
HBA1	Hemoglobin subunit alpha	Involved in oxygen transport from the lung to the various peripheral tissues.
HBA2	Hemoglobin subunit alpha	Involved in oxygen transport from the lung to the various peripheral tissues.
HBB	Hemoglobin subunit beta	Involved in oxygen transport from the lung to the various peripheral tissues.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HBA1	Other/Unknown	no		Globin, Hemoglobin_a-typ, Hemoglobin_pi
HBA2	Other/Unknown	no		Globin, Hemoglobin_a-typ, Hemoglobin_pi
HBB	Other/Unknown	no		Globin, Hemoglobin_b, Globin-like_sf

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
monocyte	3
blood	2
bone marrow	1
bone element	1
trabecular bone tissue	1
vena cava	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HBA1	133	tissue_specific	marker	monocyte, blood, bone marrow
HBA2	143	tissue_specific	marker	monocyte, blood, bone element
HBB	284	broad	marker	monocyte, trabecular bone tissue, vena cava

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HBB	454
HBA1	434
HBA2	434

Intra-cohort edges

A	B	Sources
HBA1	HBA2	biogrid_interaction, intact
HBA1	HBB	intact
HBA2	HBB	intact

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HBA1	P69905	356
HBA2	P69905	356
HBB	P68871	350

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Heme assimilation	3	3806.7×	4e-11	HBA1, HBA2, HBB
Erythrocytes take up oxygen and release carbon dioxide	3	1268.9×	2e-09	HBA1, HBA2, HBB
Erythrocytes take up carbon dioxide and release oxygen	3	878.5×	3e-09	HBA1, HBA2, HBB
Scavenging of heme from plasma	3	878.5×	3e-09	HBA1, HBA2, HBB
Heme signaling	3	215.5×	2e-07	HBA1, HBA2, HBB
Cytoprotection by HMOX1	3	184.2×	3e-07	HBA1, HBA2, HBB
Chaperone Mediated Autophagy	1	165.5×	0.009	HBB
Late endosomal microautophagy	1	108.8×	0.011	HBB
Factors involved in megakaryocyte development and platelet production	1	22.1×	0.049	HBB
Neutrophil degranulation	1	7.7×	0.124	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 3 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	3	3370.4×	2e-10	HBA1, HBA2, HBB
cellular oxidant detoxification	3	1872.4×	7e-10	HBA1, HBA2, HBB
carbon dioxide transport	3	1296.3×	2e-09	HBA1, HBA2, HBB
oxygen transport	3	1053.2×	2e-09	HBA1, HBA2, HBB
hydrogen peroxide catabolic process	3	674.1×	7e-09	HBA1, HBA2, HBB
erythrocyte development	3	526.6×	1e-08	HBA1, HBA2, HBB
response to hydrogen peroxide	3	468.1×	2e-08	HBA1, HBA2, HBB
inflammatory response	3	37.7×	3e-05	HBA1, HBA2, HBB
renal absorption	1	561.7×	0.003	HBB
blood vessel diameter maintenance	1	208.1×	0.006	HBB
positive regulation of nitric oxide biosynthetic process	1	151.8×	0.008	HBB
platelet aggregation	1	112.3×	0.010	HBB
regulation of blood pressure	1	73.9×	0.013	HBB

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 3 of 3 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
HBA1	0	0
HBA2	0	0

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
HBA1	59	Binding:46, Functional:13
HBA2	59	Binding:46, Functional:13

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	2	HBA1, HBA2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HBA1	59	HBB
HBA2	59	HBB

Clinical trials & evidence

Clinical trials

Clinical trials: 0.