Methemoglobinemia, alpha type

Summary

Methemoglobinemia, alpha type (MONDO:0020835) is a disease caused by HBA1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: HBA1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 23

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	methemoglobinemia, alpha type
Mondo ID	MONDO:0020835
OMIM	617973
UMLS	C4693798
MedGen	1635511
GARD	0016277
Is cancer (heuristic)	no

Also known as: methemoglobinemia, alpha type

Data availability: 23 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › erythrocyte disorder › hemoglobinopathy › methemoglobinemia › hereditary methemoglobinemia › methemoglobinemia, alpha type

Related subtypes (4): methemoglobin reductase deficiency, methemoglobinemia type 4, methemoglobinemia due to deficiency of methemoglobin reductase, hemoglobin M disease

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

23 retrieved; paginated sample, class counts are floors:

11 pathogenic/likely pathogenic, 6 pathogenic, 6 likely pathogenic

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
15779	NM_000558.5(HBA1):c.262C>T (p.His88Tyr)	HBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
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
15858	NM_000558.5(HBA1):c.113CCA[2] (p.Thr40del)	LOC106804613	Pathogenic	criteria provided, multiple submitters, no conflicts
15800	NM_000558.5(HBA1):c.332C>A (p.Ala111Asp)	HBA1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
15865	NM_000558.3(HBA1):c.389T>C (p.Leu130Pro)	HBA1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2502312	NM_000558.5(HBA1):c.300+1G>A	HBA1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3075901	NM_000558.5(HBA1):c.99G>A (p.Met33Ile)	HBA1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3579877	NM_000558.5(HBA1):c.95G>A (p.Arg32Lys)	HBA1	Likely pathogenic	criteria provided, single submitter
3579879	NM_000558.5(HBA1):c.184A>T (p.Lys62Ter)	LOC106804613	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 7 · 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	Definitive	Semidominant	alpha thalassemia spectrum	13

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

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
HBA1	HGNC:4823	ENSG00000206172	P69905	Hemoglobin subunit alpha	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.

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)
HBA1	Other/Unknown	no		Globin, Hemoglobin_a-typ, Hemoglobin_pi

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
blood	1
bone marrow	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HBA1	133	tissue_specific	marker	monocyte, blood, bone marrow

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HBA1	434

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HBA1	P69905	356

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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×	0.002	HBA1
Erythrocytes take up oxygen and release carbon dioxide	1	1268.9×	0.002	HBA1
Erythrocytes take up carbon dioxide and release oxygen	1	878.5×	0.002	HBA1
Scavenging of heme from plasma	1	878.5×	0.002	HBA1
Heme signaling	1	215.5×	0.005	HBA1
Cytoprotection by HMOX1	1	184.2×	0.005	HBA1

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	HBA1
cellular oxidant detoxification	1	1872.4×	0.002	HBA1
carbon dioxide transport	1	1296.3×	0.002	HBA1
oxygen transport	1	1053.2×	0.002	HBA1
hydrogen peroxide catabolic process	1	674.1×	0.002	HBA1
erythrocyte development	1	526.6×	0.002	HBA1
response to hydrogen peroxide	1	468.1×	0.002	HBA1
inflammatory response	1	37.7×	0.027	HBA1

Therapeutics

Drug target analysis

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

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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HBA1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
HBA1	59	Binding:46, Functional:13

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	1	HBA1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HBA1	59	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.