Hereditary methemoglobinemia

Summary

Hereditary methemoglobinemia (MONDO:0018963) is a disease (an umbrella term covering 5 Mondo subtypes) with 1 cohort gene and 1 clinical trial. Top therapeutic interventions include methylene blue cation.

At a glance

• Prevalence: Unknown (Worldwide)
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 1
• ClinVar variants: 3
• Phenotypes (HPO): 26
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0000961	Cyanosis	Very frequent (80-99%)
HP:0012119	Methemoglobinemia	Very frequent (80-99%)
HP:0000707	Abnormality of the nervous system	Frequent (30-79%)
HP:0001597	Abnormality of the nail	Frequent (30-79%)
HP:0002875	Exertional dyspnea	Frequent (30-79%)
HP:0025118	Lip discoloration	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000565	Esotropia	Occasional (5-29%)
HP:0000592	Blue sclerae	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0002283	Global brain atrophy	Occasional (5-29%)
HP:0002305	Athetosis	Occasional (5-29%)
HP:0002451	Limb dystonia	Occasional (5-29%)
HP:0002510	Spastic tetraplegia	Occasional (5-29%)
HP:0006808	Cerebral hypomyelination	Occasional (5-29%)
HP:0006913	Frontal cortical atrophy	Occasional (5-29%)
HP:0007112	Temporal cortical atrophy	Occasional (5-29%)
HP:0010864	Intellectual disability, severe	Occasional (5-29%)
HP:0011344	Severe global developmental delay	Occasional (5-29%)
HP:0001250	Seizure	Very rare (<1-4%)
HP:0001276	Hypertonia	Very rare (<1-4%)
HP:0001518	Small for gestational age	Very rare (<1-4%)
HP:0012448	Delayed myelination	Very rare (<1-4%)
HP:0012697	Small basal ganglia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary methemoglobinemia
Mondo ID	MONDO:0018963
MeSH	C580280
Orphanet	621
ICD-10-CM	D74.0
ICD-11	586921197
NCIT	C98898
SNOMED CT	267550008
UMLS	C0272087
MedGen	473013
GARD	0002659
Is cancer (heuristic)	no

Also known as: autosomal recessive methemoglobinemia · congenital methemoglobinemia · hereditary methemoglobinemia

Data availability: 3 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 5 Mondo subtypes.

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

Related subtypes (1): drug-induced methemoglobinemia

Subtypes (5): methemoglobin reductase deficiency, methemoglobinemia type 4, methemoglobinemia due to deficiency of methemoglobin reductase, hemoglobin M disease, methemoglobinemia, alpha type

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

3 retrieved; paginated sample, class counts are floors:

1 pathogenic, 1 uncertain significance, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
249	NM_000398.7(CYB5R3):c.611G>A (p.Cys204Tyr)	CYB5R3	Pathogenic	no assertion criteria provided
505719	NM_000398.7(CYB5R3):c.757G>A (p.Val253Met)	CYB5R3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3024129	NM_000398.7(CYB5R3):c.906A>G (p.Ter302Trp)	CYB5R3	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
CYB5R3	Definitive	Autosomal recessive	methemoglobinemia	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CYB5R3	Orphanet:621	Autosomal recessive methemoglobinemia

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
CYB5R3	HGNC:2873	ENSG00000100243	P00387	NADH-cytochrome b5 reductase 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CYB5R3	NADH-cytochrome b5 reductase 3	Catalyzes the reduction of two molecules of cytochrome b5 using NADH as the electron donor.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CYB5R3	Enzyme (other)	yes	1.6.2.2	OxRdtase_FAD/NAD-bd, Flavoprot_Pyr_Nucl_cyt_Rdtase, CBR-like

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
descending thoracic aorta	1
right coronary artery	1
thoracic aorta	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CYB5R3	294	ubiquitous	marker	right coronary artery, descending thoracic aorta, thoracic aorta

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CYB5R3	2,715

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CYB5R3	P00387	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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
Vitamin C (ascorbate) metabolism	1	1427.5×	0.006	CYB5R3
Phase I - Functionalization of compounds	1	219.6×	0.015	CYB5R3
Metabolism of water-soluble vitamins and cofactors	1	181.3×	0.015	CYB5R3
Biological oxidations	1	129.8×	0.015	CYB5R3
Metabolism of vitamins and cofactors	1	116.5×	0.015	CYB5R3
Innate Immune System	1	25.5×	0.056	CYB5R3
Neutrophil degranulation	1	23.1×	0.056	CYB5R3
Immune System	1	13.0×	0.086	CYB5R3
Metabolism	1	11.6×	0.086	CYB5R3

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 biosynthetic process	1	702.2×	0.002	CYB5R3
blood circulation	1	510.7×	0.002	CYB5R3
cholesterol biosynthetic process	1	421.3×	0.002	CYB5R3

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
CYB5R3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CYB5R3	18	Binding:18

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CYB5R3	1.6.2.2	cytochrome-b5 reductase

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	1	CYB5R3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
CYB5R3	18	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02478281	PHASE1	COMPLETED	Safety, Tolerability, and Pharmacokinetic Study of Methylene Blue Following a 1 mg/kg Intravenous Dose in Healthy Adults

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
METHYLENE BLUE CATION	4	3