Erythrocytosis, familial, 7

Summary

Erythrocytosis, familial, 7 (MONDO:0054802) is a disease caused by variants in HBA1 and HBA2, with 2 cohort genes.

At a glance

• Causal genes: HBA1 (GenCC Strong), HBA2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 70

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	erythrocytosis, familial, 7
Mondo ID	MONDO:0054802
OMIM	617981
DOID	DOID:0111631
UMLS	C4693823
MedGen	1642594
GARD	0025979
Is cancer (heuristic)	no

Also known as: ECYT7 · erythrocytosis 7

Data availability: 70 ClinVar variants · 7 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › familial polycythemia › erythrocytosis, familial, 7

Related subtypes (7): primary familial polycythemia due to EPO receptor mutation, acquired polycythemia vera, Chuvash polycythemia, erythrocytosis, familial, 3, erythrocytosis, familial, 4, erythrocytosis, familial, 5, erythrocytosis, familial, 6

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

70 retrieved; paginated sample, class counts are floors:

23 pathogenic/likely pathogenic, 14 likely pathogenic, 12 pathogenic, 11 pathogenic; other, 6 conflicting classifications of pathogenicity, 3 uncertain significance, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1048833	NM_000558.5(HBA1):c.95+2_95+6del	HBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
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
15752	NM_000558.3(HBA1):c.278G>A (p.Arg93Gln)	HBA1	Pathogenic; other	no assertion criteria provided
15776	NM_000558.5(HBA1):c.265G>T (p.Ala89Ser)	HBA1	Pathogenic; other	no assertion criteria provided
15792	NM_000558.3(HBA1):c.424C>T (p.Arg142Cys)	HBA1	Pathogenic; other	no assertion criteria provided
15807	NM_000558.5(HBA1):c.379G>C (p.Asp127His)	HBA1	Pathogenic; other	no assertion criteria provided
15844	NC_000016.10:g.173151A>T	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
15879	NM_000558.5(HBA1):c.283_300+3dup	HBA1	Pathogenic/Likely 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
15627	NM_000517.6(HBA2):c.428A>C (p.Ter143Ser)	HBA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15628	NM_000517.6(HBA2):c.266C>T (p.Ala89Val)	HBA2	Pathogenic; other	no assertion criteria provided
15630	NM_000517.6(HBA2):c.377T>C (p.Leu126Pro)	HBA2	Pathogenic	criteria provided, multiple submitters, no conflicts
15633	NM_000517.6(HBA2):c.186G>C (p.Lys62Asn)	HBA2	Pathogenic; other	no assertion criteria provided
15636	NM_000517.4(HBA2):c.142G>C (p.Asp48His)	HBA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15646	NM_000517.6(HBA2):c.418A>G (p.Lys140Glu)	HBA2	Pathogenic; other	no assertion criteria provided
15656	NM_000517.6(HBA2):c.314G>A (p.Cys105Tyr)	HBA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 24 · Orphanet: 15 · 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	erythrocytosis, familial, 7	13
HBA2	Strong	Autosomal dominant	erythrocytosis, familial, 7	11

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

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

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

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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

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

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	2
monocyte	2
bone marrow	1
bone element	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

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HBA1	434
HBA2	434

Intra-cohort edges

A	B	Sources
HBA1	HBA2	biogrid_interaction, intact

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HBA1	P69905	356
HBA2	P69905	356

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Heme assimilation	2	3806.7×	3e-07	HBA1, HBA2
Erythrocytes take up oxygen and release carbon dioxide	2	1268.9×	2e-06	HBA1, HBA2
Erythrocytes take up carbon dioxide and release oxygen	2	878.5×	2e-06	HBA1, HBA2
Scavenging of heme from plasma	2	878.5×	2e-06	HBA1, HBA2
Heme signaling	2	215.5×	3e-05	HBA1, HBA2
Cytoprotection by HMOX1	2	184.2×	3e-05	HBA1, HBA2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 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	2	3370.4×	6e-07	HBA1, HBA2
cellular oxidant detoxification	2	1872.4×	1e-06	HBA1, HBA2
carbon dioxide transport	2	1296.3×	1e-06	HBA1, HBA2
oxygen transport	2	1053.2×	2e-06	HBA1, HBA2
hydrogen peroxide catabolic process	2	674.1×	3e-06	HBA1, HBA2
erythrocyte development	2	526.6×	5e-06	HBA1, HBA2
response to hydrogen peroxide	2	468.1×	5e-06	HBA1, HBA2
inflammatory response	2	37.7×	7e-04	HBA1, HBA2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 2 of 2 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
HBA2	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
HBA2	59	Binding:46, Functional:13

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	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	—
HBA2	59	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.