Overhydrated hereditary stomatocytosis

Summary

Overhydrated hereditary stomatocytosis (MONDO:0008493) is a disease caused by RHAG (GenCC Strong), with 1 cohort gene and 2 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RHAG (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 10
• Phenotypes (HPO): 11
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		20	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

11 HPO clinical features (Orphanet curated; top 11 by frequency):

HPO ID	Term	Frequency
HP:0001878	Hemolytic anemia	Very frequent (80-99%)
HP:0001923	Reticulocytosis	Very frequent (80-99%)
HP:0004446	Stomatocytosis	Very frequent (80-99%)
HP:0005502	Increased red cell osmotic fragility	Very frequent (80-99%)
HP:0025065	Abnormal mean corpuscular volume	Very frequent (80-99%)
HP:0025547	Decreased mean corpuscular hemoglobin concentration	Very frequent (80-99%)
HP:0001046	Intermittent jaundice	Occasional (5-29%)
HP:0001744	Splenomegaly	Occasional (5-29%)
HP:0001977	Abnormal thrombosis	Occasional (5-29%)
HP:0011273	Anisocytosis	Occasional (5-29%)
HP:0025435	Increased circulating lactate dehydrogenase concentration	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	overhydrated hereditary stomatocytosis
Mondo ID	MONDO:0008493
MeSH	C566111
OMIM	185000
Orphanet	3203
DOID	DOID:0111562
ICD-11	595647587
SNOMED CT	722125003
UMLS	C1861455
MedGen	348876
GARD	0004183
Is cancer (heuristic)	no

Also known as: OHS · OHST · overhydrated hereditary stomatocytosis · Potassium sodium disorder of erythrocyte · stomatocytosis I

Data availability: 10 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › normocytic anemia › hemolytic anemia › familial hemolytic anemia › overhydrated hereditary stomatocytosis

Related subtypes (22): congenital nonspherocytic hemolytic anemia, elliptocytosis 2, southeast Asian ovalocytosis, cryohydrocytosis, dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema, abetalipoproteinemia, hemolytic anemia due to diphosphoglycerate mutase deficiency, glycogen storage disease VII, cutaneous porphyria, hereditary cryohydrocytosis with reduced stomatin, familial pseudohyperkalemia, renal tubular acidosis, distal, 4, with hemolytic anemia, elliptocytosis 1, glycogen storage disease due to aldolase A deficiency, primary CD59 deficiency, triosephosphate isomerase deficiency, dehydrated hereditary stomatocytosis 2, Rh deficiency syndrome, hereditary spherocytosis, congenital dyserythropoietic anemia, X-linked congenital hemolytic anemia, hemolytic disease of fetus and newborn, RH-induced

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

10 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 3 pathogenic, 1 likely pathogenic, 1 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
13061	NM_000324.3(RHAG):c.157+1G>A	RHAG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
218295	NM_000324.3(RHAG):c.194T>C (p.Phe65Ser)	RHAG	Pathogenic	criteria provided, multiple submitters, no conflicts
218296	NM_000324.3(RHAG):c.182T>G (p.Ile61Arg)	RHAG	Pathogenic	no assertion criteria provided
438646	NM_000324.3(RHAG):c.447T>G (p.Ile149Met)	RHAG	Pathogenic	no assertion criteria provided
13060	NM_000324.3(RHAG):c.836G>A (p.Gly279Glu)	RHAG	Likely pathogenic	criteria provided, single submitter
2442218	NM_000324.3(RHAG):c.974A>G (p.His325Arg)	RHAG	Uncertain significance	criteria provided, multiple submitters, no conflicts
3892282	NM_000324.3(RHAG):c.638T>C (p.Ile213Thr)	RHAG	Uncertain significance	criteria provided, single submitter
3892283	NM_000324.3(RHAG):c.860C>T (p.Ala287Val)	RHAG	Uncertain significance	criteria provided, single submitter
438647	NM_000324.3(RHAG):c.1007T>C (p.Leu336Ser)	RHAG	Uncertain significance	no assertion criteria provided
225454	NM_000324.3(RHAG):c.808G>A (p.Val270Ile)	RHAG	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 2 · 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
RHAG	Strong	Autosomal dominant	overhydrated hereditary stomatocytosis	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RHAG	Orphanet:3203	Overhydrated hereditary stomatocytosis
RHAG	Orphanet:71275	Rh deficiency syndrome

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
RHAG	HGNC:10006	ENSG00000112077	Q02094	Ammonium transporter Rh type A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RHAG	Ammonium transporter Rh type A	Component of the ankyrin-1 complex, a multiprotein complex involved in the stability and shape of the erythrocyte membrane.

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)
RHAG	Other/Unknown	no		RhesusRHD, NH4_transpt_AmtB-like_dom, Ammonium/urea_transptr

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
bone marrow	1
bone marrow cell	1
trabecular bone tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RHAG	140	tissue_specific	marker	trabecular bone tissue, bone marrow, bone marrow cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RHAG	1,183

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RHAG	Q02094	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Defective RHAG causes regulator type Rh-null hemolytic anemia (RHN)	1	11420.0×	4e-04	RHAG
Rhesus glycoproteins mediate ammonium transport	1	3806.7×	5e-04	RHAG
Erythrocytes take up oxygen and release carbon dioxide	1	1268.9×	0.001	RHAG
Erythrocytes take up carbon dioxide and release oxygen	1	878.5×	0.001	RHAG

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
methylammonium transmembrane transport	1	16852.0×	6e-04	RHAG
carbon dioxide transmembrane transport	1	8426.0×	6e-04	RHAG
intracellular monoatomic ion homeostasis	1	4213.0×	8e-04	RHAG
ammonium homeostasis	1	2407.4×	0.001	RHAG
ammonium transmembrane transport	1	1872.4×	0.001	RHAG
carbon dioxide transport	1	1296.3×	0.001	RHAG
obsolete inorganic cation transmembrane transport	1	936.2×	0.002	RHAG
bicarbonate transport	1	802.5×	0.002	RHAG
multicellular organismal-level iron ion homeostasis	1	581.1×	0.002	RHAG
erythrocyte development	1	526.6×	0.002	RHAG

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RHAG	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	RHAG

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)
RHAG	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02699112	Not specified	COMPLETED	Cardiac and Respiratory Function With Non-invasive Ventilation
NCT02765360	Not specified	COMPLETED	EIT Study With COPD and OHS Patients (EIT Step 2)