Rh deficiency syndrome

Summary

Rh deficiency syndrome (MONDO:0019107) is a disease caused by variants in RHAG and RHCE, with 3 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal genes: RHAG (GenCC Definitive), RHCE (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 1
• Phenotypes (HPO): 20

Clinical features

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0001878	Hemolytic anemia	Very frequent (80-99%)
HP:0001923	Reticulocytosis	Very frequent (80-99%)
HP:0005502	Increased red cell osmotic fragility	Very frequent (80-99%)
HP:0020181	Reduced haptoglobin level	Very frequent (80-99%)
HP:0032366	Positive direct antiglobulin test	Very frequent (80-99%)
HP:0002904	Hyperbilirubinemia	Frequent (30-79%)
HP:0004444	Spherocytosis	Frequent (30-79%)
HP:0004446	Stomatocytosis	Frequent (30-79%)
HP:0025435	Increased circulating lactate dehydrogenase concentration	Frequent (30-79%)
HP:0032231	Hypochromia	Frequent (30-79%)
HP:0000952	Jaundice	Occasional (5-29%)
HP:0001433	Hepatosplenomegaly	Occasional (5-29%)
HP:0001511	Intrauterine growth retardation	Occasional (5-29%)
HP:0001562	Oligohydramnios	Occasional (5-29%)
HP:0001649	Tachycardia	Occasional (5-29%)
HP:0002789	Tachypnea	Occasional (5-29%)
HP:0005268	Spontaneous abortion	Occasional (5-29%)
HP:0011273	Anisocytosis	Occasional (5-29%)
HP:0012418	Hypoxemia	Occasional (5-29%)
HP:0001972	Macrocytic anemia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Rh deficiency syndrome
Mondo ID	MONDO:0019107
MeSH	C562717
OMIM	268150
Orphanet	71275
DOID	DOID:0050641
ICD-11	1554765420
SNOMED CT	37272000
UMLS	C0272052
MedGen	75772
GARD	0012916
Is cancer (heuristic)	no

Also known as: anemia, hemolytic, Rh-null, regulator type · Rh deficiency syndrome · Rh-null syndrome · RH-null, regulator type · RHN · RHNR

Data availability: 1 ClinVar variant · 7 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 › Rh deficiency syndrome

Related subtypes (22): congenital nonspherocytic hemolytic anemia, elliptocytosis 2, southeast Asian ovalocytosis, overhydrated hereditary stomatocytosis, 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, 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

1 retrieved; paginated sample, class counts are floors:

1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
13064	NM_000324.3(RHAG):c.1067+1G>A	RHAG	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 4 · 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	Definitive	Autosomal recessive	Rh deficiency syndrome	8
RHCE	Strong	Autosomal recessive	Rh deficiency syndrome	2
RHD	Supportive	Autosomal recessive	Rh deficiency syndrome

Orphanet rare-disease linkage (cohort genes)

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

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RHAG	HGNC:10006	ENSG00000112077	Q02094	Ammonium transporter Rh type A	gencc,clinvar
RHCE	HGNC:10008	ENSG00000188672	P18577	Blood group Rh(CE) polypeptide	gencc
RHD	HGNC:10009	ENSG00000187010	Q02161	Blood group Rh(D) polypeptide	gencc

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.
RHCE	Blood group Rh(CE) polypeptide	Component of the ankyrin-1 complex, a multiprotein complex involved in the stability and shape of the erythrocyte membrane.
RHD	Blood group Rh(D) polypeptide	May be part of an oligomeric complex which is likely to have a transport or channel function in the erythrocyte membrane.

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

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
trabecular bone tissue	3
bone marrow	2
male germ line stem cell (sensu Vertebrata) in testis	2
bone marrow cell	1
buccal mucosa cell	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
RHCE	169	broad	marker	trabecular bone tissue, bone marrow, male germ line stem cell (sensu Vertebrata) in testis
RHD	170	tissue_specific	marker	buccal mucosa cell, trabecular bone tissue, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RHAG	1,183
RHCE	470
RHD	10

Intra-cohort edges

A	B	Sources
RHAG	RHCE	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RHAG	Q02094	8
RHCE	P18577	8

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RHD	Q02161	84.91

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Rhesus blood group biosynthesis	2	3806.7×	2e-07	RHCE, RHD
Defective RHAG causes regulator type Rh-null hemolytic anemia (RHN)	1	3806.7×	7e-04	RHAG
Rhesus glycoproteins mediate ammonium transport	1	1268.9×	0.001	RHAG
Erythrocytes take up oxygen and release carbon dioxide	1	423.0×	0.003	RHAG
Erythrocytes take up carbon dioxide and release oxygen	1	292.8×	0.003	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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ammonium homeostasis	3	2407.4×	4e-10	RHAG, RHCE, RHD
ammonium transmembrane transport	3	1872.4×	5e-10	RHAG, RHCE, RHD
methylammonium transmembrane transport	1	5617.3×	6e-04	RHAG
carbon dioxide transmembrane transport	1	2808.7×	9e-04	RHAG
intracellular monoatomic ion homeostasis	1	1404.3×	0.001	RHAG
carbon dioxide transport	1	432.1×	0.004	RHAG
obsolete inorganic cation transmembrane transport	1	312.1×	0.005	RHAG
bicarbonate transport	1	267.5×	0.005	RHAG
multicellular organismal-level iron ion homeostasis	1	193.7×	0.006	RHAG
erythrocyte development	1	175.5×	0.006	RHAG

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
RHCE	0	0
RHD	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	3	RHAG, RHCE, RHD

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RHAG	0	—
RHCE	0	—
RHD	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.