GeneBe

RHAG

protein-coding

Rh associated glycoprotein, the group of CD molecules|Solute carrier family 42|Blood group antigens

Gene summary

The protein encoded by this gene is erythrocyte-specific and is thought to be part of a membrane channel that transports ammonium and carbon dioxide across the blood cell membrane. The encoded protein appears to interact with Rh blood group antigens and Rh30 polypeptides. Defects in this gene are a cause of regulator type Rh-null hemolytic anemia (RHN), or Rh-deficiency syndrome.[provided by RefSeq, Mar 2009]

MANE transcript

NM_000324.3

Inheritance

AD, AR, BG

ClinVar variants

P:20U:96B:34

Top phenotype

Overhydrated hereditary stomatocytosis; Anemia, hemolytic, Rh-null, regulator type; Anemia, hemolytic,Rh-Mod type; RHAG blood group

gnomAD constraint

pLI —, LoF o/e 0.35

Max pathogenic AF

—

Genomic locus

chr6:49,605,175-49,636,839

External References & Databases

Ensembl (ENSG00000112077)NCBI Gene (6005)OMIM (180297)HGNC:10006GenCCUniProt (Q02094)AlphaFoldClinVar (RHAG)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~31.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

overhydrated hereditary stomatocytosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008493

Submitter: Orphanet

Rh deficiency syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019107

Submitter: Orphanet

overhydrated hereditary stomatocytosisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008493

Submitter: PanelApp Australia

overhydrated hereditary stomatocytosisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008493

Submitter: Labcorp Genetics (formerly Invitae)

overhydrated hereditary stomatocytosisMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0008493

Submitter: Ambry Genetics

Rh deficiency syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019107

Submitter: Ambry Genetics

Rh deficiency syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0019107

Submitter: PanelApp Australia

Rh deficiency syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0019107

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Overhydrated hereditary stomatocytosis; Anemia, hemolytic, Rh-null, regulator type; Anemia, hemolytic,Rh-Mod type; RHAG blood groupAD/AR/BG

Manifestation: Hematologic

Intervention: Hematologic

Rationale: Individuals can suffer severe anemia, which can be ameliorated by splenectomy (though splenectomy may be less beneficial in Overhydrated hereditary stomatocytosis); Individuals with Overhydrated hereditary stomatocytosis may be prone to iron overload as well as postsplenectomy thrombotic complications, and awareness may allow surveillance and management; Variants associated with a blood group may be important in specific situations (eg, related to transfusion)

Refs: 4628355; 3103426; 8563755; 8639421; 9442063; 9454778; 9746795; 9915949; 10467273; 11961248; 18931342; 19744193Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RHAG variants in ClinVar

9 Conditions Cataloged
not providedTotal: 121
not specifiedTotal: 58
Rh-null, regulator typeTotal: 12
RHAG-related disorderTotal: 10
Overhydrated hereditary stomatocytosisTotal: 9
Rh mod blood group phenotypeTotal: 3
Supravalvar aortic stenosisTotal: 1
altered red cell phenotypeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000324.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
2
clinvar
26
clinvar
 28
missense
7
clinvar
3
clinvar
92
clinvar
8
clinvar
 110
nonsense
2
clinvar
 2
start loss
1
clinvar
 1
frameshift
2
clinvar
2
clinvar
1
clinvar
 5
splice donor/acceptor (+/-2bp)
2
clinvar
2
clinvar
 4
Total13796340150

Highest pathogenic variant AF is 0.00011526706

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000324.3RefSeqNP_000315.210MANE Select
ENST00000371175.10EnsemblENSP00000360217.410MANE Select
ENST00000646272.1EnsemblENSP00000494337.19Standard
ENST00000646939.1EnsemblENSP00000494709.18Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
rhagDanio rerio

Structure: post-vent region

Quality: curved

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Amine compound SLC transporters
  • O2/CO2 exchange in erythrocytes
  • Rhesus glycoproteins mediate ammonium transport.
  • Transport of bile salts and organic acids, metal ions and amine compounds
  • SLC-mediated transmembrane transport

Biological Process

  • cellular ion homeostasis
  • carbon dioxide transport
  • monovalent inorganic cation transport
  • ammonium transport
  • bicarbonate transport

Molecular Function

  • ammonium transmembrane transporter activity
  • leak channel activity
  • ankyrin binding
  • carbon dioxide transmembrane transporter activity

Cellular Component

  • plasma membrane
  • integral component of plasma membrane
  • membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000371175
Coding exons
10
Length
31682
Individuals with no LoFs
125733
Homozygous LoFs
0
Heterozygous LoFs
14
Defined
125747
p
0.0000557
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.7741872190.8530.00001102688
Missense (PolyPhen)6799.170.675611248
Synonymous-1.539880.51.220.00000455811
Loss of Function2.73720.20.3460.00000122217

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish0.0000990.000099rare
East Asian00.0absent
Finnish0.0000460.000046rare
European (Non-Finnish)0.0000970.000097rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Associated with rhesus blood group antigen expression (PubMed:19744193). May be part of an oligomeric complex which is likely to have a transport or channel function in the erythrocyte membrane (PubMed:11062476, PubMed:11861637). Involved in ammonia transport across the erythrocyte membrane (PubMed:21849667, PubMed:22012326). Seems to act in monovalent cation transport (PubMed:18931342, PubMed:21849667). {ECO:0000269|PubMed:11062476, ECO:0000269|PubMed:11861637, ECO:0000269|PubMed:18931342, ECO:0000269|PubMed:19744193, ECO:0000269|PubMed:21849667, ECO:0000269|PubMed:22012326}.;
Disease
DISEASE: Regulator type Rh-null hemolytic anemia (RHN) [MIM:268150]: Form of chronic hemolytic anemia in which the red blood cells have a stomatocytosis and spherocytosis morphology, an increased osmotic fragility, an altered ion transport system, and abnormal membrane phospholipid organization. {ECO:0000269|PubMed:10467273, ECO:0000269|PubMed:8563755, ECO:0000269|PubMed:9454778, ECO:0000269|PubMed:9716608}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Overhydrated hereditary stomatocytosis (OHST) [MIM:185000]: An autosomal dominant disorder of red cell membrane permeability to monovalent cations, characterized by macrocytic hemolytic anemia of fluctuating severity, circulating erythrocytes with slit-like lucencies (stomata) evident on fixed, stained peripheral blood smears. OHST red cells exhibit cation leak, resulting in elevated cell sodium content with reduced potassium content. The disease is marked by splenomegaly or hepatosplenomegaly, cholelithiasis and a strong tendency for iron overload. {ECO:0000269|PubMed:18931342, ECO:0000269|PubMed:21849667, ECO:0000269|PubMed:22012326}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.0760

Intolerance Scores

LoFtool
0.437
RVIS EVS
-0.05
RVIS percentile EVS
50.22

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.278

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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