RHAG

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

Basic information

Region (hg38): 6:49605175-49636839

Links

ENSG00000112077 ∙ NCBI:6005 ∙ OMIM:180297 ∙ HGNC:10006 ∙ Uniprot:Q02094 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• overhydrated hereditary stomatocytosis (Strong), mode of inheritance: AD
• overhydrated hereditary stomatocytosis (Supportive), mode of inheritance: AD
• Rh deficiency syndrome (Supportive), mode of inheritance: AR
• Rh deficiency syndrome (Strong), mode of inheritance: AR
• Rh deficiency syndrome (Definitive), mode of inheritance: AR
• overhydrated hereditary stomatocytosis (Moderate), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Overhydrated hereditary stomatocytosis; Anemia, hemolytic, Rh-null, regulator type; Anemia, hemolytic,Rh-Mod type; RHAG blood group	AD/AR/BG	Hematologic	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)	Hematologic	4628355; 3103426; 8563755; 8639421; 9442063; 9454778; 9746795; 9915949; 10467273; 11961248; 18931342; 19744193

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the RHAG gene.

• not provided (2 variants)
• Rh-null, regulator type (2 variants)
• Overhydrated hereditary stomatocytosis (1 variants)
• Rh-null, regulator type;Overhydrated hereditary stomatocytosis (1 variants)
• RHAG-related disorder (1 variants)
• Rh deficiency syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the RHAG gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	3	2	7
missense	1	2	44	4		51
nonsense	1					1
start loss						0
frameshift		1				1
inframe indel						0
splice donor/acceptor (+/-2bp)	2	1				3
splice region			2	2	1	5
non coding			1	3	18	22
Total	4	4	47	10	20

Highest pathogenic variant AF is 0.0000460

Variants in RHAG

This is a list of pathogenic ClinVar variants found in the RHAG region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
6-49605817-C-G		not specified	Uncertain significance (Jan 22, 2025)
6-49606641-G-T			Benign (Jun 19, 2021)
6-49606843-A-G			Benign/Likely benign (Jan 14, 2025)
6-49606856-A-G			Uncertain significance (Jun 06, 2022)
6-49606866-A-T		not specified	Uncertain significance (Dec 04, 2024)
6-49606895-C-G			Likely benign (May 01, 2024)
6-49606895-C-T			Uncertain significance (Jan 24, 2023)
6-49606897-C-T			Pathogenic (Nov 19, 2024)
6-49606913-G-T		not specified	Uncertain significance (Sep 27, 2023)
6-49606921-C-A		Rh-null, regulator type	Pathogenic (Jan 01, 1999)
6-49606923-T-C			Likely pathogenic (Nov 09, 2017)
6-49606928-C-T			Benign (Jan 27, 2025)
6-49606929-G-A		RHAG-related disorder	Likely benign (Jul 11, 2019)
6-49607176-G-A		not specified	Uncertain significance (Dec 19, 2023)
6-49607180-C-T		not specified • Rh-null, regulator type	Conflicting classifications of pathogenicity (Jul 09, 2024)
6-49607181-G-A			Benign (Dec 24, 2024)
6-49607187-G-A			Conflicting classifications of pathogenicity (Feb 26, 2024)
6-49607194-A-C			Uncertain significance (Nov 02, 2022)
6-49607201-CT-C		Rh-null, regulator type	Pathogenic (Feb 01, 1996)
6-49607203-G-A		not specified	Uncertain significance (Mar 24, 2023)
6-49607210-T-C			Uncertain significance (Jan 08, 2024)
6-49607246-A-G			Uncertain significance (Oct 13, 2020)
6-49611016-T-C			Likely benign (Oct 09, 2018)
6-49611021-C-T			Uncertain significance (Mar 22, 2024)
6-49611023-C-T		Rh-null, regulator type • Rh deficiency syndrome	Pathogenic (Sep 18, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
RHAG	protein_coding	protein_coding	ENST00000371175	10	31682

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0104	0.988	125733	0	14	125747	0.0000557

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.774	187	219	0.853	0.0000110	2688
Missense in Polyphen		67	99.17	0.67561		1248
Synonymous	-1.53	98	80.5	1.22	0.00000455	811
Loss of Function	2.73	7	20.2	0.346	0.00000122	217

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000289	0.0000289
Ashkenazi Jewish	0.0000993	0.0000992
East Asian	0.00	0.00
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000969	0.0000967
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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;Transport of small molecules;Erythrocytes take up oxygen and release carbon dioxide;Erythrocytes take up carbon dioxide and release oxygen (Consensus)

Recessive Scores

• pRec: 0.0760

Intolerance Scores

• loftool: 0.437
• rvis_EVS: -0.05
• rvis_percentile_EVS: 50.22

Haploinsufficiency Scores

• pHI: 0.990
• hipred: Y
• hipred_score: 0.655
• ghis: 0.438

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.278

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Rhag
• Phenotype: homeostasis/metabolism phenotype; hematopoietic system phenotype

Zebrafish Information Network

• Gene name: rhag
• Affected structure: post-vent region
• Phenotype tag: abnormal
• Phenotype quality: curved

Gene ontology

• Biological process: cellular ion homeostasis;carbon dioxide transport;monovalent inorganic cation transport;ammonium transport;bicarbonate transport;carbon dioxide transmembrane transport;erythrocyte development;multicellular organismal iron ion homeostasis;ammonium transmembrane transport
• Cellular component: plasma membrane;integral component of plasma membrane;membrane
• Molecular function: ammonium transmembrane transporter activity;leak channel activity;ankyrin binding;carbon dioxide transmembrane transporter activity