RHAG

Summary

RHAG (Rh associated glycoprotein, HGNC:10006) is a protein-coding gene on chromosome 6p12.3, encoding Ammonium transporter Rh type A (Q02094). Component of the ankyrin-1 complex, a multiprotein complex involved in the stability and shape of the erythrocyte membrane.

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.

Source: NCBI Gene 6005 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Rh deficiency syndrome (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 6
• Clinical variants (ClinVar): 177 total — 13 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 34
• MANE Select transcript: NM_000324

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10006
Approved symbol	RHAG
Name	Rh associated glycoprotein
Location	6p12.3
Locus type	gene with protein product
Status	Approved
Aliases	RH50A, CD241, SLC42A1
Ensembl gene	ENSG00000112077
Ensembl biotype	protein_coding
OMIM	180297
Entrez	6005

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000371175, ENST00000642530, ENST00000646272, ENST00000646874, ENST00000646939, ENST00000646963

RefSeq mRNA: 1 — MANE Select: NM_000324 NM_000324

CCDS: CCDS4927

Canonical transcript exons

ENST00000371175 — 10 exons

Exon	Start	End
ENSE00000755778	49618068	49618218
ENSE00000755779	49619179	49619362
ENSE00001138856	49611024	49611145
ENSE00001138861	49612397	49612534
ENSE00001138867	49614687	49614853
ENSE00001138875	49615624	49615771
ENSE00001784545	49636656	49636839
ENSE00001835201	49605175	49605830
ENSE00003719814	49606848	49606921
ENSE00003742154	49607150	49607220

Expression profiles

Bgee: expression breadth ubiquitous, 140 present calls, max score 97.88.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 13.6235 / max 3147.2015, expressed in 129 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
73913	8.1864	113
73914	3.3540	94
73912	1.3539	76
73915	0.7292	73

Top tissues by expression

279 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
trabecular bone tissue	UBERON:0002483	97.88	gold quality
bone marrow	UBERON:0002371	93.75	gold quality
bone marrow cell	CL:0002092	89.09	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.64	gold quality
buccal mucosa cell	CL:0002336	77.35	gold quality
tibialis anterior	UBERON:0001385	76.51	silver quality
triceps brachii	UBERON:0001509	75.93	gold quality
gluteal muscle	UBERON:0002000	75.81	gold quality
tongue squamous epithelium	UBERON:0006919	74.42	gold quality
type B pancreatic cell	CL:0000169	73.30	gold quality
olfactory bulb	UBERON:0002264	73.30	gold quality
male germ cell	CL:0000015	73.05	gold quality
sperm	CL:0000019	72.82	gold quality
deltoid	UBERON:0001476	71.50	gold quality
ileal mucosa	UBERON:0000331	71.34	silver quality
cartilage tissue	UBERON:0002418	70.90	gold quality
myocardium	UBERON:0002349	70.42	gold quality
vena cava	UBERON:0004087	68.41	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	68.06	gold quality
quadriceps femoris	UBERON:0001377	67.74	gold quality
body of tongue	UBERON:0011876	67.47	gold quality
blood	UBERON:0000178	67.38	gold quality
cervix epithelium	UBERON:0004801	66.94	gold quality
parotid gland	UBERON:0001831	66.85	gold quality
vastus lateralis	UBERON:0001379	66.73	gold quality
right atrium auricular region	UBERON:0006631	66.67	gold quality
nasal cavity epithelium	UBERON:0005384	66.65	gold quality
cardiac atrium	UBERON:0002081	66.48	gold quality
orbitofrontal cortex	UBERON:0004167	66.39	gold quality
tongue	UBERON:0001723	66.03	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	70.40
E-MTAB-10042	yes	44.48
E-ANND-3	yes	9.79
E-MTAB-9388	yes	9.47
E-HCAD-9	yes	8.15
E-MTAB-9067	yes	6.60
E-CURD-126	no	112.90
E-HCAD-10	no	2.35

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA1

miRNA regulators (miRDB)

52 targeting RHAG, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-3913-5P	99.78	67.26	968
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-3618	99.69	68.57	1012
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-3122	99.50	66.33	821
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-6513-5P	99.43	67.81	1071
HSA-MIR-6839-3P	99.39	68.86	1301
HSA-MIR-6507-5P	99.36	70.46	2524
HSA-MIR-4520-2-3P	99.14	69.28	1009
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-5703	99.10	67.09	2053
HSA-MIR-7702	99.06	65.95	698

Literature-anchored findings (GeneRIF, showing 30)

• identification as a mammalian ammonium transporter (PMID:11861637)
• Cell-surface expression of RhD blood group polypeptide is posttranscriptionally regulated by the RhAG glycoprotein. (PMID:12130520)
• interactions of CD47 and RhAG and the Rh proteins with one another and with the cytoskeleton of intact erythrocytes (PMID:12393442)
• RhAG functions as a NH(4)(+)/H(+) exchanger; ammonium transport is coupled to the H(+) gradient (PMID:14966114)
• RhAG facilitates CH(3)NH(2)/NH(3) movement across the RBC membrane and represents a potential example of a gas channel in mammalian cells. (PMID:15572441)
• The combination of these polymorphisms could not be found in any control individuals, suggesting that they might be involved in genetic predisposition to migraine in this family. (PMID:16378686)
• RhAG-mediated transport is an electroneutral process that is driven by the NH4+ concentration and the transmembrane H+ gradient, effectively exchanging NH4+ for H+ in a process that results in transport of net NH3. (PMID:16563829)
• RhAG expression enhanced the ammonium-induced initial alkalinization (related to NH3 influx)& secondary acidification (related to NH4+ influx). Sub-millimolar NH4+ concentrations induced inward currents in voltage-clamped RhAG-expressing cells. (PMID:16564724)
• Review. RhAG plays a major role in the NH3 conductance of erythrocytes, but probably not in CO2 transport. (PMID:16574458)
• Rh protein, presumably the Rh-associated glycoprotein RhAG, possesses a gas channel that allows passage of CO2 in addition to NH3 (PMID:17712059)
• Reduced amounts of Rh-associated glycoprotein is associated with overhydrated hereditary stomatocytosis. (PMID:18931342)
• gas channels exhibit selectivity for CO(2) vs. NH(3) permeability, demonstrating the sequence AQP4 congruent with AQP5 > AQP1 > AmtB > RhAG. (PMID:19273840)
• that the 672C>A missense mutation in the RHAG gene could result in Rh(null) of the regulator type, and the single-amino-acid change (Ser to Arg) might be critical for assembly of the Rh antigen complex within the membrane (PMID:21682734)
• The results provide new insight into RhAG stomatocytosis mutant F65S as a combined loss-of-function/gain-of-function mutation for methylammonium/methylammonium+ transport (PMID:21849667)
• Substitution of GPB with Gp.Mur significantly reduced the expression of Rh antigen and RhAG on the Mi.III(+/+) erythrocyte membrane (PMID:21883272)
• Results provide new insights into the functional impact of the Phe65Ser mutation in RhAG. (PMID:22012326)
• Data from differentiating cultured erythroid precursor cells suggest that RhAG knockdown abolishes Rh blood group expression (RhoD [ras homolog family member D]; ICAM4 [intercellular adhesion molecule 4]; CD47 Rh-related antigen) in erythroid cells. (PMID:23417980)
• RhAG, RhBG and RhCG-exhibit significant permeability to NH3 and show for the first time that RhBG and RhCG can conduct CO2. (PMID:24077989)
• A new Rh null allele (RHAG*01N.13) of the regulator type found in a consanguineous French-speaking quebecers’family. (PMID:25296744)
• novel allele in a Brazilian pregnant woman encoding the Rhnull phenotype due to a change in RHAG exon2 c.310C>T, which leads to a premature stop codon (Gln104Stop). (PMID:26175207)
• We characterized ammonia and ammonium (NH3/NH4 (+)) transport by the rhesus-associated (Rh) glycoproteins RhAG, Rhbg, and Rhcg expressed in Xenopus oocytes. We used ion-selective microelectrodes and two-electrode voltage clamp to measure changes in intracellular pH, surface pH, and whole cell currents induced by NH3/NH4 (+) and methyl amine/ammonium (MA/MA(+)). (PMID:26354748)
• These results indicated that the 540C>A nonsense mutation in RHAG gene caused the regulator type of Rhnull phenotype in a Chinese individual. (PMID:28063760)
• A novel nucleotide deletion in RHAG allele identified in a Chinese Rhnull individual. (PMID:29266289)
• A novel RHAG mutation significantly lowers RhAG antigen expression and antigen-mediated agglutination intensity. (PMID:29508504)
• Case Report: complex RHAG genotype including a novel de novo mutation associated with overhydrated stomatocytosis. (PMID:29559519)
• Rhnull phenotype caused by a novel RHAG mutation, c.945+1G>A, in the Japanese population. (PMID:30990901)
• identified the second double-variant RHAG allele and the first one related to Rhmod phenotype. The novel allele was also confirmed to be heritable by family analyses. (PMID:31032541)
• Extensive clinical, serologic and molecular studies lead to the first reported Rhmod phenotype in Argentina. (PMID:32378229)
• The Kg-antigen, RhAG with a Lys164Gln mutation, gives rise to haemolytic disease of the newborn. (PMID:32705675)
• Rhnull phenotype in an Indian patient due to a novel c.1138 + 2 t > a mutation in the RHAG gene. (PMID:38711255)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	rhag	ENSDARG00000019253
mus_musculus	Rhag	ENSMUSG00000023926
rattus_norvegicus	Rhag	ENSRNOG00000050121
drosophila_melanogaster	Rh50	FBGN0028699
caenorhabditis_elegans		WBGENE00004358
caenorhabditis_elegans		WBGENE00004359

Paralogs (4): RHBG (ENSG00000132677), RHCG (ENSG00000140519), RHD (ENSG00000187010), RHCE (ENSG00000188672)

Protein

Protein identifiers

Ammonium transporter Rh type A — Q02094 (reviewed: Q02094)

Alternative names: Erythrocyte membrane glycoprotein Rh50, Erythrocyte plasma membrane 50 kDa glycoprotein, Rhesus blood group family type A glycoprotein, Rhesus blood group-associated ammonia channel, Rhesus blood group-associated glycoprotein

All UniProt accessions (3): Q02094, A0A2R8YEH1, Q9UHG9

UniProt curated annotations — full annotation on UniProt →

Function. Component of the ankyrin-1 complex, a multiprotein complex involved in the stability and shape of the erythrocyte membrane. Heterotrimer with RHCE (RHAG)2(RHCE), that transports ammonium and its related derivative methylammonium, in both neutral and ionic forms, across the erythrocyte membrane. The transport of NH4(+) is electrogenic and masks the NH3 transport. Also, may act as a CO2 channel. In vitro, leaks monovalent cations. Moreover in erythrocyte, regulates RHD membrane expression and is associated with rhesus blood group antigen expression.

Subunit / interactions. Homodimer. Heterotrimer; a RHCE monomer interacts with a RHAG homodimer. Component of the ankyrin-1 complex in the erythrocyte, composed of ANK1, RHCE, RHAG, SLC4A1, EPB42, GYPA, GYPB and AQP1. Interacts with GYPB (via the N-terminal); this interaction bridges the (RHAG)2(RHCE) heterotrimer with the SLC4A1 Band 3 I dimer complexed with GYPA.

Subcellular location. Membrane.

Tissue specificity. Erythrocytes.

Post-translational modifications. Glycosylated.

Disease relevance. 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. The disease is caused by variants affecting the gene represented in this entry. 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. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the ammonium transporter (TC 2.A.49) family. Rh subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q02094-1	1	yes
Q02094-2	2

RefSeq proteins (1): NP_000315* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002229	RhesusRHD	Family
IPR024041	NH4_transpt_AmtB-like_dom	Domain
IPR029020	Ammonium/urea_transptr	Homologous_superfamily

Pfam: PF00909

Catalyzed reactions (Rhea), 3 shown:

• NH4(+)(in) = NH4(+)(out) (RHEA:28747)
• methylamine(out) = methylamine(in) (RHEA:74391)
• CO2(out) = CO2(in) (RHEA:74891)

UniProt features (69 total): helix 20, topological domain 13, transmembrane region 12, sequence variant 11, turn 4, glycosylation site 2, splice variant 2, sequence conflict 2, strand 2, chain 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
7UZQ	ELECTRON MICROSCOPY	2.17
7V0K	ELECTRON MICROSCOPY	2.4
8CSX	ELECTRON MICROSCOPY	2.4
7V0S	ELECTRON MICROSCOPY	2.5
8CS9	ELECTRON MICROSCOPY	2.74
8CTE	ELECTRON MICROSCOPY	2.9
8CRT	ELECTRON MICROSCOPY	3
8CSL	ELECTRON MICROSCOPY	25

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q02094-F1	95.44	0.93

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Glycosylation sites (2): 37, 355

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1237044	Erythrocytes take up carbon dioxide and release oxygen
R-HSA-1247673	Erythrocytes take up oxygen and release carbon dioxide
R-HSA-444411	Rhesus glycoproteins mediate ammonium transport
R-HSA-5619042	Defective RHAG causes regulator type Rh-null hemolytic anemia (RHN)

MSigDB gene sets: 242 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GNF2_PRDX2, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_MYELOID_CELL_DEVELOPMENT, BHATI_G2M_ARREST_BY_2METHOXYESTRADIOL_DN, MODULE_64, GOBP_ERYTHROCYTE_HOMEOSTASIS, IVANOVA_HEMATOPOIESIS_MATURE_CELL, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, MODULE_503, GNF2_ANK1, OSWALD_HEMATOPOIETIC_STEM_CELL_IN_COLLAGEN_GEL_UP, chr6p12, MODULE_195, GOBP_ONE_CARBON_COMPOUND_TRANSPORT

GO Biological Process (10): intracellular monoatomic ion homeostasis (GO:0006873), carbon dioxide transport (GO:0015670), bicarbonate transport (GO:0015701), carbon dioxide transmembrane transport (GO:0035378), erythrocyte development (GO:0048821), multicellular organismal-level iron ion homeostasis (GO:0060586), ammonium transmembrane transport (GO:0072488), methylammonium transmembrane transport (GO:0072489), ammonium homeostasis (GO:0097272), obsolete inorganic cation transmembrane transport (GO:0098662)

GO Molecular Function (6): ammonium channel activity (GO:0008519), methylammonium transmembrane transporter activity (GO:0015200), leak channel activity (GO:0022840), ankyrin binding (GO:0030506), carbon dioxide transmembrane transporter activity (GO:0035379), protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), membrane (GO:0016020), ankyrin-1 complex (GO:0170014)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
O2/CO2 exchange in erythrocytes	2
Miscellaneous transport and binding events	1
SLC transporter disorders	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transmembrane transport	3
inorganic ion homeostasis	2
monoatomic ion homeostasis	1
intracellular chemical homeostasis	1
gas transport	1
one-carbon compound transport	1
transport	1
carbon dioxide transport	1
erythrocyte differentiation	1
myeloid cell development	1
monoatomic cation homeostasis	1
multicellular organismal-level chemical homeostasis	1
nitrogen compound transport	1
methylammonium transport	1
channel activity	1
ammonium transmembrane transport	1
amine transmembrane transporter activity	1
methylammonium transmembrane transport	1
narrow pore channel activity	1
cytoskeletal protein binding	1
transmembrane transporter activity	1
carbon dioxide transmembrane transport	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1
membrane protein complex	1

Protein interactions and networks

STRING

1156 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RHAG	CD47	Q08722	993
RHAG	GYPB	P06028	993
RHAG	H3BT10	H3BT10	966
RHAG	PPP1R3A	Q16821	916
RHAG	RHCE	P18577	899
RHAG	RBL2	Q08999	874
RHAG	GYPA	P02724	846
RHAG	EFHD1	Q9BUP0	800
RHAG	F10	P00742	781
RHAG	ANK2	Q01484	774
RHAG	ANK1	P16157	726
RHAG	EPB42	P16452	664
RHAG	EPB41	P11171	645
RHAG	AQP1	P29972	623
RHAG	ANK3	Q12955	620

IntAct

17 interactions, top by confidence:

A	B	Type	Score
RHAG	ERGIC3	psi-mi:“MI:0915”(physical association)	0.560
RHAG	UNC93A	psi-mi:“MI:0915”(physical association)	0.560
RHAG	TEX29	psi-mi:“MI:0915”(physical association)	0.560
RHAG	CREB3L3	psi-mi:“MI:0915”(physical association)	0.560
RHAG	FAM209A	psi-mi:“MI:0915”(physical association)	0.560
RHBG	PEDS1	psi-mi:“MI:0914”(association)	0.350
RHAG	CREB3L3	psi-mi:“MI:0915”(physical association)	0.000
RHAG	UNC93A	psi-mi:“MI:0915”(physical association)	0.000
RHAG	FAM209A	psi-mi:“MI:0915”(physical association)	0.000
RHAG	ERGIC3	psi-mi:“MI:0915”(physical association)	0.000
RHAG	TEX29	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (10): RHAG (Two-hybrid), RHAG (Two-hybrid), ANK1 (Reconstituted Complex), RHAG (Two-hybrid), UNC93A (Two-hybrid), FAM209A (Two-hybrid), ERGIC3 (Two-hybrid), TEX29 (Two-hybrid), RHAG (Synthetic Lethality), RHAG (Affinity Capture-MS)

ESM2 similar proteins: A0A072VHJ1, G7L1W7, G7LAA8, P40260, P41948, P53390, Q02094, Q0IIV2, Q18PF5, Q18PF6, Q19KH7, Q19KI0, Q20CR3, Q2T9S6, Q3BBX7, Q3BBX8, Q3BCQ4, Q3BCQ5, Q3BCQ7, Q4VUI0, Q4VUZ1, Q5NVA3, Q5U4V1, Q68FT6, Q69D47, Q69D48, Q69T29, Q6DCG4, Q6WRY0, Q6XL41, Q7T070, Q7T3R4, Q7TNK7, Q7TNN9, Q84KJ6, Q84KJ7, Q851M9, Q8BUX5, Q8JI14, Q8S230

Diamond homologs: B8ZYW3, I3R0S7, O04161, O26757, O26759, O28525, O28528, O29285, O66515, P54144, P54145, P54147, P54148, P58905, P69680, P69681, P72935, Q02094, Q07429, Q18PF5, Q18PF6, Q19KI0, Q20605, Q21565, Q2T9S6, Q3BBX7, Q3BBX8, Q3BCQ4, Q3BCQ5, Q58739, Q5U4V1, Q60366, Q69D47, Q6K9G1, Q6K9G3, Q6XL41, Q7T070, Q7T3R4, Q7XQ12, Q8CF94

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
RHAG	“form complex”	“Ankyrin complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

177 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	4
Uncertain significance	95
Likely benign	31
Benign	18

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
13057	NM_000324.3(RHAG):c.154_157delinsGA (p.Pro52fs)	Pathogenic
13058	NM_000324.3(RHAG):c.1086del (p.Ala363fs)	Pathogenic
13059	NM_000324.3(RHAG):c.236G>A (p.Ser79Asn)	Pathogenic
13062	NM_000324.3(RHAG):c.946-1G>A	Pathogenic
13064	NM_000324.3(RHAG):c.1067+1G>A	Pathogenic
13066	NM_000324.3(RHAG):c.1139G>T (p.Gly380Val)	Pathogenic
1323529	NM_000324.3(RHAG):c.471C>A (p.Tyr157Ter)	Pathogenic
218295	NM_000324.3(RHAG):c.194T>C (p.Phe65Ser)	Pathogenic
218296	NM_000324.3(RHAG):c.182T>G (p.Ile61Arg)	Pathogenic
2671849	NM_000324.3(RHAG):c.920C>T (p.Ser307Phe)	Pathogenic
2671850	NM_000324.3(RHAG):c.544G>A (p.Gly182Ser)	Pathogenic
3725598	NM_000324.3(RHAG):c.1163G>A (p.Trp388Ter)	Pathogenic
438646	NM_000324.3(RHAG):c.447T>G (p.Ile149Met)	Pathogenic
1068333	NM_000324.3(RHAG):c.1139-2A>G	Likely pathogenic
13060	NM_000324.3(RHAG):c.836G>A (p.Gly279Glu)	Likely pathogenic
3341954	NM_000324.3(RHAG):c.1034G>A (p.Gly345Asp)	Likely pathogenic
3381008	NM_000324.3(RHAG):c.212del (p.Phe71fs)	Likely pathogenic

SpliceAI

1018 predictions. Top by Δscore:

Variant	Effect	Δscore
6:49611022:A:AC	donor_gain	1.0000
6:49611023:C:CC	donor_gain	1.0000
6:49614682:CTTA:C	donor_loss	1.0000
6:49614683:TTA:T	donor_loss	1.0000
6:49614684:TACC:T	donor_loss	1.0000
6:49614685:A:AC	donor_gain	1.0000
6:49614685:ACCAT:A	donor_loss	1.0000
6:49614686:C:CC	donor_gain	1.0000
6:49614852:CC:C	acceptor_gain	1.0000
6:49614853:CC:C	acceptor_gain	1.0000
6:49614854:C:CG	acceptor_loss	1.0000
6:49614855:T:A	acceptor_loss	1.0000
6:49615618:ACTC:A	donor_loss	1.0000
6:49615619:CTCA:C	donor_loss	1.0000
6:49615620:TCA:T	donor_loss	1.0000
6:49615621:CACC:C	donor_loss	1.0000
6:49615622:A:AC	donor_gain	1.0000
6:49615622:A:C	donor_loss	1.0000
6:49615623:C:CC	donor_gain	1.0000
6:49615623:CCAAT:C	donor_gain	1.0000
6:49615768:AGGC:A	acceptor_gain	1.0000
6:49615769:GGC:G	acceptor_gain	1.0000
6:49615770:GC:G	acceptor_gain	1.0000
6:49615771:CC:C	acceptor_gain	1.0000
6:49615771:CCTG:C	acceptor_loss	1.0000
6:49615772:C:CC	acceptor_gain	1.0000
6:49615772:C:CG	acceptor_loss	1.0000
6:49615773:T:A	acceptor_loss	1.0000
6:49618214:TCATG:T	acceptor_gain	1.0000
6:49618215:CATGC:C	acceptor_gain	1.0000

AlphaMissense

2693 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:49614830:A:G	W222R	0.994
6:49614830:A:T	W222R	0.994
6:49614839:A:G	W219R	0.994
6:49614839:A:T	W219R	0.994
6:49612443:C:T	G300E	0.993
6:49614819:A:C	F225L	0.993
6:49614819:A:T	F225L	0.993
6:49614821:A:G	F225L	0.993
6:49615733:A:C	F177L	0.993
6:49615733:A:T	F177L	0.993
6:49615735:A:G	F177L	0.993
6:49612444:C:A	G300W	0.992
6:49615624:C:A	G214W	0.992
6:49619307:G:C	F71L	0.991
6:49619307:G:T	F71L	0.991
6:49619309:A:G	F71L	0.991
6:49611114:T:G	D326A	0.990
6:49611115:C:G	D326H	0.990
6:49614841:A:G	L218P	0.990
6:49618159:C:A	G134V	0.990
6:49612506:C:T	G279E	0.989
6:49614853:C:T	G214E	0.989
6:49619330:C:A	G64W	0.989
6:49611087:C:T	G335D	0.988
6:49612512:A:T	L277H	0.988
6:49615624:C:G	G214R	0.988
6:49615624:C:T	G214R	0.988
6:49615721:A:C	F181L	0.988
6:49615721:A:T	F181L	0.988
6:49615723:A:G	F181L	0.988

dbSNP variants (sampled 300 via entrez): RS1000103640 (6:49612991 A>C,G), RS1000328978 (6:49624420 G>A), RS1000392416 (6:49624696 T>G), RS1000430392 (6:49633466 A>G), RS1000527437 (6:49628298 A>T), RS1000597010 (6:49629248 T>C), RS1000611916 (6:49608914 G>A,T), RS1000668466 (6:49635090 T>C), RS1000683385 (6:49607501 A>G), RS1000861811 (6:49629808 G>A), RS1000952255 (6:49607358 C>A,G), RS1001036560 (6:49633203 T>C), RS1001107622 (6:49623417 G>T), RS1001128415 (6:49624392 A>G), RS1001365630 (6:49625976 C>G)

Disease associations

OMIM: gene MIM:180297 | disease phenotypes: MIM:185000, MIM:268150

GenCC curated gene-disease

Disease	Classification	Inheritance
Rh deficiency syndrome	Definitive	Autosomal recessive
overhydrated hereditary stomatocytosis	Strong	Autosomal dominant

Mondo (2): overhydrated hereditary stomatocytosis (MONDO:0008493), Rh deficiency syndrome (MONDO:0019107)

Orphanet (2): Overhydrated hereditary stomatocytosis (Orphanet:3203), Rh deficiency syndrome (Orphanet:71275)

HPO phenotypes

34 total (30 of 34 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000952	Jaundice
HP:0001046	Intermittent jaundice
HP:0001433	Hepatosplenomegaly
HP:0001511	Intrauterine growth retardation
HP:0001562	Oligohydramnios
HP:0001649	Tachycardia
HP:0001744	Splenomegaly
HP:0001878	Hemolytic anemia
HP:0001923	Reticulocytosis
HP:0001972	Macrocytic anemia
HP:0001977	Abnormal thrombosis
HP:0002204	Pulmonary embolism
HP:0002240	Hepatomegaly
HP:0002789	Tachypnea
HP:0002904	Hyperbilirubinemia
HP:0003575	Increased intracellular sodium
HP:0003623	Neonatal onset
HP:0004444	Spherocytosis
HP:0004446	Stomatocytosis
HP:0005268	Miscarriage
HP:0005502	Increased red cell osmotic fragility
HP:0005518	Increased mean corpuscular volume
HP:0006579	Prolonged neonatal jaundice
HP:0008282	Unconjugated hyperbilirubinemia
HP:0011273	Anisocytosis
HP:0012378	Fatigue
HP:0012418	Hypoxemia
HP:0020181	Reduced haptoglobin level
HP:0025065	Abnormal mean corpuscular volume

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST003121_3	Alcohol dependence	1.000000e-06
GCST90002391_49	Mean corpuscular hemoglobin concentration	1.000000e-14
GCST90002396_327	Mean reticulocyte volume	4.000000e-12
GCST90002397_466	Mean spheric corpuscular volume	4.000000e-28
GCST90002405_199	Reticulocyte count	5.000000e-13
GCST90002406_218	Reticulocyte fraction of red cells	4.000000e-13

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0010701	mean reticulocyte volume
EFO:0007986	reticulocyte count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C562717	Rh Deficiency Syndrome (supp.)
C566111	Stomatocytosis I (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — SLC42 family of Rhesus glycoprotein ammonium transporters

CTD chemical–gene interactions

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
cobaltous chloride	decreases expression	1
abrine	increases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Doxorubicin	decreases expression	1
Valproic Acid	affects expression	1
Cadmium Chloride	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C0XF	BEL-A RHAG KO	Transformed cell line	Sex unspecified
CVCL_C0XI	BEL-A 5x KO	Transformed cell line	Sex unspecified

Clinical trials (associated diseases)

2 trials via MONDO — disease-level, not drug-specific.

Trial	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)