RHBG

Summary

RHBG (Rh family B glycoprotein, HGNC:14572) is a protein-coding gene on chromosome 1q22, encoding Ammonium transporter Rh type B (Q9H310). Ammonium transporter involved in the maintenance of acid-base homeostasis.

This gene encodes one of two non-erythroid members of the Rhesus (Rh) protein family. Non-erythroid Rh protein family members are mainly expressed in the kidney and belong to the methylammonium-ammonium permease/ammonia transporters superfamily. All Rh family proteins are predicted to be transmembrane proteins with 12 membrane spanning domains and intracytoplasmic N- and C-termini. Alternative splicing of this gene results in multiple transcript variants.

Source: NCBI Gene 57127 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 96 total
• MANE Select transcript: NM_020407

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14572
Approved symbol	RHBG
Name	Rh family B glycoprotein
Location	1q22
Locus type	gene with protein product
Status	Approved
Aliases	SLC42A2
Ensembl gene	ENSG00000132677
Ensembl biotype	protein_coding
OMIM	607079
Entrez	57127

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 6 protein_coding, 4 nonsense_mediated_decay, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000451864, ENST00000467375, ENST00000494874, ENST00000537040, ENST00000612897, ENST00000613460, ENST00000618120, ENST00000620376, ENST00000622297, ENST00000863933, ENST00000863934, ENST00000863935, ENST00000947082, ENST00000947083

RefSeq mRNA: 6 — MANE Select: NM_020407 NM_001256395, NM_001256396, NM_001412175, NM_001412176, NM_001412177, NM_020407

CCDS: CCDS41414

Canonical transcript exons

ENST00000537040 — 10 exons

Exon	Start	End
ENSE00002220052	156381806	156381943
ENSE00003640367	156382748	156382869
ENSE00003717451	156381347	156381513
ENSE00003720434	156377301	156377487
ENSE00003727508	156377990	156378140
ENSE00003729942	156382068	156382201
ENSE00003741507	156378252	156378399
ENSE00003744142	156384527	156384600
ENSE00003745089	156384777	156385219
ENSE00003845299	156369211	156369436

Expression profiles

Bgee: expression breadth ubiquitous, 127 present calls, max score 89.12.

FANTOM5 (CAGE): breadth broad, TPM avg 0.6511 / max 139.1337, expressed in 192 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
5724	0.5774	181
5725	0.0737	31

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar cortex	UBERON:0002129	89.12	gold quality
cerebellar hemisphere	UBERON:0002245	89.02	gold quality
metanephros cortex	UBERON:0010533	88.50	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.32	gold quality
cerebellum	UBERON:0002037	87.85	gold quality
lower esophagus mucosa	UBERON:0035834	87.04	gold quality
tendon of biceps brachii	UBERON:0008188	85.76	silver quality
adult mammalian kidney	UBERON:0000082	85.02	gold quality
left ovary	UBERON:0002119	84.25	gold quality
buccal mucosa cell	CL:0002336	82.86	gold quality
renal medulla	UBERON:0000362	82.51	gold quality
cerebellar vermis	UBERON:0004720	80.67	gold quality
right lobe of liver	UBERON:0001114	80.46	gold quality
right ovary	UBERON:0002118	79.69	gold quality
ovary	UBERON:0000992	79.19	gold quality
skin of leg	UBERON:0001511	78.11	gold quality
kidney	UBERON:0002113	77.36	gold quality
substantia nigra pars reticulata	UBERON:0001966	77.04	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.08	silver quality
substantia nigra pars compacta	UBERON:0001965	75.82	gold quality
skin of abdomen	UBERON:0001416	75.79	gold quality
lateral globus pallidus	UBERON:0002476	75.71	gold quality
lateral nuclear group of thalamus	UBERON:0002736	75.39	gold quality
zone of skin	UBERON:0000014	74.57	gold quality
cortex of kidney	UBERON:0001225	72.92	gold quality
subthalamic nucleus	UBERON:0001906	72.91	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	72.84	gold quality
liver	UBERON:0002107	72.66	gold quality
vena cava	UBERON:0004087	72.64	gold quality
cardia of stomach	UBERON:0001162	71.52	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	38.89
E-ANND-3	yes	3.40

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

17 targeting RHBG, 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-149-5P	99.25	67.16	1315
HSA-MIR-6878-3P	99.24	64.23	920
HSA-MIR-6852-3P	98.54	67.60	1468
HSA-MIR-4436B-3P	98.25	65.26	1494
HSA-MIR-6735-5P	98.24	65.36	1488
HSA-MIR-3130-5P	98.14	66.00	711
HSA-MIR-7843-5P	98.12	65.26	1421
HSA-MIR-4632-5P	97.82	65.38	1470
HSA-MIR-6879-5P	97.77	65.52	1521
HSA-MIR-6865-3P	97.54	64.67	684
HSA-MIR-10398-5P	97.12	64.94	1051
HSA-MIR-6762-5P	96.55	64.62	972
HSA-MIR-6845-5P	96.55	64.65	969
HSA-MIR-6726-5P	95.97	63.72	841
HSA-MIR-920	95.97	63.95	811
HSA-MIR-4300	95.85	64.56	1003
HSA-MIR-5591-5P	95.85	64.76	1002

Literature-anchored findings (GeneRIF, showing 12)

• Electric current measurements and intracellular pHi determinations suggest that RhBG acts as an electroneutral NH4+-H+ exchanger. (PMID:15284342)
• RhBG requires a tyrosine-based signal and ankyrin-G for basolateral targeting and membrane (PMID:15611082)
• RhBG and RhCG facilitate ammonium movement across the plasma membrane; these results favor the hypothesis that these Rh glycoproteins, together with their homolog RhAG, constitute a family of NH3 channels in mammalian cells. (PMID:15929723)
• Phosphorylation and ankyrin-G binding of the C-terminal domain regulate targeting and function of the ammonium transporter RhBG (PMID:18635543)
• This study concludes that under normal conditions, RhCG is the major putative ammonia transporter expressed in the human kidney and RhBG is not expressed at detectable levels. (PMID:19357182)
• Rhbg and Rhcg may contribute to bronchial epithelial cell ammonia metabolism and suggest that they do not contribute to pulmonary carbon dioxide transport. (PMID:19429772)
• human kidney expresses basolateral RhBG protein in connecting segment, type A intercalated cells, and non-A, non-B cells (PMID:23324176)
• RhAG, RhBG and RhCG-exhibit significant permeability to NH3 and show for the first time that RhBG and RhCG can conduct CO2. (PMID:24077989)
• Rh B Glycoprotein (Rhbg) and Rh C Glycoprotein (Rhcg) are identified as ammonia transporters. They are expressed in specific cell populations and membrane domains in distal renal epithelial cells, where they facilitate ammonia secretion. (PMID:24647713)
• Kidney AE1 actually associates with epithelial ankyrin-G and renal ammonium transporter RhBG, which also binds ankyrin-G. (PMID:25616663)
• RHBG expression as a direct target of beta-catenin regulation. (PMID:26029888)
• Ammonia transporter RhBG initiates downstream signaling and functional responses by activating NFkappaB. (PMID:39052834)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	rhbg	ENSDARG00000009018
mus_musculus	Rhbg	ENSMUSG00000104445
rattus_norvegicus	Rhbg	ENSRNOG00000019412
drosophila_melanogaster	Rh50	FBGN0028699
caenorhabditis_elegans		WBGENE00004358
caenorhabditis_elegans		WBGENE00004359

Paralogs (4): RHAG (ENSG00000112077), RHCG (ENSG00000140519), RHD (ENSG00000187010), RHCE (ENSG00000188672)

Protein

Protein identifiers

Ammonium transporter Rh type B — Q9H310 (reviewed: Q9H310)

Alternative names: Rhesus blood group family type B glycoprotein

All UniProt accessions (4): Q9H310, A0A087WTF7, A0A087WUR4, F6Q468

UniProt curated annotations — full annotation on UniProt →

Function. Ammonium transporter involved in the maintenance of acid-base homeostasis. Transports ammonium and its related derivative methylammonium across the basolateral plasma membrane of epithelial cells likely contributing to renal transepithelial ammonia transport and ammonia metabolism. May transport either NH4(+) or NH3 ammonia species predominantly mediating an electrogenic NH4(+) transport. May act as a CO2 channel providing for renal acid secretion.

Subunit / interactions. Interacts (via C-terminus) with ANK2 and ANK3; required for targeting to the basolateral membrane.

Subcellular location. Cell membrane. Basolateral cell membrane.

Tissue specificity. Specifically expressed in kidney. Also detected in liver and ovary.

Post-translational modifications. N-glycosylated.

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

Isoforms (5)

UniProt ID	Names	Canonical?
Q9H310-1	1	yes
Q9H310-2	2, RhBG-2A
Q9H310-3	3
Q9H310-4	4, RhBG-1A
Q9H310-5	5

RefSeq proteins (6): NP_001243324, NP_001243325, NP_001399104, NP_001399105, NP_001399106, NP_065140* (*=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 (43 total): topological domain 13, transmembrane region 12, splice variant 5, sequence variant 4, mutagenesis site 4, region of interest 2, chain 1, glycosylation site 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H310-F1	93.70	0.88

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 (1): 49

Mutagenesis-validated functional residues (4):

Position	Phenotype
178	impairs protein stability resulting in loss of transporter activity.
419	loss of interaction with ank3. intracellular retention; when associated with a-420 and a-421.
420	partial loss of interaction with ank3. intracellular retention; when associated with a-419 and a-421.
421	partial loss of interaction with ank3. intracellular retention; when associated with a-419 and a-420.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-444411	Rhesus glycoproteins mediate ammonium transport

MSigDB gene sets: 71 (showing top): SHEPARD_BMYB_MORPHOLINO_UP, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, MARTINEZ_RB1_TARGETS_DN, GOBP_ONE_CARBON_COMPOUND_TRANSPORT, GOBP_GAS_TRANSPORT, GOBP_TRANSEPITHELIAL_TRANSPORT, chr1q22, CHIANG_LIVER_CANCER_SUBCLASS_INTERFERON_DN, GOBP_TRANSMEMBRANE_TRANSPORT, CHIANG_LIVER_CANCER_SUBCLASS_CTNNB1_UP, KONDO_PROSTATE_CANCER_HCP_WITH_H3K27ME3, GINESTIER_BREAST_CANCER_ZNF217_AMPLIFIED_DN, GOBP_HOMEOSTATIC_PROCESS, GOBP_CHEMICAL_HOMEOSTASIS

GO Biological Process (4): transepithelial ammonium transport (GO:0070634), ammonium transmembrane transport (GO:0072488), ammonium homeostasis (GO:0097272), carbon dioxide transmembrane transport (GO:0035378)

GO Molecular Function (3): ammonium channel activity (GO:0008519), ankyrin binding (GO:0030506), carbon dioxide transmembrane transporter activity (GO:0035379)

GO Cellular Component (4): plasma membrane (GO:0005886), spectrin-associated cytoskeleton (GO:0014731), basolateral plasma membrane (GO:0016323), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Miscellaneous transport and binding events	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nitrogen compound transport	2
transmembrane transport	2
transepithelial transport	1
inorganic ion homeostasis	1
carbon dioxide transport	1
channel activity	1
ammonium transmembrane transport	1
cytoskeletal protein binding	1
transmembrane transporter activity	1
carbon dioxide transmembrane transport	1
membrane	1
cell periphery	1
cytoskeleton	1
basal plasma membrane	1
plasma membrane region	1
cellular anatomical structure	1

Protein interactions and networks

STRING

768 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RHBG	SLC9A2	Q9UBY0	602
RHBG	SLC9A3	P48764	600
RHBG	SLC26A4	O43511	563
RHBG	AQP6	Q13520	494
RHBG	GLUL	P15104	492
RHBG	SLC12A1	Q13621	478
RHBG	SLC9A4	Q6AI14	472
RHBG	FAM187A	A6NFU0	467
RHBG	SLC4A4	Q9Y6R1	435
RHBG	ITPKC	Q96DU7	418
RHBG	SLC4A7	Q9Y6M7	416
RHBG	SDS	P20132	413
RHBG	FUT9	Q9Y231	406
RHBG	CA2	P00918	398
RHBG	SORD	Q00796	391

IntAct

3 interactions, top by confidence:

A	B	Type	Score
RHBG	SH2B1	psi-mi:“MI:0915”(physical association)	0.370
RHBG	PEDS1	psi-mi:“MI:0914”(association)	0.350

BioGRID (25): KRTAP19-1 (Two-hybrid), KRTAP19-2 (Two-hybrid), CYSRT1 (Two-hybrid), ALDOA (Affinity Capture-MS), C1GALT1C1 (Affinity Capture-MS), ESRP1 (Affinity Capture-MS), MFSD9 (Affinity Capture-MS), PALD1 (Affinity Capture-MS), TMEM189 (Affinity Capture-MS), PIK3R2 (Affinity Capture-MS), PRPF39 (Affinity Capture-MS), RHAG (Affinity Capture-MS), SEMA4F (Affinity Capture-MS), SIDT2 (Affinity Capture-MS), SLC11A2 (Affinity Capture-MS)

ESM2 similar proteins: O88298, P18577, P58873, Q02094, Q02161, Q0IIV2, Q18PF6, Q19KI0, Q20CR3, Q28426, Q28427, Q28446, Q28481, Q28812, Q28813, Q28814, Q28849, Q2T9S6, Q3BBX8, Q3BCQ4, Q3BCQ5, Q3BCQ7, Q4VUI0, Q4VUZ1, Q5NVA3, Q5U4V1, Q68FT6, Q69D47, Q6DCG4, Q6WRY0, Q7T070, Q7TNK7, Q7TNN9, Q8BUX5, Q8CBB2, Q8CF94, Q8JI14, Q8WMW0, Q8WMW2, Q8WNQ5

Diamond homologs: A0A072VHJ1, B8ZYW3, G7L1W7, G7LAA8, I3R0S7, O04161, O26757, O26759, O28525, O28528, P54144, P54145, P54147, P54148, P58905, P72935, Q07429, Q18PF6, Q19KH7, Q19KI0, Q21565, Q2T9S6, Q3BBX7, Q3BBX8, Q3BCQ4, Q3BCQ5, Q4VUZ1, Q58739, Q60366, Q69D47, Q6K9G1, Q6K9G3, Q7T3R4, Q7TNN9, Q7XQ12, Q8MXY0, Q95JD3, Q95JD4, Q95M75, Q95M77

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	78
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1909 predictions. Top by Δscore:

Variant	Effect	Δscore
1:156369401:G:GG	donor_gain	1.0000
1:156369437:G:GG	donor_gain	1.0000
1:156378137:GGGG:G	donor_gain	1.0000
1:156378138:GGGG:G	donor_gain	1.0000
1:156369400:A:AG	donor_gain	0.9900
1:156369435:AA:A	donor_gain	0.9900
1:156369436:AGTG:A	donor_loss	0.9900
1:156369437:GT:G	donor_loss	0.9900
1:156369438:T:A	donor_loss	0.9900
1:156369439:GAGT:G	donor_loss	0.9900
1:156377462:G:GA	donor_gain	0.9900
1:156377983:T:G	acceptor_gain	0.9900
1:156377988:A:AG	acceptor_gain	0.9900
1:156377988:AGCAT:A	acceptor_gain	0.9900
1:156377989:G:GA	acceptor_gain	0.9900
1:156377989:GC:G	acceptor_gain	0.9900
1:156377989:GCAT:G	acceptor_gain	0.9900
1:156377989:GCATG:G	acceptor_gain	0.9900
1:156378013:C:CA	acceptor_gain	0.9900
1:156378014:G:A	acceptor_gain	0.9900
1:156378112:A:AG	donor_gain	0.9900
1:156378116:G:GG	donor_gain	0.9900
1:156378138:GGG:G	donor_gain	0.9900
1:156378139:GG:G	donor_gain	0.9900
1:156378139:GGG:G	donor_gain	0.9900
1:156378140:GG:G	donor_gain	0.9900
1:156378140:GGTGA:G	donor_loss	0.9900
1:156378142:T:C	donor_loss	0.9900
1:156378246:CCCCA:C	acceptor_loss	0.9900
1:156378247:CCCAG:C	acceptor_loss	0.9900

AlphaMissense

2981 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000016833 (1:156365121 C>A,G,T), RS1000022441 (1:156371040 GT>G), RS1000278758 (1:156375643 T>C), RS1000922658 (1:156369444 C>A,T), RS1001161667 (1:156382529 G>A,C), RS1001415476 (1:156374333 C>T), RS1001531016 (1:156367985 A>G), RS1001900486 (1:156364316 C>G), RS1002035258 (1:156376793 G>A,T), RS1002089404 (1:156377143 A>G), RS1002390098 (1:156379089 G>C), RS1002418168 (1:156373084 G>A), RS1002630157 (1:156373759 G>A), RS1002722928 (1:156378821 G>A,T), RS1002924469 (1:156366821 G>A)

Disease associations

OMIM: gene MIM:607079 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001521_7	Subcutaneous adipose tissue	9.000000e-06
GCST001523_34	Visceral adipose tissue adjusted for BMI	5.000000e-06
GCST005023_4	Initial pursuit acceleration	1.000000e-06
GCST005023_46	Initial pursuit acceleration	3.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0008434	initial pursuit acceleration

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

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases methylation	3
bisphenol A	affects expression, decreases expression	2
lasiocarpine	decreases expression	1
methyleugenol	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
K 7174	decreases expression	1
Hydrogen Peroxide	affects expression	1
Quercetin	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Triclosan	increases expression	1
8-Bromo Cyclic Adenosine Monophosphate	decreases expression	1
Cyclosporine	decreases expression	1
Cadmium Chloride	decreases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1
Vitamin K 3	affects expression	1

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D4DE	HEK-RHBG-KO-c2	Transformed cell line	Female
CVCL_D4H6	HCT116-RHBG-KO-c16	Cancer cell line	Male
CVCL_D4H7	HCT116-RHBG-KO-c23	Cancer cell line	Male

Clinical trials (associated diseases)

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