SLC9B2

Summary

SLC9B2 (solute carrier family 9 member B2, HGNC:25143) is a protein-coding gene on chromosome 4q24, encoding Sodium/hydrogen exchanger 9B2 (Q86UD5). Electroneutral Na(+) Li(+)/H(+) antiporter that extrudes Na(+) or Li(+) in exchange for external protons across the membrane.

Sodium hydrogen antiporters, such as NHEDC2, convert the proton motive force established by the respiratory chain or the F1F0 mitochondrial ATPase into sodium gradients that drive other energy-requiring processes, transduce environmental signals into cell responses, or function in drug efflux (Xiang et al., 2007 [PubMed 18000046]).

Source: NCBI Gene 133308 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 92 total
• Druggable target: yes
• MANE Select transcript: NM_178833

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25143
Approved symbol	SLC9B2
Name	solute carrier family 9 member B2
Location	4q24
Locus type	gene with protein product
Status	Approved
Aliases	FLJ23984, NHA2
Ensembl gene	ENSG00000164038
Ensembl biotype	protein_coding
OMIM	611789
Entrez	133308

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 25 protein_coding, 4 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000362026, ENST00000394785, ENST00000503103, ENST00000503230, ENST00000503818, ENST00000505838, ENST00000506288, ENST00000508136, ENST00000510976, ENST00000512806, ENST00000515424, ENST00000890692, ENST00000890693, ENST00000890694, ENST00000890695, ENST00000890696, ENST00000890697, ENST00000890698, ENST00000890699, ENST00000890700, ENST00000890701, ENST00000890702, ENST00000890703, ENST00000890704, ENST00000890705, ENST00000890706, ENST00000890707, ENST00000971268, ENST00000971269, ENST00000971270

RefSeq mRNA: 12 — MANE Select: NM_178833 NM_001300754, NM_001300756, NM_001370199, NM_001370200, NM_001370201, NM_001370202, NM_001370203, NM_001370204, NM_001370205, NM_001370206, NM_001370207, NM_178833

CCDS: CCDS3662, CCDS75173, CCDS75174

Canonical transcript exons

ENST00000394785 — 12 exons

Exon	Start	End
ENSE00001080711	103031700	103031808
ENSE00001080713	103057801	103057971
ENSE00001080714	103048893	103049020
ENSE00001080716	103044890	103044996
ENSE00001080718	103047051	103047226
ENSE00001338592	103028747	103028883
ENSE00001519558	103022253	103026591
ENSE00001953365	103076184	103076761
ENSE00003483738	103066327	103066507
ENSE00003529461	103050240	103050382
ENSE00003539662	103043296	103043445
ENSE00003556766	103067461	103067592

Expression profiles

Bgee: expression breadth ubiquitous, 210 present calls, max score 96.74.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.1709 / max 169.5902, expressed in 1725 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
53438	7.1603	1665
53434	3.3162	1271
53436	1.0874	636
53437	0.9732	600
53439	0.3219	150
53441	0.1178	39
53433	0.0744	16
53440	0.0653	35
53435	0.0543	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	96.74	gold quality
cortical plate	UBERON:0005343	94.68	gold quality
prefrontal cortex	UBERON:0000451	93.89	gold quality
calcaneal tendon	UBERON:0003701	92.92	gold quality
tibia	UBERON:0000979	92.06	gold quality
Brodmann (1909) area 9	UBERON:0013540	91.46	gold quality
cerebellar hemisphere	UBERON:0002245	90.59	gold quality
right frontal lobe	UBERON:0002810	90.50	gold quality
cerebellar cortex	UBERON:0002129	90.45	gold quality
liver	UBERON:0002107	90.27	gold quality
right hemisphere of cerebellum	UBERON:0014890	89.82	gold quality
islet of Langerhans	UBERON:0000006	89.64	gold quality
right lobe of liver	UBERON:0001114	89.64	gold quality
anterior cingulate cortex	UBERON:0009835	89.56	gold quality
frontal cortex	UBERON:0001870	89.05	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	89.04	gold quality
cerebellum	UBERON:0002037	88.99	gold quality
neocortex	UBERON:0001950	88.93	gold quality
ganglionic eminence	UBERON:0004023	88.03	gold quality
tendon	UBERON:0000043	86.65	gold quality
cartilage tissue	UBERON:0002418	86.53	gold quality
hypothalamus	UBERON:0001898	86.52	gold quality
cerebral cortex	UBERON:0000956	85.95	gold quality
ventricular zone	UBERON:0003053	85.72	gold quality
stromal cell of endometrium	CL:0002255	85.70	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	85.04	gold quality
smooth muscle tissue	UBERON:0001135	84.89	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.80	gold quality
epithelial cell of pancreas	CL:0000083	84.69	gold quality
bone marrow cell	CL:0002092	84.09	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	15.72
E-MTAB-10042	yes	9.41
E-MTAB-6075	no	159.17
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

76 targeting SLC9B2, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-323A-3P	99.79	70.30	1739
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-6516-3P	99.65	68.57	1238
HSA-MIR-561-3P	99.64	70.90	3647

Literature-anchored findings (GeneRIF, showing 8)

• NHA-oc/NHA2 displays the expected activities of a bona fide cation-proton antiporter and plays a key role(s) in normal osteoclast differentiation and function (PMID:17988971)
• Na+/H+ antiporter genes may contribute to sodium-lithium countertransport activity and salt homeostasis in humans[NHA1 and NHA2] (PMID:18000046)
• restricted to the distal convoluted tubule in the kidney (PMID:18508966)
• cluster of essential, highly conserved titratable residues located in an assembly region made of two discontinuous helices of inverted topology, each interrupted by an extended chain (PMID:20053353)
• mutation in AA residues V161 and F357 reduced ability of transfected BW31a cells to remove intracellular Na and grow in NaCl-medium; yeast expressing F357 F437 cannot grow in 0.4M NaCl, suggesting these residues also essential for antiporter activity (PMID:20713131)
• the ubiquitous tissue distribution of NHA2 suggests that H(+)-coupled transport is more widespread. The coexistence of Na(+) and H(+)-driven chemiosmotic circuits has implications for salt and pH regulation in the kidney. (PMID:22948142)
• The exchange activity of NHA2 (SLC9B2) is electroneutral, despite harboring the 2 conserved aspartic acid residues found in NapA and other bacterial homologues. The equivalent residue to K305 in human NHA2 has been replaced with arginine, which is a mutation that makes NapA electroneutral. A transmembrane embedded lysine residue is essential for electrogenic transport in Na(+)/H(+) antiporters. (PMID:28154142)
• Allosteric links between the hydrophilic N-terminus and transmembrane core of human Na[+] /H[+] antiporter NHA2. (PMID:36177733)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	SLC9B2	ENSDARG00000052700
mus_musculus	Slc9b2	ENSMUSG00000037994
rattus_norvegicus	Slc9b2	ENSRNOG00000023404
drosophila_melanogaster	Nha1	FBGN0031865
drosophila_melanogaster	Nha2	FBGN0263390
caenorhabditis_elegans		WBGENE00009617
caenorhabditis_elegans		WBGENE00009618
caenorhabditis_elegans		WBGENE00010214

Paralogs (1): SLC9B1 (ENSG00000164037)

Protein

Protein identifiers

Sodium/hydrogen exchanger 9B2 — Q86UD5 (reviewed: Q86UD5)

Alternative names: Na(+)/H(+) exchanger NHA2, Na(+)/H(+) exchanger-like domain-containing protein 2, Sodium/hydrogen exchanger-like domain-containing protein 2, Solute carrier family 9 subfamily B member 2

All UniProt accessions (6): A0A0C4DGB3, B7Z676, D6R9P2, D6RGJ7, E9PE63, Q86UD5

UniProt curated annotations — full annotation on UniProt →

Function. Electroneutral Na(+) Li(+)/H(+) antiporter that extrudes Na(+) or Li(+) in exchange for external protons across the membrane. Uses the proton gradient/membrane potential to extrude sodium. Contributes to the regulation of intracellular pH and sodium homeostasis. Also able to mediate Na(+)/Li(+) antiporter activity in kidney. May play a physiological role in renal tubular function and blood pressure homeostasis. Plays an important role for insulin secretion and clathrin-mediated endocytosis in beta-cells. Involved in sperm motility and fertility. It is controversial whether SLC9B2 plays a role in osteoclast differentiation or not.

Subunit / interactions. Homodimer. Dimerization is essential for SLC9B2 activity. Lipids seem to play a role in the stabilization of the dimerization subdomain.

Subcellular location. Cell membrane. Mitochondrion membrane. Endosome membrane. Recycling endosome membrane. Cytoplasmic vesicle. Secretory vesicle. Synaptic vesicle membrane. Cell projection. Cilium. Flagellum membrane. Basolateral cell membrane. Apical cell membrane.

Tissue specificity. Widely expressed. High levels detected in the distal tubules of the kidney nephron. Detected in red blood cells (at protein level).

Activity regulation. Allosterically inhibited by the N-terminal domain. Inhibited by phloretin.

Miscellaneous. The subcellular localization of SLC9B2 remains controversial. Was initially thought to partially localize to mitochondria. However SLC9B2 does not seem to contain a mitochondrial targeting sequence. It was later established that its localizes predominantly in plasma membrane or intracellularly to endosomes and lysosomes. In another recent study, endogenous SLC9B2 in the distal tubular cell line mpkDCT4 is detected in recycling endosomes but absent in plasma membrane.

Similarity. Belongs to the monovalent cation:proton antiporter 1 (CPA1) transporter (TC 2.A.36) family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q86UD5-1	1	yes
Q86UD5-2	2

RefSeq proteins (12): NP_001287683, NP_001287685, NP_001357128, NP_001357129, NP_001357130, NP_001357131, NP_001357132, NP_001357133, NP_001357134, NP_001357135, NP_001357136, NP_849155* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006153	Cation/H_exchanger_TM	Domain
IPR038770	Na+/solute_symporter_sf	Homologous_superfamily
IPR051843	CPA1_transporter	Family

Pfam: PF00999

Catalyzed reactions (Rhea), 3 shown:

• Na(+)(in) + H(+)(out) = Na(+)(out) + H(+)(in) (RHEA:29419)
• Li(+)(out) + H(+)(in) = Li(+)(in) + H(+)(out) (RHEA:72407)
• Li(+)(in) + Na(+)(out) = Li(+)(out) + Na(+)(in) (RHEA:72415)

UniProt features (92 total): helix 21, mutagenesis site 20, topological domain 15, transmembrane region 14, turn 6, binding site 4, sequence variant 3, compositionally biased region 2, splice variant 2, strand 2, chain 1, region of interest 1, modified residue 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
9QUB	ELECTRON MICROSCOPY	2.7
9QUW	ELECTRON MICROSCOPY	2.9
7B4L	ELECTRON MICROSCOPY	3.1
7B4M	ELECTRON MICROSCOPY	7.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86UD5-F1	78.24	0.40

Antibody-complex structures (SAbDab): 2 — 9QUB, 9QUW

Functional residue map

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

Ligand- & substrate-binding residues (4): 244; 275; 278; 279

Post-translational modifications (1): 49

Mutagenesis-validated functional residues (20):

Position	Phenotype
47	decreases na(+) li(+)/h(+) antiporter activity.
56	decreases na(+) li(+)/h(+) antiporter activity.
57	does not affect na(+) li(+)/h(+) antiporter activity; when associated with a-58.
57	decreases na(+) li(+)/h(+) antiporter activity; when associated with k-58.
58	does not affect tna(+) li(+)/h(+) antiporter activity; when associated with a-57.
58	decreases na(+) li(+)/h(+) antiporter activity; when associated with k-57.
215	abolishes na(+) li(+)/h(+) antiporter activity. shifts the specificity of the transporter from na(+) to li(+); when asso
238	abolishes na(+) li(+)/h(+) antiporter activity. changes subcellular localization. retained in the er.
240	does not affect plasma membrane localization. change in the substrate specificity with a preference for li(+) over na(+)
246	does not affect plasma membrane localization. less sensitive to phloretin inhibition.
246	does not affect plasma membrane localization. abolishes antiporter activity. less sensitive to phloretin inhibition.
278–279	loss of ion transport activity; does not rescue insulin secretion defect induced by knockdown of slc9b2 in min6 cells.
278	abolishes na(+) li(+)/h(+) antiporter activity. does not affect plasma membrane localization.
382	does not affect plasma membrane localization. decreases the substrate specificity for li(+).
406	does not affect plasma membrane localization. decreases na(+) li(+)/h(+) antiporter activity.
432	abolishes na(+) li(+)/h(+) antiporter activity. shifts the specificity from na(+) to li(+); when associated with r-215.
432	loss of ion transport activity.
432	does not affect plasma membrane localization. decreases the substrate specificity for li(+).

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels
R-HSA-382551	Transport of small molecules
R-HSA-983712	Ion channel transport

MSigDB gene sets: 224 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GOBP_MYELOID_CELL_DIFFERENTIATION, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, chr4q24, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_MYELOID_CELL_DEVELOPMENT, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_INSULIN_SECRETION, GOBP_CELLULAR_RESPONSE_TO_CARBOHYDRATE_STIMULUS, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_BONE_CELL_DEVELOPMENT, GOBP_HORMONE_TRANSPORT, GOBP_VESICLE_MEDIATED_TRANSPORT

GO Biological Process (14): sodium ion transport (GO:0006814), lithium ion transport (GO:0010351), flagellated sperm motility (GO:0030317), monoatomic ion transmembrane transport (GO:0034220), sodium ion homeostasis (GO:0055078), regulation of insulin secretion involved in cellular response to glucose stimulus (GO:0061178), clathrin-dependent endocytosis (GO:0072583), obsolete inorganic cation transmembrane transport (GO:0098662), positive regulation of osteoclast development (GO:2001206), monoatomic ion transport (GO:0006811), monoatomic cation transport (GO:0006812), sodium ion transmembrane transport (GO:0035725), transmembrane transport (GO:0055085), proton transmembrane transport (GO:1902600)

GO Molecular Function (6): lithium:proton antiporter activity (GO:0010348), sodium:proton antiporter activity (GO:0015385), identical protein binding (GO:0042802), protein binding (GO:0005515), antiporter activity (GO:0015297), oxidoreductase activity (GO:0016491)

GO Cellular Component (19): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), plasma membrane (GO:0005886), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), synaptic vesicle membrane (GO:0030672), mitochondrial membrane (GO:0031966), recycling endosome (GO:0055037), recycling endosome membrane (GO:0055038), sperm principal piece (GO:0097228), endosome (GO:0005768), cilium (GO:0005929), endosome membrane (GO:0010008), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), motile cilium (GO:0031514), cell projection (GO:0042995), synapse (GO:0045202), intracellular vesicle (GO:0097708)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Ion channel transport	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
metal ion transport	2
monoatomic ion transport	2
transport	2
monoatomic cation transmembrane transport	2
metal cation:proton antiporter activity	2
cytoplasm	2
intracellular membrane-bounded organelle	2
plasma membrane region	2
endosome	2
cilium-dependent cell motility	1
cilium movement involved in cell motility	1
sperm motility	1
transmembrane transport	1
monoatomic cation homeostasis	1
inorganic ion homeostasis	1
insulin secretion involved in cellular response to glucose stimulus	1
regulation of insulin secretion	1
regulation of cellular localization	1
receptor-mediated endocytosis	1
osteoclast development	1
positive regulation of osteoclast differentiation	1
regulation of osteoclast development	1
sodium ion transport	1
cellular process	1
sodium ion transmembrane transporter activity	1
protein binding	1
binding	1
secondary active transmembrane transporter activity	1
catalytic activity	1
organelle inner membrane	1
mitochondrial membrane	1
membrane	1
cell periphery	1
basal plasma membrane	1
apical part of cell	1
synaptic vesicle	1
exocytic vesicle membrane	1
mitochondrion	1
mitochondrial envelope	1

Protein interactions and networks

STRING

752 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC9B2	SLC9A5	Q14940	936
SLC9B2	SLC9A6	Q92581	917
SLC9B2	SLC9A2	Q9UBY0	899
SLC9B2	SLC9A1	P19634	891
SLC9B2	SLC9A7	Q96T83	889
SLC9B2	SLC9A8	Q9Y2E8	800
SLC9B2	SLC9A9	Q8IVB4	783
SLC9B2	SLC9C2	Q5TAH2	657
SLC9B2	SLC9C1	Q4G0N8	637
SLC9B2	CPA2	P48052	594
SLC9B2	SLC9A4	Q6AI14	585
SLC9B2	CPA1	P15085	465
SLC9B2	SLC9A3	P48764	463
SLC9B2	CLCN7	P51798	407
SLC9B2	SLC22A15	Q8IZD6	378

IntAct

7 interactions, top by confidence:

A	B	Type	Score
PGRMC2	SLC9B2	psi-mi:“MI:0915”(physical association)	0.560
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350
SLC9B2	EIF3D	psi-mi:“MI:0914”(association)	0.350
SLC9B2	PGRMC2	psi-mi:“MI:0915”(physical association)	0.000
SLC9B2	UBA1	psi-mi:“MI:0220”(ubiquitination reaction)	0.000

BioGRID (82): PGRMC2 (Two-hybrid), SLC9B2 (Proximity Label-MS), SLC9B2 (Proximity Label-MS), SLC9B2 (Proximity Label-MS), SLC9B2 (Proximity Label-MS), SLC9B2 (Affinity Capture-MS), SLC9B2 (Affinity Capture-MS), ABCA3 (Affinity Capture-MS), ABCB1 (Affinity Capture-MS), ABCF1 (Affinity Capture-MS), ACAD11 (Affinity Capture-MS), AIMP2 (Affinity Capture-MS), ALDH18A1 (Affinity Capture-MS), ALYREF (Affinity Capture-MS), ATP11C (Affinity Capture-MS)

ESM2 similar proteins: A0A2K2AIF4, A0A2K2BF92, A0A6P3HVI0, A1L272, A2SWM2, B8AF63, B9H7I1, B9N9Y7, E2RFJ3, E7EXX2, O02228, O54902, O77741, O80605, P41251, P49279, P49280, P49281, P49282, P51027, P56436, P57057, P70553, Q0D7E4, Q27946, Q27981, Q5M7K3, Q5R6B8, Q5R839, Q653V6, Q6DIV6, Q6PF45, Q6YK44, Q86UD5, Q8AVC3, Q8BJA2, Q8CH36, Q8H4H5, Q8IVJ1, Q8L4X4

Diamond homologs: A0A6P3HVI0, A4IHB9, A6NJY1, Q4R7S2, Q4ZJI4, Q5BKR2, Q5R6B8, Q86UD5, Q8C0X2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	75
Likely benign	0
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

2797 predictions. Top by Δscore:

Variant	Effect	Δscore
4:103026469:T:TA	donor_gain	1.0000
4:103050236:ATAC:A	donor_loss	1.0000
4:103050237:TACCT:T	donor_loss	1.0000
4:103050238:A:C	donor_loss	1.0000
4:103050378:CATGC:C	acceptor_gain	1.0000
4:103050379:ATGC:A	acceptor_gain	1.0000
4:103050380:TGC:T	acceptor_gain	1.0000
4:103050381:GC:G	acceptor_gain	1.0000
4:103050382:CCT:C	acceptor_gain	1.0000
4:103050383:C:CC	acceptor_gain	1.0000
4:103050383:CTTGA:C	acceptor_loss	1.0000
4:103050384:T:C	acceptor_gain	1.0000
4:103050384:T:TC	acceptor_gain	1.0000
4:103050389:C:CT	acceptor_gain	1.0000
4:103050390:G:T	acceptor_gain	1.0000
4:103057972:C:CC	acceptor_gain	1.0000
4:103065705:T:TA	donor_gain	1.0000
4:103082079:A:AC	donor_gain	1.0000
4:103082080:C:CC	donor_gain	1.0000
4:103082080:CTT:C	donor_gain	1.0000
4:103082082:T:TA	donor_gain	1.0000
4:103082174:C:CC	acceptor_gain	1.0000
4:103082181:C:CT	acceptor_gain	1.0000
4:103082181:C:T	acceptor_gain	1.0000
4:103082182:A:T	acceptor_gain	1.0000
4:103082870:CCT:C	donor_gain	1.0000
4:103085345:TCAC:T	donor_loss	1.0000
4:103085347:A:C	donor_loss	1.0000
4:103085460:CTC:C	acceptor_gain	1.0000
4:103085469:G:GC	acceptor_gain	1.0000

AlphaMissense

3460 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:103047112:G:C	S276R	0.997
4:103047112:G:T	S276R	0.997
4:103047114:T:G	S276R	0.997
4:103048894:C:G	G238R	0.997
4:103028759:C:A	K460N	0.996
4:103028759:C:G	K460N	0.996
4:103031752:A:C	F401L	0.996
4:103031752:A:T	F401L	0.996
4:103031754:A:G	F401L	0.996
4:103047082:G:C	F286L	0.996
4:103047082:G:T	F286L	0.996
4:103047084:A:G	F286L	0.996
4:103048893:C:T	G238D	0.996
4:103026479:G:T	A502D	0.995
4:103047086:C:T	G285D	0.995
4:103047197:A:T	V248D	0.995
4:103047120:C:G	A274P	0.994
4:103048909:A:G	W233R	0.994
4:103048909:A:T	W233R	0.994
4:103026503:G:T	A494E	0.993
4:103026581:C:T	G468E	0.993
4:103028770:A:G	W457R	0.993
4:103028770:A:T	W457R	0.993
4:103028844:C:G	R432P	0.993
4:103026561:C:G	A475P	0.992
4:103026572:G:T	A471D	0.992
4:103028758:C:G	A461P	0.992
4:103028772:G:T	A456E	0.992
4:103047119:G:T	A274D	0.992
4:103047206:G:T	S245Y	0.992

dbSNP variants (sampled 300 via entrez): RS1000013799 (4:103032222 A>G,T), RS1000122566 (4:103019760 A>G), RS1000292997 (4:103039700 T>C,G), RS1000453183 (4:103055961 G>A), RS1000501906 (4:103071181 GATATAT>G,GATAT,GATATATAT), RS1000502069 (4:103056135 A>G), RS1000521632 (4:103046334 G>C), RS1000526639 (4:103039184 T>A,C), RS1000790578 (4:103051782 G>T), RS1000852311 (4:103051227 G>C), RS1000857766 (4:103068558 G>A), RS1000904780 (4:103078296 G>A), RS1000908429 (4:103068873 C>T), RS1000969730 (4:103050782 AT>A), RS1001006200 (4:103017886 A>C)

Disease associations

OMIM: gene MIM:611789 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST006867_34	Type 2 diabetes	6.000000e-10
GCST007930_177	Medication use (agents acting on the renin-angiotensin system)	7.000000e-09
GCST008745_47	Estimated glomerular filtration rate in non-diabetics	1.000000e-09
GCST008747_180	Estimated glomerular filtration rate	2.000000e-12
GCST008747_99	Estimated glomerular filtration rate	7.000000e-13

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009931	Agents acting on the renin-angiotensin system use measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5209631 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — SLC9 family of sodium/hydrogen exchangers

CTD chemical–gene interactions

39 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	8
Aflatoxin B1	decreases expression, decreases methylation, increases methylation	3
bisphenol A	decreases expression, increases expression	2
entinostat	decreases expression, affects cotreatment	2
belinostat	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
triphenyl phosphate	affects expression	1
trichostatin A	decreases expression	1
sodium arsenite	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
perfluorooctane sulfonic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Vorinostat	decreases expression	1
Acetaminophen	decreases expression	1
Allergens	increases expression	1
Atrazine	decreases expression	1
Vehicle Emissions	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Caffeine	decreases phosphorylation	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Gallic Acid	decreases expression	1
Lithium	affects cotreatment, affects transport	1
Methapyrilene	increases methylation	1
Nickel	increases expression	1
Phloretin	decreases activity	1

ChEMBL screening assays

1 unique, capped per target: 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5209623	Functional	Inhibition of the Sodium/Hydrogen Exchanger-Like Domain-Containing Protein 2 (NHA2, SLC9B2) as assessed by a sensor pH-sensitive genetically encoded fluorescent sensor (pHAxensor) in HEK-293 cells stably transfected with SLC9B2 (PubChem AID	pH biosensor based assay for SLC9B2 using HEK-293 SLC9B2 OE cells

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D4R0	HCT116-SLC9B2-KO-c2	Cancer cell line	Male
CVCL_D4R1	HCT116-SLC9B2-KO-c8	Cancer cell line	Male
CVCL_D9S7	Ubigene HEK293 SLC9B2 KO	Transformed cell line	Female
CVCL_E0P8	Ubigene HeLa SLC9B2 KO	Cancer cell line	Female
CVCL_TP34	HAP1 SLC9B2 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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