SLC9A5

Summary

SLC9A5 (solute carrier family 9 member A5, HGNC:11078) is a protein-coding gene on chromosome 16q22.1, encoding Sodium/hydrogen exchanger 5 (Q14940). Plasma membrane Na(+)/H(+) antiporter.

Enables arrestin family protein binding activity and sodium:proton antiporter activity. Involved in regulation of intracellular pH and sodium ion transmembrane transport. Located in several cellular components, including focal adhesion; neuron spine; and recycling endosome membrane. Implicated in end stage renal disease.

Source: NCBI Gene 6553 — RefSeq curated summary.

At a glance

• GWAS associations: 12
• Clinical variants (ClinVar): 127 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004594

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11078
Approved symbol	SLC9A5
Name	solute carrier family 9 member A5
Location	16q22.1
Locus type	gene with protein product
Status	Approved
Aliases	NHE5
Ensembl gene	ENSG00000135740
Ensembl biotype	protein_coding
OMIM	600477
Entrez	6553

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 12 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000299798, ENST00000561472, ENST00000563723, ENST00000564704, ENST00000564812, ENST00000566345, ENST00000566626, ENST00000566638, ENST00000567247, ENST00000897491, ENST00000897492, ENST00000897493, ENST00000928276, ENST00000928277, ENST00000928278, ENST00000928279, ENST00000928280

RefSeq mRNA: 6 — MANE Select: NM_004594 NM_001323971, NM_001323972, NM_001323973, NM_001323974, NM_001323975, NM_004594

CCDS: CCDS42178

Canonical transcript exons

ENST00000299798 — 16 exons

Exon	Start	End
ENSE00000921181	67255753	67255930
ENSE00002616124	67248979	67249201
ENSE00003492310	67259820	67259946
ENSE00003518509	67258318	67258447
ENSE00003538038	67270738	67272191
ENSE00003563661	67256911	67257113
ENSE00003585698	67252542	67252844
ENSE00003589229	67255393	67255471
ENSE00003596900	67255021	67255184
ENSE00003598627	67259573	67259661
ENSE00003602874	67257345	67257434
ENSE00003617593	67256469	67256689
ENSE00003621567	67257531	67257601
ENSE00003675161	67266088	67266225
ENSE00003677697	67265040	67265106
ENSE00003686962	67264352	67264522

Expression profiles

Bgee: expression breadth ubiquitous, 170 present calls, max score 87.35.

FANTOM5 (CAGE): breadth broad, TPM avg 1.0632 / max 23.7365, expressed in 562 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154611	0.6208	335
154609	0.3351	183
154610	0.1072	54

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	87.35	gold quality
cerebellar hemisphere	UBERON:0002245	86.98	gold quality
cerebellar cortex	UBERON:0002129	86.86	gold quality
spleen	UBERON:0002106	86.53	gold quality
cerebellum	UBERON:0002037	85.16	gold quality
stromal cell of endometrium	CL:0002255	82.45	gold quality
nucleus accumbens	UBERON:0001882	80.44	gold quality
putamen	UBERON:0001874	78.71	gold quality
caudate nucleus	UBERON:0001873	78.40	gold quality
cerebellar vermis	UBERON:0004720	77.91	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.82	gold quality
right frontal lobe	UBERON:0002810	77.50	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	75.62	silver quality
apex of heart	UBERON:0002098	75.02	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	74.84	gold quality
right testis	UBERON:0004534	74.76	gold quality
left testis	UBERON:0004533	74.54	gold quality
Brodmann (1909) area 9	UBERON:0013540	74.31	gold quality
anterior cingulate cortex	UBERON:0009835	73.96	gold quality
cingulate cortex	UBERON:0003027	73.95	gold quality
prefrontal cortex	UBERON:0000451	73.86	gold quality
inferior olivary complex	UBERON:0002127	73.60	gold quality
sural nerve	UBERON:0015488	73.43	gold quality
frontal cortex	UBERON:0001870	73.01	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	72.94	gold quality
neocortex	UBERON:0001950	72.76	gold quality
brain	UBERON:0000955	72.60	gold quality
telencephalon	UBERON:0001893	72.53	gold quality
testis	UBERON:0000473	72.25	gold quality
hypothalamus	UBERON:0001898	71.86	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.75

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

81 targeting SLC9A5, 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-4283	100.00	66.42	2097
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-18A-3P	99.56	65.68	1092
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-6081	99.48	66.07	1446

Literature-anchored findings (GeneRIF, showing 8)

• observations demonstrate that NHE5 is localized to the recycling endosomal pathway and is dynamically regulated by phosphatidylinositol 3’-kinase and by the state of F-actin assembly (PMID:12205089)
• beta-Arrestins bind and decrease cell-surface abundance of the Na+/H+ exchanger NHE5 isoform. (PMID:15699339)
• RACK1 activates NHE5 both by integrin-dependent and independent pathways, which may coordinate cellular ion homeostasis during cell-matrix adhesion. (PMID:16920332)
• SCAMP2 regulates NHE5 transit through recycling endosomes and promotes its surface targeting in an Arf6-dependent manner. (PMID:19276089)
• discrete elements of an elaborate sorting signal in NHE5 contribute to beta-arrestin2 binding and trafficking along the recycling endosomal pathway. (PMID:21296876)
• overexpression of NHE5 inhibits spine growth in response to neuronal activity (PMID:21551074)
• These data reveal a unique role for AMPK and NHE5 in regulating the pH homeostasis of hippocampal neurons during metabolic stress. (PMID:24936055)
• High NHE5 expression is associated with glioma. (PMID:31595389)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc9a5	ENSDARG00000078560
mus_musculus	Slc9a5	ENSMUSG00000014786
rattus_norvegicus	Slc9a5	ENSRNOG00000028844
drosophila_melanogaster	Nhe3	FBGN0028703
drosophila_melanogaster	Nhe2	FBGN0040297
caenorhabditis_elegans		WBGENE00003730
caenorhabditis_elegans		WBGENE00003732
caenorhabditis_elegans		WBGENE00003733
caenorhabditis_elegans		WBGENE00003734

Paralogs (10): SLC9A7 (ENSG00000065923), SLC9A3 (ENSG00000066230), SLC9A1 (ENSG00000090020), SLC9A2 (ENSG00000115616), SLC9C2 (ENSG00000162753), SLC9C1 (ENSG00000172139), SLC9A4 (ENSG00000180251), SLC9A9 (ENSG00000181804), SLC9A8 (ENSG00000197818), SLC9A6 (ENSG00000198689)

Protein

Protein identifiers

Sodium/hydrogen exchanger 5 — Q14940 (reviewed: Q14940)

Alternative names: Na(+)/H(+) exchanger 5, Solute carrier family 9 member 5

All UniProt accessions (5): Q14940, H3BNY2, J3KSB3, J3KSE2, J3QRV1

UniProt curated annotations — full annotation on UniProt →

Function. Plasma membrane Na(+)/H(+) antiporter. Mediates the electroneutral exchange of intracellular H(+) ions for extracellular Na(+) in 1:1 stoichiometry, thus regulating intracellular pH homeostasis, in particular in neural tissues. Acts as a negative regulator of dendritic spine growth. Plays a role in postsynaptic remodeling and signaling. Can also contribute to organellar pH regulation, with consequences for receptor tyrosine kinase trafficking.

Subunit / interactions. Interacts with CHP1 and CHP2. Interacts with ARRB2; facilitates the endocytosis of SLC9A5 from the plasma membrane. Interacts with RACK1; this interaction positively regulates SLC9A5 activity and promotes SLC9A5 localization to focal adhesions. Interacts with SCAMP2; this interaction regulates SLC9A5 cell-surface targeting and SLC9A5 activity.

Subcellular location. Cell membrane. Recycling endosome membrane. Cell projection. Dendritic spine membrane. Synaptic cell membrane. Cell junction. Focal adhesion.

Tissue specificity. Mainly expressed in brain. Expressed in neurons of the central and peripheral nervous system. Expressed also in testis, spleen, and skeletal muscle.

Post-translational modifications. Phosphorylated by PRKAA2; promotes its accumulation at the cell surface. Phosphorylated by CSNK2A1 in a manner favoring its beta-arrestin binding and endocytosis.

Activity regulation. ATP-depletion almost completely abolishes SLC9A5 activity. Inhibited by amiloride compounds.

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

RefSeq proteins (6): NP_001310900, NP_001310901, NP_001310902, NP_001310903, NP_001310904, NP_004585* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004709	NaH_exchanger	Family
IPR006153	Cation/H_exchanger_TM	Domain
IPR018410	Na/H_exchanger_3/5	Family
IPR018422	Cation/H_exchanger_CPA1	Family

Pfam: PF00999

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (46 total): topological domain 13, transmembrane region 12, mutagenesis site 12, region of interest 4, compositionally biased region 2, chain 1, glycosylation site 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14940-F1	64.34	0.23

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): 199

Mutagenesis-validated functional residues (12):

Position	Phenotype
697–698	does not disrupt the binding of arrb2. impaired endocytosis of slc9a5.
702	abolishes slc9a5 phosphorylation by csnk2a1 and abolishes csnk2a1-mediated binding of arrb2; when associated with a-709;
702	abolishes slc9a5 phosphorylation by csnk2a1 and abolishes csnk2a1-mediated binding of arrb2; when associated with d-709;
709	abolishes slc9a5 phosphorylation by csnk2a1 and abolishes csnk2a1-mediated binding of arrb2; when associated with a-702;
709	abolishes slc9a5 phosphorylation by csnk2a1 and abolishes csnk2a1-mediated binding of arrb2; when associated with d-702;
711	abolishes slc9a5 phosphorylation by csnk2a1 and abolishes csnk2a1-mediated binding of arrb2; when associated with a-702;
711	abolishes slc9a5 phosphorylation by csnk2a1 and abolishes csnk2a1-mediated binding of arrb2; when associated with d-702;
712	abolishes slc9a5 phosphorylation by csnk2a1 and abolishes csnk2a1-mediated binding of arrb2; when associated with a-702;
712	abolishes slc9a5 phosphorylation by csnk2a1 and abolishes csnk2a1-mediated binding of arrb2; when associated with d-702;
714	abolishes slc9a5 phosphorylation by csnk2a1 and abolishes csnk2a1-mediated binding of arrb2; when associated with a-702;
714	abolishes slc9a5 phosphorylation by csnk2a1 and abolishes csnk2a1-mediated binding of arrb2; when associated with d-702;
722–723	does not disrupt the binding of arrb2. does not affect endocytosis of slc9a5.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-425986	Sodium/Proton exchangers
R-HSA-382551	Transport of small molecules
R-HSA-425393
R-HSA-425407	SLC-mediated transmembrane transport

MSigDB gene sets: 182 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, E2F_Q4, chr16q22, E2F4DP1_01, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, MEF2_02, GGGTGGRR_PAX4_03, USF_C, GOBP_MONOATOMIC_CATION_TRANSPORT, E2F1DP1_01, E2F1DP2_01, NF1_Q6_01, GOMF_PROTON_TRANSMEMBRANE_TRANSPORTER_ACTIVITY, GOBP_REGULATION_OF_PH, GOBP_MONOATOMIC_ION_HOMEOSTASIS

GO Biological Process (10): monoatomic ion transport (GO:0006811), sodium ion transmembrane transport (GO:0035725), regulation of intracellular pH (GO:0051453), potassium ion transmembrane transport (GO:0071805), sodium ion import across plasma membrane (GO:0098719), monoatomic cation transport (GO:0006812), sodium ion transport (GO:0006814), regulation of pH (GO:0006885), transmembrane transport (GO:0055085), proton transmembrane transport (GO:1902600)

GO Molecular Function (5): sodium:proton antiporter activity (GO:0015385), potassium:proton antiporter activity (GO:0015386), arrestin family protein binding (GO:1990763), protein binding (GO:0005515), antiporter activity (GO:0015297)

GO Cellular Component (12): plasma membrane (GO:0005886), focal adhesion (GO:0005925), membrane (GO:0016020), dendritic spine membrane (GO:0032591), neuron spine (GO:0044309), synapse (GO:0045202), recycling endosome membrane (GO:0055038), endosome (GO:0005768), cell projection (GO:0042995), postsynaptic membrane (GO:0045211), anchoring junction (GO:0070161), synaptic membrane (GO:0097060)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metal ion SLC transporters	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
monoatomic cation transmembrane transport	3
transport	2
metal cation:proton antiporter activity	2
cellular anatomical structure	2
synaptic membrane	2
cell junction	2
sodium ion transport	1
regulation of pH	1
intracellular monoatomic cation homeostasis	1
regulation of biological quality	1
potassium ion transport	1
sodium ion transmembrane transport	1
inorganic cation import across plasma membrane	1
monoatomic ion transport	1
metal ion transport	1
monoatomic cation homeostasis	1
biological regulation	1
cellular process	1
sodium ion transmembrane transporter activity	1
solute:potassium antiporter activity	1
protein binding	1
binding	1
secondary active transmembrane transporter activity	1
membrane	1
cell periphery	1
cell-substrate junction	1
neuron projection membrane	1
dendrite membrane	1
dendritic spine	1
neuron projection	1
endosome membrane	1
recycling endosome	1
endomembrane system	1
cytoplasmic vesicle	1
postsynapse	1
synapse	1
plasma membrane region	1

Protein interactions and networks

STRING

744 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC9A5	SLC9B2	Q86UD5	936
SLC9A5	SLC9C1	Q4G0N8	645
SLC9A5	SLC9B1	Q4ZJI4	616
SLC9A5	SLC9A7	Q96T83	585
SLC9A5	ARRB1	P49407	525
SLC9A5	SLC26A6	Q9BXS9	508
SLC9A5	SLC4A7	Q9Y6M7	490
SLC9A5	SLC9A1	P19634	473
SLC9A5	NHERF1	O14745	469
SLC9A5	SLC4A10	Q6U841	464
SLC9A5	SLC4A4	Q9Y6R1	453
SLC9A5	ATP1A4	Q13733	448
SLC9A5	SLC4A8	Q2Y0W8	446
SLC9A5	SLC9C2	Q5TAH2	401
SLC9A5	SLC4A3	P48751	393

IntAct

7 interactions, top by confidence:

A	B	Type	Score
CDKN1A	CDK14	psi-mi:“MI:0914”(association)	0.770
RBM25	PRPF40A	psi-mi:“MI:0914”(association)	0.560
SLC9A5	PRKAB2	psi-mi:“MI:0914”(association)	0.530
SLC9A5	FGA	psi-mi:“MI:0914”(association)	0.350
SLC9A5	NBAS	psi-mi:“MI:0914”(association)	0.350
dnaX	SLC9A5	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (123): SLC9A5 (Reconstituted Complex), SLC9A5 (Reconstituted Complex), GNB2L1 (Two-hybrid), SLC9A5 (Affinity Capture-Western), SLC9A5 (Reconstituted Complex), SLC9A5 (Affinity Capture-Western), RAP1GDS1 (Affinity Capture-MS), PRKAA1 (Affinity Capture-MS), PRKAB2 (Affinity Capture-MS), SLC9A5 (Affinity Capture-MS), DIRAS1 (Affinity Capture-MS), PRKAB1 (Affinity Capture-MS), HSPA8 (Affinity Capture-MS), SLC9A5 (Affinity Capture-MS), FGG (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2K1Q8, A0A494BA31, B1MTL0, B2RXE2, D3ZBP4, E9Q3M5, F1MH07, O18917, O62667, O88269, P02730, P04919, P04920, P13808, P15575, P16283, P23347, P23348, P23562, P48746, P48751, Q14940, Q14AT5, Q2Y0W8, Q32LP4, Q5DTL9, Q5RB85, Q5RD44, Q60825, Q6IFT6, Q6IWH7, Q6RI88, Q6RVG2, Q6SJP2, Q6U841, Q80ZA5, Q8JZR6, Q8K4V2, Q8NG04, Q8TDZ2

Diamond homologs: A1L3P4, B2RXE2, D3ZJ86, D4A7H1, F7B113, G3X939, M5A7P9, O13726, P19634, P23791, P26431, P26432, P26433, P26434, P48761, P48762, P48763, P48764, Q01345, Q04121, Q14940, Q28362, Q3ZAS0, Q4L208, Q4R8V4, Q552S0, Q56XP4, Q58916, Q5ZJ75, Q61165, Q68KI4, Q6AI14, Q84WG1, Q8BLV3, Q8BUE1, Q8BZ00, Q8IVB4, Q8R4D1, Q8RWU6, Q8S396

SIGNOR signaling

14 interactions.

A	Effect	B	Mechanism
SLC9A5	“down-regulates quantity”	hydron	relocalization
SLC9A5	“up-regulates quantity”	sodium(1+)	relocalization
GRK2	“down-regulates activity”	SLC9A5	phosphorylation
ARRB1	“down-regulates activity”	SLC9A5	relocalization
ARRB2	“down-regulates activity”	SLC9A5	relocalization
CSNK2A1	“down-regulates activity”	SLC9A5	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	114
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3388 predictions. Top by Δscore:

Variant	Effect	Δscore
16:67237764:CGGGA:C	acceptor_gain	1.0000
16:67237765:GGGA:G	acceptor_gain	1.0000
16:67237766:GGA:G	acceptor_gain	1.0000
16:67237767:GA:G	acceptor_gain	1.0000
16:67237767:GAC:G	acceptor_loss	1.0000
16:67237768:AC:A	acceptor_loss	1.0000
16:67237769:C:CC	acceptor_gain	1.0000
16:67238027:CACTT:C	donor_loss	1.0000
16:67238028:ACTTA:A	donor_loss	1.0000
16:67238029:CTTA:C	donor_loss	1.0000
16:67238030:TTA:T	donor_loss	1.0000
16:67238031:TAC:T	donor_loss	1.0000
16:67238032:A:AC	donor_gain	1.0000
16:67238032:A:C	donor_loss	1.0000
16:67238033:C:CC	donor_gain	1.0000
16:67238033:C:T	donor_loss	1.0000
16:67238033:CCAGG:C	donor_gain	1.0000
16:67238126:GCG:G	acceptor_gain	1.0000
16:67238127:CG:C	acceptor_gain	1.0000
16:67238127:CGC:C	acceptor_gain	1.0000
16:67238128:GC:G	acceptor_loss	1.0000
16:67238129:C:CC	acceptor_gain	1.0000
16:67238129:CTG:C	acceptor_loss	1.0000
16:67238963:CTTTG:C	acceptor_gain	1.0000
16:67238964:TTTG:T	acceptor_gain	1.0000
16:67238965:TTG:T	acceptor_gain	1.0000
16:67238966:TG:T	acceptor_gain	1.0000
16:67238968:C:CC	acceptor_gain	1.0000
16:67238968:CTGG:C	acceptor_loss	1.0000
16:67238969:T:A	acceptor_loss	1.0000

AlphaMissense

5794 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:67256514:C:A	N319K	1.000
16:67256514:C:G	N319K	1.000
16:67256587:T:C	F344L	1.000
16:67256589:C:A	F344L	1.000
16:67256589:C:G	F344L	1.000
16:67256599:G:C	G348R	1.000
16:67252604:G:C	G84R	0.999
16:67255084:A:G	D185G	0.999
16:67255093:C:A	A188D	0.999
16:67255107:T:C	F193L	0.999
16:67255109:T:A	F193L	0.999
16:67255109:T:G	F193L	0.999
16:67255153:G:A	G208D	0.999
16:67255169:C:A	N213K	0.999
16:67255169:C:G	N213K	0.999
16:67255170:G:C	D214H	0.999
16:67255171:A:C	D214A	0.999
16:67256597:T:A	L347H	0.999
16:67256599:G:T	G348C	0.999
16:67256600:G:A	G348D	0.999
16:67257003:G:A	G409R	0.999
16:67257003:G:C	G409R	0.999
16:67257003:G:T	G409W	0.999
16:67257004:G:A	G409E	0.999
16:67257345:G:C	G446R	0.999
16:67257552:G:C	A483P	0.999
16:67258427:G:C	A536P	0.999
16:67249186:A:C	S58R	0.998
16:67249188:T:A	S58R	0.998
16:67249188:T:G	S58R	0.998

dbSNP variants (sampled 300 via entrez): RS1000245770 (16:67249360 G>A), RS1000355797 (16:67257336 T>C), RS1000678201 (16:67247545 C>G,T), RS1000733577 (16:67253376 T>C), RS1000791430 (16:67255253 G>A,T), RS1000848365 (16:67253013 C>G), RS1000852823 (16:67263473 C>G), RS1000983093 (16:67261375 G>C), RS1000986592 (16:67263015 T>A), RS1001104070 (16:67268440 G>A), RS1001351969 (16:67260975 A>G,T), RS1001518103 (16:67247124 C>A,T), RS1001730108 (16:67254860 TCTC>T), RS1002037606 (16:67248595 C>G,T), RS1002072899 (16:67260598 C>G,T)

Disease associations

OMIM: gene MIM:600477 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST010002_113	Refractive error	2.000000e-14
GCST011348_42	High density lipoprotein cholesterol levels	5.000000e-40
GCST90002385_80	High light scatter reticulocyte count	1.000000e-10
GCST90002386_286	High light scatter reticulocyte percentage of red cells	2.000000e-11
GCST90002397_242	Mean spheric corpuscular volume	1.000000e-10
GCST90002405_310	Reticulocyte count	9.000000e-13
GCST90002406_435	Reticulocyte fraction of red cells	7.000000e-14
GCST90020024_743	A body shape index	4.000000e-13
GCST90020025_210	Waist-to-hip ratio adjusted for BMI	1.000000e-10
GCST90020027_1	Waist-hip index	1.000000e-11
GCST90020029_569	Waist circumference adjusted for body mass index	4.000000e-08
GCST90020029_570	Waist circumference adjusted for body mass index	6.000000e-17

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0007986	reticulocyte count
EFO:0007789	BMI-adjusted waist circumference
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3058 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 63,705 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL945	AMILORIDE	4	63,705

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

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
amiloride	Inhibition	4.68	pKi

ChEMBL bioactivities

17 potent at pChembl≥5 of 34 total, top 12 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.54	IC50	291	nM	CHEMBL3892788
6.43	Ki	370	nM	N,N-HEXAMETHYLENEAMILORIDE
6.43	IC50	370	nM	CHEMBL466311
6.38	Ki	420	nM	5-(N-ETHYL-N-ISOPROPYL)AMILORIDE
6.38	IC50	420	nM	5-(N-ETHYL-N-ISOPROPYL)AMILORIDE
5.82	IC50	1510	nM	N,N-HEXAMETHYLENEAMILORIDE
5.51	IC50	3110	nM	CHEMBL5565656
5.47	IC50	3360	nM	CHEMBL51879
5.34	IC50	4540	nM	CHEMBL5568323
5.32	IC50	4750	nM	CHEMBL5542750
5.25	IC50	5580	nM	CHEMBL5560204
5.05	IC50	8830	nM	CHEMBL5567224

PubChem BioAssay actives

8 with measured affinity, of 38 total; 8 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(3R)-1-[(1S,2S)-4,6-dichloro-1-[4-(3,5-dimethyl-1,2,4-triazol-4-yl)-2-fluorophenoxy]-2,3-dihydro-1H-inden-2-yl]pyrrolidin-3-ol;hydrochloride	1321774: Inhibition of human NHE5 expressed in LAP1 cell assessed as intracellular pH recovery measured for 2 mins by CECF-AM dye based FLIPR assay	ic50	0.2910	uM
3-amino-5-(azepan-1-yl)-6-chloro-N-(diaminomethylidene)pyrazine-2-carboxamide	2083739: Inhibition of human NHE5 transfected in chinese hamster PS120 cells measured after 9 mins by BCECF-AM staining based NH4Cl pre-pulse method	ic50	1.5100	uM
3-amino-N-(diaminomethylidene)-5-[2-hydroxyethyl(methyl)amino]-6-(4-methylphenyl)pyrazine-2-carboxamide	2083739: Inhibition of human NHE5 transfected in chinese hamster PS120 cells measured after 9 mins by BCECF-AM staining based NH4Cl pre-pulse method	ic50	3.1100	uM
trans-(1R,3R)-N-(diaminomethylidene)-3-(2,3-dihydro-1-benzofuran-4-yl)-2,2-dimethylcyclopropane-1-carboxamide	143810: Compound is screened in AP1 cells expressing human NHE-5 for sodium hydrogen exchange activity	ic50	3.3600	uM
3-amino-6-[3,5-bis(trifluoromethyl)phenyl]-N-(diaminomethylidene)-5-[2-hydroxyethyl(methyl)amino]pyrazine-2-carboxamide	2083739: Inhibition of human NHE5 transfected in chinese hamster PS120 cells measured after 9 mins by BCECF-AM staining based NH4Cl pre-pulse method	ic50	4.5400	uM
3-amino-N-(diaminomethylidene)-6-(2,4-dichlorophenyl)-5-[2-hydroxyethyl(methyl)amino]pyrazine-2-carboxamide	2083739: Inhibition of human NHE5 transfected in chinese hamster PS120 cells measured after 9 mins by BCECF-AM staining based NH4Cl pre-pulse method	ic50	4.7500	uM
3-amino-6-(4-chlorophenyl)-N-(diaminomethylidene)-5-[2-hydroxyethyl(methyl)amino]pyrazine-2-carboxamide	2083739: Inhibition of human NHE5 transfected in chinese hamster PS120 cells measured after 9 mins by BCECF-AM staining based NH4Cl pre-pulse method	ic50	5.5800	uM
3-amino-N-(diaminomethylidene)-5-[2-hydroxyethyl(methyl)amino]-6-[4-(trifluoromethyl)phenyl]pyrazine-2-carboxamide	2083739: Inhibition of human NHE5 transfected in chinese hamster PS120 cells measured after 9 mins by BCECF-AM staining based NH4Cl pre-pulse method	ic50	8.8300	uM

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
entinostat	increases expression	1
3-iodothyronamine	affects uptake	1
abrine	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
NSC 689534	affects binding, increases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Fulvestrant	decreases methylation	1
Benzo(a)pyrene	decreases methylation	1
Cisplatin	affects cotreatment, decreases expression	1
Copper	affects binding, increases expression	1
Estradiol	affects cotreatment, increases expression	1
Lead	affects expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
1-Methyl-4-phenylpyridinium	increases expression	1
Cadmium Chloride	increases expression	1
Copper Sulfate	increases expression	1
Acrylamide	increases expression	1

ChEMBL screening assays

11 unique, capped per target: 10 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3861050	Binding	Inhibition of human NHE5 expressed in LAP1 cell assessed as intracellular pH recovery measured for 2 mins by CECF-AM dye based FLIPR assay	Discovery and Optimization of 1-Phenoxy-2-aminoindanes as Potent, Selective, and Orally Bioavailable Inhibitors of the Na+/H+ Exchanger Type 3 (NHE3). — J Med Chem
CHEMBL748619	Functional	Compound is screened in AP1 cells expressing human NHE-5 for sodium hydrogen exchange activity	Arylcyclopropanecarboxyl guanidines as novel, potent, and selective inhibitors of the sodium hydrogen exchanger isoform-1. — J Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D4QS	HCT116-SLC9A5-KO-c7	Cancer cell line	Male
CVCL_D4QT	HCT116-SLC9A5-KO-c8	Cancer cell line	Male

Clinical trials (associated diseases)

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