SLC9A1

Summary

SLC9A1 (solute carrier family 9 member A1, HGNC:11071) is a protein-coding gene on chromosome 1p36.11, encoding Sodium/hydrogen exchanger 1 (P19634). Electroneutral Na(+) /H(+) antiporter that extrudes Na(+) in exchange for external protons driven by the inward sodium ion chemical gradient, protecting cells from acidification that occurs from metabolism.

This gene encodes a Na+/H+ antiporter that is a member of the solute carrier family 9. The encoded protein is a plasma membrane transporter that is expressed in the kidney and intestine. This protein plays a central role in regulating pH homeostasis, cell migration and cell volume. This protein may also be involved in tumor growth.

Source: NCBI Gene 6548 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Lichtenstein-Knorr syndrome (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 256 total — 4 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 21
• Druggable target: yes — 6 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_003047

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11071
Approved symbol	SLC9A1
Name	solute carrier family 9 member A1
Location	1p36.11
Locus type	gene with protein product
Status	Approved
Aliases	PPP1R143
Ensembl gene	ENSG00000090020
Ensembl biotype	protein_coding
OMIM	107310
Entrez	6548

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000263980, ENST00000374084, ENST00000374086, ENST00000374089, ENST00000447808, ENST00000490329, ENST00000854572, ENST00000854573

RefSeq mRNA: 1 — MANE Select: NM_003047 NM_003047

CCDS: CCDS295

Canonical transcript exons

ENST00000263980 — 12 exons

Exon	Start	End
ENSE00000760795	27103223	27103312
ENSE00000956128	27113826	27114286
ENSE00000956129	27107648	27107865
ENSE00000956130	27105885	27106087
ENSE00001322091	27153983	27155125
ENSE00003465108	27109527	27109777
ENSE00003519340	27101725	27101826
ENSE00003605464	27102673	27102743
ENSE00003621391	27102385	27102558
ENSE00003639805	27102016	27102130
ENSE00003652161	27098809	27100644
ENSE00003653658	27101203	27101275

Expression profiles

Bgee: expression breadth ubiquitous, 273 present calls, max score 96.67.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.8220 / max 407.8062, expressed in 1812 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11217	21.5574	1807
11218	1.1999	724
201430	0.6449	369
201429	0.4171	230
201427	0.3325	160
201428	0.2595	96
11220	0.1695	70
11219	0.1651	47
201426	0.0761	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	96.67	gold quality
mucosa of transverse colon	UBERON:0004991	95.68	gold quality
oocyte	CL:0000023	93.06	gold quality
placenta	UBERON:0001987	92.84	gold quality
body of stomach	UBERON:0001161	92.45	gold quality
stromal cell of endometrium	CL:0002255	92.21	gold quality
pylorus	UBERON:0001166	91.51	gold quality
transverse colon	UBERON:0001157	91.26	gold quality
putamen	UBERON:0001874	90.89	gold quality
mucosa of urinary bladder	UBERON:0001259	90.86	silver quality
nasal cavity epithelium	UBERON:0005384	90.61	gold quality
stomach	UBERON:0000945	90.52	gold quality
saliva-secreting gland	UBERON:0001044	90.47	gold quality
jejunal mucosa	UBERON:0000399	90.36	gold quality
duodenum	UBERON:0002114	90.25	gold quality
right frontal lobe	UBERON:0002810	89.32	gold quality
lower esophagus mucosa	UBERON:0035834	89.30	gold quality
mammary duct	UBERON:0001765	89.03	gold quality
right atrium auricular region	UBERON:0006631	88.84	gold quality
colon	UBERON:0001155	88.82	gold quality
olfactory bulb	UBERON:0002264	88.80	gold quality
type B pancreatic cell	CL:0000169	88.72	gold quality
secondary oocyte	CL:0000655	88.72	gold quality
minor salivary gland	UBERON:0001830	88.72	gold quality
large intestine	UBERON:0000059	88.69	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	88.66	gold quality
epithelium of mammary gland	UBERON:0003244	88.64	gold quality
caudate nucleus	UBERON:0001873	88.57	gold quality
cardiac atrium	UBERON:0002081	88.53	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.37	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.21

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, CEBPB, CEBPD, HIF1A, NR2F1, PPARA, PPARG, TCF3, TFAP2A

miRNA regulators (miRDB)

139 targeting SLC9A1, 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-9-5P	100.00	72.28	2361
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-548J-3P	99.94	72.61	4881

Literature-anchored findings (GeneRIF, showing 40)

• Anion exchanger isoform 2 operates in parallel with Na(+)/H(+) exchanger isoform 1 during regulatory cell volume decrease. (PMID:11852051)
• Data indicate for the first time that two acid extruders, Na(+)-H(+) exchanger and Na(+)-HCO(3)(-) symporter, exist functionally and pH(i) dependently in human atrial cardiomyocytes. (PMID:12065894)
• serum-independent activation of NHE1 by bound CHP2 is one of the key mechanisms for the maintenance of high pH(i) and the resistance to serum deprivation-induced cell death in malignantly transformed cells (PMID:12226101)
• MCT1 and NHE1 genes play important regulation roles in proliferation and growth of tumor cells, probably by affecting pHi. (PMID:12479094)
• both Arg(440) in IL5 and Gly residues in the conserved segment of TM11 appear to constitute important elements for proper functioning of the putative “pH(i) sensor” of Na(+)/H(+) exchanger 1. (PMID:12562776)
• Regulation of placental NHE-1 not due to differences in C-terminus structure. Suppression regulated post-transcriptionally. Change in NHE-1 may contribute to adequate provision of electrolytes and nutrients to fetus. (PMID:12682826)
• identification in human reticulocytes and erythrocytes of an alternative splicing of NHE lacking the amiloride binding site (PMID:12765964)
• Both Pro167 and Pro168 are strictly required for NHE function and may play critical roles in the structure of transmembrane segment IV of the NHE. (PMID:14680478)
• Association of NHE1 with calcineurin B homologous protein (CHP) is crucial for maintenance of the pH(i) sensitivity of NHE1; tightly bound Ca2+ ions may serve as important structural elements in the pHi sensor of NHE1. (PMID:15035633)
• NHE1 promotes cell survival by dual mechanisms: by defending cell volume and pH(i) through Na(+)/H(+) exchange and by functioning as a scaffold for recruitment of a signalplex that includes ERM, phosphoinositide 3-kinase, and Akt (PMID:15096511)
• Children with higher baseline Na-Li countertransporter(CT) had greater blood pressure change than children in lower baseline Na-Li CT and were associated with greater risk of high blood pressure compared to lower Na-Li CT. (PMID:15269707)
• Results describe the topogenesis of a hydrophobic lumenal loop segment between transmembrane segments 9 and 10 of human sodium/hydrogen exchanger isoform 1. (PMID:15465015)
• The relative fluorescence density of NHE-1 is significantly higher in isolated liver nuclei of human, when compared with those of rabbit and rat. (PMID:15523538)
• The antagonistic roles of RhoA and Rac1 in cell motility/invasion and cytoskeletal organization in breast cancer may be due to their concerted action on NHE1 activity as a convergence point. (PMID:15535843)
• acidic aa sequence is critical in proper conformation of the cytosolic domain, calmodulin binding, and in activity (PMID:15610042)
• Transmembrane (TM) segment IV of Na+/H+ exchanger isoform 1 (NHE1) is an unusually structured TM segment exquisitely sensitive to mutagenesis and Phe161 is a pore-lining residue. (PMID:15677483)
• NHE activity in the microvillus of syncytiotrophoblasts is attributable predominantly to NHE1. (PMID:15772858)
• The results suggest that PP1 is an important regulatory phosphatase of NHE1, that it can bind to and dephosphorylate the protein, and that it regulates NHE1 activity in vivo. (PMID:15823043)
• a pseudopodial-located RhoA/ROCK/p38/NHE1 signal module is regulated by Protein Kinase A gating and then regulates invasion in breast cancer cell lines (PMID:15843433)
• Data show that the Na+/H+ exchanger (NHE), NHE1, is functionally active in HEK 293 cells, and resides in lipid rafts or caveolae, which may create cellular microdomains where pH(i) is tightly regulated. (PMID:16002403)
• In conclusion, EGF protects esophageal epithelial cells against acid through NHE activation via Ca(2+)/calmodulin and the PKC pathway. (PMID:16306134)
• carbonic anhydrase II binds to the penultimate group of 13 amino acids of the cytoplasmic tail of NHE1. a novel phosphorylation-regulated CAII binding site exists in distal amino acids of the NHE1 tail. (PMID:16475831)
• crystallographic analysis of the human calcineurin homologous protein CHP2 bound to the cytoplasmic region of the Na+/H+ exchanger NHE1 (PMID:16511206)
• These findings suggest that CHP serves as an obligatory subunit that is required both for supporting the basic activity and regulating the pH-sensing of NHE1 via interactions between distinct parts of these proteins [CHP2]. (PMID:16710297)
• TM VII is a critical transmembrane segment structured as an interrupted helix, with several residues that are essential to both protein function and sensitivity to inhibition. (PMID:16861220)
• helix formation of the cytoplasmic region of NHE1 by calcineurin B homologous protein 1 is a prerequisite for generating the active form of NHE1 (PMID:17050540)
• data support the view that dimerization of two active subunits are required for NHE1 to possess the exchange activity in the neutral pH(i) range (PMID:17073455)
• the existence of a positive feedback loop between NHE1 and ERK can pose a barrier against apoptosis. (PMID:17167226)
• Both intact Ser(770) and Ser(771) were required for sustained acidosis-mediated activation of NHE1 (PMID:17209041)
• The NHERF1 PDZ2 domain regulates PKA-RhoA-p38-mediated NHE1 activation and invasion in breast tumor cells. (PMID:17332506)
• Review. The role of NHE-1 hyperactivity in cardiac overload, ischemia/reperfusion injury, and myocardial hypertrophy is discussed. (PMID:17339567)
• Vpr-mediated NHE1 dyregulation is in part through GR pathway (PMID:17349711)
• We highlight evidence for the nontransport functions of NHE1 and describe how the structural functions are integrated with ion translocation to regulate a range of cellular processes[review] (PMID:17565280)
• Results support the view that the multiple charged residues identified in this study, along with several basic residues reported previously, participate in the regulation of the intracellular pH sensing of Na+/H+ exchanger 1. (PMID:17662110)
• Epidermal growth factor upregulates NHE1 by post-translational regulation that is important for cervical cancer cell invasiveness. (PMID:17894388)
• These data provide the first evidence that both EGF and S1P stimulate NHE activity in the syncytiotrophoblast; they appear to do so predominantly by activating the NHE1 isoform. (PMID:17913870)
• NHE1 activity generates a proton gradient at the cell surface accompanied by the cells’ ability to respond to changes in pH in melanoma (PMID:17916606)
• T84 human colon cells contain three isoforms of the Na+/H+ exchanger, NHE1, NHE2, and NHE4, but not the Cl-dependent NHE (PMID:17943310)
• Model structure of the Na+/H+ exchanger 1 in human and E. coli (PMID:17981808)
• Three MAPKs exhibit unique interrelationships with the Na(+)/H(+) exchanger, NHE1, after osmotic cell shrinkage:ERK1/2, JNK1/2 and p38 MAPK. (PMID:17982256)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	SLC9A1	ENSDARG00000067784
danio_rerio	slc9a1b	ENSDARG00000097339
mus_musculus	Slc9a1	ENSMUSG00000028854
rattus_norvegicus	Slc9a1	ENSRNOG00000007982
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), SLC9A2 (ENSG00000115616), SLC9A5 (ENSG00000135740), SLC9C2 (ENSG00000162753), SLC9C1 (ENSG00000172139), SLC9A4 (ENSG00000180251), SLC9A9 (ENSG00000181804), SLC9A8 (ENSG00000197818), SLC9A6 (ENSG00000198689)

Protein

Protein identifiers

Sodium/hydrogen exchanger 1 — P19634 (reviewed: P19634)

Alternative names: APNH, Na(+)/H(+) antiporter, amiloride-sensitive, Na(+)/H(+) exchanger 1, Solute carrier family 9 member 1

All UniProt accessions (2): P19634, B1ALD5

UniProt curated annotations — full annotation on UniProt →

Function. Electroneutral Na(+) /H(+) antiporter that extrudes Na(+) in exchange for external protons driven by the inward sodium ion chemical gradient, protecting cells from acidification that occurs from metabolism. Exchanges intracellular H(+) ions for extracellular Na(+) in 1:1 stoichiometry. Plays a key role in maintening intracellular pH neutral and cell volume, and thus is important for cell growth, proliferation, migration and survival. In addition, can transport lithium Li(+) and also functions as a Na(+)/Li(+) antiporter. SLC9A1 also functions in membrane anchoring and organization of scaffolding complexes that coordinate signaling inputs.

Subunit / interactions. Homodimer; dimerization is crucial for its function. Oligomer. Interacts with CALM1 in a calcium-dependent manner. Interacts with TESC. Interacts (via the C-terminal domain) with CHP1; the interaction occurs at the plasma membrane in a calcium-dependent manner and facilitates the maturation, cell surface expression, and function of SLC9A3. Interacts with CHP2; the interaction occurs in a calcium-dependent manner. Interacts with EZR; regulates the cytoskeletal interactions of SLC9A1 and promotes stress fiber formation.

Subcellular location. Cell membrane. Basolateral cell membrane.

Tissue specificity. Kidney and intestine.

Post-translational modifications. O-glycosylated. Ubiquitinated, leading to its degradation by the proteasome. Ubiquitination is reduced by CHP1. Phosphorylation at Thr-779 increases SLC9A1 activity. Specifically dephosphorylated at Thr-779 by PPP3CA that negatively regulates SLC9A1 activity. Phosphorylation at Ser-648 by AKT1 reduces SLC9A1 binding to CALM1. Palmitoylated; may play a major role in SLC9A1 regulation.

Disease relevance. Lichtenstein-Knorr syndrome (LIKNS) [MIM:616291] An autosomal recessive neurologic disorder characterized by progressive cerebellar ataxia and severe progressive sensorineural hearing loss. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated at acidic pHs. Inhibited by amiloride and 5-amino-substituted derivatives. Inhibited by cariporide and eniporide. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) bind and differentially regulate SLC9A1 activity.

Domain organisation. The C-terminal intracellular domain is subject to extensive post-translational modifications and binding partner interactions which regulate transporter activity, scaffolding functions, downstream events and localization.

Miscellaneous. Predicted models used for more than 20 years predicted 10-12 transmembrane segments. More recently, the structure of SLC9A1 has been solved and reveals that SLC9A1 possesses 13 transmembrane regions.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P19634-1	1	yes
P19634-2	2

RefSeq proteins (1): NP_003038* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001970	NHE-1-like	Family
IPR004709	NaH_exchanger	Family
IPR006153	Cation/H_exchanger_TM	Domain
IPR018422	Cation/H_exchanger_CPA1	Family
IPR032103	NHE_CaM-bd	Domain

Pfam: PF00999, PF16644

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 (157 total): mutagenesis site 50, helix 24, modified residue 15, topological domain 14, transmembrane region 13, region of interest 11, strand 9, turn 6, glycosylation site 6, sequence variant 3, site 2, splice variant 2, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

20 structures.

PDB	Method	Resolution (Å)
6NUC	X-RAY DIFFRACTION	1.9
6NUF	X-RAY DIFFRACTION	1.9
9NXE	X-RAY DIFFRACTION	2.09
2YGG	X-RAY DIFFRACTION	2.23
6NUU	X-RAY DIFFRACTION	2.3
2BEC	X-RAY DIFFRACTION	2.7
23XK	ELECTRON MICROSCOPY	3.1
23XO	ELECTRON MICROSCOPY	3.16
23XM	ELECTRON MICROSCOPY	3.24
7DSW	ELECTRON MICROSCOPY	3.3
7DSV	ELECTRON MICROSCOPY	3.4
7DSX	ELECTRON MICROSCOPY	3.5
1Y4E	SOLUTION NMR
2E30	SOLUTION NMR
2HTG	SOLUTION NMR
2KBV	SOLUTION NMR
2L0E	SOLUTION NMR
2MDF	SOLUTION NMR
6BJF	SOLUTION NMR
6ZBI	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P19634-F1	67.92	0.20

Functional residue map

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

Catalytic / active sites (2): 161 (channel pore-lining); 370 (not glycosylated)

Post-translational modifications (15): 599, 602, 603, 605, 648, 693, 697, 703, 723, 726, 729, 779, 785, 787, 796

Glycosylation sites (6): 42, 56, 61, 62, 68, 75

Mutagenesis-validated functional residues (50):

Position	Phenotype
262	abolishes sodium:proton antiporter activity.
267	abolishes sodium:proton antiporter activity.
309	abolishes membrane localization.
391	abolishes plasma membrane localization. reduces greatly sodium:proton antiporter activity.
518	reduces interaction with chp1 and the exchange activity; when associated with q-522.
522	reduces interaction with chp1 and the exchange activity; when associated with q-518.
526–531	inhibits interaction with chp1 and the exchange activity. chpi does not localize at the cell membrane. abolishes interac
526–531	inhibits interaction with chp1 and the exchange activity. chpi does not localize at the cell membrane.
526	reduces interaction with chp1 and the exchange activity; when associated with q-527.
527	reduces interaction with chp1 and the exchange activity; when associated with q-526.
530	reduces interaction with chp1 and the exchange activity; when associated with q-531.
531	reduces interaction with chp1 and the exchange activity; when associated with q-530.
534	strongly reduced interaction with chp2.
537	strongly reduced interaction with chp2.
577	decreases sodium:proton antiporter activity by 50%; when associated with a-578.
578	decreases sodium:proton antiporter activity by 50%; when associated with a-577.
779	does not affect plasma membrane localization.
155	almost complete loss of activity.
156	almost complete loss of activity.
157	reduces activity.
158	almost complete loss of activity.
159	almost complete loss of activity.
160	reduces activity.
161	reduces activity.

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-2160916	Hyaluronan degradation
R-HSA-425986	Sodium/Proton exchangers
R-HSA-1430728	Metabolism
R-HSA-1630316	Glycosaminoglycan metabolism
R-HSA-2142845	Hyaluronan metabolism
R-HSA-382551	Transport of small molecules
R-HSA-425393
R-HSA-425407	SLC-mediated transmembrane transport
R-HSA-71387	Metabolism of carbohydrates and carbohydrate derivatives

MSigDB gene sets: 467 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, GOBP_RESPONSE_TO_ELECTRICAL_STIMULUS, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_RESPONSE_TO_MUSCLE_STRETCH, GOBP_RESPONSE_TO_COLD, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_CELLULAR_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOBP_FOCAL_ADHESION_ASSEMBLY

GO Biological Process (46): monoatomic ion transport (GO:0006811), intracellular sodium ion homeostasis (GO:0006883), regulation of pH (GO:0006885), response to acidic pH (GO:0010447), positive regulation of cardiac muscle hypertrophy (GO:0010613), regulation of cardiac muscle contraction by calcium ion signaling (GO:0010882), cell migration (GO:0016477), maintenance of cell polarity (GO:0030011), hyaluronan catabolic process (GO:0030214), positive regulation of cell growth (GO:0030307), cellular response to insulin stimulus (GO:0032869), positive regulation of mitochondrial membrane permeability (GO:0035794), response to muscle stretch (GO:0035994), sodium ion export across plasma membrane (GO:0036376), positive regulation of apoptotic process (GO:0043065), negative regulation of apoptotic process (GO:0043066), positive regulation of action potential (GO:0045760), positive regulation of transcription by RNA polymerase II (GO:0045944), stem cell differentiation (GO:0048863), protein complex oligomerization (GO:0051259), regulation of intracellular pH (GO:0051453), regulation of stress fiber assembly (GO:0051492), regulation of focal adhesion assembly (GO:0051893), cardiac muscle cell differentiation (GO:0055007), cellular response to cold (GO:0070417), positive regulation of calcineurin-NFAT signaling cascade (GO:0070886), cellular response to antibiotic (GO:0071236), cellular response to electrical stimulus (GO:0071257), cellular response to mechanical stimulus (GO:0071260), cellular response to hypoxia (GO:0071456), cellular response to acidic pH (GO:0071468), potassium ion transmembrane transport (GO:0071805), cellular response to epinephrine stimulus (GO:0071872), cardiac muscle cell contraction (GO:0086003), regulation of cardiac muscle cell membrane potential (GO:0086036), regulation of the force of heart contraction by cardiac conduction (GO:0086092), sodium ion import across plasma membrane (GO:0098719), positive regulation of the force of heart contraction (GO:0098735), proton transmembrane transport (GO:1902600), regulation of the force of heart contraction (GO:0002026)

GO Molecular Function (13): calcium ion binding (GO:0005509), calmodulin binding (GO:0005516), phospholipid binding (GO:0005543), phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), sodium:proton antiporter activity (GO:0015385), potassium:proton antiporter activity (GO:0015386), protein phosphatase 2B binding (GO:0030346), protein-macromolecule adaptor activity (GO:0030674), identical protein binding (GO:0042802), calcium-dependent protein binding (GO:0048306), molecular adaptor activity (GO:0060090), protein binding (GO:0005515), antiporter activity (GO:0015297)

GO Cellular Component (18): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), plasma membrane (GO:0005886), focal adhesion (GO:0005925), cell surface (GO:0009986), intercalated disc (GO:0014704), membrane (GO:0016020), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), lamellipodium (GO:0030027), T-tubule (GO:0030315), membrane raft (GO:0045121), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), cation-transporting ATPase complex (GO:0090533), sarcolemma (GO:0042383), transporter complex (GO:1990351)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Hyaluronan metabolism	1
Metal ion SLC transporters	1
Metabolism of carbohydrates and carbohydrate derivatives	1
Glycosaminoglycan metabolism	1
Transport of small molecules	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
protein binding	4
apoptotic process	2
regulation of apoptotic process	2
metal cation:proton antiporter activity	2
binding	2
cytoplasm	2
plasma membrane region	2
transport	1
intracellular monoatomic cation homeostasis	1
sodium ion homeostasis	1
monoatomic cation homeostasis	1
biological regulation	1
response to pH	1
cardiac muscle hypertrophy	1
regulation of cardiac muscle hypertrophy	1
positive regulation of muscle hypertrophy	1
calcium-mediated signaling	1
regulation of cardiac muscle contraction	1
cardiac muscle contraction	1
cell motility	1
establishment or maintenance of cell polarity	1
glycosaminoglycan catabolic process	1
hyaluronan metabolic process	1
regulation of cell growth	1
cell growth	1
positive regulation of growth	1
positive regulation of cellular process	1
response to insulin	1
cellular response to peptide hormone stimulus	1
regulation of mitochondrial membrane permeability	1
positive regulation of membrane permeability	1
response to mechanical stimulus	1
sodium ion transmembrane transport	1
export across plasma membrane	1
positive regulation of programmed cell death	1
negative regulation of programmed cell death	1
action potential	1
positive regulation of biological process	1
regulation of action potential	1

Protein interactions and networks

STRING

1726 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC9A1	EZR	P15311	985
SLC9A1	MSN	P26038	974
SLC9A1	RDX	P35241	939
SLC9A1	CA2	P00918	938
SLC9A1	TESC	Q96BS2	936
SLC9A1	CALML3	P27482	935
SLC9A1	CALML6	Q8TD86	935
SLC9A1	CALML4	Q96GE6	935
SLC9A1	CALML5	Q9NZT1	935
SLC9A1	SLC9C1	Q4G0N8	925
SLC9A1	SLC9B2	Q86UD5	891
SLC9A1	CALM1	P02593	885
SLC9A1	SLC4A4	Q9Y6R1	743
SLC9A1	SLC4A7	Q9Y6M7	736
SLC9A1	CD44	P16070	733

IntAct

107 interactions, top by confidence:

A	B	Type	Score
ENTREP1	WWP2	psi-mi:“MI:0914”(association)	0.850
CHP2	SLC9A1	psi-mi:“MI:0407”(direct interaction)	0.780
SLC9A1	TESC	psi-mi:“MI:0407”(direct interaction)	0.720
TESC	SLC9A1	psi-mi:“MI:0407”(direct interaction)	0.720
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
YWHAB	SLC9A1	psi-mi:“MI:0914”(association)	0.680
YWHAB	SLC9A1	psi-mi:“MI:0407”(direct interaction)	0.680
SLC9A1	YWHAB	psi-mi:“MI:0914”(association)	0.680
STX12	SNAP23	psi-mi:“MI:0914”(association)	0.640
CHP1	SLC9A1	psi-mi:“MI:0407”(direct interaction)	0.620
	CHP2	psi-mi:“MI:0407”(direct interaction)	0.560
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
IPPK	TMEM223	psi-mi:“MI:0914”(association)	0.530
SEMA7A	SGPL1	psi-mi:“MI:0914”(association)	0.530
PTGER3	PIK3R2	psi-mi:“MI:0914”(association)	0.530
FUT1	GOLIM4	psi-mi:“MI:0914”(association)	0.530
CCDC107	PLD2	psi-mi:“MI:0914”(association)	0.530
GALNT6	NDUFS4	psi-mi:“MI:0914”(association)	0.530
TCTN2	TPST2	psi-mi:“MI:0914”(association)	0.530
AOC3	AOC2	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM120B	psi-mi:“MI:0914”(association)	0.530

BioGRID (190): SLC9A1 (Affinity Capture-MS), SLC9A1 (Affinity Capture-MS), SLC9A1 (Affinity Capture-MS), SLC9A1 (Affinity Capture-MS), SLC9A1 (Two-hybrid), MAP3K14 (Reconstituted Complex), MAP3K14 (Affinity Capture-Western), SLC9A1 (Biochemical Activity), SLC9A1 (Proximity Label-MS), SLC9A1 (Proximity Label-MS), SLC9A1 (Affinity Capture-MS), SLC9A1 (Affinity Capture-MS), SLC9A1 (Affinity Capture-MS), SLC9A1 (Affinity Capture-MS), SLC9A1 (Affinity Capture-MS)

ESM2 similar proteins: A1L3P4, A4IHB9, D3ZJ86, D4A7H1, F7B113, O00341, O16452, O54701, P19634, P23791, P26431, P26432, P26434, P31596, P35449, P43004, P43006, P48761, P48762, P48763, P48764, P50482, Q01345, Q28036, Q3ZAS0, Q4R335, Q56XP4, Q61165, Q68KI4, Q6AI14, Q6DFC0, Q84WG1, Q8BLV3, Q8BUE1, Q8BUN9, Q8BYR8, Q8BZ00, Q8IVB4, Q8JZR4, Q8RWU6

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

15 interactions.

A	Effect	B	Mechanism
MAPK14	up-regulates	SLC9A1	phosphorylation
MAPK1	up-regulates	SLC9A1	phosphorylation
RPS6K	up-regulates	SLC9A1	phosphorylation
SLC9A1	“down-regulates quantity”	hydron	relocalization
SLC9A1	“up-regulates quantity”	sodium(1+)	relocalization
ROCK1	“up-regulates activity”	SLC9A1	phosphorylation
MAP3K14	“up-regulates activity”	SLC9A1	phosphorylation
RPS6KA3	“up-regulates activity”	SLC9A1	phosphorylation
SGK1	“up-regulates activity”	SLC9A1	phosphorylation
RPS6KA1	up-regulates	SLC9A1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	2
Uncertain significance	122
Likely benign	92
Benign	12

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
2170523	NM_003047.5(SLC9A1):c.529del (p.Leu177fs)	Pathogenic
3247945	NC_000001.10:g.(?27434119)(27440797_?)del	Pathogenic
3720188	NM_003047.5(SLC9A1):c.961C>T (p.Arg321Ter)	Pathogenic
978078	NM_003047.5(SLC9A1):c.862del (p.Ile288fs)	Pathogenic
1331440	NM_003047.5(SLC9A1):c.1048_1052dup (p.Gly352fs)	Likely pathogenic
189315	NM_003047.5(SLC9A1):c.913G>A (p.Gly305Arg)	Likely pathogenic

SpliceAI

2576 predictions. Top by Δscore:

Variant	Effect	Δscore
1:27100644:TCTGG:T	acceptor_loss	1.0000
1:27100645:C:CC	acceptor_gain	1.0000
1:27100653:C:CT	acceptor_gain	1.0000
1:27100654:A:T	acceptor_gain	1.0000
1:27101197:CCTTA:C	donor_loss	1.0000
1:27101198:CTTAC:C	donor_loss	1.0000
1:27101199:TTAC:T	donor_loss	1.0000
1:27101200:TACCT:T	donor_loss	1.0000
1:27101201:A:AC	donor_gain	1.0000
1:27101201:ACC:A	donor_loss	1.0000
1:27101202:C:CC	donor_gain	1.0000
1:27101202:C:G	donor_loss	1.0000
1:27101271:TTGAT:T	acceptor_gain	1.0000
1:27101272:TGAT:T	acceptor_gain	1.0000
1:27101273:GAT:G	acceptor_gain	1.0000
1:27101274:AT:A	acceptor_gain	1.0000
1:27101275:TCTGA:T	acceptor_loss	1.0000
1:27101276:C:CC	acceptor_gain	1.0000
1:27101276:CT:C	acceptor_loss	1.0000
1:27101277:T:G	acceptor_loss	1.0000
1:27101280:C:CT	acceptor_gain	1.0000
1:27101281:A:T	acceptor_gain	1.0000
1:27101720:GCTAC:G	donor_loss	1.0000
1:27101721:CTACC:C	donor_loss	1.0000
1:27101722:TA:T	donor_loss	1.0000
1:27101723:ACCT:A	donor_loss	1.0000
1:27101724:C:CA	donor_loss	1.0000
1:27101724:CCTT:C	donor_gain	1.0000
1:27101727:T:A	donor_gain	1.0000
1:27101822:CGCAG:C	acceptor_gain	1.0000

AlphaMissense

5327 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:27102047:A:G	L635P	1.000
1:27102452:C:G	A585P	1.000
1:27102727:A:G	L531P	1.000
1:27102730:A:G	L530P	1.000
1:27103281:A:G	L506S	1.000
1:27103293:A:G	L502P	1.000
1:27103312:C:G	G496R	1.000
1:27105994:C:T	G459E	1.000
1:27105995:C:A	G459W	1.000
1:27105995:C:G	G459R	1.000
1:27105995:C:T	G459R	1.000
1:27106006:C:T	G455E	1.000
1:27106007:C:A	G455W	1.000
1:27106007:C:G	G455R	1.000
1:27106007:C:T	G455R	1.000
1:27107735:C:G	G399R	1.000
1:27107745:G:C	F395L	1.000
1:27107745:G:T	F395L	1.000
1:27107747:A:G	F395L	1.000
1:27107806:G:A	S375F	1.000
1:27109665:C:T	G309D	1.000
1:27109666:C:G	G309R	1.000
1:27109678:C:A	G305W	1.000
1:27113838:G:C	D267E	1.000
1:27113838:G:T	D267E	1.000
1:27113839:T:A	D267V	1.000
1:27113839:T:C	D267G	1.000
1:27113839:T:G	D267A	1.000
1:27113840:C:G	D267H	1.000
1:27113841:A:C	N266K	1.000

dbSNP variants (sampled 300 via entrez): RS1000001371 (1:27141136 A>T), RS1000085970 (1:27123585 A>T), RS1000100906 (1:27102930 C>G,T), RS1000126554 (1:27146366 T>A), RS1000195153 (1:27153554 G>A), RS1000251902 (1:27117517 C>G), RS1000304173 (1:27139427 C>G), RS1000354051 (1:27122624 G>C), RS1000371502 (1:27153796 G>A,C), RS1000434808 (1:27123804 C>T), RS1000560470 (1:27104478 C>T), RS1000689345 (1:27121172 A>G), RS1000777179 (1:27141619 C>T), RS1000863945 (1:27115971 C>A), RS1000891425 (1:27127055 C>T)

Disease associations

OMIM: gene MIM:107310 | disease phenotypes: MIM:616291, MIM:614756

GenCC curated gene-disease

Disease	Classification	Inheritance
Lichtenstein-Knorr syndrome	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Lichtenstein-Knorr syndrome	Moderate	AR

Mondo (2): Lichtenstein-Knorr syndrome (MONDO:0014572), cerebellar dysfunction with variable cognitive and behavioral abnormalities (MONDO:0013886)

Orphanet (2): Progressive autosomal recessive ataxia-deafness syndrome (Orphanet:448251), Non-progressive cerebellar ataxia with intellectual disability (Orphanet:314647)

HPO phenotypes

21 total (21 of 21 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0000639	Nystagmus
HP:0000957	Cafe-au-lait spot
HP:0001251	Ataxia
HP:0001260	Dysarthria
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0001310	Dysmetria
HP:0001756	Vestibular hyporeflexia
HP:0002066	Gait ataxia
HP:0002070	Limb ataxia
HP:0002075	Dysdiadochokinesis
HP:0002345	Action tremor
HP:0002522	Areflexia of lower limbs
HP:0003676	Progressive
HP:0004322	Short stature
HP:0006855	Cerebellar vermis atrophy
HP:0011463	Childhood onset
HP:0012046	Areflexia of upper limbs
HP:0031936	Delayed ability to walk

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009207_1	Lateral ventricle volume	9.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008487	lateral ventricle volume measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2781 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

6 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 65,988 (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
CHEMBL2105423	SABIPORIDE	2	75
CHEMBL2107802	RIMEPORIDE	2	160
CHEMBL355862	ZONIPORIDE	2	241
CHEMBL436559	CARIPORIDE	2	1,678
CHEMBL64360	ENIPORIDE	2	129

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	6.0	pKi

ChEMBL bioactivities

365 potent at pChembl≥5 of 400 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.80	IC50	0.016	nM	CHEMBL465179
9.72	IC50	0.19	nM	N,N-HEXAMETHYLENEAMILORIDE
9.32	IC50	0.48	nM	CHEMBL392093
9.00	IC50	1	nM	CHEMBL3980085
9.00	IC50	1	nM	CHEMBL3900790
8.70	IC50	2	nM	CHEMBL3900457
8.70	IC50	2	nM	CHEMBL64889
8.52	IC50	3	nM	CHEMBL419578
8.43	IC50	3.7	nM	5-(N-ETHYL-N-ISOPROPYL)AMILORIDE
8.34	IC50	4.6	nM	CHEMBL384143
8.30	IC50	5	nM	CHEMBL2170611
8.30	IC50	5	nM	ENIPORIDE
8.30	IC50	5	nM	CHEMBL113443
8.30	IC50	5	nM	CHEMBL112903
8.27	IC50	5.4	nM	CHEMBL211924
8.22	IC50	6	nM	BI 9627
8.22	IC50	6	nM	CHEMBL51363
8.22	IC50	6	nM	CHEMBL5532364
8.19	IC50	6.5	nM	CHEMBL217698
8.13	IC50	7.4	nM	CHEMBL213568
8.10	IC50	8	nM	CHEMBL394633
8.10	IC50	8	nM	CHEMBL51950
8.05	IC50	9	nM	CHEMBL51879
8.05	IC50	9	nM	CHEMBL395897
8.00	IC50	10	nM	CHEMBL2170608
8.00	IC50	10	nM	CHEMBL51879
8.00	IC50	10	nM	CHEMBL232748
8.00	IC50	10	nM	CHEMBL5562362
7.96	IC50	11	nM	CHEMBL2170609
7.92	IC50	12	nM	CHEMBL321198
7.92	IC50	12	nM	CHEMBL395898
7.85	IC50	14	nM	CHEMBL2170617
7.85	IC50	14	nM	CHEMBL2170615
7.85	IC50	14	nM	CHEMBL297962
7.85	IC50	14	nM	CHEMBL5715927
7.82	IC50	15	nM	CHEMBL2170603
7.82	IC50	15	nM	CHEMBL2169894
7.82	IC50	15	nM	CHEMBL2170632
7.82	IC50	15	nM	CHEMBL385944
7.82	IC50	15	nM	CHEMBL232940
7.80	IC50	16	nM	CHEMBL2170607
7.80	IC50	16	nM	CHEMBL397141
7.77	IC50	17	nM	CHEMBL110637
7.77	IC50	17	nM	CHEMBL5550005
7.75	IC50	18	nM	CHEMBL2170618
7.75	IC50	18	nM	CHEMBL2170637
7.75	IC50	18	nM	CHEMBL2170636
7.75	IC50	18	nM	CHEMBL2170635
7.72	IC50	19	nM	CHEMBL2170612
7.72	IC50	19	nM	CHEMBL2170639

PubChem BioAssay actives

340 with measured affinity, of 428 total; 50 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
N-(diaminomethylidene)-3-methylsulfonyl-4-propan-2-ylbenzamide	2135388: Inhibition of human NHE-1	ic50	<0.0001	uM
3-amino-6-chloro-N-(diaminomethylidene)-5-(dimethylamino)pyrazine-2-carboxamide	2135388: Inhibition of human NHE-1	ic50	<0.0001	uM
N-(diaminomethylidene)-2-methyl-5-methylsulfonyl-4-pyrrol-1-ylbenzamide	2135388: Inhibition of human NHE-1	ic50	<0.0001	uM
3-amino-5-(azepan-1-yl)-6-chloro-N-(diaminomethylidene)pyrazine-2-carboxamide	2135388: Inhibition of human NHE-1	ic50	0.0002	uM
N-(diaminomethylidene)-5-(2,5-dichlorophenyl)-3-pyrrolidin-1-ylfuran-2-carboxamide	298722: Inhibition of human NHE1 expressed in PS120 cells	ic50	0.0005	uM
N-(diaminomethylidene)-2-methyl-5-methylsulfonyl-4-propan-2-ylbenzamide	2074155: Inhibition of NHE1 in human Platelet assessed as reduction in 22Na+ uptake	ic50	0.0020	uM
trans-(1R,3R)-3-(3-bromo-4-fluorophenyl)-N-(diaminomethylidene)-2,2-dimethylcyclopropane-1-carboxamide	143805: Screened in AP1 cells expressing human NHE-1 for sodium hydrogen exchange activity	ic50	0.0030	uM
3-amino-6-chloro-N-(diaminomethylidene)-5-[ethyl(propan-2-yl)amino]pyrazine-2-carboxamide	2135388: Inhibition of human NHE-1	ic50	0.0037	uM
2-[5-(4-fluoro-3-methylphenyl)-4-[4-(5-methyl-1H-imidazol-4-yl)piperidin-1-yl]pyrimidin-2-yl]acetonitrile	270790: Inhibition of human NHE1 expressed in Ap1 cell line	ic50	0.0046	uM
trans-(1R,3R)-N-(diaminomethylidene)-3-(2,5-dichlorophenyl)-2,2-dimethylcyclopropane-1-carboxamide	143805: Screened in AP1 cells expressing human NHE-1 for sodium hydrogen exchange activity	ic50	0.0050	uM
trans-(1R,3R)-N-(diaminomethylidene)-3-(3-ethyl-4-fluorophenyl)-2,2-dimethylcyclopropane-1-carboxamide	143805: Screened in AP1 cells expressing human NHE-1 for sodium hydrogen exchange activity	ic50	0.0050	uM
4-(1-acetylpiperidin-4-yl)-N-(diaminomethylidene)-2-methyl-5-(trifluoromethyl)benzamide	701661: Inhibition of NHE1 in human HT-29 cells assessed as intracellular pH change after 30 mins	ic50	0.0050	uM
4-[1-[5-(3-chloro-4-fluorophenyl)pyrimidin-4-yl]piperidin-4-yl]-5-methyl-1H-imidazol-2-amine	270790: Inhibition of human NHE1 expressed in Ap1 cell line	ic50	0.0054	uM
trans-(1R,3R)-N-(diaminomethylidene)-3-(3,5-dichlorophenyl)-2,2-dimethylcyclopropane-1-carboxamide	143805: Screened in AP1 cells expressing human NHE-1 for sodium hydrogen exchange activity	ic50	0.0060	uM
N-(diaminomethylidene)-13-oxo-1-azatricyclo[6.5.1.04,14]tetradeca-2,4(14),5,7-tetraene-2-carboxamide	2074157: Inhibition of NHE1 (unknown origin)	ic50	0.0060	uM
4-(1-acetylpiperidin-4-yl)-N-(diaminomethylidene)-3-(trifluoromethyl)benzamide	701661: Inhibition of NHE1 in human HT-29 cells assessed as intracellular pH change after 30 mins	ic50	0.0060	uM
5-(4-fluoro-3-methylphenyl)-2-methoxy-4-[4-(5-methyl-1H-imidazol-4-yl)piperidin-1-yl]pyrimidine	270790: Inhibition of human NHE1 expressed in Ap1 cell line	ic50	0.0065	uM
5-(4-fluoro-3-methylphenyl)-4-[4-(5-methyl-1H-imidazol-4-yl)piperidin-1-yl]-2-propan-2-yloxypyrimidine	270790: Inhibition of human NHE1 expressed in Ap1 cell line	ic50	0.0074	uM
4-[(1R,3R)-3-(3,5-dichlorophenyl)-2,2-dimethylcyclopropyl]-5-methyl-1H-imidazol-2-amine	205299: Inhibition of sodium dependent recovery of pH following imposed acidosis in AP1 cell line expressing the human NHE-1 isoform.	ic50	0.0080	uM
3-amino-N-(diaminomethylidene)-5-(2,5-dichlorophenyl)furan-2-carboxamide	298722: Inhibition of human NHE1 expressed in PS120 cells	ic50	0.0080	uM
N-(diaminomethylidene)-5-(2,5-dichlorophenyl)-3-(dimethylamino)furan-2-carboxamide	298722: Inhibition of human NHE1 expressed in PS120 cells	ic50	0.0090	uM
trans-(1R,3R)-N-(diaminomethylidene)-3-(2,3-dihydro-1-benzofuran-4-yl)-2,2-dimethylcyclopropane-1-carboxamide	143805: Screened in AP1 cells expressing human NHE-1 for sodium hydrogen exchange activity	ic50	0.0090	uM
5-(5-chloro-2-methoxyphenyl)-N-(diaminomethylidene)-3-methylfuran-2-carboxamide	298722: Inhibition of human NHE1 expressed in PS120 cells	ic50	0.0100	uM
N-(diaminomethylidene)-4-[1-(2-methoxyacetyl)piperidin-4-yl]-3-(trifluoromethyl)benzamide	701661: Inhibition of NHE1 in human HT-29 cells assessed as intracellular pH change after 30 mins	ic50	0.0100	uM
5-bromo-N-(diaminomethylidene)naphthalene-2-carboxamide	2074157: Inhibition of NHE1 (unknown origin)	ic50	0.0100	uM
N-(diaminomethylidene)-4-(1-propanoylpiperidin-4-yl)-3-(trifluoromethyl)benzamide	701661: Inhibition of NHE1 in human HT-29 cells assessed as intracellular pH change after 30 mins	ic50	0.0110	uM
trans-(1R,3R)-N-(diaminomethylidene)-3-(3-methoxyphenyl)-2,2-dimethylcyclopropane-1-carboxamide	143805: Screened in AP1 cells expressing human NHE-1 for sodium hydrogen exchange activity	ic50	0.0120	uM
5-(5-chloro-2-methoxyphenyl)-N-(diaminomethylidene)-3-(dimethylamino)furan-2-carboxamide	298722: Inhibition of human NHE1 expressed in PS120 cells	ic50	0.0120	uM
trans-(1R,3R)-3-(3-chlorophenyl)-N-(diaminomethylidene)-2,2-dimethylcyclopropane-1-carboxamide	143805: Screened in AP1 cells expressing human NHE-1 for sodium hydrogen exchange activity	ic50	0.0140	uM
N-(diaminomethylidene)-4-[1-(4-sulfamoylbenzoyl)piperidin-4-yl]-3-(trifluoromethyl)benzamide	701661: Inhibition of NHE1 in human HT-29 cells assessed as intracellular pH change after 30 mins	ic50	0.0140	uM
N-(diaminomethylidene)-4-[1-(1-methylimidazole-2-carbonyl)piperidin-4-yl]-3-(trifluoromethyl)benzamide	701661: Inhibition of NHE1 in human HT-29 cells assessed as intracellular pH change after 30 mins	ic50	0.0140	uM
5-(3-chloro-4-fluorophenyl)-2-methoxy-4-[4-(5-methyl-1H-imidazol-4-yl)piperidin-1-yl]pyrimidine	270790: Inhibition of human NHE1 expressed in Ap1 cell line	ic50	0.0150	uM
3-amino-5-(5-chloro-2-methoxyphenyl)-N-(diaminomethylidene)furan-2-carboxamide	298722: Inhibition of human NHE1 expressed in PS120 cells	ic50	0.0150	uM
N-(diaminomethylidene)-4-[1-(4-methylsulfonylbenzoyl)piperidin-4-yl]-3-(trifluoromethyl)benzamide	701661: Inhibition of NHE1 in human HT-29 cells assessed as intracellular pH change after 30 mins	ic50	0.0150	uM
4-(1-acetylpiperidin-4-yl)-N-(diaminomethylidene)-2-methyl-5-methylsulfonylbenzamide	701661: Inhibition of NHE1 in human HT-29 cells assessed as intracellular pH change after 30 mins	ic50	0.0150	uM
N-(diaminomethylidene)-2-methyl-5-methylsulfonyl-4-(1-propanoylpiperidin-4-yl)benzamide	701661: Inhibition of NHE1 in human HT-29 cells assessed as intracellular pH change after 30 mins	ic50	0.0150	uM
N-(diaminomethylidene)-5-(2,5-dichlorophenyl)-3-methylfuran-2-carboxamide	298722: Inhibition of human NHE1 expressed in PS120 cells	ic50	0.0160	uM
4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-N-(diaminomethylidene)-3-(trifluoromethyl)benzamide	701661: Inhibition of NHE1 in human HT-29 cells assessed as intracellular pH change after 30 mins	ic50	0.0160	uM
trans-(1R,3R)-N-(diaminomethylidene)-3-(4-fluoro-3-propan-2-ylphenyl)-2,2-dimethylcyclopropane-1-carboxamide	143805: Screened in AP1 cells expressing human NHE-1 for sodium hydrogen exchange activity	ic50	0.0170	uM
N-(diaminomethylidene)-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxamide	2074157: Inhibition of NHE1 (unknown origin)	ic50	0.0170	uM
N-(diaminomethylidene)-4-[1-(pyridine-3-carbonyl)piperidin-4-yl]-3-(trifluoromethyl)benzamide	701661: Inhibition of NHE1 in human HT-29 cells assessed as intracellular pH change after 30 mins	ic50	0.0180	uM
N-(diaminomethylidene)-4-[1-(3-methylimidazole-4-carbonyl)piperidin-4-yl]-3-(trifluoromethyl)benzamide	701661: Inhibition of NHE1 in human HT-29 cells assessed as intracellular pH change after 30 mins	ic50	0.0180	uM
N-(diaminomethylidene)-4-[1-(pyridine-2-carbonyl)piperidin-4-yl]-3-(trifluoromethyl)benzamide	701661: Inhibition of NHE1 in human HT-29 cells assessed as intracellular pH change after 30 mins	ic50	0.0180	uM
N-(diaminomethylidene)-4-[1-(pyridine-4-carbonyl)piperidin-4-yl]-3-(trifluoromethyl)benzamide	701661: Inhibition of NHE1 in human HT-29 cells assessed as intracellular pH change after 30 mins	ic50	0.0180	uM
N-(diaminomethylidene)-4-[1-(6-oxo-1H-pyridine-3-carbonyl)piperidin-4-yl]-3-(trifluoromethyl)benzamide	701661: Inhibition of NHE1 in human HT-29 cells assessed as intracellular pH change after 30 mins	ic50	0.0190	uM
4-(1-acetylpiperidin-4-yl)-N-(diaminomethylidene)-2-methoxy-5-(trifluoromethyl)benzamide	701661: Inhibition of NHE1 in human HT-29 cells assessed as intracellular pH change after 30 mins	ic50	0.0190	uM
5-(4-fluoro-3-methylphenyl)-4-[4-(5-methyl-1H-imidazol-4-yl)piperidin-1-yl]pyrimidine	270790: Inhibition of human NHE1 expressed in Ap1 cell line	ic50	0.0210	uM
N-(diaminomethylidene)-4-[1-(4-hydroxybenzoyl)piperidin-4-yl]-3-(trifluoromethyl)benzamide	701661: Inhibition of NHE1 in human HT-29 cells assessed as intracellular pH change after 30 mins	ic50	0.0210	uM
4-(1-acetylpiperidin-4-yl)-N-(diaminomethylidene)-3-methylsulfonylbenzamide	701661: Inhibition of NHE1 in human HT-29 cells assessed as intracellular pH change after 30 mins	ic50	0.0220	uM
5-(3-chlorophenyl)-N-(diaminomethylidene)-3-methylfuran-2-carboxamide	298722: Inhibition of human NHE1 expressed in PS120 cells	ic50	0.0240	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, increases expression	3
cariporide	decreases activity	3
Benzo(a)pyrene	decreases methylation, increases expression, increases methylation	3
Cadmium Chloride	increases expression, decreases expression, increases abundance	3
bisphenol A	affects methylation, increases expression	2
ethylisopropylamiloride	decreases activity, increases abundance	2
perfluoro-n-nonanoic acid	increases expression, decreases expression	2
Acetaminophen	increases expression	2
Air Pollutants	affects expression, increases abundance, increases expression	2
Arsenic	affects methylation, affects cotreatment, increases abundance, increases expression	2
Doxorubicin	decreases expression, decreases activity, increases abundance, decreases response to substance	2
Protons	affects transport	2
Sodium	decreases reaction, affects cotreatment, affects transport	2
Tobacco Smoke Pollution	increases expression	2
Valproic Acid	affects expression, increases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
afimoxifene	decreases expression, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
zinc chloride	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
beta-methylcholine	affects expression	1
pentanal	decreases expression	1
3-methylsulfonyl-4-piperidinobenzoyl guanidine	decreases activity	1
perfluorooctane sulfonic acid	increases expression	1

ChEMBL screening assays

36 unique, capped per target: 28 binding, 7 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1912991	Binding	Inhibition of NHE1	Synthesis and preliminary evaluation of amiloride analogs as inhibitors of the urokinase-type plasminogen activator (uPA). — Bioorg Med Chem Lett
CHEMBL4002822	ADMET	Inhibition of platelet NHE1 in human platelet rich plasma assessed as decrease in platelet swelling preincubated for 3 mins followed by sodium propionate addition measured after 4 mins by spectrophotometric method	Sodium hydrogen exchanger inhibitory activity of benzotriazole derivatives. — Eur J Med Chem
CHEMBL5210090	Functional	Affinity Phenotypic Cellular interaction (Human platelet swelling inhibition (hPSA) assay) EUB0000545a SLC9A1	Affinity Phenotypic Cellular Literature for EUbOPEN Chemogenomics Library wave 3

Cellosaurus cell lines

11 cell lines: 10 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1Z3	Abcam A-549 SLC9A1 KO	Cancer cell line	Male
CVCL_D2D5	Abcam HCT 116 SLC9A1 KO	Cancer cell line	Male
CVCL_D2P7	Abcam THP-1 SLC9A1 KO	Cancer cell line	Male
CVCL_D4QQ	HCT116-SLC9A1-KO-c12	Cancer cell line	Male
CVCL_D4QR	HCT116-SLC9A1-KO-c5	Cancer cell line	Male
CVCL_D8AL	Ubigene A-549 SLC9A1 KO	Cancer cell line	Male
CVCL_D8VH	Ubigene HCT 116 SLC9A1 KO	Cancer cell line	Male
CVCL_D9S6	Ubigene HEK293 SLC9A1 KO	Transformed cell line	Female
CVCL_E0P5	Ubigene HeLa SLC9A1 KO	Cancer cell line	Female
CVCL_TP18	HAP1 SLC9A1 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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