NHERF2

Summary

NHERF2 (NHERF family PDZ scaffold protein 2, HGNC:11076) is a protein-coding gene on chromosome 16p13.3, encoding Na(+)/H(+) exchange regulatory cofactor NHE-RF2 (Q15599). Scaffold protein that connects plasma membrane proteins with members of the ezrin/moesin/radixin family and thereby helps to link them to the actin cytoskeleton and to regulate their surface expression.

This gene encodes a member of the NHERF family of PDZ scaffolding proteins. These proteins mediate many cellular processes by binding to and regulating the membrane expression and protein-protein interactions of membrane receptors and transport proteins. The encoded protein plays a role in intestinal sodium absorption by regulating the activity of the sodium/hydrogen exchanger 3, and may also regulate the cystic fibrosis transmembrane regulator (CFTR) ion channel. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 9351 — RefSeq curated summary.

At a glance

• GWAS associations: 13
• Clinical variants (ClinVar): 104 total — 1 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_001130012

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11076
Approved symbol	NHERF2
Name	NHERF family PDZ scaffold protein 2
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Aliases	SIP-1, TKA-1, NHERF-2, E3KARP, OCTS2
Ensembl gene	ENSG00000065054
Ensembl biotype	protein_coding
OMIM	606553
Entrez	9351

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 13 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000424542, ENST00000432365, ENST00000561844, ENST00000563587, ENST00000564033, ENST00000565086, ENST00000565855, ENST00000566198, ENST00000567504, ENST00000901524, ENST00000901525, ENST00000901526, ENST00000960133, ENST00000960134, ENST00000960135

RefSeq mRNA: 5 — MANE Select: NM_001130012 NM_001130012, NM_001252073, NM_001252075, NM_001252076, NM_004785

CCDS: CCDS45382, CCDS45383, CCDS58407

Canonical transcript exons

ENST00000424542 — 7 exons

Exon	Start	End
ENSE00000665163	2029582	2029782
ENSE00001652372	2037826	2039026
ENSE00001720069	2026902	2027218
ENSE00003459324	2036324	2036503
ENSE00003556781	2036728	2036881
ENSE00003560936	2037538	2037600
ENSE00003588346	2036955	2036998

Expression profiles

Bgee: expression breadth ubiquitous, 179 present calls, max score 99.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 36.1651 / max 435.9813, expressed in 1632 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
152170	27.0796	1597
152179	6.4533	673
152178	0.9109	450
152180	0.6835	265
152172	0.2338	117
152173	0.1769	93
152182	0.1676	45
152183	0.1335	57
152177	0.0883	45
152174	0.0780	17

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	99.58	gold quality
right lung	UBERON:0002167	99.54	gold quality
metanephros cortex	UBERON:0010533	99.06	gold quality
right lobe of liver	UBERON:0001114	98.92	gold quality
upper lobe of left lung	UBERON:0008952	98.77	gold quality
right lobe of thyroid gland	UBERON:0001119	98.76	gold quality
right atrium auricular region	UBERON:0006631	98.27	gold quality
right coronary artery	UBERON:0001625	98.07	gold quality
left lobe of thyroid gland	UBERON:0001120	97.95	gold quality
omental fat pad	UBERON:0010414	97.64	gold quality
left uterine tube	UBERON:0001303	97.57	gold quality
left coronary artery	UBERON:0001626	97.56	gold quality
mucosa of stomach	UBERON:0001199	97.52	gold quality
peritoneum	UBERON:0002358	97.49	gold quality
body of stomach	UBERON:0001161	97.48	gold quality
endocervix	UBERON:0000458	97.46	gold quality
adenohypophysis	UBERON:0002196	97.37	gold quality
sural nerve	UBERON:0015488	97.10	gold quality
tibial nerve	UBERON:0001323	97.09	gold quality
ascending aorta	UBERON:0001496	96.90	gold quality
thoracic aorta	UBERON:0001515	96.88	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.86	gold quality
minor salivary gland	UBERON:0001830	96.80	gold quality
upper lobe of lung	UBERON:0008948	96.67	gold quality
right frontal lobe	UBERON:0002810	96.66	gold quality
descending thoracic aorta	UBERON:0002345	96.65	gold quality
body of uterus	UBERON:0009853	96.64	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.47	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.44	gold quality
right uterine tube	UBERON:0001302	96.40	gold quality

Single-cell (SCXA)

Detected in 19 experiment(s), a significant marker in 17.

Experiment	Marker?	Max mean expression
E-GEOD-124263	yes	3784.15
E-CURD-126	yes	2716.36
E-GEOD-134144	yes	2344.37
E-HCAD-11	yes	2251.58
E-GEOD-135922	yes	1604.88
E-MTAB-10137	yes	719.23
E-MTAB-8271	yes	522.74
E-GEOD-86618	yes	62.21
E-CURD-114	yes	52.72
E-HCAD-1	yes	49.88
E-MTAB-8410	yes	35.02
E-HCAD-10	yes	34.34
E-CURD-46	yes	27.06
E-HCAD-13	yes	11.49
E-MTAB-10553	yes	8.98

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

69 targeting NHERF2, 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-7110-3P	100.00	73.18	2486
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-6870-5P	99.99	68.55	2115
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-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-548P	99.98	72.25	3784
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-106A-3P	99.53	67.58	995

Literature-anchored findings (GeneRIF, showing 31)

• Plasma membrane Ca2+ ATPase isoform 2b interacts preferentially with Na+/H+ exchanger regulatory factor 2 in apical plasma membranes (PMID:11786550)
• E3KARP has a restricted tissue distribution with the highest expression being found in lung. It is largely colocalized with moesin and radixin, especially in the alveoli of the lung, as well as being highly enriched in the renal corpuscle. (PMID:11893083)
• Na(+)/H(+ ) exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling. (PMID:12075354)
• A2BR binds to E3KARP upon agonist stimulation. (PMID:12080047)
• When the second PDZ domain of E3KARP is bound to down regulated in adenoma (dra) gene product, a structural link is built between the functionally coupled Na+/H+ and Cl-/HCO3- exchangers in the proximal colon. (PMID:12369822)
• NHERF2 and SGK1 interact to enhance ROMK1 activity by enhancing abundance of channel protein in cell membrane, allowing integration of genomic regulation and activation of SGK1 and NHERF2 in control of ROMK1 activity and renal K(+) excretion. (PMID:12444200)
• NHERF2, with ROMK1 and SGK1 has a role in regulating protein abundance in the plasma membrane and K(+) current (PMID:14623317)
• demonstration of the significance of SGK1 and NHERF2 as TRPV5 modulators which are likely to participate in the regulation of calcium homeostasis by 1,25(OH)2D3 (PMID:15665527)
• LPA2 is the major LPA receptor in colon cancer cells and cellular signals by LPA2 are largely mediated through its ability to interact with NHERF2. (PMID:15728708)
• the function of SIP-1/NHERF2 as an SRY cofactor during testis determination is conserved between human and mouse (PMID:16166090)
• analysis of NHERF recognition by ERM proteins (PMID:16615918)
• N-cadherin and beta-catenin play role in cell migration via PDGF-Rbeta-mediated signaling through the scaffolding molecule NHERF2 (PMID:17229887)
• While the presence of forskolin results in an increase in OCTN2 protein expression, the increase in uptake capacity may be compensated by the decreased expression of PDZK1, NHERF1 or NHERF2. (PMID:19091402)
• The results of this study revealed that NHERF-2 can interact with GLAST in astrocytes to enhance GLAST stability and activity. (PMID:20430067)
• NHERF1 and NHERF2 exhibit isotype-specific effects on G protein activation. (PMID:20562104)
• The authors generated a HeLa cell line stably expressing HA-tagged NHERF2 and found that Map, EspI and NleH1 colocalize and interact with intracellular NHERF2 via their C-terminal PDZ-binding motif. (PMID:20618342)
• Apical scaffolding protein NHERF2 modulates the localization of alternatively spliced plasma membrane Ca2+ pump 2B variants in polarized epithelial cells. (PMID:20663896)
• MAGI-3 competes with NHERF-2 to negatively regulate LPA2 receptor signaling in colon cancer cells. (PMID:21134377)
• WNK4 and NHERF2 synergistically regulate TRPV5 by enhancing its forward trafficking and increasing its stability at plasma membrane, respectively. (PMID:21187068)
• Data show that both NHERF2 and NHERF1 are involved in setting NHE3 activity. (PMID:21191106)
• NHERF-2 is a negative regulator of endothelial proliferation and may have important roles in endothelial homeostasis and vascular modeling. (PMID:22343917)
• CaMKII inhibition of NHE3 reguires NHEF2. (PMID:22371496)
• AnxA2 and NHERF2 form a scaffold complex that links adjacent Tir molecules at the plasma membrane forming a lattice that could be involved in retention and dissemination of other effectors at the bacterial attachment site. (PMID:22587461)
• functional regulation of C3aR by NHERFs in human mast cells (PMID:23284683)
• NHERF2 domain was functionally significant in NHE3 regulation, being necessary for stimulation by lysophosphatidic acid of activity and increased mobility of NHE3 (PMID:23612977)
• Data indicate that the tails promote different microvillar localizations for EBP50 and E3KARP, which localized along the full length and to the base of microvilli, respectively. (PMID:23985317)
• Crystal structure of NHERF2 PDZ1 domain complex with C-terminal LPA2 sequence. The PDZ1-LPA2 binding specificity is achieved by hydrogen bonds and hydrophobic contacts with the last four LPA2 residues contributing to specific interactions. (PMID:24613836)
• Lysophosphatidic acid stimulation of NHE3 exocytosis in polarized epithelial cells occurs with release from NHERF2 via ERK-PLC-PKCdelta signaling. (PMID:24760985)
• Moreover, the S303D mutation enhances the in vivo dynamics of the E3KARP tail alone, whereas in vitro the interaction of E3KARP with active ezrin is unaffected by S303D (PMID:26310448)
• Studies support a role for NHERF-1 and NHERF-2 (Na+/H+ exchanger regulatory factors 1 and 2) in regulating the distribution of Group II metabotropic glutamate receptor (mGluRs) in the murine brain, while conversely the effects of the mGluR2/3 PDZ-binding motifs on receptor signaling are likely mediated by interactions with other PDZ scaffold proteins beyond the NHERF proteins. (PMID:28392297)
• PDZ domain-containing protein NHERF-2 is a novel target of HPV-16 and HPV-18 E proteins. (PMID:31597772)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000074231
danio_rerio		ENSDARG00000113474
mus_musculus	Nherf2	ENSMUSG00000002504
rattus_norvegicus	Nherf2	ENSRNOG00000002997
drosophila_melanogaster	CG10939	FBGN0010620

Paralogs (3): NHERF1 (ENSG00000109062), NHERF4 (ENSG00000172367), PDZK1 (ENSG00000174827)

Protein

Protein identifiers

Na(+)/H(+) exchange regulatory cofactor NHE-RF2 — Q15599 (reviewed: Q15599)

Alternative names: NHE3 kinase A regulatory protein E3KARP, SRY-interacting protein 1, Sodium-hydrogen exchanger regulatory factor 2, Solute carrier family 9 isoform A3 regulatory factor 2, Tyrosine kinase activator protein 1

All UniProt accessions (5): Q15599, H3BMF5, H3BN50, H3BQS0, H3BUQ9

UniProt curated annotations — full annotation on UniProt →

Function. Scaffold protein that connects plasma membrane proteins with members of the ezrin/moesin/radixin family and thereby helps to link them to the actin cytoskeleton and to regulate their surface expression. Necessary for cAMP-mediated phosphorylation and inhibition of SLC9A3. May also act as scaffold protein in the nucleus.

Subunit / interactions. Homodimer, and heterodimer with NHERF1. Binds PDZK1. Found in a complex with EZR, PODXL and NHERF2. Interacts (via the PDZ domains) with PODXL (via the C-terminal PDZ-binding motif DTHL); interaction is detected in glomerular epithelium cells. Binds ADRB2, SLC9A3, P2RY1, P2YR2, SRY, RDX and LPAR2. Interacts with MCC and PODXL. Interacts with SGK1 and KCNJ1/ROMK1. Interacts (via the PDZ domains) with SLC26A6 isoform 4 and isoform 5.

Subcellular location. Endomembrane system. Nucleus. Apical cell membrane.

Tissue specificity. Widely expressed.

Isoforms (3)

UniProt ID	Names	Canonical?
Q15599-1	1	yes
Q15599-2	2
Q15599-3	3

RefSeq proteins (5): NP_001123484, NP_001239002, NP_001239004, NP_001239005, NP_004776 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001478	PDZ	Domain
IPR015098	EBP50_C	Domain
IPR017300	NHERF-1/NHERF-2	Family
IPR036034	PDZ_sf	Homologous_superfamily
IPR051067	NHER	Family

Pfam: PF00595, PF09007

UniProt features (35 total): strand 10, modified residue 6, helix 5, splice variant 3, sequence conflict 3, compositionally biased region 3, domain 2, region of interest 2, chain 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
4P0C	X-RAY DIFFRACTION	1.34
2HE4	X-RAY DIFFRACTION	1.45
2OCS	X-RAY DIFFRACTION	1.5
2D11	X-RAY DIFFRACTION	2.81

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15599-F1	69.36	0.09

Functional residue map

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

Post-translational modifications (6): 254, 269, 280, 303, 130, 183

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 155 (showing top): GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, MARTINEZ_RB1_TARGETS_DN, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, GROSS_HYPOXIA_VIA_ELK3_UP, MODULE_157, GOCC_APICAL_PLASMA_MEMBRANE, AFFAR_YY1_TARGETS_UP, GOMF_G_PROTEIN_COUPLED_RECEPTOR_BINDING, PID_LYSOPHOSPHOLIPID_PATHWAY, MORF_PDPK1, CUI_TCF21_TARGETS_2_DN, GOMF_SIGNALING_RECEPTOR_BINDING

GO Biological Process (2): protein-containing complex assembly (GO:0065003), protein localization to plasma membrane (GO:0072659)

GO Molecular Function (10): signaling receptor binding (GO:0005102), beta-catenin binding (GO:0008013), phosphatase binding (GO:0019902), type 2 metabotropic glutamate receptor binding (GO:0031799), type 3 metabotropic glutamate receptor binding (GO:0031800), identical protein binding (GO:0042802), protein-membrane adaptor activity (GO:0043495), cadherin binding (GO:0045296), protein binding (GO:0005515), molecular adaptor activity (GO:0060090)

GO Cellular Component (7): nucleus (GO:0005634), plasma membrane (GO:0005886), focal adhesion (GO:0005925), endomembrane system (GO:0012505), apical plasma membrane (GO:0016324), extracellular exosome (GO:0070062), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	3
G protein-coupled glutamate receptor binding	2
binding	2
cellular anatomical structure	2
cellular component assembly	1
protein-containing complex organization	1
protein localization to membrane	1
protein localization to cell periphery	1
enzyme binding	1
protein-macromolecule adaptor activity	1
cell adhesion molecule binding	1
molecular_function	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
cell-substrate junction	1
vacuole	1
plasma membrane	1
apical part of cell	1
plasma membrane region	1
extracellular vesicle	1

Protein interactions and networks

STRING

1476 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NHERF2	EZR	P15311	995
NHERF2	SLC9A3	P48764	993
NHERF2	PODXL	O00592	954
NHERF2	LPAR2	Q9HBW0	943
NHERF2	MSN	P26038	897
NHERF2	CFTR	P13569	891
NHERF2	RDX	P35241	856
NHERF2	SLC26A3	P40879	829
NHERF2	NHERF1	O14745	818
NHERF2	ADRB2	P07550	793
NHERF2	TRIP6	Q15654	785
NHERF2	GOPC	Q9HD26	783
NHERF2	PLCB1	Q9NQ66	762
NHERF2	ACTN4	O43707	724
NHERF2	TJP1	Q07157	723

IntAct

691 interactions, top by confidence:

A	B	Type	Score
CFTR	NHERF2	psi-mi:“MI:0915”(physical association)	0.940
NHERF2	CFTR	psi-mi:“MI:0914”(association)	0.940
CFTR	NHERF2	psi-mi:“MI:0407”(direct interaction)	0.940
NHERF2	CFTR	psi-mi:“MI:0407”(direct interaction)	0.940
KIFAP3	KIF3B	psi-mi:“MI:0914”(association)	0.900
YAP1	NHERF2	psi-mi:“MI:0407”(direct interaction)	0.900
TBC1D10A	NHERF2	psi-mi:“MI:0407”(direct interaction)	0.780
CFTR	CFTR	psi-mi:“MI:0407”(direct interaction)	0.770
PODXL	NHERF2	psi-mi:“MI:0915”(physical association)	0.770
NHERF2	PODXL	psi-mi:“MI:0914”(association)	0.770
PODXL	NHERF2	psi-mi:“MI:0407”(direct interaction)	0.770
PHLPP2	NHERF1	psi-mi:“MI:0914”(association)	0.760
NHERF2	SRY	psi-mi:“MI:0915”(physical association)	0.730
WWTR1	NHERF2	psi-mi:“MI:0407”(direct interaction)	0.720
SLC26A3	NHERF2	psi-mi:“MI:0407”(direct interaction)	0.720
CFTR	XPO1	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710

BioGRID (249): SLC9A3R2 (Affinity Capture-MS), ANXA11 (Co-fractionation), ATXN2L (Co-fractionation), LSM12 (Co-fractionation), MARS2 (Co-fractionation), NDUFV1 (Co-fractionation), TOMM40 (Co-fractionation), PRKCA (Reconstituted Complex), SLC9A3R2 (Affinity Capture-Western), LPAR2 (Reconstituted Complex), SLC9A3R2 (Proximity Label-MS), SLC9A3R2 (Affinity Capture-MS), SLC9A3R2 (Affinity Capture-MS), SLC9A3R2 (Affinity Capture-MS), SLC9A3R2 (Affinity Capture-MS)

ESM2 similar proteins: A8MUH7, B1AK53, D2I3C6, O14745, O14976, O15085, O35071, O35787, O43896, O70145, O77775, O88951, O88952, P00520, P00521, P19838, P19878, P70271, P70441, P98150, Q00653, Q0P5F3, Q15599, Q28619, Q2KIB6, Q3SZK8, Q4L1J4, Q4R6G4, Q570Y9, Q5F425, Q5RAA5, Q5RC07, Q5ZM14, Q63618, Q6RHR9, Q792I0, Q8C033, Q8SQG9, Q8TB45, Q920G2

Diamond homologs: A0A8C0TYJ0, A0A8P0N4K0, A5PKA5, F1MCA7, G5ECY0, O14907, O14910, O35274, O35867, O55164, O61967, O62674, O62675, O62676, O88951, O88952, P31016, P57105, P70175, P70587, P78352, P97879, Q0P5E6, Q0P5F3, Q12959, Q13424, Q13425, Q13884, Q14160, Q15599, Q22638, Q28626, Q28C55, Q2KIB6, Q32LE7, Q32LM6, Q3T0C9, Q3UHD6, Q4H4B6, Q5EBL8

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ARAF	“up-regulates activity”	SLC9A3R2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 139 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Sensory processing of sound by inner hair cells of the cochlea	7	11.3×	2e-03
RHOQ GTPase cycle	6	10.8×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
regulation of cytosolic calcium ion concentration	5	15.7×	3e-03
cellular response to cAMP	6	14.3×	1e-03
monoatomic ion transport	8	10.2×	7e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	90
Likely benign	6
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2423303	NC_000016.9:g.(?2079753)(2100460_?)del	Pathogenic

SpliceAI

1440 predictions. Top by Δscore:

Variant	Effect	Δscore
16:2027215:CCAG:C	donor_loss	1.0000
16:2027217:AG:A	donor_loss	1.0000
16:2027218:GGTG:G	donor_loss	1.0000
16:2027219:GTGGG:G	donor_loss	1.0000
16:2029574:C:CA	acceptor_gain	1.0000
16:2029579:CAG:C	acceptor_loss	1.0000
16:2029581:G:GA	acceptor_loss	1.0000
16:2029780:AAGGT:A	donor_loss	1.0000
16:2029781:AGG:A	donor_loss	1.0000
16:2029782:GGTAT:G	donor_loss	1.0000
16:2029783:G:GA	donor_loss	1.0000
16:2029784:T:G	donor_loss	1.0000
16:2036878:G:GT	donor_gain	1.0000
16:2036879:A:T	donor_gain	1.0000
16:2036950:CACA:C	acceptor_loss	1.0000
16:2036952:CA:C	acceptor_loss	1.0000
16:2036953:A:AG	acceptor_gain	1.0000
16:2036954:G:A	acceptor_loss	1.0000
16:2036954:G:GG	acceptor_gain	1.0000
16:2036999:G:A	donor_loss	1.0000
16:2037000:T:A	donor_loss	1.0000
16:2037536:A:AG	acceptor_gain	1.0000
16:2037537:G:GG	acceptor_gain	1.0000
16:2037537:GCTCA:G	acceptor_gain	1.0000
16:2037597:TGAGG:T	donor_loss	1.0000
16:2037599:AGGT:A	donor_loss	1.0000
16:2037602:T:A	donor_loss	1.0000
16:2029580:AGGT:A	acceptor_gain	0.9900
16:2029580:AGGTG:A	acceptor_gain	0.9900
16:2029581:GGT:G	acceptor_gain	0.9900

AlphaMissense

2174 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:2027072:T:C	F23L	1.000
16:2027073:T:C	F23S	1.000
16:2027074:C:A	F23L	1.000
16:2027074:C:G	F23L	1.000
16:2036397:T:C	F163S	1.000
16:2027070:G:A	G22D	0.999
16:2027079:T:A	L25Q	0.999
16:2027079:T:C	L25P	0.999
16:2027112:T:A	I36N	0.999
16:2027210:C:G	H69D	0.999
16:2027212:C:A	H69Q	0.999
16:2027212:C:G	H69Q	0.999
16:2029595:T:A	I76N	0.999
16:2029595:T:C	I76T	0.999
16:2029595:T:G	I76S	0.999
16:2036394:G:A	G162E	0.999
16:2036396:T:C	F163L	0.999
16:2036398:C:A	F163L	0.999
16:2036398:C:G	F163L	0.999
16:2036403:T:A	L165Q	0.999
16:2036403:T:C	L165P	0.999
16:2036478:T:A	L190H	0.999
16:2036780:T:A	I216N	0.999
16:2036807:T:C	L225P	0.999
16:2036813:T:A	V227D	0.999
16:2027069:G:C	G22R	0.998
16:2027070:G:T	G22V	0.998
16:2027073:T:G	F23C	0.998
16:2027075:C:G	H24D	0.998
16:2027166:A:G	D54G	0.998

dbSNP variants (sampled 300 via entrez): RS1000073525 (16:2033047 G>T), RS1000172330 (16:2037427 C>G), RS1000236373 (16:2038117 C>T), RS1000382192 (16:2034041 C>T), RS1000423815 (16:2035255 C>T), RS1000432647 (16:2029205 A>G), RS1000733748 (16:2034240 G>T), RS1001228580 (16:2025592 G>A), RS1001366603 (16:2025138 G>A,C,T), RS1001488257 (16:2027857 G>A), RS1001553993 (16:2034287 T>C), RS1001577587 (16:2032804 G>A), RS1001901385 (16:2034848 C>T), RS1002096039 (16:2035811 G>A,T), RS1002180466 (16:2031618 G>A)

Disease associations

OMIM: gene MIM:606553 | disease phenotypes: MIM:613254

GenCC curated gene-disease

Mondo (1): tuberous sclerosis 2 (MONDO:0013199)

Orphanet (1): Tuberous sclerosis complex (Orphanet:805)

HPO phenotypes

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

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST007094_95	Diastolic blood pressure	1.000000e-09
GCST007099_253	Systolic blood pressure	3.000000e-07
GCST007270_5	Systolic blood pressure	1.000000e-30
GCST007271_1	Diastolic blood pressure	1.000000e-29
GCST007272_10	Pulse pressure	5.000000e-10
GCST010083_188	Hemoglobin levels	2.000000e-12
GCST90002383_237	Hematocrit	6.000000e-14
GCST90002384_355	Hemoglobin	5.000000e-19
GCST90002385_72	High light scatter reticulocyte count	5.000000e-10
GCST90002401_106	Platelet distribution width	6.000000e-15
GCST90002403_665	Red blood cell count	5.000000e-15
GCST90002403_666	Red blood cell count	2.000000e-09
GCST90002405_356	Reticulocyte count	2.000000e-11

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure
EFO:0005763	pulse pressure measurement
EFO:0004509	hemoglobin measurement
EFO:0004348	hematocrit
EFO:0007986	reticulocyte count
EFO:0007984	platelet component distribution width
EFO:0004305	erythrocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C566021	Tuberous Sclerosis 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4739686 (SINGLE PROTEIN)

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

ChEMBL bioactivities

8 potent at pChembl≥5 of 8 total, top 8 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.25	Kd	560	nM	CHEMBL4763464
5.86	Kd	1370	nM	CHEMBL4756359
5.73	Kd	1870	nM	CHEMBL4756115
5.55	Kd	2820	nM	CHEMBL4763464
5.39	Kd	4070	nM	CHEMBL4756115
5.22	Kd	6040	nM	CHEMBL4789294
5.13	Kd	7480	nM	CHEMBL4756359
5.12	Kd	7660	nM	CHEMBL4789294

PubChem BioAssay actives

8 with measured affinity, of 8 total; 4 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
(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2R)-2-[[(2S)-3-(1-benzothiophen-3-yl)-2-[[(2S)-2-[[(2S)-5-carbamimidamido-2-[[(2S)-5-carbamimidamido-2-[[(2R)-5-carbamimidamido-2-[[(2R)-2-[[2-[2-[2-[(3’,6’-dihydroxy-3-oxospiro[2-benzofuran-1,9’-xanthene]-5-carbonyl)amino]ethoxy]ethoxy]acetyl]amino]-3-sulfanylpropanoyl]amino]pentanoyl]amino]pentanoyl]amino]pentanoyl]amino]-3-naphthalen-2-ylpropanoyl]amino]propanoyl]amino]-3-methyl-3-sulfanylbutanoyl]amino]-3,3-dimethylbutanoyl]amino]-3-hydroxybutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3,3-dimethylbutanoic acid	1701514: Binding affinity to NHERF2 PDZ1 domain (unknown origin) expressed in Escherichia coli BL21 incubated for 1 hr by fluorescence polarization based competition assay	kd	0.5600	uM
(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2R)-2-[[(2S)-1-[(2S)-3-(1-benzothiophen-3-yl)-2-[[(2S)-2-[[(2S)-5-carbamimidamido-2-[[(2S)-5-carbamimidamido-2-[[(2R)-5-carbamimidamido-2-[[(2R)-2-[[2-[2-[2-[(3’,6’-dihydroxy-3-oxospiro[2-benzofuran-1,9’-xanthene]-5-yl)carbamothioylamino]ethoxy]ethoxy]acetyl]amino]-3-sulfanylpropanoyl]amino]pentanoyl]amino]pentanoyl]amino]pentanoyl]amino]-3-naphthalen-2-ylpropanoyl]amino]propanoyl]piperidine-2-carbonyl]amino]-3-methyl-3-sulfanylbutanoyl]amino]-3-hydroxybutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3,3-dimethylbutanoic acid	1701514: Binding affinity to NHERF2 PDZ1 domain (unknown origin) expressed in Escherichia coli BL21 incubated for 1 hr by fluorescence polarization based competition assay	kd	1.3700	uM
5-[[3-[[(2R)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2R)-1-[[(2S,3R)-1-[[(2S)-5-carbamimidamido-1-[[(1S)-1-carboxy-2,2-dimethylpropyl]amino]-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-methyl-1-oxo-3-sulfanylbutan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-naphthalen-2-yl-1-oxopropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxo-3-sulfanylpropan-2-yl]amino]-3-oxopropyl]carbamothioylamino]-2-(3-hydroxy-6-oxoxanthen-9-yl)benzoic acid	1701514: Binding affinity to NHERF2 PDZ1 domain (unknown origin) expressed in Escherichia coli BL21 incubated for 1 hr by fluorescence polarization based competition assay	kd	1.8700	uM
(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2R)-2-[[(2S)-1-[(2S)-3-(1-benzothiophen-3-yl)-2-[[(2S)-2-[[(2S)-5-carbamimidamido-2-[[(2S)-5-carbamimidamido-2-[[(2R)-5-carbamimidamido-2-[[(2R)-2-[[2-[2-[2-[(3’,6’-dihydroxy-3-oxospiro[2-benzofuran-1,9’-xanthene]-5-yl)carbamothioylamino]ethoxy]ethoxy]acetyl]amino]-3-sulfanylpropanoyl]amino]pentanoyl]amino]pentanoyl]amino]pentanoyl]amino]-3-naphthalen-2-ylpropanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methyl-3-sulfanylbutanoyl]amino]-3-hydroxybutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3,3-dimethylbutanoic acid	1701514: Binding affinity to NHERF2 PDZ1 domain (unknown origin) expressed in Escherichia coli BL21 incubated for 1 hr by fluorescence polarization based competition assay	kd	6.0400	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases expression	3
sodium arsenite	increases abundance, increases expression, affects cotreatment	2
Tetrachlorodibenzodioxin	affects expression, increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
FR900359	affects phosphorylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
aflatoxin B2	decreases methylation	1
coumarin	decreases phosphorylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
bis-N,N-dimethylamino-2-(N-methylpyrrolyl)methyl cyclopentadienyl titanium (IV)	decreases expression	1
Irinotecan	increases expression	1
Acetaminophen	increases expression	1
Ampicillin	increases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Cadmium	decreases expression, increases abundance	1
Caffeine	increases phosphorylation	1
Cisplatin	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Environmental Pollutants	affects expression	1
Estradiol	affects binding, increases expression	1
Ivermectin	decreases expression	1
Lead	affects expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Manganese	increases expression, affects cotreatment, increases abundance	1
Mercury	increases expression	1
Methotrexate	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4706336	Binding	Binding affinity to NHERF2 PDZ1 domain (unknown origin) expressed in Escherichia coli BL21 incubated for 1 hr by fluorescence polarization based competition assay	Cyclic Peptidyl Inhibitors against CAL/CFTR Interaction for Treatment of Cystic Fibrosis. — J Med Chem

Cellosaurus cell lines

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

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

Cellosaurus	Name	Category	Sex
CVCL_B3HL	Abcam HEK293T SLC9A3R2 KO	Transformed cell line	Female
CVCL_TP22	HAP1 SLC9A3R2 (-) 1	Cancer cell line	Male
CVCL_TP23	HAP1 SLC9A3R2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02201212	PHASE2	COMPLETED	Everolimus for Cancer With TSC1 or TSC2 Mutation
NCT05103358	PHASE2	ACTIVE_NOT_RECRUITING	Phase 2 Basket Trial of Nab-sirolimus in Patients With Malignant Solid Tumors With Pathogenic Alterations in TSC1/TSC2 Genes (PRECISION 1)
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT03817515	Not specified	APPROVED_FOR_MARKETING	Expanded Access for ABI-009 in Patients With Advanced PEComa and Patients With a Malignancy With Relevant Genetic Mutations or mTOR Pathway Activation