TNS2

Summary

TNS2 (tensin 2, HGNC:19737) is a protein-coding gene on chromosome 12q13.13, encoding Tensin-2 (Q63HR2). Tyrosine-protein phosphatase which regulates cell motility, proliferation and muscle-response to insulin.

The protein encoded by this gene belongs to the tensin family. Tensin is a focal adhesion molecule that binds to actin filaments and participates in signaling pathways. This protein plays a role in regulating cell migration. Alternative splicing occurs at this locus and three transcript variants encoding three distinct isoforms have been identified.

Source: NCBI Gene 23371 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nephrotic syndrome (Strong, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 576 total
• MANE Select transcript: NM_170754

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19737
Approved symbol	TNS2
Name	tensin 2
Location	12q13.13
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1075, C1-TEN
Ensembl gene	ENSG00000111077
Ensembl biotype	protein_coding
OMIM	607717
Entrez	23371

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 12 retained_intron, 10 protein_coding, 1 nonsense_mediated_decay

ENST00000314250, ENST00000314276, ENST00000379902, ENST00000546602, ENST00000546759, ENST00000546772, ENST00000547223, ENST00000549311, ENST00000549498, ENST00000549700, ENST00000549789, ENST00000550048, ENST00000550660, ENST00000551302, ENST00000551583, ENST00000551693, ENST00000552168, ENST00000552403, ENST00000552570, ENST00000602335, ENST00000851665, ENST00000851666, ENST00000851667

RefSeq mRNA: 6 — MANE Select: NM_170754 NM_001416202, NM_001416203, NM_001416204, NM_015319, NM_170754, NM_198316

CCDS: CCDS8842, CCDS8843, CCDS8844

Canonical transcript exons

ENST00000314250 — 29 exons

Exon	Start	End
ENSE00000000366	53063744	53064379
ENSE00000746468	53058316	53058445
ENSE00000746469	53058572	53058637
ENSE00002319235	53050065	53050260
ENSE00003460455	53055568	53055690
ENSE00003468068	53055186	53055236
ENSE00003485679	53052455	53052492
ENSE00003486005	53055781	53055845
ENSE00003489435	53062620	53062697
ENSE00003496408	53062376	53062453
ENSE00003512668	53063349	53063417
ENSE00003536238	53059047	53060258
ENSE00003552731	53051855	53051963
ENSE00003556378	53061380	53061469
ENSE00003572493	53060675	53061264
ENSE00003578203	53060405	53060555
ENSE00003578694	53062153	53062245
ENSE00003579986	53058714	53058827
ENSE00003590267	53057567	53057679
ENSE00003610593	53057013	53057096
ENSE00003612079	53057773	53057833
ENSE00003615777	53053965	53054014
ENSE00003618658	53063563	53063592
ENSE00003626730	53053774	53053812
ENSE00003635593	53054270	53054441
ENSE00003652724	53058027	53058102
ENSE00003654154	53061815	53061940
ENSE00003674610	53053411	53053449
ENSE00003680263	53063089	53063257

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 99.33.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.1601 / max 403.2337, expressed in 1358 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
125692	12.4342	1171
125691	3.6065	826
125690	2.2824	806
125689	0.3589	165
125697	0.2333	135
125694	0.1223	66
125696	0.0621	29
125698	0.0603	18

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	99.33	gold quality
peripheral nervous system	UBERON:0000010	99.32	gold quality
mucosa of stomach	UBERON:0001199	99.32	gold quality
tibial nerve	UBERON:0001323	99.32	gold quality
endocervix	UBERON:0000458	99.23	gold quality
right ovary	UBERON:0002118	99.20	gold quality
left uterine tube	UBERON:0001303	99.14	gold quality
body of uterus	UBERON:0009853	99.12	gold quality
left ovary	UBERON:0002119	99.09	gold quality
omental fat pad	UBERON:0010414	99.08	gold quality
metanephros cortex	UBERON:0010533	99.08	gold quality
right lung	UBERON:0002167	99.07	gold quality
right lobe of thyroid gland	UBERON:0001119	99.05	gold quality
peritoneum	UBERON:0002358	99.04	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.01	gold quality
right coronary artery	UBERON:0001625	99.00	gold quality
lower esophagus	UBERON:0013473	98.99	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.99	gold quality
left coronary artery	UBERON:0001626	98.98	gold quality
left lobe of thyroid gland	UBERON:0001120	98.94	gold quality
right adrenal gland	UBERON:0001233	98.91	gold quality
popliteal artery	UBERON:0002250	98.91	gold quality
tibial artery	UBERON:0007610	98.91	gold quality
descending thoracic aorta	UBERON:0002345	98.89	gold quality
coronary artery	UBERON:0001621	98.88	gold quality
right adrenal gland cortex	UBERON:0035827	98.85	gold quality
aorta	UBERON:0000947	98.81	gold quality
adipose tissue of abdominal region	UBERON:0007808	98.80	gold quality
thoracic aorta	UBERON:0001515	98.74	gold quality
ascending aorta	UBERON:0001496	98.72	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	21.39
E-GEOD-135922	yes	21.00
E-MTAB-6678	yes	11.24
E-GEOD-134144	yes	7.96
E-GEOD-84465	yes	6.24

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

25 targeting TNS2, 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-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-4690-5P	99.65	66.24	813
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-4721	99.26	66.05	818
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-6885-5P	98.71	64.33	902
HSA-MIR-6728-3P	98.63	67.63	1534
HSA-MIR-767-3P	98.61	67.69	1192
HSA-MIR-4664-5P	98.17	65.07	1020
HSA-MIR-6787-5P	97.54	63.85	457
HSA-MIR-4296	96.35	63.55	1233
HSA-MIR-6828-3P	96.06	67.61	1155

Literature-anchored findings (GeneRIF, showing 21)

• Interaction of Axl receptor tyrosine kinase with C1-TEN. (PMID:12470648)
• C1 domain-containing phosphatase and TENsin homologue (C1-TEN) appears to be a novel intracellular phosphatase that negatively regulates the Akt/Protein kinase B signaling cascade (PMID:15817639)
• variant 3 significantly promoted the cell growth and motility of HCC cells; clonal transfectants of variant 3 were more closely packed and resulted in a higher saturation density than in the control vector transfectants (PMID:17006924)
• Tensins may represent a novel group of metastasis suppressors in the kidney, the loss of which leads to greater tumor cell motility and consequent metastasis. (PMID:19194507)
• DLC1 interaction with tensin2 through this novel focal adhesion binding site contributes to the growth-suppressive activity of DLC1. (PMID:19440389)
• Differential proteolytic cleavage of Tensin2 can liberate domains with discrete localisations and functions, which has implications for the role of Tensins in cancer cell survival and motility. (PMID:19747564)
• Data suggest that the interaction between START-GAP1 and tensin2 occurs in a PTB domain-dependent manner. manner.ty=0 (PMID:19895840)
• focal adhesion-localized tensin 2 negatively regulates DLC1 to permit Rho-mediated actomyosin contraction and remodeling of collagen fibers (PMID:20069572)
• Tensin2, in addition to regulating cytoskeletal dynamics, influences phosphoinositide-Akt signalling through its PTPase domain. (PMID:20678486)
• Here, we report complete chemical shift assignments of the SH2 domain of human tensin2 determined by triple resonance experiments. (PMID:21461930)
• Tensin2 is an important new mediator in TPO/c-Mpl pathway and has a positive affect on cellular growth, at least in part through its effect on the PI3K/Akt signaling. (PMID:21527831)
• Tensin2 SH2 domain was identified to interact with nonphosphorylated ligand (DLC-1) as well as phosphorylated ligand. (PMID:21765928)
• Results identified tensin2 as a Syk-binding protein. (PMID:22019427)
• The tumor suppressor DLC1 utilizes a novel binding site for tensin2 PTB domain interaction (PMID:22645138)
• Pulldown studies in human cells using Myc-tagged Tensin2 constructs revealed that DISC1 specifically interacts with the C-terminal PTB domain of Tensin2 in a phosphorylation-independent manner. (PMID:23233134)
• p62 expression increased but C1-Ten protein decreased during muscle differentiation, supporting a role for p62 as a physiological regulator of C1-Ten. (PMID:25101860)
• Patients with low TNS2 expression showed poor relapse-free survival rates for breast and lung cancers. These results strongly suggest a role of tensin2 in suppressing cell transformation and reduction of tumorigenicity. (PMID:27203214)
• Study observed significant increase in C1-Ten level in diabetic kidney and in high glucose-induced damaged podocytes. C1-Ten acts as a protein tyrosine phosphatase (PTPase) at the nephrin-PI3K binding site and renders PI3K for IRS-1, thereby activating mTORC1. These findings demonstrate the relationship between nephrin dephosphorylation and the mTORC1 pathway, mediated by C1-Ten PTPase activity. (PMID:28955049)
• Collectively,these findings suggest that the interaction between the C1-Ten/Tensin2 SH2 domain and PtdIns(3,4,5)P3 produces a negative feedback loop of insulin signaling through IRS-1. (PMID:30092354)
• Axl binds to and phosphorylates TNS2 and that Axl/TNS2/IRS-1 cross-talk may potentially play a critical role in glucose metabolism of cancer cells. (PMID:30419905)
• Novel candidate factors predicting the effect of S-1 adjuvant chemotherapy of pancreatic cancer. (PMID:33753854)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tns2	ENSMUSG00000037003
rattus_norvegicus	Tns2	ENSRNOG00000010588
drosophila_melanogaster	PVRAP	FBGN0052406
drosophila_melanogaster	Egfrap	FBGN0053993
caenorhabditis_elegans		WBGENE00020867

Paralogs (1): TNS4 (ENSG00000131746)

Protein

Protein identifiers

Tensin-2 — Q63HR2 (reviewed: Q63HR2)

Alternative names: C1 domain-containing phosphatase and tensin homolog, Tensin-like C1 domain-containing phosphatase

All UniProt accessions (4): Q63HR2, F8VV64, H0YID7, R4GMX1

UniProt curated annotations — full annotation on UniProt →

Function. Tyrosine-protein phosphatase which regulates cell motility, proliferation and muscle-response to insulin. Phosphatase activity is mediated by binding to phosphatidylinositol-3,4,5-triphosphate (PtdIns(3,4,5)P3) via the SH2 domain. In muscles and under catabolic conditions, dephosphorylates IRS1 leading to its degradation and muscle atrophy. Negatively regulates PI3K-AKT pathway activation. Dephosphorylates nephrin NPHS1 in podocytes which regulates activity of the mTORC1 complex. Under normal glucose conditions, NPHS1 outcompetes IRS1 for binding to phosphatidylinositol 3-kinase (PI3K) which balances mTORC1 activity but high glucose conditions lead to up-regulation of TNS2, increased NPHS1 dephosphorylation and activation of mTORC1, contributing to podocyte hypertrophy and proteinuria. Required for correct podocyte morphology, podocyte-glomerular basement membrane interaction and integrity of the glomerular filtration barrier. Enhances RHOA activation in the presence of DLC1. Plays a role in promoting DLC1-dependent remodeling of the extracellular matrix.

Subunit / interactions. Interacts with AXL. Interacts with SYK; leading to its phosphorylation. Interacts with SQSTM1 (via PB1 domain); the interaction leads to sequestration of TNS2 in cytoplasmic aggregates with SQSTM1 and promotes TNS2 ubiquitination and proteasomal degradation.

Subcellular location. Cell junction. Focal adhesion. Cell membrane. Cytoplasm.

Tissue specificity. Detected in heart, kidney, brain, thymus, spleen, liver, placenta, lung, skeletal muscle and small intestine.

Post-translational modifications. Ubiquitinated following sequestration in cytoplasmic aggregates with SQSTM1, leading to proteasomal degradation.

Domain organisation. The SH3 domain mediates binding to phosphatidylinositol-3,4,5-triphosphate (PtdIns(3,4,5)P3). It is also required to ensure podocyte integrity while the phosphatase domain is dispensible for podocyte maintenance.

Induction. By high glucose levels in differentiated podocytes (at protein level).

Similarity. Belongs to the PTEN phosphatase protein family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q63HR2-1	1	yes
Q63HR2-2	2
Q63HR2-4	4
Q63HR2-5	5
Q63HR2-6	6

RefSeq proteins (6): NP_001403131, NP_001403132, NP_001403133, NP_056134, NP_736610, NP_938072 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000980	SH2	Domain
IPR002219	PKC_DAG/PE	Domain
IPR006020	PTB/PI_dom	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR013625	PTB	Domain
IPR014020	Tensin_C2-dom	Domain
IPR029021	Prot-tyrosine_phosphatase-like	Homologous_superfamily
IPR029023	Tensin_phosphatase	Domain
IPR033929	Tensin_PTB	Domain
IPR035012	Tensin-like_SH2	Domain
IPR035892	C2_domain_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR046349	C1-like_sf	Homologous_superfamily
IPR051484	Tensin_PTEN_phosphatase	Family

Pfam: PF00017, PF00130, PF08416, PF10409

Catalyzed reactions (Rhea), 1 shown:

• O-phospho-L-tyrosyl-[protein] + H2O = L-tyrosyl-[protein] + phosphate (RHEA:10684)

UniProt features (96 total): modified residue 25, strand 21, mutagenesis site 8, sequence conflict 8, helix 8, compositionally biased region 6, region of interest 5, domain 4, splice variant 4, sequence variant 2, turn 2, chain 1, active site 1, zinc finger region 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
3HQC	X-RAY DIFFRACTION	1.8
2DKQ	SOLUTION NMR
2KNO	SOLUTION NMR
2L6K	SOLUTION NMR
2LOZ	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q63HR2-F1	59.20	0.25

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 (1): 231 (phosphocysteine intermediate)

Post-translational modifications (25): 91, 118, 120, 455, 456, 466, 474, 481, 483, 555, 820, 825, 830, 832, 835, 845, 910, 931, 941, 972 …

Mutagenesis-validated functional residues (8):

Position	Phenotype
231	loss of tyrosine-protein phosphatase activity. reduced irs1 degradation under catabolic conditions. abolishes inhibition
1142	6-fold reduction in affinity for ptdins(3,4,5)p3 and reduced irs1 dephosphorylation but does not affect cell membrane lo
1155	6-fold reduction in affinity for ptdins(3,4,5)p3 and reduced irs1 dephosphorylation but does not affect cell membrane lo
1157	6-fold reduction in affinity for ptdins(3,4,5)p3 and reduced irs1 dephosphorylation but does not affect cell membrane lo
1165	does not affect affinity for ptdins(3,4,5)p3. reduced affinity for tyrosine-phosphorylated peptide.
1209	does not affect affinity for ptdins(3,4,5)p3; when associated with q-1212 and q-1214.
1212	does not affect affinity for ptdins(3,4,5)p3; when associated with q-1209 and q-1214.
1214	does not affect affinity for ptdins(3,4,5)p3; when associated with q-1209 and q-1212.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 205 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, RNGTGGGC_UNKNOWN, GCM_MAP4K4, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, YAO_HOXA10_TARGETS_VIA_PROGESTERONE_UP, FISCHER_G1_S_CELL_CYCLE, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_RESPONSE_TO_INSULIN_STIMULUS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_GROWTH, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_1, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELLULAR_RESPONSE_TO_INSULIN_STIMULUS, EFC_Q6, CAIRO_HEPATOBLASTOMA_CLASSES_DN

GO Biological Process (9): kidney development (GO:0001822), negative regulation of cell population proliferation (GO:0008285), response to muscle activity (GO:0014850), cellular homeostasis (GO:0019725), collagen metabolic process (GO:0032963), multicellular organism growth (GO:0035264), peptidyl-tyrosine dephosphorylation (GO:0035335), negative regulation of insulin receptor signaling pathway (GO:0046627), multicellular organismal-level homeostasis (GO:0048871)

GO Molecular Function (9): protein tyrosine phosphatase activity (GO:0004725), zinc ion binding (GO:0008270), lipid binding (GO:0008289), kinase binding (GO:0019900), identical protein binding (GO:0042802), phosphoprotein phosphatase activity (GO:0004721), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (5): cytoplasm (GO:0005737), plasma membrane (GO:0005886), focal adhesion (GO:0005925), membrane (GO:0016020), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
homeostatic process	2
multicellular organismal process	2
binding	2
cellular anatomical structure	2
animal organ development	1
renal system development	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
response to activity	1
metabolic process	1
developmental growth	1
protein dephosphorylation	1
insulin receptor signaling pathway	1
negative regulation of signal transduction	1
regulation of insulin receptor signaling pathway	1
negative regulation of cellular response to insulin stimulus	1
phosphoprotein phosphatase activity	1
transition metal ion binding	1
enzyme binding	1
protein binding	1
phosphatase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
cation binding	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
cell-substrate junction	1
cell junction	1

Protein interactions and networks

STRING

1688 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNS2	DLC1	Q96QB1	904
TNS2	AXL	P30530	866
TNS2	VCL	P18206	785
TNS2	SRC	P12931	740
TNS2	TLN2	Q9Y4G6	650
TNS2	PXN	P49023	641
TNS2	TLN1	Q9Y490	636
TNS2	SPTAN1	Q13813	584
TNS2	STARD13	Q9Y3M8	581
TNS2	CAST	P20810	580
TNS2	BCAR1	P56945	555
TNS2	PTK2	Q05397	551
TNS2	CAPN2	P17655	545
TNS2	STARD8	Q92502	531
TNS2	GRB2	P29354	491

IntAct

386 interactions, top by confidence:

A	B	Type	Score
KRTAP12-2	TNS2	psi-mi:“MI:0915”(physical association)	0.720
TNS2	ZNF417	psi-mi:“MI:0915”(physical association)	0.720
TNS2	TEKT5	psi-mi:“MI:0915”(physical association)	0.720
TNS2	ZNF587	psi-mi:“MI:0915”(physical association)	0.720
TNS2	KRTAP12-2	psi-mi:“MI:0915”(physical association)	0.720
TEKT5	TNS2	psi-mi:“MI:0915”(physical association)	0.720
ZNF417	TNS2	psi-mi:“MI:0915”(physical association)	0.720
TNS2	KPRP	psi-mi:“MI:0915”(physical association)	0.700
TNS2	OTX1	psi-mi:“MI:0915”(physical association)	0.700
TNS2	KRTAP1-3	psi-mi:“MI:0915”(physical association)	0.700
SHFL	TNS2	psi-mi:“MI:0915”(physical association)	0.670
TNS2	YWHAB	psi-mi:“MI:2364”(proximity)	0.570
TNS2	ZNF250	psi-mi:“MI:0915”(physical association)	0.560
PKP1	TNS2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-5	TNS2	psi-mi:“MI:0915”(physical association)	0.560
TNS2	KRTAP10-7	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-8	TNS2	psi-mi:“MI:0915”(physical association)	0.560
TNS2	REL	psi-mi:“MI:0915”(physical association)	0.560
TNS2		psi-mi:“MI:0915”(physical association)	0.560

BioGRID (284): TENC1 (Two-hybrid), TENC1 (Two-hybrid), TENC1 (Two-hybrid), C19orf66 (Two-hybrid), ZNF250 (Two-hybrid), ZNF587 (Two-hybrid), REEP6 (Two-hybrid), TBC1D16 (Two-hybrid), TEKT5 (Two-hybrid), ZNF417 (Two-hybrid), KRTAP12-2 (Two-hybrid), KRTAP10-7 (Two-hybrid), KRTAP10-5 (Two-hybrid), KRTAP10-8 (Two-hybrid), KRTAP10-3 (Two-hybrid)

ESM2 similar proteins: A1YF56, A2AEV7, A6NCS4, A7Y7W2, D3ZJK7, E1BEA8, F1MUS9, O15534, O35973, O43435, O43638, O60248, O75333, O77728, O94983, O95935, O95947, P22736, P46099, P51666, P56261, P57082, P70325, P70327, Q03484, Q0V8F0, Q15744, Q497V6, Q5DTT2, Q61660, Q61663, Q63HR2, Q64731, Q66JL1, Q6PZD9, Q6ZQN5, Q80Y50, Q810F8, Q861Q9, Q8AV66

Diamond homologs: E9Q0S6, G5EE01, H2L045, O08586, O14976, O54857, P60483, P60484, P97874, Q04205, Q32PJ7, Q4R6N0, Q4V8I3, Q54JL7, Q5SSZ5, Q63HR2, Q68CZ2, Q6NR09, Q8BZ33, Q8CGB6, Q8H106, Q8IZW8, Q8T9S7, Q99KY4, Q9FLZ5, Q9GLM4, Q9HBL0, Q9LT75, Q9PUT6, O94526, P56180, Q9P7H1, P53916, O75061, Q27974, Q5F4C0, Q6XPS3, Q80TZ3, Q96D96, A6QLK6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
AXL	“up-regulates quantity”	TNS2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 114 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
Keratinization	11	8.9×	9e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	340
Likely benign	133
Benign	43

Top pathogenic / likely-pathogenic (0)

SpliceAI

4279 predictions. Top by Δscore:

Variant	Effect	Δscore
12:53052451:CTA:C	acceptor_loss	1.0000
12:53052453:A:AG	acceptor_gain	1.0000
12:53052453:A:C	acceptor_loss	1.0000
12:53052454:G:A	acceptor_loss	1.0000
12:53052454:G:GC	acceptor_gain	1.0000
12:53052454:GTCT:G	acceptor_gain	1.0000
12:53052493:GT:G	donor_loss	1.0000
12:53052494:T:A	donor_loss	1.0000
12:53054435:G:GG	donor_gain	1.0000
12:53054438:CCTGG:C	donor_loss	1.0000
12:53054440:TG:T	donor_loss	1.0000
12:53054441:GG:G	donor_loss	1.0000
12:53054442:G:GG	donor_gain	1.0000
12:53054443:T:A	donor_loss	1.0000
12:53055674:T:TA	donor_gain	1.0000
12:53057008:CCCA:C	acceptor_loss	1.0000
12:53057011:A:C	acceptor_loss	1.0000
12:53057011:AG:A	acceptor_gain	1.0000
12:53057011:AGGGC:A	acceptor_gain	1.0000
12:53057012:G:GT	acceptor_loss	1.0000
12:53057012:GG:G	acceptor_gain	1.0000
12:53057012:GGGC:G	acceptor_gain	1.0000
12:53057012:GGGCG:G	acceptor_gain	1.0000
12:53057093:GTCG:G	donor_gain	1.0000
12:53058312:CCAGG:C	acceptor_loss	1.0000
12:53058313:CAG:C	acceptor_loss	1.0000
12:53058315:GGT:G	acceptor_gain	1.0000
12:53058315:GGTA:G	acceptor_gain	1.0000
12:53058315:GGTAA:G	acceptor_gain	1.0000
12:53058441:GACTG:G	donor_gain	1.0000

AlphaMissense

9052 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:53051915:T:C	C46R	1.000
12:53051957:T:C	C60R	1.000
12:53061893:T:C	L1176P	1.000
12:53061899:T:C	L1178P	1.000
12:53063239:T:C	L1325P	1.000
12:53051917:T:G	C46W	0.999
12:53051958:G:A	C60Y	0.999
12:53051959:C:G	C60W	0.999
12:53052481:T:C	C71R	0.999
12:53054413:T:C	L165P	0.999
12:53055583:T:A	W197R	0.999
12:53055583:T:C	W197R	0.999
12:53058089:A:T	K361I	0.999
12:53061827:T:C	L1154P	0.999
12:53061851:T:C	F1162S	0.999
12:53061854:T:C	L1163P	0.999
12:53061857:T:A	I1164N	0.999
12:53061860:G:T	R1165M	0.999
12:53061865:A:C	S1167R	0.999
12:53061867:T:A	S1167R	0.999
12:53061867:T:G	S1167R	0.999
12:53061874:T:C	F1170L	0.999
12:53061876:C:A	F1170L	0.999
12:53061876:C:G	F1170L	0.999
12:53061890:G:A	G1175E	0.999
12:53061893:T:A	L1176Q	0.999
12:53061896:C:A	A1177D	0.999
12:53062174:T:A	V1199D	0.999
12:53062177:G:C	R1200P	0.999
12:53062182:T:C	F1202L	0.999

dbSNP variants (sampled 300 via entrez): RS1000199957 (12:53049898 G>A), RS1000535992 (12:53048455 A>C), RS1000608080 (12:53048614 G>A,C), RS1000920846 (12:53062828 A>G), RS1000925114 (12:53056833 C>T), RS1001151212 (12:53055118 A>C,T), RS1001201458 (12:53051334 G>A,C), RS1001724453 (12:53045084 G>A,C,T), RS1001829882 (12:53050113 C>T), RS1002015040 (12:53061395 A>G), RS1002123389 (12:53056162 C>T), RS1002365218 (12:53056790 C>T), RS1002372764 (12:53050000 G>A,T), RS1002404532 (12:53047335 G>A,C), RS1002606915 (12:53064110 T>C)

Disease associations

OMIM: gene MIM:607717 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
nephrotic syndrome	Strong	Autosomal recessive

Mondo (1): nephrotic syndrome (MONDO:0005377)

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001147_14	Prostate cancer	5.000000e-09
GCST010796_3114	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004327	electrocardiography

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009404	Nephrotic Syndrome	C12.050.351.968.419.630.643; C12.200.777.419.630.643; C12.950.419.630.643

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation	2
Tobacco Smoke Pollution	decreases expression	2
Cyclosporine	decreases expression	2
Cadmium Chloride	increases expression, decreases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
bisphenol A	increases expression	1
lead acetate	decreases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
aflatoxin B2	increases methylation	1
methacrylaldehyde	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Leflunomide	increases expression	1
Acrolein	affects cotreatment, increases expression	1
Caffeine	decreases phosphorylation	1
Cisplatin	affects cotreatment, increases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00308321	PHASE4	UNKNOWN	Long Term Tapering or Standard Steroids for Nephrotic Syndrome
NCT01021540	PHASE4	COMPLETED	Prospective Study Evaluating the Effect of Repository Corticotropin in the Treatment of Various Nephrotic Syndromes
NCT01028287	PHASE4	COMPLETED	Adrenocorticotropic Hormone (ACTH) Treatment of Nephrotic Range Proteinuria in Diabetic Nephropathy (NRDN)
NCT01162005	PHASE4	COMPLETED	Therapeutic Effect of Tacrolimus on Primary Nephrotic Syndrome in Children
NCT01895894	PHASE4	COMPLETED	Mycophenolate Mofetil in Pediatric Steroid Dependent Nephrotic Syndrome
NCT02238418	PHASE4	COMPLETED	Efficacy of Usual Vitamin D Supplementation and Its Impact on Children and Adolescents Calciuria.
NCT02382575	PHASE4	UNKNOWN	Efficacy and Safety of Rituximab to That of Calcineurin Inhibitors in Children With Steroid Resistant Nephrotic Syndrome
NCT02427880	PHASE4	COMPLETED	Role of Acetazolamide and Hydrochlorothiazide Followed by Furosemide in Treating Nephrotic Edema
NCT03210688	PHASE4	COMPLETED	Active Vitamin D And Reduced Dose Prednisolone for Treatment in Minimal Change Nephropathy
NCT03347357	PHASE4	COMPLETED	Pharmacokinetics of Tacrolimus in Children
NCT05696977	PHASE4	UNKNOWN	Effect of Obesity on Cyclosporine Blood Trough Level in Nephrotic Syndrome Patients
NCT05966818	PHASE4	UNKNOWN	Effect of Dapagliflozin in Non-Diabetic Patients With Nephrotic Syndrome.
NCT06026787	PHASE4	COMPLETED	Clinical Value of Adding Dapagliflozin in Patients With Nephrotic Syndrome
NCT00354731	PHASE3	COMPLETED	Efficacy of Pentoxifylline on Primary Nephrotic Syndrome
NCT00615667	PHASE3	COMPLETED	Prospective, Multicenter Study of the Efficacy and Tolerance of Tacrolimus on Refractory Nephrotic Syndrome (RNS)
NCT00981838	PHASE3	COMPLETED	Rituximab in Multirelapsing Minimal Change Disease (MCD) or Focal Segmental Glomerulosclerosis (FSGS)
NCT01197040	PHASE3	COMPLETED	Evaluation of Low Dose Corticosteroids Efficiency, Associated With Myfortic ® in the Treatment of Nephrotic Syndrome
NCT01309477	PHASE3	COMPLETED	The Efficacy and Tolerance of Tacrolimus Sustained-release Capsules on Refractory Nephrotic Syndrome (RNS)
NCT02132195	PHASE3	COMPLETED	Adrenocorticotropic Hormone (ACTH) for Frequently Relapsing and Steroid Dependent Nephrotic Syndrome
NCT02257697	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Mizoribine in the Treatment of Refractory Nephrotic Syndrome
NCT02438982	PHASE3	COMPLETED	Efficacy and Safety of Rituximab to That of Calcineurin Inhibitors in Children With Steroid Dependent Nephrotic Syndrome
NCT03141970	PHASE3	COMPLETED	Prednisolone Trial in Children Younger Than 4 Years
NCT03501459	PHASE3	UNKNOWN	Lymphocyte Markers As Predictors Of Responsiveness To Rituximab Among Patients With Idiopathic Nephrotic Syndrome
NCT05079789	PHASE3	TERMINATED	Amiloride in Nephrotic Syndrome
NCT05716880	PHASE3	RECRUITING	Ketoanalogues for Muscle Mass Loss in Nephrotic Syndrome
NCT06635720	PHASE3	ACTIVE_NOT_RECRUITING	REduced-dose Steroid PrOtocol for Childhood Nephrotic SyndromE (RESPONSE)
NCT00001212	PHASE2	COMPLETED	Drug Therapy in Lupus Nephropathy
NCT00001959	PHASE2	COMPLETED	Pirfenidone to Treat Kidney Disease (Focal Segmental Glomerulosclerosis)
NCT00004466	PHASE2	TERMINATED	Pilot Study of Atorvastatin in Children With Chronic Hyperlipidemia Secondary to Nephrotic Syndrome
NCT00004990	PHASE2	COMPLETED	Once-A-Month Steroid Treatment for Patients With Focal Segmental Glomerulosclerosis
NCT00977977	PHASE2	RECRUITING	Rituximab Plus Cyclosporine in Idiopathic Membranous Nephropathy
NCT02394106	PHASE2	TERMINATED	Ofatumumab in Children With Drug Resistant Idiopathic Nephrotic Syndrome
NCT02394119	PHASE2	COMPLETED	Ofatumumab Versus Rituximab in Children With Steroid and Calcineurin Inhibitor Dependent Idiopathic Nephrotic Syndrome
NCT02592798	PHASE2	COMPLETED	Pilot Study to Evaluate the Safety and Efficacy of Abatacept in Adults and Children 6 Years and Older With Excessive Loss of Protein in the Urine Due to Either Focal Segmental Glomerulosclerosis (FSGS) or Minimal Change Disease (MCD)
NCT02966717	PHASE2	UNKNOWN	Rituximab Combined With MSCs in the Treatment of PNS (3-4 Stage of CKD)
NCT03004001	PHASE2	TERMINATED	Effect of PCSK9-Antibody (Alirocumab) on Dyslipidemia Secondary to Nephrotic Syndrome
NCT03949855	PHASE2	RECRUITING	Belimumab With Rituximab for Primary Membranous Nephropathy
NCT05599815	PHASE2	WITHDRAWN	Part 1 - A Clinical Trial in Patients With Frequently Relapsing and Steroid-Dependent Nephrotic Syndrome
NCT05704400	PHASE2	UNKNOWN	Efficacy of Anti-CD20 Ab Associated With Anti-CD38 in the Childhood Multidrug Dependent and Resistant Nephrotic Syndrome
NCT06983028	PHASE2	RECRUITING	Atacicept in Multiple Glomerular Diseases