SPINT2

Summary

SPINT2 (serine peptidase inhibitor, Kunitz type 2, HGNC:11247) is a protein-coding gene on chromosome 19q13.2, encoding Kunitz-type protease inhibitor 2 (O43291). Inhibitor of HGFAC.

This gene encodes a transmembrane protein with two extracellular Kunitz domains that inhibits a variety of serine proteases. The protein inhibits HGF activator which prevents the formation of active hepatocyte growth factor. This gene is a putative tumor suppressor, and mutations in this gene result in congenital sodium diarrhea. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 10653 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic congenital sodium diarrhea (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 212 total — 11 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 17
• Druggable target: yes
• MANE Select transcript: NM_021102

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11247
Approved symbol	SPINT2
Name	serine peptidase inhibitor, Kunitz type 2
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Aliases	Kop, HAI-2, HAI2
Ensembl gene	ENSG00000167642
Ensembl biotype	protein_coding
OMIM	605124
Entrez	10653

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 19 protein_coding, 3 retained_intron

ENST00000301244, ENST00000454580, ENST00000585357, ENST00000587090, ENST00000587334, ENST00000587516, ENST00000589749, ENST00000590210, ENST00000590510, ENST00000590738, ENST00000592007, ENST00000902577, ENST00000902578, ENST00000902579, ENST00000918438, ENST00000918439, ENST00000918440, ENST00000918441, ENST00000964700, ENST00000964701, ENST00000964702, ENST00000964703

RefSeq mRNA: 2 — MANE Select: NM_021102 NM_001166103, NM_021102

CCDS: CCDS12510, CCDS54261

Canonical transcript exons

ENST00000301244 — 7 exons

Exon	Start	End
ENSE00001115183	38289138	38289191
ENSE00001115184	38264573	38264998
ENSE00001301285	38291840	38292615
ENSE00003556261	38290119	38290280
ENSE00003663311	38290537	38290575
ENSE00003689068	38283627	38283797
ENSE00003787686	38287876	38287935

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 99.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 86.7165 / max 1212.0676, expressed in 1245 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
175604	30.8547	987
175607	24.0466	1069
175605	23.4116	1106
175602	2.8737	765
175600	2.4537	672
175601	1.5695	632
175603	1.0050	441
175606	0.4123	242
175599	0.0894	33

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
type B pancreatic cell	CL:0000169	99.47	gold quality
mucosa of transverse colon	UBERON:0004991	99.47	gold quality
parotid gland	UBERON:0001831	99.34	gold quality
islet of Langerhans	UBERON:0000006	99.32	gold quality
pituitary gland	UBERON:0000007	99.28	gold quality
adenohypophysis	UBERON:0002196	99.27	gold quality
left lobe of thyroid gland	UBERON:0001120	99.21	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.21	gold quality
right lobe of thyroid gland	UBERON:0001119	99.18	gold quality
right uterine tube	UBERON:0001302	99.18	gold quality
left testis	UBERON:0004533	99.17	gold quality
right testis	UBERON:0004534	99.17	gold quality
thyroid gland	UBERON:0002046	99.05	gold quality
palpebral conjunctiva	UBERON:0001812	99.03	gold quality
ascending aorta	UBERON:0001496	99.01	gold quality
thoracic aorta	UBERON:0001515	99.00	gold quality
nasal cavity epithelium	UBERON:0005384	98.96	gold quality
saliva-secreting gland	UBERON:0001044	98.94	gold quality
rectum	UBERON:0001052	98.88	gold quality
trachea	UBERON:0003126	98.86	gold quality
endometrium epithelium	UBERON:0004811	98.86	gold quality
pharyngeal mucosa	UBERON:0000355	98.82	gold quality
minor salivary gland	UBERON:0001830	98.82	gold quality
nasal cavity mucosa	UBERON:0001826	98.78	gold quality
esophagus mucosa	UBERON:0002469	98.75	gold quality
mouth mucosa	UBERON:0003729	98.74	gold quality
body of pancreas	UBERON:0001150	98.72	gold quality
skin of abdomen	UBERON:0001416	98.70	gold quality
descending thoracic aorta	UBERON:0002345	98.69	gold quality
colonic mucosa	UBERON:0000317	98.67	gold quality

Single-cell (SCXA)

Detected in 36 experiment(s), a significant marker in 31.

Experiment	Marker?	Max mean expression
E-HCAD-31	yes	3178.88
E-MTAB-9154	yes	1643.32
E-GEOD-124472	yes	1589.28
E-HCAD-10	yes	1089.19
E-MTAB-9388	yes	1088.06
E-MTAB-6701	yes	1064.82
E-MTAB-10485	yes	1014.57
E-MTAB-8559	yes	801.79
E-MTAB-8205	yes	538.39
E-GEOD-93593	yes	475.34
E-MTAB-8271	yes	389.28
E-HCAD-32	yes	270.73
E-HCAD-1	yes	245.19
E-HCAD-4	yes	64.30
E-MTAB-8410	yes	58.48

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, NKX3-1, NR1I3, TBPL1

miRNA regulators (miRDB)

33 targeting SPINT2, 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-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-4679	99.76	69.19	1229
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-2116-3P	99.74	64.32	889
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-580-5P	99.28	70.94	1776
HSA-MIR-296-3P	99.21	66.56	474
HSA-MIR-138-2-3P	98.91	68.33	1643
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-4272	98.76	68.74	1810
HSA-MIR-4752	98.71	68.04	833
HSA-MIR-6868-3P	98.63	69.64	2259
HSA-MIR-1248	98.47	67.54	1314
HSA-MIR-6791-3P	97.45	64.31	1123
HSA-MIR-6829-3P	97.45	64.31	1137
HSA-MIR-8056	97.15	64.49	769
HSA-MIR-5194	96.77	63.91	1021
HSA-MIR-6738-5P	96.33	63.61	815

Literature-anchored findings (GeneRIF, showing 40)

• The active form of HGFA is specifically complexed with the membrane-form HAI-1 (serine peptidase inhibitor, Kunitz type 1), but not with HAI-2/PB (serine peptidase inhibitor, Kunitz type 2), on the surface of epithelial cells expressing both inhibitors. (PMID:11013244)
• bik-R can physically interact with the CD44v isoforms containing epitope v9 and function as a repressor to down-regulate PMA-stimulated uPA expression, at least in part, by preventing clustering of CD44v isoforms containing epitope v9. (PMID:11777908)
• Bikunin downregulates constitutive & PMA-stimulated uPAR mRNA & protein Through suppression of upstream ERK cascade targets, whether cells were treated with exogenous bikunin or transfected with bikunin gene. (PMID:12180971)
• Urinary levels provide insight into proteinase/proteinase inhibitor imbalance in patients with inflammatory diseases. (PMID:12211652)
• Bikunin was colocalized with tryptase in dermal mast cells, and a small quantity of bikunin was also deposited in the intercellular spaces in FE and ADL. (PMID:12522575)
• there is a distinct regulation of hepatocyte growth factor activator inhibitor type 2 gene expression in testis and that HAI-2 may play a role in the process of spermatogenesis (PMID:12553733)
• overexpression of bikunin is associated with suppression of invasion and peritoneal carcinomatosis of ovarian cancer cell line (PMID:12569552)
• cDNA microarray analysis of gene expression regulated by bikunin in an ovarian cell line, including the pattern of gene expression leading to a block in cell invasion. (PMID:12571229)
• Study demonstrates that the expression of HAI-2/PB is under methylation control to a variable extent in glioma cell lines, in comparison to the other tested neoplasm cell lines (brain, breast, prostate, liver). (PMID:14558597)
• Frequent hypermethylation of SPINT2 gene in human hepatocellular carcinoma (PMID:14695180)
• Low level of HAI-2 is associated with breast cancer (PMID:14734471)
• The use of high hydrostatic pressure (1000-3000 bar) for the refolding of bikunin aggregates was investigated. (PMID:15388859)
• suppresses lipopolysaccharide-induced lethality through down-regulation of tumor necrosis factor- alpha and interleukin-1 beta in macrophages. (PMID:15717269)
• Epigenetic inactivation of HAI-2/SPINT2 causes loss of RCC tumor suppressor activity and implicates abnormalities of the MET pathway in clear cell and papillary sporadic RCC. (PMID:15930277)
• There are no significant differences in serum HAI-2 levels among prostate cancer subgroups according to clinical stage. (PMID:16353247)
• hepatocyte growth factor activator inhibitor 2 is regulated by hypoxia in breast cancer (PMID:17255277)
• HAI2 hypermethylation is associated with hepatocellular carcinoma (PMID:18358501)
• Low HAI-2 expression in cervical cancer may be associated with a poor prognosis. (PMID:18689863)
• Unlike HAI-1 and matriptase, HAI-2 expression is detected in non-epithelial cells of brain and lymph nodes, suggesting that HAI-2 may also be involved in inhibition of serine proteases other than matriptase (PMID:18713750)
• data support the role of SPINT2 as a putative tumor suppressor gene in medulloblastoma and further implicate dysregulation of the HGF/MET signaling pathway in the pathogenesis of medulloblastoma (PMID:19047176)
• HAI-2 is a candidate tumour suppressor gene that is frequently hypermethylated and underexpressed in human HCCs, and the KD-1 domain of HAI-2 is the key region responsible for its anti-invasive function (PMID:19107935)
• HAI-1 and HAI-2 may possibly be therapeutic target for treatment approaches in ovarian cancer. (PMID:19148468)
• Syndromic congenital sodium diarrhea is a distinct diseas entity cause by SPINT2 loss-of-function mutations. (PMID:19185281)
• syndromic tufting enteropathy may be related to a SPINT2 mutation seen in congenital sodium diarrhea [case report] (PMID:20009592)
• Epigenetic inactivation of HAI-2/SPINT2 contributes to gastric carcinogenesis and may be a potential biomarker for gastric cancer. (PMID:20063316)
• HAI-2 protein is significantly decreased in malignant prostate cancer lesions as compared to normal and benign prostate hyperplasia lesions, and that the most poorly differentiated tumors have the lowest level of HAI-2 expression. (PMID:20687215)
• Low HAI-2 is associated with endometrial cancer. (PMID:20715109)
• HAI-1 and -2 are overexpressed in the liver in cholangiopathies with ductular reactions and are possibly involved in liver fibrosis and hepatic differentiation. (PMID:21898507)
• HAI-2 is an inhibitor of matriptase-2 that modulates the synthesis of hepcidin. (PMID:23293962)
• The role of hepatocyte growth factor activator inhibitor-2 (HAI-2) in prostate cancer cell migration, invasion, tumorigenicity and metastasis. (PMID:24121274)
• established SPINT2 as a second gene associated with congenital tufting enteropathy (PMID:24142340)
• The tumor suppressor gene SPINT2 is commonly silenced by promoter hypermethylation in human esophageal squamous cell carcinoma and SPINT2 hypermethylation is correlated with poor overall survival. (PMID:24269829)
• results suggest that the SPINT2 underexpression in the MSC from MDS patients is probably involved in the adhesion of progenitors to the bone marrow niche, through an increased HGF and SDF-1 signaling pathway. (PMID:24410667)
• a missense mutation in the serine protease inhibitor SPINT2 may have a role in congenital sodium diarrhea (PMID:24722141)
• Matriptase inhibition by HAI-2 requires the translocation of HAI-2 to the cell surface, a process which is observed in some breast cancer cells but not in mammary epithelial cells. (PMID:25786220)
• Epigenetic silencing of SPINT2 promotes cancer cell motility in malignant melanoma. (PMID:25910030)
• study the methylation status of the promoter region of Serine peptidase inhibitor/hepatocyte growth factor activator inhibitor type 2 (SPINT2/HAI-2) (PMID:26030814)
• N-glycan branching regulates HAI-2 through different subcellular distribution and subsequently access to different target proteases (PMID:26171609)
• It suggests an involvement of SPINT2 in PCa tumorigenesis, probably in association with a post-translational regulation of SPINT2. (PMID:26442953)
• This study presented a molecular characterization of congenital tufting enteropathy Italian patients, and identified one mutation in the SPINT2 gene (PMID:26684320)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	spint2	ENSDARG00000069476
mus_musculus	Spint2	ENSMUSG00000074227
rattus_norvegicus	Spint2	ENSRNOG00000020636
drosophila_melanogaster	CG7565	FBGN0035833
caenorhabditis_elegans		WBGENE00008449
caenorhabditis_elegans		WBGENE00010792
caenorhabditis_elegans		WBGENE00015355
caenorhabditis_elegans		WBGENE00021939

Paralogs (13): TFPI (ENSG00000003436), EPPIN (ENSG00000101448), TFPI2 (ENSG00000105825), AMBP (ENSG00000106927), LRP11 (ENSG00000120256), WFIKKN1 (ENSG00000127578), KIAA0319 (ENSG00000137261), KIAA0319L (ENSG00000142687), SPINT4 (ENSG00000149651), WFDC8 (ENSG00000158901), SPINT1 (ENSG00000166145), WFIKKN2 (ENSG00000173714), WFDC6 (ENSG00000243543)

Protein

Protein identifiers

Kunitz-type protease inhibitor 2 — O43291 (reviewed: O43291)

Alternative names: Hepatocyte growth factor activator inhibitor type 2, Placental bikunin

All UniProt accessions (8): A0A140VJV6, O43291, K7EJS4, K7EKC8, K7EKQ0, K7EM91, K7ES27, K7ESI5

UniProt curated annotations — full annotation on UniProt →

Function. Inhibitor of HGFAC. Also inhibits plasmin, and plasma and tissue kallikrein. Inhibits serine protease activity of TMPRSS13. Inhibits serine protease activity of ST14/matriptase and PRSS8/prostasin in vitro.

Subunit / interactions. Interacts with TMPRSS13; the interaction promotes the phosphorylation and cell membrane localization of TMPRSS13.

Subcellular location. Cell membrane. Cytoplasm.

Tissue specificity. Expressed in placenta, kidney, pancreas, prostate, testis, thymus, and trachea.

Disease relevance. Diarrhea 3, secretory sodium, congenital, with or without other congenital anomalies (DIAR3) [MIM:270420] A disease characterized by life-threatening secretory diarrhea, severe metabolic acidosis and hyponatremia. Hyponatremia is secondary to extraordinarily high fecal sodium loss, with low or normal excretion of urinary sodium, in the absence of infectious, autoimmune and endocrine causes. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. This inhibitor contains two inhibitory domains.

Isoforms (2)

UniProt ID	Names	Canonical?
O43291-1	1	yes
O43291-2	2

RefSeq proteins (2): NP_001159575, NP_066925* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002223	Kunitz_BPTI	Domain
IPR020901	Prtase_inh_Kunz-CS	Conserved_site
IPR036880	Kunitz_BPTI_sf	Homologous_superfamily

Pfam: PF00014

UniProt features (39 total): sequence variant 8, disulfide bond 6, sequence conflict 4, strand 4, site 2, glycosylation site 2, topological domain 2, turn 2, domain 2, signal peptide 1, chain 1, splice variant 1, transmembrane region 1, helix 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4U32	X-RAY DIFFRACTION	1.65

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43291-F1	81.66	0.55

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): 143–144 (reactive bond); 48–49 (reactive bond)

Disulfide bonds (6): 38–88, 47–71, 63–84, 133–183, 142–166, 158–179

Glycosylation sites (2): 57, 94

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-6806942	MET Receptor Activation
R-HSA-8852405	Signaling by MST1
R-HSA-162582	Signal Transduction
R-HSA-6806834	Signaling by MET
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases

MSigDB gene sets: 423 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_LABYRINTHINE_LAYER_DEVELOPMENT, FLECHNER_PBL_KIDNEY_TRANSPLANT_REJECTED_VS_OK_UP, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, LU_IL4_SIGNALING, GOBP_EPITHELIAL_CELL_DEVELOPMENT, JAEGER_METASTASIS_DN, GCANCTGNY_MYOD_Q6, CMYB_01, GOBP_NEGATIVE_REGULATION_OF_CELL_CELL_ADHESION, MCBRYAN_PUBERTAL_TGFB1_TARGETS_DN, WEIGEL_OXIDATIVE_STRESS_BY_TBH_AND_H2O2, GOBP_NEURAL_TUBE_DEVELOPMENT

GO Biological Process (8): neural tube closure (GO:0001843), establishment or maintenance of cell polarity (GO:0007163), negative regulation of cell-cell adhesion (GO:0022408), epithelial cell morphogenesis involved in placental branching (GO:0060672), basement membrane organization (GO:0071711), cellular response to BMP stimulus (GO:0071773), negative regulation of cell motility (GO:2000146), negative regulation of neural precursor cell proliferation (GO:2000178)

GO Molecular Function (3): endopeptidase inhibitor activity (GO:0004866), serine-type endopeptidase inhibitor activity (GO:0004867), peptidase inhibitor activity (GO:0030414)

GO Cellular Component (5): extracellular region (GO:0005576), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Signaling by Receptor Tyrosine Kinases	2
Signaling by MET	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
primary neural tube formation	1
tube closure	1
cellular process	1
negative regulation of cell adhesion	1
regulation of cell-cell adhesion	1
cell-cell adhesion	1
epithelial cell morphogenesis	1
embryonic morphogenesis	1
branching involved in labyrinthine layer morphogenesis	1
epithelial cell differentiation involved in embryonic placenta development	1
extracellular matrix organization	1
cellular response to growth factor stimulus	1
response to BMP	1
negative regulation of locomotion	1
negative regulation of cellular process	1
cell motility	1
regulation of cell motility	1
negative regulation of cell population proliferation	1
neural precursor cell proliferation	1
regulation of neural precursor cell proliferation	1
endopeptidase activity	1
peptidase inhibitor activity	1
endopeptidase regulator activity	1
serine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
intracellular anatomical structure	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1078 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPINT2	HGFAC	Q04756	939
SPINT2	C19orf33	Q9GZP8	860
SPINT2	EPCAM	P16422	821
SPINT2	ST14	Q9Y5Y6	777
SPINT2	PDYN	P01213	753
SPINT2	PNOC	Q13519	720
SPINT2	MYO5B	Q9ULV0	705
SPINT2	PRSS8	Q16651	700
SPINT2	PPP1R14A	Q96A00	658
SPINT2	HPN	P05981	647
SPINT2	DMTN	Q08495	573
SPINT2	AP5M1	Q9H0R1	548
SPINT2	KLK1	P06870	530
SPINT2	SLC26A3	P40879	519
SPINT2	HPRT1	P00492	515

IntAct

39 interactions, top by confidence:

A	B	Type	Score
CENPH	NDC80	psi-mi:“MI:0914”(association)	0.800
KLHL22	METTL15	psi-mi:“MI:0914”(association)	0.640
SPINT2		psi-mi:“MI:0915”(physical association)	0.610
	SPINT2	psi-mi:“MI:0407”(direct interaction)	0.610
	SPINT2	psi-mi:“MI:0915”(physical association)	0.610
	SPINT2	psi-mi:“MI:0403”(colocalization)	0.610
ILK	HAX1	psi-mi:“MI:0914”(association)	0.530
SPINT2	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
CENPH	PSMD11	psi-mi:“MI:0914”(association)	0.530
TBC1D15	UBXN8	psi-mi:“MI:0914”(association)	0.530
ANKH	FAM234B	psi-mi:“MI:0914”(association)	0.530
MEP1B	SPINT2	psi-mi:“MI:0915”(physical association)	0.370
SPINT2		psi-mi:“MI:0915”(physical association)	0.370
FAM189B	KLRG2	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
	TMEM223	psi-mi:“MI:0914”(association)	0.350
SMIM22	SPINT2	psi-mi:“MI:0914”(association)	0.350
DCAF4	IGLL5	psi-mi:“MI:0914”(association)	0.350
CACNA1C	DISP2	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
ST14	LIPT2	psi-mi:“MI:0914”(association)	0.350
SPINT2		psi-mi:“MI:0914”(association)	0.350
SPINT2	SPAG9	psi-mi:“MI:0914”(association)	0.350
MFSD10	NDUFS8	psi-mi:“MI:0914”(association)	0.350
MFSD5	ILVBL	psi-mi:“MI:0914”(association)	0.350
MFSD8	STXBP3	psi-mi:“MI:0914”(association)	0.350
MFSD9	PGRMC1	psi-mi:“MI:0914”(association)	0.350

BioGRID (309): SPINT2 (Affinity Capture-RNA), SPINT2 (Affinity Capture-MS), SPINT2 (Affinity Capture-MS), TUBGCP2 (Affinity Capture-MS), LSR (Affinity Capture-MS), ATP12A (Affinity Capture-MS), LIN54 (Affinity Capture-MS), TBC1D9B (Affinity Capture-MS), TBC1D15 (Affinity Capture-MS), ATP2A3 (Affinity Capture-MS), ITPRIPL1 (Affinity Capture-MS), FNDC3A (Affinity Capture-MS), ZNF696 (Affinity Capture-MS), OCRL (Affinity Capture-MS), ABCA3 (Affinity Capture-MS)

ESM2 similar proteins: A4K2P0, A5X2X1, A6MFL2, A7X3V4, A7X3V7, A7X4K1, A8Y7N4, A8Y7N7, A8Y7N8, A8Y7N9, A8Y7P5, B2BS84, B2KTG1, B5KF95, B5KF96, B5KL34, B5KL36, B5L5Q8, B7S4N9, D4A2Z2, E5AJX3, F6ULY1, H6VC05, I2G9B4, O35536, O43278, O43291, O95925, P00974, P00991, P00992, P01173, P01174, P04815, Q08E66, Q29100, Q2ES46, Q3UW55, Q4KUS1, Q6T6S5

Diamond homologs: A0A1D0BND9, A0A3G2FQK2, A0A6B7FA07, A0A6B7FBD3, A0A6B7FEJ3, A0A6P8HC43, A5X2X1, A8Y7N9, A8Y7P0, A8Y7P6, B1B5I8, B2BS84, B5KF95, B5KL37, B5KL38, B5L5R7, B6RLX2, B6ZIW0, C0HJF3, C0HK74, C0HLB2, C0HMC7, C1IC52, C8YJ94, D8KY58, G3LH89, H2A0N1, H2A0P0, O35536, O43278, O43291, O54819, O76840, P00978, P00990, P00991, P02760, P04365, P04366, P0DJ50

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 48 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.

GO biological processes:

GO term	Partners	Fold	FDR
transmembrane transport	5	22.2×	8e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	6
Uncertain significance	62
Likely benign	106
Benign	12

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
1394791	NM_021102.4(SPINT2):c.3G>A (p.Met1Ile)	Pathogenic
157607	NM_021102.4(SPINT2):c.502G>A (p.Gly168Ser)	Pathogenic
3062101	NM_021102.4(SPINT2):c.166_167dup (p.Asn57fs)	Pathogenic
3242708	NC_000019.9:g.(?38755533)(38755658_?)del	Pathogenic
3611761	NM_021102.4(SPINT2):c.1A>G (p.Met1Val)	Pathogenic
5204	NM_021102.4(SPINT2):c.593-1G>A	Pathogenic
5205	NM_021102.4(SPINT2):c.488A>G (p.Tyr163Cys)	Pathogenic
5206	NM_021102.4(SPINT2):c.337+2T>C	Pathogenic
5207	NM_021102.4(SPINT2):c.553+2T>A	Pathogenic
5208	NM_021102.4(SPINT2):c.1A>T (p.Met1Leu)	Pathogenic
635284	NM_021102.4(SPINT2):c.447G>A (p.Trp149Ter)	Pathogenic
1068083	NM_021102.4(SPINT2):c.391+2T>C	Likely pathogenic
1321871	NM_021102.4(SPINT2):c.386A>G (p.Tyr129Cys)	Likely pathogenic
1810227	NM_021102.4(SPINT2):c.442C>T (p.Arg148Cys)	Likely pathogenic
1936006	NM_021102.4(SPINT2):c.278-2A>G	Likely pathogenic
1943857	NM_021102.4(SPINT2):c.553+1G>A	Likely pathogenic
2500740	NM_021102.4(SPINT2):c.421C>G (p.Pro141Ala)	Likely pathogenic

SpliceAI

1537 predictions. Top by Δscore:

Variant	Effect	Δscore
19:38252353:C:CT	acceptor_gain	1.0000
19:38252354:A:T	acceptor_gain	1.0000
19:38252891:TACC:T	donor_loss	1.0000
19:38252972:CTC:C	acceptor_gain	1.0000
19:38252973:TCCTA:T	acceptor_loss	1.0000
19:38252975:CT:C	acceptor_loss	1.0000
19:38252982:C:CT	acceptor_gain	1.0000
19:38256134:CTCAC:C	donor_loss	1.0000
19:38256135:TCA:T	donor_loss	1.0000
19:38256137:A:AC	donor_gain	1.0000
19:38256137:ACCAT:A	donor_loss	1.0000
19:38256138:C:CA	donor_loss	1.0000
19:38256138:C:CC	donor_gain	1.0000
19:38256138:CCATG:C	donor_gain	1.0000
19:38287933:GTG:G	donor_gain	1.0000
19:38289133:TTCA:T	acceptor_loss	1.0000
19:38289134:TCA:T	acceptor_loss	1.0000
19:38289136:A:AG	acceptor_gain	1.0000
19:38289137:G:GA	acceptor_gain	1.0000
19:38289137:GCT:G	acceptor_gain	1.0000
19:38289137:GCTC:G	acceptor_gain	1.0000
19:38290116:TA:T	acceptor_loss	1.0000
19:38290117:A:AC	acceptor_loss	1.0000
19:38290117:A:AG	acceptor_gain	1.0000
19:38290118:G:GA	acceptor_gain	1.0000
19:38290118:G:GT	acceptor_loss	1.0000
19:38290118:GA:G	acceptor_gain	1.0000
19:38290118:GAA:G	acceptor_gain	1.0000
19:38290118:GAAT:G	acceptor_gain	1.0000
19:38290256:G:GT	donor_gain	1.0000

AlphaMissense

1636 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:38290209:T:G	F161C	0.991
19:38290199:T:A	C158S	0.990
19:38290200:G:C	C158S	0.990
19:38283717:T:G	F66C	0.989
19:38283770:T:A	C84S	0.988
19:38283771:G:C	C84S	0.988
19:38290208:T:C	F161L	0.987
19:38290210:C:A	F161L	0.987
19:38290210:C:G	F161L	0.987
19:38290240:C:A	N171K	0.987
19:38290240:C:G	N171K	0.987
19:38290124:T:A	C133S	0.986
19:38290125:G:C	C133S	0.986
19:38290223:T:A	C166S	0.986
19:38290224:G:C	C166S	0.986
19:38283707:T:A	C63S	0.985
19:38283708:G:C	C63S	0.985
19:38283716:T:C	F66L	0.985
19:38283718:T:A	F66L	0.985
19:38283718:T:G	F66L	0.985
19:38290174:G:C	W149C	0.985
19:38290174:G:T	W149C	0.985
19:38290239:A:T	N171I	0.985
19:38290151:T:A	C142S	0.984
19:38290152:G:C	C142S	0.984
19:38290200:G:A	C158Y	0.984
19:38290220:G:T	G165C	0.983
19:38283747:A:T	N76I	0.982
19:38290170:G:C	R148P	0.982
19:38290178:T:C	F151L	0.982

dbSNP variants (sampled 300 via entrez): RS1000016753 (19:38267423 G>A), RS1000273993 (19:38272922 A>G,T), RS1000315679 (19:38284119 G>A), RS1000376213 (19:38278475 A>G), RS1000406065 (19:38278859 A>G), RS1000479549 (19:38272349 A>G), RS1000527013 (19:38263089 G>A), RS1000783602 (19:38267654 G>GGA,GGC), RS1000890287 (19:38284123 G>A), RS1000932361 (19:38282718 G>T), RS1000961235 (19:38263352 C>T), RS1000989966 (19:38279767 C>T), RS1001207823 (19:38289274 G>A,C), RS1001285388 (19:38290323 G>A,T), RS1001345371 (19:38279448 G>A)

Disease associations

OMIM: gene MIM:605124 | disease phenotypes: MIM:270420

GenCC curated gene-disease

Disease	Classification	Inheritance
syndromic congenital sodium diarrhea	Definitive	Autosomal recessive
congenital secretory sodium diarrhea 3	Strong	Autosomal recessive

Mondo (3): congenital secretory sodium diarrhea 3 (MONDO:0010036), congenital sodium diarrhea (MONDO:0015170), syndromic congenital sodium diarrhea (MONDO:0034204)

Orphanet (1): Congenital sodium diarrhea (Orphanet:103908)

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000073	Ureteral duplication
HP:0000075	Renal duplication
HP:0000143	Rectovaginal fistula
HP:0000175	Cleft palate
HP:0000256	Macrocephaly
HP:0000316	Hypertelorism
HP:0000369	Low-set ears
HP:0000453	Choanal atresia
HP:0000588	Optic disc coloboma
HP:0000973	Cutis laxa
HP:0001561	Polyhydramnios
HP:0002023	Anal atresia
HP:0002566	Intestinal malrotation
HP:0003270	Abdominal distention
HP:0005208	Secretory diarrhea
HP:0200020	Corneal erosion

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST004603_273	Platelet count	3.000000e-16
GCST006585_424	Blood protein levels	0.000000e+00
GCST90002401_264	Platelet distribution width	1.000000e-18
GCST90002402_561	Platelet count	7.000000e-21
GCST90011898_85	Alanine aminotransferase levels	1.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count
EFO:0007984	platelet component distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066288 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.75	Kd	17.57	nM	CHEMBL5653589
7.75	ED50	17.57	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149473: Binding affinity to human SPINT2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0176	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression	2
chloropicrin	decreases expression	2
Decitabine	decreases expression, decreases reaction, affects expression	2
Cisplatin	affects response to substance, affects expression	2
Lead	affects expression, decreases expression	2
Smoke	decreases expression, decreases reaction, increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Tretinoin	decreases expression, increases expression	2
tert-Butylhydroperoxide	decreases expression	2
methylmercuric chloride	decreases expression	1
pirinixic acid	increases activity, increases expression, affects binding	1
bisphenol A	decreases methylation	1
trichostatin A	decreases reaction, affects expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	decreases methylation	1
nickel sulfate	decreases expression	1
benazol P	affects expression	1
bicalutamide	increases expression	1
di-n-butylphosphoric acid	affects expression	1
corosolic acid	increases expression	1
ICG 001	increases expression	1
jinfukang	increases expression	1
(+)-JQ1 compound	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	increases expression	1
Ethanol	affects cotreatment, increases abundance, increases expression	1
Benzo(a)pyrene	decreases methylation	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652515	Binding	Binding affinity to human SPINT2 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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