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): 217 total — 11 pathogenic, 7 likely-pathogenic
• GTEx eGene: eQTL in 29 tissues, sQTL in 25 (q < 0.05)
• Phenotypes (HPO): 17
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.94 (unconstrained)
• 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: 32 — 26 protein_coding, 3 retained_intron, 3 nonsense_mediated_decay

MANE Select: ENST00000301244

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 5, TSL 3: 4

ENST00000301244, ENST00000454580, ENST00000585357, ENST00000587090, ENST00000587334, ENST00000587516, ENST00000589749, ENST00000590210, ENST00000590510, ENST00000590738, ENST00000592007, ENST00000902577, ENST00000902578, ENST00000902579, ENST00000918438, ENST00000918439, ENST00000918440, ENST00000918441, ENST00000964700, ENST00000964701, ENST00000964702, ENST00000964703, ENST00001004208, ENST00001042163, ENST00001042165, ENST00001042166, ENST00001087681, ENST00001087683, ENST00001087685, ENST00001087686, ENST00001087687, ENST00001142089

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.

Highest expression (Bgee): type B pancreatic cell, mucosa of transverse colon, parotid gland, islet of Langerhans, pituitary gland.

Genetic regulation across tissues (GTEx eQTL / sQTL)

SPINT2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 29 tissues and its splicing (sQTL) in 25 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 54 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Artery Aorta	sqtl	4.1e-47	-1.05	19:38301201:A:G
Artery Tibial	eqtl	3.1e-27	-0.44	19:38263036:A:C
Cells EBV-transformed lymphocytes	eqtl	2.8e-25	+0.58	19:38266372:C:A
Nerve Tibial	eqtl	9.4e-24	-0.43	19:38266372:C:A
Esophagus Muscularis	sqtl	7.4e-22	-0.85	19:38302956:G:C
Skin Not Sun Exposed Suprapubic	sqtl	2.2e-21	+0.80	19:38313539:G:A
Thyroid	sqtl	4.0e-21	-0.52	19:38301201:A:G
Heart Left Ventricle	sqtl	1.9e-19	-0.84	19:38359051:T:C
Esophagus Mucosa	sqtl	2.6e-18	+0.76	19:38287112:C:T
Lung	sqtl	4.1e-17	-0.58	19:38301201:A:G
Adipose Subcutaneous	eqtl	6.6e-17	-0.28	19:38258750:C:G
Skin Sun Exposed Lower leg	sqtl	5.1e-15	+0.53	19:38268764:C:T
Pancreas	sqtl	1.2e-13	-0.68	19:38301201:A:G
Whole Blood	sqtl	1.0e-12	+0.48	19:38304255:T:C
Minor Salivary Gland	sqtl	1.1e-12	-0.85	19:38301201:A:G
Stomach	eqtl	2.0e-12	-0.21	19:38264348:G:A
Stomach	sqtl	1.8e-11	+0.66	19:38264348:G:A
Artery Aorta	eqtl	2.1e-10	-0.23	19:38263036:A:C
Esophagus Gastroesophageal Junction	sqtl	7.9e-10	-0.69	19:38305938:T:TC
Adipose Visceral Omentum	eqtl	1.3e-07	-0.25	19:38263036:A:C

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

showing 100 of 299 tissues 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
renal medulla	UBERON:0000362	98.63	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.59	gold quality
lower esophagus mucosa	UBERON:0035834	98.59	gold quality
skin of leg	UBERON:0001511	98.58	gold quality
metanephros cortex	UBERON:0010533	98.57	gold quality
pancreas	UBERON:0001264	98.54	gold quality
duodenum	UBERON:0002114	98.52	gold quality
ileal mucosa	UBERON:0000331	98.42	gold quality
bronchus	UBERON:0002185	98.42	gold quality
epithelium of bronchus	UBERON:0002031	98.40	gold quality
esophagus squamous epithelium	UBERON:0006920	98.38	gold quality
gingiva	UBERON:0001828	98.36	gold quality
gingival epithelium	UBERON:0001949	98.36	gold quality
epithelium of nasopharynx	UBERON:0001951	98.34	gold quality
nasopharynx	UBERON:0001728	98.32	gold quality
bronchial epithelial cell	CL:0002328	98.23	gold quality
tongue squamous epithelium	UBERON:0006919	98.22	gold quality
zone of skin	UBERON:0000014	98.20	gold quality
oocyte	CL:0000023	98.18	gold quality
right lung	UBERON:0002167	98.18	gold quality
squamous epithelium	UBERON:0006914	97.98	gold quality
gall bladder	UBERON:0002110	97.94	gold quality
right coronary artery	UBERON:0001625	97.91	gold quality
epithelium of esophagus	UBERON:0001976	97.90	gold quality
adult mammalian kidney	UBERON:0000082	97.89	gold quality
jejunal mucosa	UBERON:0000399	97.89	gold quality
upper arm skin	UBERON:0004263	97.89	gold quality
nipple	UBERON:0002030	97.83	gold quality
testis	UBERON:0000473	97.77	gold quality
upper lobe of left lung	UBERON:0008952	97.70	gold quality
corpus epididymis	UBERON:0004359	97.69	gold quality
superior surface of tongue	UBERON:0007371	97.65	gold quality
upper lobe of lung	UBERON:0008948	97.60	gold quality
hair follicle	UBERON:0002073	97.44	gold quality
tonsil	UBERON:0002372	97.41	gold quality
penis	UBERON:0000989	97.39	gold quality
oral cavity	UBERON:0000167	97.35	gold quality
mucosa of urinary bladder	UBERON:0001259	97.35	gold quality
tongue	UBERON:0001723	97.34	gold quality
cervix epithelium	UBERON:0004801	97.33	gold quality
mammary duct	UBERON:0001765	97.29	gold quality
secondary oocyte	CL:0000655	96.96	gold quality
epithelium of mammary gland	UBERON:0003244	96.94	gold quality
lung	UBERON:0002048	96.82	gold quality
caput epididymis	UBERON:0004358	96.75	gold quality
placenta	UBERON:0001987	96.73	gold quality
eye	UBERON:0000970	96.71	gold quality
pancreatic ductal cell	CL:0002079	96.65	gold quality
body of tongue	UBERON:0011876	96.55	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.54	gold quality
kidney	UBERON:0002113	96.47	gold quality
monocyte	CL:0000576	96.45	gold quality
bone marrow cell	CL:0002092	96.43	gold quality
upper leg skin	UBERON:0004262	96.34	gold quality
pylorus	UBERON:0001166	96.25	gold quality
left ovary	UBERON:0002119	96.24	gold quality
urinary bladder	UBERON:0001255	96.13	gold quality
transverse colon	UBERON:0001157	96.12	gold quality
mononuclear cell	CL:0000842	96.10	gold quality
prefrontal cortex	UBERON:0000451	96.10	gold quality
mammalian vulva	UBERON:0000997	96.09	gold quality
adult organism	UBERON:0007023	96.09	gold quality
prostate gland	UBERON:0002367	96.00	gold quality
leukocyte	CL:0000738	95.93	gold quality
urethra	UBERON:0000057	95.87	gold quality
cortex of kidney	UBERON:0001225	95.87	gold quality
germinal epithelium of ovary	UBERON:0001304	95.87	gold quality
cortical plate	UBERON:0005343	95.62	gold quality
metanephros	UBERON:0000081	95.51	gold quality
ovary	UBERON:0000992	95.51	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

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Salivary gland	tissue	474.7	medium
Pituitary gland	tissue	408.8
Thyroid gland	tissue	301.2	medium
Colon	tissue	278.3	medium
Epididymis	tissue	254.6	medium
Small intestine	tissue	251.4	medium
Parathyroid gland	tissue	237.7	medium
Rectum	tissue	236.3	medium
Duodenum	tissue	232.9	medium
Stomach 1	tissue	207.1	medium
Skin 1	tissue	185.6	medium
Pancreas	tissue	184.5	medium
Fallopian tube	tissue	178.6	medium
Prostate	tissue	170.7	medium
Breast	tissue	167.4	medium
Esophagus	tissue	165.4	low
Vagina	tissue	151.8	not detected
Placenta	tissue	147.1	high
Kidney	tissue	139.8	medium
Cervix	tissue	137.0	medium
Testis	tissue	136.1	medium
Urinary bladder	tissue	130.9	medium
Lung	tissue	130.4	medium
Choroid plexus	tissue	112.9
Seminal vesicle	tissue	105.0	high
Gallbladder	tissue	98.7	medium
Tonsil	tissue	95.0	medium
Thymus	tissue	77.0
Bone marrow	tissue	76.6	medium
Ovary	tissue	71.4	medium
Appendix	tissue	61.6	medium
Locus coeruleus	tissue	58.0
Spleen	tissue	45.6	low
Nucleus accumbens	tissue	45.0
Hippocampus	tissue	42.9	medium
Adrenal gland	tissue	42.1	low
Postcentral gyrus	tissue	41.9
Endometrium 1	tissue	41.8	medium
Lymph node	tissue	35.0	medium
Retina	tissue	21.9
Smooth muscle	tissue	17.8	not detected
Caudate putamen	tissue	17.8
Hypothalamus	tissue	16.9
Spinal cord	tissue	15.8
Pons	tissue	14.0
Substantia nigra	tissue	13.7
Heart muscle	tissue	12.7	not detected
Periaqueductal gray	tissue	12.5
Frontal cortex	tissue	11.6
Hippocampal formation	tissue	11.6
Thalamus	tissue	11.4
Septum	tissue	11.1
Midbrain	tissue	11.0
Superior colliculi	tissue	11.0
Medulla oblongata	tissue	10.9
Liver	tissue	9.9	low
Adipose tissue	tissue	9.8	low
Corpus callosum	tissue	8.7
Amygdala	tissue	6.5
Ventral forebrain	tissue	5.7

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Blood vessel (334.3), Arcuate nucleus (139.1), Ventromedial nucleus (90.1), Paraventricular nucleus (81.5), Lateral hypothalamic area (80.3).

Regulation

Is transcription factor: no

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

miRNA regulators (miRDB)

Targeting SPINT2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 33 miRNAs:

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

Functional genomics

gnomAD constraint: pLI 0.000107, LOEUF 0.935, missense Z 1.11 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000301244 — one region, missense o/e 0.83.

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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1338031) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 9 distinct phenotype terms.

Mouse phenotype (MP)	Records
exencephaly	1
abnormal ectoderm development	1
abnormal gastrulation	1
abnormal neural tube morphology	1
abnormal neural tube closure	1
embryonic lethality between implantation and placentation, complete penetrance	1
embryonic lethality during organogenesis, complete penetrance	1
preweaning lethality, complete penetrance	1
embryonic lethality between implantation and placentation, incomplete penetrance	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Actinia tenebrosa	A0A6P8HC43	100.0%	Diamond
Cyriopagopus schmidti	B2ZBB6	100.0%	Diamond
Cyriopagopus hainanus	D2Y2C2	100.0%	Diamond
Actinia equina	P0DMW8	100.0%	Diamond
Anemonia viridis	P0DN06	100.0%	Diamond
Macaca mulatta	P29216	100.0%	Diamond
Macaca fascicularis	P53601	100.0%	Diamond
Capra hircus	P62756	100.0%	Diamond
Ovis aries	P62757	100.0%	Diamond
Sus scrofa	P79307	100.0%	Diamond
Pan troglodytes	Q5IS80	100.0%	Diamond
Cavia porcellus	Q60495	100.0%	Diamond
Saimiri sciureus	Q95241	100.0%	Diamond
Anemonia sulcata	Q9TWF9	98.3%	Diamond
Lychas mucronatus	P0DJ45	97.5%	Diamond
Tabanus yao	C1IBY4	97.4%	Diamond
Rhipicephalus microplus	Q8WPI2	95.8%	Diamond
Bos taurus	P00975	93.2%	Diamond
Radianthus crispa	P16344	91.1%	Diamond
Haemaphysalis longicornis	B6ZIW0	90.1%	Diamond
Haemaphysalis doenitzi	C0HMC7	90.1%	Diamond
Mesocricetus auratus	Q60559	86.8%	Diamond
Meriones unguiculatus	Q62577	86.8%	Diamond
Equus caballus	P04365	86.6%	Diamond
Dichotomyctere fluviatilis	O73683	83.9%	Diamond
Takifugu rubripes	O93279	80.4%	Diamond
Notamacropus eugenii	O62845	76.8%	Diamond
Anthopleura aff. xanthogrammica	P81547	76.4%	Diamond
Palythoa caribaeorum	P0DQQ9	72.5%	Diamond
Oryctolagus cuniculus	P19761	72.1%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
SNORD152	snoRNA	109623473
SIPA1L3	protein-coding	23094
DPF1	protein-coding	8193
PPP1R14A	protein-coding	94274
C19orf33	protein-coding	64073
YIF1B	protein-coding	90522
KCNK6	protein-coding	9424
CATSPERG	protein-coding	57828
PSMD8	protein-coding	5714

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 by resolution:

PDB	Title	Method	Resolution (Å)
4U32	Human mesotrypsin complexed with HAI-2 Kunitz domain 1	X-RAY DIFFRACTION	1.65

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Transporters, Accessory Factors Involved in Transport, Predicted membrane proteins, Predicted intracellular proteins, Plasma proteins, Cancer-related genes, Candidate cancer biomarkers, Disease related genes, Potential drug targets, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): golgi apparatus; vesicles

Antibody reliability (HPA): IH approved · IF enhanced

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)

Position	Role
143–144	reactive bond
48–49	reactive bond

Disulfide bonds (6)

Type	Positions
Disulfide bond	38–88, 47–71, 63–84, 133–183, 142–166, 158–179

Glycosylation sites (2)

Type	Positions
N-linked (glcnac…) asparagine	57, 94

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 5; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

5 pathways:

ID	Pathway	Evidence
R-HSA-6806942	MET Receptor Activation	curated
R-HSA-8852405	Signaling by MST1	curated
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 (4): epithelial cell morphogenesis (GO:0003382), establishment or maintenance of cell polarity (GO:0007163), negative regulation of cell-cell adhesion (GO:0022408), negative regulation of cell motility (GO:2000146)

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

3 top-level categories:

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

GO top-level categories

25 GO namespaces:

Category	Terms
cellular anatomical structure	3
cell morphogenesis	1
epithelial cell development	1
cellular process	1
negative regulation of cell adhesion	1
regulation of cell-cell adhesion	1
cell-cell adhesion	1
negative regulation of locomotion	1
negative regulation of cellular process	1
cell motility	1
regulation of cell motility	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

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 5 of 12 annotations. The rest are phylogenetic / computational / electronic (IEA).

5 experimentally-supported GO terms:

GO term	NS	Evidence
negative regulation of cell motility	BP	direct assay
negative regulation of cell-cell adhesion	BP	direct assay
Golgi apparatus	CC	direct assay
cytoplasm	CC	direct assay
serine-type endopeptidase inhibitor activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 964 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPINT2	HGFAC	Q04756	931
SPINT2	C19orf33	Q9GZP8	849
SPINT2	EPCAM	P16422	818
SPINT2	ST14	Q9Y5Y6	756
SPINT2	PNOC	Q13519	717
SPINT2	PRSS8	Q16651	679
SPINT2	MYO5B	Q9ULV0	645
SPINT2	PPP1R14A	Q96A00	644
SPINT2	HPN	P05981	625
SPINT2	PDYN	P01213	570
SPINT2	AP5M1	Q9H0R1	552
SPINT2	NEUROG3	Q9Y4Z2	549
SPINT2	KLK1	P06870	510
SPINT2	FOXP1	Q9H334	504
SPINT2	SLC26A3	P40879	503

IntAct

Human interaction partners of SPINT2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

4 partners by confidence:

Partner	Interaction type	MIscore	Records
UPK3BL1	association	0.530	2
MEP1B	physical association	0.370	1
SMIM22	association	0.350	1
SPAG9	association	0.350	1

BioGRID (309 interactions; top human partners by supporting records): TBC1D15 (Affinity Capture-MS; 4 records), ASPHD2 (Affinity Capture-MS; 3 records), ATP12A (Affinity Capture-MS; 3 records), ATP2A3 (Affinity Capture-MS; 3 records), ATP8B2 (Affinity Capture-MS; 3 records), BAG3 (Affinity Capture-MS; 3 records), C1orf112 (Affinity Capture-MS; 3 records), CCZ1 (Affinity Capture-MS; 3 records), CKAP5 (Affinity Capture-MS; 3 records), CNTNAP1 (Affinity Capture-MS; 3 records), CYP51A1 (Affinity Capture-MS; 3 records), DAGLB (Affinity Capture-MS; 3 records), DHRS7 (Affinity Capture-MS; 3 records), DPH1 (Affinity Capture-MS; 3 records), EGFL7 (Affinity Capture-MS; 3 records)

Disease & clinical

Genetic variants

Variant evidence for SPINT2: 217 ClinVar records (18 pathogenic / likely pathogenic); 5 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	7
Uncertain significance	63
Likely benign	108
Benign	9

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 18 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
5205	NM_021102.4(SPINT2):c.488A>G (p.Tyr163Cys)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
3062101	NM_021102.4(SPINT2):c.166_167dup (p.Asn57fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1394791	NM_021102.4(SPINT2):c.3G>A (p.Met1Ile)	Pathogenic	criteria provided, single submitter	1
3611761	NM_021102.4(SPINT2):c.1A>G (p.Met1Val)	Pathogenic	criteria provided, single submitter	1
1068083	NM_021102.4(SPINT2):c.391+2T>C	Likely pathogenic	criteria provided, single submitter	2
1810227	NM_021102.4(SPINT2):c.442C>T (p.Arg148Cys)	Likely pathogenic	criteria provided, single submitter	1
1936006	NM_021102.4(SPINT2):c.278-2A>G	Likely pathogenic	criteria provided, single submitter	1
1943857	NM_021102.4(SPINT2):c.553+1G>A	Likely pathogenic	criteria provided, single submitter	1
2500740	NM_021102.4(SPINT2):c.421C>G (p.Pro141Ala)	Likely pathogenic	criteria provided, single submitter	1
4942029	NM_021102.4(SPINT2):c.387T>A (p.Tyr129Ter)	Likely pathogenic	criteria provided, single submitter	1
3242708	NC_000019.9:g.(?38755533)(38755658_?)del	Pathogenic	criteria provided, single submitter	1
5204	NM_021102.4(SPINT2):c.593-1G>A	Pathogenic	no assertion criteria provided	1
5206	NM_021102.4(SPINT2):c.337+2T>C	Pathogenic	no assertion criteria provided	1
5207	NM_021102.4(SPINT2):c.553+2T>A	Pathogenic	no assertion criteria provided	1
5208	NM_021102.4(SPINT2):c.1A>T (p.Met1Leu)	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore SPINT2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 43 predictions of 487):

Position(s)	Effect	Δscore	Sites
19:38289136–38289137	acceptor_loss	1.0000	6
19:38290117–38290118	acceptor_loss	1.0000	4
19:38290281–38290282	donor_loss	1.0000	3
19:38290535–38290536	acceptor_loss	1.0000	6
19:38290576–38290577	donor_loss	1.0000	4
19:38291885–38291886	acceptor_gain	1.0000	2
19:38264999–38265000	donor_loss	0.9900	5
19:38287874–38287875	acceptor_loss	0.9900	6
19:38289192–38289193	donor_loss	0.9900	6
19:38290105	acceptor_gain	0.9900

AlphaMissense

314 missense substitutions predicted likely pathogenic (of 1,636 scored), across 76 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
N171	8	0.969	0.987
F66	8	0.920	0.989
N76	8	0.905	0.982
C158	7	0.972	0.990
C63	7	0.966	0.985
C142	7	0.960	0.984
C133	7	0.959	0.986
C179	7	0.959	0.982
C166	7	0.956	0.986
C84	7	0.954	0.988
F161	7	0.949	0.991
C183	7	0.944	0.980
C71	7	0.940	0.977
F151	7	0.922	0.982
C88	7	0.916	0.976
C47	7	0.915	0.974
W149	7	0.909	0.985
W54	7	0.887	0.977
C38	7	0.870	0.924
N169	7	0.840	0.953

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	0.000327
Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA)	unfavorable	0.00034

Disease associations

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

GenCC curated gene-disease

2 curated gene-disease records:

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

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (5 panels, 3 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

5 panels:

Panel	Rating
Choanal atresia	green
Fetal anomalies	green
Intestinal failure or congenital diarrhoea	green
Limb disorders	amber
Paediatric disorders	amber

Mondo (2): congenital secretory sodium diarrhea 3 (MONDO:0010036), syndromic congenital sodium diarrhea (MONDO:0034204)

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

HPO phenotypes

17 phenotypes (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:

Study	Trait	p-value
GCST006585_2792	Blood protein levels	0.000000e+00
GCST90002402_406	Platelet count	7e-21
GCST90002401_245	Platelet distribution width	1e-18
GCST004603_273	Platelet count	3e-16
GCST90011898_158	Alanine aminotransferase levels	1e-8

EFO canonical traits (from GWAS)

2 canonical traits:

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 (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

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	affects expression, decreases expression, decreases reaction	2
Cisplatin	affects expression, affects response to substance	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	affects binding, increases activity, increases expression	1
bisphenol A	decreases methylation	1
trichostatin A	affects expression, decreases reaction	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)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for SPINT2 across ~30M SureChEMBL compounds — explore on Sugi Predict.