SPINK4

Summary

SPINK4 (serine peptidase inhibitor Kazal type 4, HGNC:16646) is a protein-coding gene on chromosome 9p13.3, encoding Serine protease inhibitor Kazal-type 4 (O60575).

Predicted to enable serine-type endopeptidase inhibitor activity. Predicted to be located in extracellular region.

Source: NCBI Gene 27290 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 24 total
• MANE Select transcript: NM_014471

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16646
Approved symbol	SPINK4
Name	serine peptidase inhibitor Kazal type 4
Location	9p13.3
Locus type	gene with protein product
Status	Approved
Aliases	PEC-60, MGC133107
Ensembl gene	ENSG00000122711
Ensembl biotype	protein_coding
OMIM	613929
Entrez	27290

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000379721, ENST00000379725

RefSeq mRNA: 1 — MANE Select: NM_014471 NM_014471

CCDS: CCDS6536

Canonical transcript exons

ENST00000379721 — 4 exons

Exon	Start	End
ENSE00000832777	33245112	33245152
ENSE00000832778	33246616	33246728
ENSE00001482272	33240167	33240269
ENSE00001933837	33248426	33248567

Expression profiles

Bgee: expression breadth ubiquitous, 146 present calls, max score 99.68.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.6042 / max 172.5546, expressed in 55 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
96439	0.6042	55

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	99.68	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	98.05	gold quality
rectum	UBERON:0001052	96.58	gold quality
jejunal mucosa	UBERON:0000399	96.11	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.92	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.72	gold quality
duodenum	UBERON:0002114	93.35	gold quality
small intestine	UBERON:0002108	93.26	gold quality
colonic mucosa	UBERON:0000317	93.05	gold quality
vermiform appendix	UBERON:0001154	93.02	gold quality
caecum	UBERON:0001153	91.54	gold quality
mucosa of transverse colon	UBERON:0004991	91.53	gold quality
pancreatic ductal cell	CL:0002079	83.61	silver quality
transverse colon	UBERON:0001157	80.65	gold quality
jejunum	UBERON:0002115	80.27	gold quality
intestine	UBERON:0000160	76.67	gold quality
diaphragm	UBERON:0001103	74.95	gold quality
type B pancreatic cell	CL:0000169	74.30	gold quality
epithelial cell of pancreas	CL:0000083	73.54	silver quality
smooth muscle tissue	UBERON:0001135	72.79	gold quality
endometrium epithelium	UBERON:0004811	72.56	gold quality
large intestine	UBERON:0000059	71.84	gold quality
islet of Langerhans	UBERON:0000006	71.76	gold quality
adrenal tissue	UBERON:0018303	70.83	gold quality
colon	UBERON:0001155	70.74	gold quality
olfactory bulb	UBERON:0002264	70.00	gold quality
mucosa of urinary bladder	UBERON:0001259	65.84	silver quality
tongue squamous epithelium	UBERON:0006919	65.63	gold quality
vastus lateralis	UBERON:0001379	65.27	gold quality
colonic epithelium	UBERON:0000397	65.17	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	21583.90
E-CURD-46	yes	12926.18
E-MTAB-8410	yes	5950.84
E-MTAB-7316	yes	40.92
E-ANND-3	no	2.38

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SPDEF

Literature-anchored findings (GeneRIF, showing 2)

• this study shows that downregulated SPINK4 is associated with poor survival in colorectal cancer (PMID:31888570)
• SPINK4 modulates inhibition of glycolysis against colorectal cancer progression. (PMID:38747892)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	spink4	ENSDARG00000091609
mus_musculus	Spink4	ENSMUSG00000028415
rattus_norvegicus	Spink4	ENSRNOG00000008252

Protein

Protein identifiers

Serine protease inhibitor Kazal-type 4 — O60575 (reviewed: O60575)

Alternative names: Peptide PEC-60 homolog

All UniProt accessions (3): O60575, Q5VZE7, V9HWG8

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Secreted.

RefSeq proteins (1): NP_055286* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002350	Kazal_dom	Domain
IPR036058	Kazal_dom_sf	Homologous_superfamily
IPR039932	Spink4-like	Family

Pfam: PF00050

UniProt features (8 total): disulfide bond 3, signal peptide 1, chain 1, domain 1, site 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60575-F1	84.92	0.48

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): 48–49 (reactive bond)

Disulfide bonds (3): 37–68, 46–65, 54–86

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 0 (showing top):

GO Biological Process (1): response to xenobiotic stimulus (GO:0009410)

GO Molecular Function (3): serine-type endopeptidase inhibitor activity (GO:0004867), protein binding (GO:0005515), peptidase inhibitor activity (GO:0030414)

GO Cellular Component (1): extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to chemical	1
serine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
binding	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
cellular anatomical structure	1

Protein interactions and networks

STRING

612 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPINK4	REG4	Q9BYZ8	532
SPINK4	TFF3	Q07654	512
SPINK4	SPDEF	O95238	499
SPINK4	SPINK13	Q1W4C9	492
SPINK4	SPINK6	Q6UWN8	483
SPINK4	ITLN1	Q8WWA0	467
SPINK4	AGR2	O95994	460
SPINK4	SPINK5	Q9NQ38	452
SPINK4	SPINK9	Q5DT21	446
SPINK4	SPINK14	Q6IE38	442
SPINK4	D6RI10	D6RI10	437
SPINK4	CLCA1	A8K7I4	431
SPINK4	SPINK1	P00995	410
SPINK4	SPINK7	P58062	389
SPINK4	ZG16	O60844	378

IntAct

7 interactions, top by confidence:

A	B	Type	Score
SPINK4	SGTB	psi-mi:“MI:0915”(physical association)	0.560
SPINK4	PLXNA2	psi-mi:“MI:0914”(association)	0.530
FXYD1	SPINK4	psi-mi:“MI:0914”(association)	0.350
SPINK4	SGTB	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (18): LAMA3 (Affinity Capture-MS), HTRA1 (Affinity Capture-MS), MINPP1 (Affinity Capture-MS), MICA (Affinity Capture-MS), PLXNA2 (Affinity Capture-MS), SPPL2B (Affinity Capture-MS), CERCAM (Affinity Capture-MS), TMEM67 (Affinity Capture-MS), SGTB (Two-hybrid), CERCAM (Affinity Capture-MS), MINPP1 (Affinity Capture-MS), DCAF10 (Affinity Capture-MS), PLXNA2 (Affinity Capture-MS), SPPL2B (Affinity Capture-MS), TMEM67 (Affinity Capture-MS)

ESM2 similar proteins: A0A1Q1NL17, A0A3G5BID2, B4QW11, D0MVC9, D3GGZ8, K7WMX6, L0GB04, O55159, O60575, O97176, P00995, P00996, P01005, P09036, P09655, P09656, P0DKM7, P0DPZ9, P0DQC4, P0DQC5, P0DQC9, P0DQD0, P0DQG2, P0DQV2, P0DRJ1, P0DXW5, P0DXX0, P16422, P20155, P26461, P37109, P41998, P81481, Q09553, Q09TK7, Q177W0, Q1WER1, Q3T0L5, Q5DT21, Q5MGC9

Diamond homologs: A2ASQ1, A5YT95, G4V4G1, O00468, O35679, O60575, O62650, O93390, O95633, P07214, P09486, P0DKM8, P0DKT1, P10184, P10669, P13213, P16895, P16975, P19883, P20112, P21674, P23499, P25304, P31514, P31515, P31696, P36233, P36377, P36378, P37109, P47931, P50291, Q12841, Q14515, Q1LZB9, Q58D84, Q5R767, Q5R9Y1, Q62356, Q62632

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	22
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

454 predictions. Top by Δscore:

Variant	Effect	Δscore
9:33245110:A:AG	acceptor_gain	1.0000
9:33245111:G:GG	acceptor_gain	1.0000
9:33245111:GAA:G	acceptor_gain	1.0000
9:33246725:GGAT:G	donor_gain	1.0000
9:33246726:GAT:G	donor_gain	1.0000
9:33246726:GATG:G	donor_gain	1.0000
9:33246729:G:GG	donor_gain	1.0000
9:33240267:GGG:G	donor_gain	0.9900
9:33240268:GGG:G	donor_gain	0.9900
9:33245105:GTTTC:G	acceptor_loss	0.9900
9:33245106:TTTCA:T	acceptor_loss	0.9900
9:33245107:TTCA:T	acceptor_loss	0.9900
9:33245108:TCA:T	acceptor_loss	0.9900
9:33245109:CA:C	acceptor_loss	0.9900
9:33245110:AGA:A	acceptor_loss	0.9900
9:33245111:G:GA	acceptor_loss	0.9900
9:33245111:GA:G	acceptor_gain	0.9900
9:33245148:GAATG:G	donor_gain	0.9900
9:33246613:C:G	acceptor_gain	0.9900
9:33246614:A:AG	acceptor_gain	0.9900
9:33246615:G:GG	acceptor_gain	0.9900
9:33246615:GCC:G	acceptor_gain	0.9900
9:33246615:GCCC:G	acceptor_gain	0.9900
9:33246615:GCCCA:G	acceptor_gain	0.9900
9:33246728:TGT:T	donor_loss	0.9900
9:33246729:G:GA	donor_loss	0.9900
9:33246730:T:TC	donor_loss	0.9900
9:33248421:CCTA:C	acceptor_loss	0.9900
9:33248422:CTA:C	acceptor_loss	0.9900
9:33248423:TAGA:T	acceptor_loss	0.9900

AlphaMissense

559 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:33248466:T:A	C86S	0.984
9:33248467:G:C	C86S	0.984
9:33246673:T:A	C54S	0.982
9:33246674:G:C	C54S	0.982
9:33248466:T:C	C86R	0.979
9:33246715:T:A	C68S	0.977
9:33246716:G:C	C68S	0.977
9:33246715:T:C	C68R	0.975
9:33248468:C:G	C86W	0.974
9:33246622:T:A	C37S	0.971
9:33246623:G:C	C37S	0.971
9:33246725:G:C	R71P	0.970
9:33246717:C:G	C68W	0.969
9:33246713:T:C	L67P	0.967
9:33246673:T:C	C54R	0.964
9:33246623:G:A	C37Y	0.963
9:33246677:G:A	G55D	0.962
9:33246706:T:A	C65S	0.962
9:33246707:G:C	C65S	0.962
9:33246716:G:A	C68Y	0.958
9:33246675:C:G	C54W	0.955
9:33246695:A:G	Y61C	0.955
9:33246622:T:C	C37R	0.950
9:33246682:G:C	D57H	0.950
9:33246673:T:G	C54G	0.949
9:33246674:G:A	C54Y	0.949
9:33246682:G:T	D57Y	0.946
9:33246676:G:T	G55C	0.945
9:33246624:T:G	C37W	0.944
9:33246617:C:A	P35H	0.943

dbSNP variants (sampled 300 via entrez): RS1000085858 (9:33245454 T>C,G), RS1000494958 (9:33243597 C>T), RS1000645423 (9:33238590 A>T), RS1000905796 (9:33238770 C>G), RS1001580543 (9:33241276 C>A,T), RS1002326591 (9:33239753 C>T), RS1002478261 (9:33245615 C>A), RS1002582026 (9:33245300 T>C,G), RS1002858901 (9:33244117 C>A,T), RS1002992611 (9:33242159 T>C), RS1003081401 (9:33241298 A>G), RS1003143844 (9:33248576 G>A), RS1003250723 (9:33248235 G>A), RS1003255533 (9:33248853 A>G), RS1003449687 (9:33242816 C>T)

Disease associations

OMIM: gene MIM:613929 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST003123_21	Severe influenza A (H1N1) infection	9.000000e-11
GCST003124_25	Mild influenza (H1N1) infection	1.000000e-13
GCST003125_4	Influenza A (H1N1) infection	1.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:1001488	influenza A (H1N1)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
propionaldehyde	increases methylation	1
bisphenol A	decreases expression	1
nonanal	increases methylation	1
n-hexanal	increases methylation	1
butyraldehyde	increases methylation	1
caprylic aldehyde	increases methylation	1
hydroquinone	decreases expression	1
pentanal	increases methylation	1
heptanal	increases methylation	1
Estradiol	increases expression	1
Fluorouracil	affects expression	1
Malathion	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Zinc	decreases expression	1
Cadmium Chloride	decreases expression	1

Clinical trials (associated diseases)

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