SPINK2

Summary

SPINK2 (serine peptidase inhibitor Kazal type 2, HGNC:11245) is a protein-coding gene on chromosome 4q12, encoding Serine protease inhibitor Kazal-type 2 (P20155). As a strong inhibitor of acrosin, it is required for normal spermiogenesis.

This gene encodes a member of the family of serine protease inhibitors of the Kazal type (SPINK). The encoded protein acts as a trypsin and acrosin inhibitor in the genital tract and is localized in the spermatozoa. The protein has been associated with the progression of lymphomas. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 6691 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spermatogenic failure 29 (Strong, GenCC)
• GWAS associations: 8
• Clinical variants (ClinVar): 16 total — 1 pathogenic
• Phenotypes (HPO): 11
• MANE Select transcript: NM_001271718

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11245
Approved symbol	SPINK2
Name	serine peptidase inhibitor Kazal type 2
Location	4q12
Locus type	gene with protein product
Status	Approved
Aliases	HUSI-II
Ensembl gene	ENSG00000128040
Ensembl biotype	protein_coding
OMIM	605753
Entrez	6691

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 retained_intron

ENST00000248701, ENST00000504762, ENST00000506738, ENST00000509707, ENST00000618802, ENST00000707144

RefSeq mRNA: 6 — MANE Select: NM_001271718 NM_001271718, NM_001271719, NM_001271720, NM_001271721, NM_001271722, NM_021114

CCDS: CCDS3508, CCDS63971, CCDS63972, CCDS75128

Canonical transcript exons

ENST00000506738 — 4 exons

Exon	Start	End
ENSE00000877981	56811685	56811794
ENSE00000877982	56820536	56820579
ENSE00001171343	56809861	56810184
ENSE00003844905	56821458	56821701

Expression profiles

Bgee: expression breadth ubiquitous, 177 present calls, max score 99.97.

FANTOM5 (CAGE): breadth broad, TPM avg 4.5113 / max 1001.3438, expressed in 213 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
52226	4.3257	209
52225	0.1667	24
52222	0.0094	3
52224	0.0049	2
52223	0.0046	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	99.97	gold quality
cauda epididymis	UBERON:0004360	99.71	gold quality
seminal vesicle	UBERON:0000998	99.58	gold quality
right testis	UBERON:0004534	99.43	gold quality
left testis	UBERON:0004533	99.34	gold quality
adult organism	UBERON:0007023	98.95	gold quality
epididymis	UBERON:0001301	98.38	gold quality
testis	UBERON:0000473	97.81	gold quality
male germ cell	CL:0000015	97.32	gold quality
sperm	CL:0000019	97.13	gold quality
caput epididymis	UBERON:0004358	95.50	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.99	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.86	gold quality
right atrium auricular region	UBERON:0006631	76.07	gold quality
bone marrow	UBERON:0002371	75.84	gold quality
monocyte	CL:0000576	74.71	gold quality
mononuclear cell	CL:0000842	74.32	gold quality
leukocyte	CL:0000738	74.12	gold quality
cardiac atrium	UBERON:0002081	74.05	gold quality
mucosa of transverse colon	UBERON:0004991	72.88	gold quality
gluteal muscle	UBERON:0002000	72.23	silver quality
vagina	UBERON:0000996	70.79	gold quality
rectum	UBERON:0001052	69.86	gold quality
type B pancreatic cell	CL:0000169	69.35	gold quality
lymph node	UBERON:0000029	68.83	gold quality
bone marrow cell	CL:0002092	68.75	silver quality
choroid plexus epithelium	UBERON:0003911	67.74	gold quality
epithelial cell of pancreas	CL:0000083	67.67	gold quality
adenohypophysis	UBERON:0002196	67.64	gold quality
granulocyte	CL:0000094	67.06	gold quality

Single-cell (SCXA)

Detected in 23 experiment(s), a significant marker in 21.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	4329.64
E-GEOD-124263	yes	2856.61
E-MTAB-10432	yes	2501.54
E-HCAD-6	yes	1543.10
E-GEOD-76312	yes	1233.70
E-MTAB-9067	yes	923.98
E-HCAD-4	yes	814.69
E-MTAB-7407	yes	731.40
E-MTAB-10042	yes	679.19
E-CURD-112	yes	632.08
E-CURD-55	yes	574.32
E-CURD-77	yes	501.11
E-MTAB-8207	yes	497.42
E-ANND-5	yes	405.45
E-CURD-6	yes	350.28

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

14 targeting SPINK2, 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-6768-5P	99.92	67.36	1942
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4320	99.75	65.80	793
HSA-MIR-7151-5P	99.37	67.82	613
HSA-MIR-4311	99.31	70.47	3041
HSA-MIR-10526-3P	97.86	64.97	1342
HSA-MIR-6765-3P	97.83	64.59	1165
HSA-MIR-6783-5P	97.67	67.21	1528
HSA-MIR-346	97.01	66.97	662
HSA-MIR-4764-3P	96.81	67.94	580

Literature-anchored findings (GeneRIF, showing 4)

• Data showed that the expression level of SPINK2 is significantly elevated in most leukemia cell lines except B-lymphoblast TK-6 cells. Data demonstrated that Arg(24) at the P1 site is crucial for the specificity of SPINK2 on target enzyme. (PMID:19422058)
• These results demonstrate that SPINK2 is necessary to neutralize proteases during their cellular transit toward the acrosome and that its deficiency induces a pathological continuum ranging from oligoasthenoteratozoospermia in heterozygotes to azoospermia in homozygotes. (PMID:28554943)
• Investigated whether tazarotene-induced gene 1 protein (TIG1) affects the activity of urokinase plasminogen-type activator, which is negatively regulated by serine peptidase inhibitor Kazal type 2 (SPINK2), potentially preventing epithelial mesenchymal transition and suppressing cell migration and invasion. (PMID:31886233)
• SPINK2 Protein Expression Is an Independent Adverse Prognostic Marker in AML and Is Potentially Implicated in the Regulation of Ferroptosis and Immune Response. (PMID:37298647)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Spink2	ENSMUSG00000053030
rattus_norvegicus	Spink2	ENSRNOG00000066503

Paralogs (5): SPINK7 (ENSG00000145879), SPINK14 (ENSG00000196800), SPINK9 (ENSG00000204909), SPINK13 (ENSG00000214510), SPINK8 (ENSG00000229453)

Protein

Protein identifiers

Serine protease inhibitor Kazal-type 2 — P20155 (reviewed: P20155)

Alternative names: Acrosin-trypsin inhibitor, Epididymis tissue protein Li 172, HUSI-II

All UniProt accessions (5): P20155, A0A087WTA9, A0AA34QVT9, D6RC51, D6RI10

UniProt curated annotations — full annotation on UniProt →

Function. As a strong inhibitor of acrosin, it is required for normal spermiogenesis. It probably hinders premature activation of proacrosin and other proteases, thus preventing the cascade of events leading to spermiogenesis defects. May be involved in the regulation of serine protease-dependent germ cell apoptosis. It also inhibits trypsin.

Subcellular location. Secreted. Cytoplasmic vesicle. Secretory vesicle. Acrosome.

Tissue specificity. Expressed in epididymis (at protein level).

Disease relevance. Spermatogenic failure 29 (SPGF29) [MIM:618091] An autosomal recessive infertility disorder caused by spermatogenesis defects that result in non-obstructive azoospermia or oligozoospermia. When produced, spermatozoa are immotile and have abnormal morphology, primarily defects of the acrosome and head-neck junction. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (6): NP_001258647, NP_001258648, NP_001258649, NP_001258650, NP_001258651, NP_066937 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002350	Kazal_dom	Domain
IPR036058	Kazal_dom_sf	Homologous_superfamily
IPR042167	SPINK2	Family

Pfam: PF00050

UniProt features (19 total): strand 5, mutagenesis site 4, disulfide bond 3, helix 2, signal peptide 1, chain 1, domain 1, site 1, modified residue 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6KBR	X-RAY DIFFRACTION	2
2JXD	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P20155-F1	85.61	0.53

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): 46–47 (reactive bond)

Post-translational modifications (1): 24

Disulfide bonds (3): 36–66, 44–63, 52–84

Mutagenesis-validated functional residues (4):

Position	Phenotype
47	reduces inhibitory activity towards trypsin.
48	reduces inhibitory activity towards trypsin.
45	no effect on inhibitory activity towards trypsin.
46	loss of inhibitory activity towards trypsin.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 161 (showing top): MULLIGHAN_NPM1_SIGNATURE_3_UP, GOCC_SECRETORY_GRANULE, GOBP_VESICLE_ORGANIZATION, GOBP_MALE_GAMETE_GENERATION, GRAHAM_CML_QUIESCENT_VS_NORMAL_QUIESCENT_DN, GOBP_SECRETORY_GRANULE_ORGANIZATION, GOBP_CELLULAR_COMPONENT_ASSEMBLY_INVOLVED_IN_MORPHOGENESIS, MODULE_379, SHEDDEN_LUNG_CANCER_GOOD_SURVIVAL_A4, GRAHAM_CML_QUIESCENT_VS_NORMAL_DIVIDING_DN, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_UP, TAKEDA_TARGETS_OF_NUP98_HOXA9_FUSION_10D_UP, GOBP_ACROSOME_ASSEMBLY, GOBP_ORGANELLE_ASSEMBLY, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM

GO Biological Process (2): acrosome assembly (GO:0001675), spermatid development (GO:0007286)

GO Molecular Function (4): endopeptidase inhibitor activity (GO:0004866), serine-type endopeptidase inhibitor activity (GO:0004867), protein binding (GO:0005515), peptidase inhibitor activity (GO:0030414)

GO Cellular Component (3): acrosomal vesicle (GO:0001669), extracellular region (GO:0005576), cytoplasmic vesicle (GO:0031410)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
developmental process involved in reproduction	1
spermatid development	1
cellular component assembly involved in morphogenesis	1
cellular process involved in reproduction in multicellular organism	1
secretory granule organization	1
organelle assembly	1
germ cell development	1
spermatid differentiation	1
endopeptidase activity	1
peptidase inhibitor activity	1
endopeptidase regulator activity	1
serine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
binding	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
secretory granule	1
cellular anatomical structure	1
cytoplasm	1
intracellular vesicle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

31 interactions, top by confidence:

A	B	Type	Score
KRTAP5-9	SPINK2	psi-mi:“MI:0915”(physical association)	0.560
ADAMTSL4	SPINK2	psi-mi:“MI:0915”(physical association)	0.560
SPINK2	NOTCH2NLA	psi-mi:“MI:0915”(physical association)	0.560
	SPINK2	psi-mi:“MI:0915”(physical association)	0.560
SPINK2	KRTAP5-9	psi-mi:“MI:0915”(physical association)	0.560
NOTCH2NLA	SPINK2	psi-mi:“MI:0915”(physical association)	0.560
SPINK2	ADAMTSL4	psi-mi:“MI:0915”(physical association)	0.560
SPINK2	KLK4	psi-mi:“MI:0407”(direct interaction)	0.560
KLK4	SPINK2	psi-mi:“MI:0407”(direct interaction)	0.560
SPINK2	GRN	psi-mi:“MI:0915”(physical association)	0.560
SPINK2	WFS1	psi-mi:“MI:0915”(physical association)	0.560
SPINK2	STRN	psi-mi:“MI:0914”(association)	0.530
SPINK2	RARRES1	psi-mi:“MI:0915”(physical association)	0.460
RARRES1	SPINK2	psi-mi:“MI:0915”(physical association)	0.460
SPINK2	RARRES1	psi-mi:“MI:0403”(colocalization)	0.460
MAPK8IP2	SPINK2	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (43): SPINK2 (Two-hybrid), ADAMTSL4 (Two-hybrid), KRTAP10-3 (Two-hybrid), NOTCH2NL (Two-hybrid), SPINK2 (Two-hybrid), GCHFR (Affinity Capture-MS), ATP5S (Affinity Capture-MS), NUDT8 (Affinity Capture-MS), MIPEP (Affinity Capture-MS), DCAF15 (Affinity Capture-MS), CTTNBP2NL (Affinity Capture-MS), PRTFDC1 (Affinity Capture-MS), UBR2 (Affinity Capture-MS), PDP2 (Affinity Capture-MS), IDE (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, D3ZVP0, O35679, O60575, O62650, O95633, P00995, P00996, P00997, P00998, P01003, P01005, P04542, P05560, P09036, P09655, P09656, P0C7L1, P0DKM8, P0DKM9, P0DKT1, P0DKT2, P0DKT3, P0DKT4, P0DKT5, P10184, P10669, P11706, P16226, P19883, P20155, P21674, P25304, P31514, P31696, P34953, P37109, P47931, P50291

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	11
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
559843	NM_001271718.2(SPINK2):c.206-3C>G	Pathogenic

SpliceAI

440 predictions. Top by Δscore:

Variant	Effect	Δscore
4:56820528:CTACT:C	donor_loss	0.9900
4:56820530:ACTTA:A	donor_loss	0.9900
4:56820532:TTAC:T	donor_loss	0.9900
4:56820533:T:TG	donor_loss	0.9900
4:56820534:A:AG	donor_loss	0.9900
4:56820580:C:CC	acceptor_gain	0.9900
4:56820534:A:AC	donor_gain	0.9800
4:56820535:C:CC	donor_gain	0.9800
4:56821450:T:A	donor_gain	0.9800
4:56821552:CCCAA:C	donor_gain	0.9800
4:56820527:GCTAC:G	donor_loss	0.9700
4:56820576:GAGG:G	acceptor_gain	0.9700
4:56820578:GG:G	acceptor_gain	0.9700
4:56821603:GCTAC:G	donor_loss	0.9700
4:56821604:CTA:C	donor_loss	0.9700
4:56821605:TACCT:T	donor_loss	0.9700
4:56821606:ACCTG:A	donor_loss	0.9700
4:56811795:C:CC	acceptor_gain	0.9600
4:56820577:AGGC:A	acceptor_loss	0.9600
4:56820578:GGC:G	acceptor_loss	0.9600
4:56820579:GC:G	acceptor_loss	0.9600
4:56820580:C:CG	acceptor_loss	0.9600
4:56820581:T:A	acceptor_loss	0.9600
4:56821602:CGCTA:C	donor_loss	0.9600
4:56810180:CTTCC:C	acceptor_gain	0.9500
4:56810185:C:CC	acceptor_gain	0.9500
4:56811791:TTGG:T	acceptor_gain	0.9500
4:56811792:TGG:T	acceptor_gain	0.9500
4:56821608:C:A	donor_loss	0.9500
4:56810181:TTCCC:T	acceptor_loss	0.9400

AlphaMissense

848 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:56811697:C:G	C66S	0.992
4:56811698:A:T	C66S	0.992
4:56811706:C:G	C63S	0.992
4:56811707:A:T	C63S	0.992
4:56811739:C:G	C52S	0.992
4:56811740:A:T	C52S	0.992
4:56811763:C:G	C44S	0.991
4:56811764:A:T	C44S	0.991
4:56810143:C:G	C84S	0.989
4:56810144:A:T	C84S	0.989
4:56811712:T:A	N61I	0.986
4:56810142:G:C	C84W	0.985
4:56811707:A:G	C63R	0.985
4:56811711:A:C	N61K	0.985
4:56811711:A:T	N61K	0.985
4:56811698:A:G	C66R	0.984
4:56811787:C:G	C36S	0.984
4:56811788:A:T	C36S	0.984
4:56810144:A:G	C84R	0.982
4:56811764:A:G	C44R	0.982
4:56811740:A:G	C52R	0.980
4:56811696:G:C	C66W	0.979
4:56811697:C:T	C66Y	0.979
4:56811732:A:C	S54R	0.979
4:56811732:A:T	S54R	0.979
4:56811734:T:G	S54R	0.979
4:56811739:C:T	C52Y	0.979
4:56810143:C:T	C84Y	0.977
4:56811730:T:G	D55A	0.977
4:56811730:T:A	D55V	0.976

dbSNP variants (sampled 300 via entrez): RS1000292979 (4:56822711 A>G), RS1000513280 (4:56817115 T>C), RS1000615499 (4:56821370 G>C), RS10007921 (4:56815434 T>A), RS1000916461 (4:56815560 C>T), RS10015630 (4:56812976 A>G,T), RS1001675296 (4:56810470 A>G), RS1002175237 (4:56820315 C>A), RS1002185254 (4:56814386 A>G), RS1002286390 (4:56819970 A>G), RS1002296247 (4:56820240 C>T), RS1002398071 (4:56814506 G>A,C), RS1002449943 (4:56820863 T>A), RS10024887 (4:56821772 A>G), RS10024985 (4:56821867 A>G,T)

Disease associations

OMIM: gene MIM:605753 | disease phenotypes: MIM:618091

GenCC curated gene-disease

Disease	Classification	Inheritance
spermatogenic failure 29	Strong	Autosomal recessive

Mondo (1): spermatogenic failure 29 (MONDO:0054733)

Orphanet (0):

HPO phenotypes

11 total (11 of 11 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000027	Azoospermia
HP:0000118	Phenotypic abnormality
HP:0000837	Increased circulating gonadotropin level
HP:0003251	Male infertility
HP:0008669	Abnormal spermatogenesis
HP:0008734	Decreased testicular size
HP:0011462	Young adult onset
HP:0011961	Non-obstructive azoospermia
HP:0011962	Obstructive azoospermia
HP:0012208	Immotile sperm

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST002987_5	Stroke	1.000000e-06
GCST003264_903	Post bronchodilator FEV1/FVC ratio	1.000000e-06
GCST003473_5	Aggressiveness in attention deficit hyperactivity disorder	9.000000e-06
GCST003720_40	Migraine	3.000000e-09
GCST006493_10	Systemic sclerosis	8.000000e-06
GCST006585_2443	Blood protein levels	4.000000e-29
GCST010479_66	Coronary artery disease	3.000000e-08
GCST010867_57	Coronary artery disease	4.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	9
trichostatin A	increases expression	2
entinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
methylmercuric chloride	decreases expression	1
propionaldehyde	increases expression	1
decabromobiphenyl ether	affects expression	1
butyraldehyde	increases expression	1
pentanal	increases expression	1
tamibarotene	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	1
belinostat	increases expression	1
ICG 001	decreases expression	1
dorsomorphin	decreases expression, affects cotreatment, increases expression	1
theaflavin-3,3’-digallate	affects expression	1
Arsenic Trioxide	decreases expression	1
Aldehydes	increases expression	1
Benzo(a)pyrene	affects methylation	1
Carbamazepine	affects expression	1
Dimethyl Sulfoxide	affects expression	1
Diuron	decreases expression	1
Tretinoin	decreases expression	1
Cadmium Chloride	decreases expression	1
S-Nitrosoglutathione	decreases expression	1

Clinical trials (associated diseases)

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