PI16

Summary

PI16 (peptidase inhibitor 16, HGNC:21245) is a protein-coding gene on chromosome 6p21.2, encoding Peptidase inhibitor 16 (Q6UXB8). May inhibit cardiomyocyte growth.

Predicted to enable peptidase inhibitor activity. Predicted to act upstream of or within negative regulation of cell growth involved in cardiac muscle cell development. Predicted to be located in extracellular region. Predicted to be active in extracellular space.

Source: NCBI Gene 221476 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 67 total
• MANE Select transcript: NM_153370

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21245
Approved symbol	PI16
Name	peptidase inhibitor 16
Location	6p21.2
Locus type	gene with protein product
Status	Approved
Aliases	MGC45378, dJ90K10.5, MSMBBP, CD364
Ensembl gene	ENSG00000164530
Ensembl biotype	protein_coding
Entrez	221476

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 13 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000373674, ENST00000491324, ENST00000611814, ENST00000647861, ENST00000892901, ENST00000892902, ENST00000892903, ENST00000892904, ENST00000968219, ENST00000968220, ENST00000968221, ENST00000968222, ENST00000968223, ENST00000968224

RefSeq mRNA: 2 — MANE Select: NM_153370 NM_001199159, NM_153370

CCDS: CCDS34440

Canonical transcript exons

ENST00000373674 — 7 exons

Exon	Start	End
ENSE00001085216	36962935	36963612
ENSE00001085223	36961451	36961560
ENSE00001171886	36961886	36961974
ENSE00001461200	36964386	36964837
ENSE00001461208	36954738	36954931
ENSE00002453116	36959145	36959366
ENSE00003498546	36963823	36963962

Expression profiles

Bgee: expression breadth ubiquitous, 231 present calls, max score 97.76.

FANTOM5 (CAGE): breadth broad, TPM avg 9.9863 / max 908.1116, expressed in 419 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
67582	7.9674	324
67577	0.8463	72
67576	0.3374	60
67579	0.2676	93
67578	0.2162	67
67575	0.1385	50
67580	0.1213	45
67581	0.0550	31
67584	0.0366	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper arm skin	UBERON:0004263	97.76	gold quality
apex of heart	UBERON:0002098	97.16	gold quality
mucosa of stomach	UBERON:0001199	97.03	gold quality
right atrium auricular region	UBERON:0006631	96.50	gold quality
vena cava	UBERON:0004087	96.47	gold quality
cardiac atrium	UBERON:0002081	96.12	gold quality
pancreatic ductal cell	CL:0002079	96.10	silver quality
right coronary artery	UBERON:0001625	95.89	gold quality
endocervix	UBERON:0000458	95.31	gold quality
kidney epithelium	UBERON:0004819	94.41	gold quality
trachea	UBERON:0003126	93.74	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	93.67	gold quality
tibial nerve	UBERON:0001323	93.61	gold quality
cardia of stomach	UBERON:0001162	93.59	gold quality
coronary artery	UBERON:0001621	92.82	gold quality
spinal cord	UBERON:0002240	92.75	gold quality
left coronary artery	UBERON:0001626	92.49	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.34	gold quality
lower esophagus muscularis layer	UBERON:0035833	91.69	gold quality
lower esophagus	UBERON:0013473	91.60	gold quality
body of tongue	UBERON:0011876	91.51	gold quality
gall bladder	UBERON:0002110	91.18	gold quality
cardiac muscle of right atrium	UBERON:0003379	91.15	gold quality
ectocervix	UBERON:0012249	90.89	gold quality
lateral nuclear group of thalamus	UBERON:0002736	90.63	gold quality
saphenous vein	UBERON:0007318	90.36	gold quality
vagina	UBERON:0000996	90.22	gold quality
skin of leg	UBERON:0001511	90.18	gold quality
substantia nigra	UBERON:0002038	89.63	gold quality
uterine cervix	UBERON:0000002	89.38	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

16 targeting PI16, 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-1193	100.00	65.93	529
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-4520-3P	98.75	66.55	963
HSA-MIR-4433A-3P	97.75	62.82	1435
HSA-MIR-4286	97.20	64.37	1587
HSA-MIR-1913	97.07	66.20	1417
HSA-MIR-5192	96.89	63.35	879
HSA-MIR-550B-2-5P	96.56	64.61	646
HSA-MIR-4296	96.35	63.55	1233
HSA-MIR-6821-3P	95.21	66.79	578

Literature-anchored findings (GeneRIF, showing 8)

• A new blood protein PSP94-binding protein (PSPBP) is identified that binds prostate secretory protein of 94 amino acids (PSP94). (PMID:15344909)
• a novel and independent prognostic markers following radical prostatectomy for prostate cancer. (PMID:17062675)
• PI16-positive Treg showed enhanced in vitro migration towards the inflammatory chemokines CCL17 and CCL20, suggesting they can migrate to sites of inflammation (PMID:22533972)
• at high endothelial shear stress, PI16 contributes to inhibition of MMP2 protease activity, protection that can be reversed during inflammation (PMID:27996045)
• this study shows that skin-homing CD8(+) T cells preferentially express GPI-anchored peptidase inhibitor 16 (PMID:30365157)
• this study shows that Peptidase inhibitor 16 identifies a human regulatory T-cell subset with reduced FOXP3 expression over the first year of recent onset type 1 diabetes (PMID:31127857)
• Peptidase inhibitor 16 promotes inflammatory arthritis by suppressing Foxp3 expression via regulating K48-linked ubiquitin degradation Bmi-1 in regulatory T cells. (PMID:38147957)
• Peptidase inhibitor 16 promotes proliferation of pancreatic ductal adenocarcinoma cells through OASL signaling. (PMID:38353288)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Pi16	ENSMUSG00000024011
rattus_norvegicus	Pi16	ENSRNOG00000000525

Protein

Protein identifiers

Peptidase inhibitor 16 — Q6UXB8 (reviewed: Q6UXB8)

Alternative names: Cysteine-rich secretory protein 9, PSP94-binding protein

All UniProt accessions (1): Q6UXB8

UniProt curated annotations — full annotation on UniProt →

Function. May inhibit cardiomyocyte growth.

Subunit / interactions. Interacts with PSP94/MSMB.

Subcellular location. Secreted.

Tissue specificity. Expressed in prostate, testis, ovary and intestine. Concentrates in prostate cancer patient’s sera.

Post-translational modifications. N- and O-glycosylated. O-glycosylated with core 1 or possibly core 8 glycans.

Miscellaneous. May serve as a marker following prostatectomy for prostate cancer.

Similarity. Belongs to the CRISP family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6UXB8-1	1	yes
Q6UXB8-2	2

RefSeq proteins (2): NP_001186088, NP_699201* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001283	CRISP-related	Family
IPR014044	CAP_dom	Domain
IPR018244	Allrgn_V5/Tpx1_CS	Conserved_site
IPR035940	CAP_sf	Homologous_superfamily

Pfam: PF00188

UniProt features (17 total): region of interest 4, glycosylation site 3, sequence variant 2, sequence conflict 2, compositionally biased region 2, signal peptide 1, chain 1, splice variant 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UXB8-F1	63.62	0.39

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Glycosylation sites (3): 403, 409, 114

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 138 (showing top): GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, GOBP_GROWTH, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_NEGATIVE_REGULATION_OF_ORGAN_GROWTH, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, GOBP_REGULATION_OF_ORGAN_GROWTH, GOBP_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION, GOBP_MUSCLE_ADAPTATION

GO Biological Process (1): negative regulation of cell growth involved in cardiac muscle cell development (GO:0061052)

GO Molecular Function (2): peptidase inhibitor activity (GO:0030414), protein binding (GO:0005515)

GO Cellular Component (2): obsolete extracellular space (GO:0005615), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of cardiac muscle hypertrophy	1
negative regulation of cell growth	1
negative regulation of striated muscle cell differentiation	1
negative regulation of cardiac muscle tissue growth	1
cell growth involved in cardiac muscle cell development	1
regulation of cell growth involved in cardiac muscle cell development	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

914 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PI16	MSMB	P08118	844
PI16	SERPINI2	O75830	670
PI16	NCOA4	Q13772	638
PI16	KLK3	P07288	566
PI16	CEP290	O15078	519
PI16	EZH2	Q15910	499
PI16	MFAP5	Q13361	435
PI16	SERPINB4	P48594	432
PI16	COL14A1	Q05707	399
PI16	ZNF80	P51504	396
PI16	CLEC3B	P05452	391
PI16	PCOLCE2	Q9UKZ9	390
PI16	AFAP1L2	Q8N4X5	389
PI16	CREB1	P16220	384
PI16	COL1A1	P02452	380

IntAct

23 interactions, top by confidence:

A	B	Type	Score
TNFRSF21	PI16	psi-mi:“MI:0407”(direct interaction)	0.600
PI16	TNFRSF21	psi-mi:“MI:0407”(direct interaction)	0.600
TNFRSF21	PI16	psi-mi:“MI:0403”(colocalization)	0.600
PLP1	PI16	psi-mi:“MI:0915”(physical association)	0.560
ATP6V0C	PI16	psi-mi:“MI:0915”(physical association)	0.560
PI16	TMEM86A	psi-mi:“MI:0915”(physical association)	0.560
TMBIM6	PI16	psi-mi:“MI:0915”(physical association)	0.560
PI16	TMEM60	psi-mi:“MI:0915”(physical association)	0.560
STRIT1	PI16	psi-mi:“MI:0915”(physical association)	0.560
TRPV2	PI16	psi-mi:“MI:0915”(physical association)	0.370
PLP1	PI16	psi-mi:“MI:0915”(physical association)	0.000
ATP6V0C	PI16	psi-mi:“MI:0915”(physical association)	0.000
STRIT1	PI16	psi-mi:“MI:0915”(physical association)	0.000
TMEM86A	PI16	psi-mi:“MI:0915”(physical association)	0.000
TMBIM6	PI16	psi-mi:“MI:0915”(physical association)	0.000
TMEM60	PI16	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (11): PI16 (Two-hybrid), PI16 (Two-hybrid), PI16 (Two-hybrid), PI16 (Two-hybrid), ATP6V0C (Two-hybrid), LOC100507537 (Two-hybrid), ANXA1 (Affinity Capture-MS), ANXA1 (Affinity Capture-Western), IKBKG (Affinity Capture-Western), PI16 (Affinity Capture-Western), PI16 (Affinity Capture-Western)

ESM2 similar proteins: A0A1B0GV85, A2ALI5, A2APT9, B0BN44, B1ARY8, B6ZI38, O14836, O35188, O55145, O60279, O60667, P07141, P09603, P0C8S2, P28906, P40225, P40226, P42705, P78423, Q06154, Q08DV9, Q13261, Q1ERP8, Q28270, Q2TB54, Q3UY90, Q4V9H3, Q4W8E7, Q5F267, Q5R770, Q60819, Q64314, Q6PAL1, Q6PCP7, Q6UXB8, Q80XI1, Q8BLK9, Q8CAE9, Q8CBC4, Q8JZQ0

Diamond homologs: A0A182GL09, A0A1S4EWW7, A0A218QX58, A1BQQ5, A6MFK9, A6QLZ7, A8S6B6, A9QQ26, A9YME1, B2MVK7, B9URJ1, C0ITL3, D4B327, D4P2Y4, F8J2D4, G3CJR9, O19010, O43692, P0CB15, P0DMB9, P0DMT4, P0DPU0, P0DPU1, P0DPU2, P0DPU5, P0DPV2, P0DSI3, P10736, P10737, P12020, P16562, P16563, P35759, P35760, P35778, P35779, P35780, P35781, P35782, P35783

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	57
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1464 predictions. Top by Δscore:

Variant	Effect	Δscore
6:36959300:GC:G	donor_gain	1.0000
6:36948426:G:T	donor_gain	0.9900
6:36959140:TGCAG:T	acceptor_gain	0.9900
6:36959142:CAGAG:C	acceptor_loss	0.9900
6:36959143:A:AC	acceptor_loss	0.9900
6:36959143:A:AG	acceptor_gain	0.9900
6:36959144:G:GG	acceptor_gain	0.9900
6:36959144:G:GT	acceptor_loss	0.9900
6:36959144:GA:G	acceptor_gain	0.9900
6:36959144:GAGA:G	acceptor_gain	0.9900
6:36959144:GAGAT:G	acceptor_gain	0.9900
6:36959345:GAT:G	donor_gain	0.9900
6:36959362:CGCAG:C	donor_loss	0.9900
6:36959363:GCAGG:G	donor_loss	0.9900
6:36959364:CAG:C	donor_loss	0.9900
6:36959365:AG:A	donor_loss	0.9900
6:36959366:GGTGT:G	donor_loss	0.9900
6:36959367:GTGTG:G	donor_loss	0.9900
6:36962929:TATCA:T	acceptor_loss	0.9900
6:36962930:ATCAG:A	acceptor_loss	0.9900
6:36962931:TCA:T	acceptor_loss	0.9900
6:36962932:CAGA:C	acceptor_loss	0.9900
6:36962933:A:AG	acceptor_gain	0.9900
6:36962933:A:T	acceptor_loss	0.9900
6:36962934:G:GG	acceptor_gain	0.9900
6:36963026:GAAAA:G	donor_gain	0.9900
6:36948401:CCAGG:C	donor_loss	0.9800
6:36948402:CAG:C	donor_loss	0.9800
6:36948404:GG:G	donor_loss	0.9800
6:36948405:GTC:G	donor_loss	0.9800

AlphaMissense

2971 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:36959291:G:C	W106C	1.000
6:36959291:G:T	W106C	1.000
6:36959150:G:C	W59C	0.999
6:36959150:G:T	W59C	0.999
6:36959201:G:C	W76C	0.999
6:36959201:G:T	W76C	0.999
6:36959289:T:A	W106R	0.999
6:36959289:T:C	W106R	0.999
6:36959237:T:A	N88K	0.998
6:36959237:T:G	N88K	0.998
6:36961459:G:C	W134C	0.998
6:36961459:G:T	W134C	0.998
6:36961544:T:A	C163S	0.998
6:36961545:G:A	C163Y	0.998
6:36961545:G:C	C163S	0.998
6:36959148:T:A	W59R	0.997
6:36959148:T:C	W59R	0.997
6:36959229:G:T	G86C	0.997
6:36959233:A:T	E87V	0.997
6:36959234:G:C	E87D	0.997
6:36959234:G:T	E87D	0.997
6:36959366:G:C	Q131H	0.997
6:36959366:G:T	Q131H	0.997
6:36961481:T:A	C142S	0.997
6:36961482:G:C	C142S	0.997
6:36961544:T:C	C163R	0.997
6:36961546:C:G	C163W	0.997
6:36961551:A:G	Y165C	0.997
6:36959193:T:A	C74S	0.996
6:36959194:G:C	C74S	0.996

dbSNP variants (sampled 300 via entrez): RS1000123836 (6:36947767 C>G,T), RS1000185126 (6:36959684 G>A), RS1000254375 (6:36953490 C>A), RS1000523582 (6:36958561 T>C), RS1000627460 (6:36964061 C>T), RS1000658537 (6:36964367 G>A), RS1000705760 (6:36948540 C>T), RS1001372673 (6:36953047 C>A), RS1001413431 (6:36960742 G>A), RS1001509381 (6:36965047 G>A), RS1001665094 (6:36959179 C>T), RS1001775021 (6:36947836 G>A), RS1001823508 (6:36964755 G>A), RS1001856105 (6:36963697 G>A,T), RS1001984247 (6:36955565 G>T)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST000628_2	Chemerin levels	6.000000e-06
GCST002481_11	Acne (severe)	2.000000e-06
GCST006414_142	Atrial fibrillation	1.000000e-13
GCST006479_31	Diverticular disease	3.000000e-06
GCST012299_8	Schizophrenia, bipolar disorder or major depressive disorder x sex interaction (3df)	4.000000e-06
GCST012310_15	Schizophrenia x sex interaction	5.000000e-06
GCST012311_18	Schizophrenia x sex interaction	3.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004573	chemerin measurement
EFO:0009959	diverticular disease
EFO:0008343	sex interaction measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
propionaldehyde	increases expression	1
bisphenol A	affects cotreatment, increases methylation	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
Poly(amidoamine)	decreases expression	1
Fulvestrant	increases methylation, affects cotreatment	1
Acetaminophen	decreases expression	1
Doxorubicin	decreases expression	1
Latex	decreases expression	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment, decreases expression	1
Phthalic Acids	increases methylation	1
Silicon Dioxide	decreases expression	1

Clinical trials (associated diseases)

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