WFDC1

Summary

WFDC1 (WAP four-disulfide core domain 1, HGNC:15466) is a protein-coding gene on chromosome 16q24.1, encoding WAP four-disulfide core domain protein 1 (Q9HC57). Has growth inhibitory activity.

This gene encodes a member of the WAP-type four disulfide core domain family. The WAP-type four-disulfide core domain contains eight cysteines forming four disulfide bonds at the core of the protein, and functions as a protease inhibitor in many family members. This gene is mapped to chromosome 16q24, an area of frequent loss of heterozygosity in cancers, including prostate, breast and hepatocellular cancers and Wilms’ tumor. This gene is downregulated in many cancer types and may be involved in the inhibition of cell proliferation. The encoded protein may also play a role in the susceptibility of certain CD4 memory T cells to human immunodeficiency virus infection. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 58189 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 77 total
• MANE Select transcript: NM_021197

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15466
Approved symbol	WFDC1
Name	WAP four-disulfide core domain 1
Location	16q24.1
Locus type	gene with protein product
Status	Approved
Aliases	PS20
Ensembl gene	ENSG00000103175
Ensembl biotype	protein_coding
OMIM	605322
Entrez	58189

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 19 protein_coding, 2 retained_intron

ENST00000219454, ENST00000567056, ENST00000568638, ENST00000613603, ENST00000622779, ENST00000879882, ENST00000879883, ENST00000879884, ENST00000879885, ENST00000879886, ENST00000879887, ENST00000879888, ENST00000879889, ENST00000879890, ENST00000879891, ENST00000879892, ENST00000879893, ENST00000943489, ENST00000943490, ENST00000943491, ENST00000943492

RefSeq mRNA: 3 — MANE Select: NM_021197 NM_001282466, NM_001282467, NM_021197

CCDS: CCDS10946

Canonical transcript exons

ENST00000219454 — 7 exons

Exon	Start	End
ENSE00000695409	84318272	84318355
ENSE00000695410	84319431	84319571
ENSE00000875046	84294878	84295115
ENSE00000875047	84312961	84313153
ENSE00002594078	84329322	84329844
ENSE00003546815	84326882	84326955
ENSE00003649235	84324419	84324460

Expression profiles

Bgee: expression breadth ubiquitous, 241 present calls, max score 98.32.

FANTOM5 (CAGE): breadth broad, TPM avg 5.4993 / max 1061.8311, expressed in 454 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
155318	1.9761	294
155314	1.2030	249
155316	0.6368	144
155317	0.5562	171
155315	0.4970	106
155321	0.2307	131
155320	0.1667	89
155313	0.1050	34
155319	0.0935	52
155312	0.0344	22

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
saphenous vein	UBERON:0007318	98.32	gold quality
right coronary artery	UBERON:0001625	97.53	gold quality
seminal vesicle	UBERON:0000998	96.92	gold quality
blood vessel layer	UBERON:0004797	96.86	gold quality
pigmented layer of retina	UBERON:0001782	96.85	gold quality
retina	UBERON:0000966	96.83	gold quality
nipple	UBERON:0002030	95.97	gold quality
popliteal artery	UBERON:0002250	95.73	gold quality
tibial artery	UBERON:0007610	95.73	gold quality
urethra	UBERON:0000057	95.66	gold quality
cardia of stomach	UBERON:0001162	95.52	gold quality
coronary artery	UBERON:0001621	95.22	gold quality
mucosa of urinary bladder	UBERON:0001259	95.04	gold quality
left coronary artery	UBERON:0001626	94.92	gold quality
placenta	UBERON:0001987	94.81	gold quality
cauda epididymis	UBERON:0004360	93.91	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.70	gold quality
gall bladder	UBERON:0002110	93.22	gold quality
prostate gland	UBERON:0002367	93.01	gold quality
urinary bladder	UBERON:0001255	92.75	gold quality
aorta	UBERON:0000947	92.28	gold quality
pylorus	UBERON:0001166	91.95	gold quality
periodontal ligament	UBERON:0008266	88.99	gold quality
vena cava	UBERON:0004087	88.75	gold quality
fundus of stomach	UBERON:0001160	88.57	gold quality
adrenal cortex	UBERON:0001235	88.27	gold quality
left adrenal gland	UBERON:0001234	88.25	gold quality
left adrenal gland cortex	UBERON:0035825	88.20	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	87.85	gold quality
ascending aorta	UBERON:0001496	87.83	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-11121	yes	1095.26
E-MTAB-7316	yes	831.31
E-GEOD-134144	yes	580.50
E-MTAB-6701	yes	56.71
E-HCAD-11	yes	10.33
E-ANND-3	yes	5.36

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

23 targeting WFDC1, 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-6780A-5P	99.88	66.69	2776
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-4663	99.62	65.33	957
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-377-3P	99.37	70.18	1905
HSA-MIR-532-3P	99.34	65.76	1195
HSA-MIR-3160-3P	99.07	64.78	955
HSA-MIR-3194-3P	98.83	66.22	1167
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-7155-5P	98.65	66.14	1290
HSA-MIR-5691	98.23	67.02	1335
HSA-MIR-6805-3P	98.23	67.02	1334
HSA-MIR-93-3P	98.15	66.65	1309
HSA-MIR-10398-5P	97.12	64.94	1051
HSA-MIR-6085	96.57	64.11	621
HSA-MIR-6813-5P	94.68	64.20	588

Literature-anchored findings (GeneRIF, showing 10)

• results suggest a minor role, if any, of WFDC1 in hepatocarcinogenesis (PMID:12032731)
• WFDC1/ps20 is down regulated but not frequently mutated in prostate cancer. It is expressed predominantly in the normal prostatic stroma. It might play a role in the maintenance of the normal extra cellular matrix milieu in the prostate. (PMID:15305342)
• ps20 promoted HIV entry via fusion and augmented CD54 integrin expression (PMID:17942534)
• data suggest an important role for WFDC1 in inhibiting proliferation of both tumors and senescent cells. Finally, we suggest that the downregulation of WFDC1 might serve as a biomarker for cellular transformation (PMID:18842679)
• our data suggest an important role for WFDC1 in inhibiting proliferation of both tumors and senescent cells (PMID:18842679)
• suggests that the tumor suppressive function of WFDC1 may be partially a result of up-regulated Dkk1 gene expression, which is known to be a potent inhibitor of the Wnt signaling pathway (PMID:19488830)
• HIV-1 virus transfer among primary CD4+ T-lymphocytes was promoted by ectopic ps20 expression or by exogenous addition of recombinant ps20. (PMID:21545747)
• Prostrate stromal 20 overexpression upregulates expression of cyclooxygenase-2 (COX-2) in LNCaP and WPMY-1 cells, and induces expression of a growth-suppressive phenotype, which inhibits proliferation of PCa cells by ps20-expressing WPMY-1 conditioned media. (PMID:27115470)
• Phylogenetic, molecular evolution and structural analyses of the WFDC1/prostate stromal protein 20. (PMID:30423385)
• Molecular structure, gene expression and functional role of WFDC1 in angiogenesis and cancer. (PMID:33615507)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	wfdc1	ENSDARG00000058003
mus_musculus	Wfdc1	ENSMUSG00000023336
rattus_norvegicus	Wfdc1	ENSRNOG00000015904

Protein

Protein identifiers

WAP four-disulfide core domain protein 1 — Q9HC57 (reviewed: Q9HC57)

Alternative names: Prostate stromal protein ps20, ps20 growth inhibitor

All UniProt accessions (2): Q9HC57, A0A087WY77

UniProt curated annotations — full annotation on UniProt →

Function. Has growth inhibitory activity.

Subcellular location. Secreted.

RefSeq proteins (3): NP_001269395, NP_001269396, NP_067020* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008197	WAP_dom	Domain
IPR036645	Elafin-like_sf	Homologous_superfamily
IPR042357	WFDC1	Family

Pfam: PF00095

UniProt features (14 total): disulfide bond 4, sequence variant 3, sequence conflict 2, region of interest 2, signal peptide 1, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HC57-F1	68.08	0.18

Functional residue map

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

Disulfide bonds (4): 66–96, 78–100, 83–95, 89–104

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 130 (showing top): GOBP_REGULATION_OF_WOUND_HEALING, GOBP_INFLAMMATORY_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, GOBP_GROWTH, MEF2_02, CHANDRAN_METASTASIS_DN, TANG_SENESCENCE_TP53_TARGETS_UP, GOBP_WOUND_HEALING, CAIRO_HEPATOBLASTOMA_CLASSES_DN, GOBP_REGULATION_OF_RESPONSE_TO_WOUNDING, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_NEGATIVE_REGULATION_OF_DEFENSE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_INFLAMMATORY_RESPONSE

GO Biological Process (4): regulation of cell growth (GO:0001558), negative regulation of cell growth (GO:0030308), negative regulation of inflammatory response (GO:0050728), negative regulation of wound healing (GO:0061045)

GO Molecular Function (2): serine-type endopeptidase inhibitor activity (GO:0004867), peptidase inhibitor activity (GO:0030414)

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
cell growth	2
negative regulation of response to external stimulus	2
regulation of growth	1
regulation of cellular component organization	1
regulation of cell growth	1
negative regulation of growth	1
negative regulation of cellular process	1
inflammatory response	1
negative regulation of defense response	1
regulation of inflammatory response	1
wound healing	1
regulation of wound healing	1
negative regulation of response to wounding	1
serine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
cellular anatomical structure	1

Protein interactions and networks

STRING

404 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WFDC1	SLPI	P03973	646
WFDC1	SORBS2	O94875	582
WFDC1	PROS1	P07225	523
WFDC1	CDH13	P55290	489
WFDC1	HTRA3	P83110	469
WFDC1	CBFA2T3	O75081	456
WFDC1	WFDC11	Q8NEX6	412
WFDC1	PI3	P19957	396
WFDC1	WFDC2	Q14508	390
WFDC1	WFDC13	Q8IUB5	389
WFDC1	A0A494C0M2	A0A494C0M2	384
WFDC1	RB1	P06400	381
WFDC1	FAM237B	A0A1B0GVD1	372
WFDC1	PTS	Q03393	368
WFDC1	DDIT4L	Q96D03	348

IntAct

7 interactions, top by confidence:

A	B	Type	Score
WFDC1	EZR	psi-mi:“MI:0915”(physical association)	0.370
WFDC1	XRCC2	psi-mi:“MI:0915”(physical association)	0.370
WFDC1	FOSL1	psi-mi:“MI:0915”(physical association)	0.370
RAB40B	WFDC1	psi-mi:“MI:0915”(physical association)	0.370
ZNF677	WFDC1	psi-mi:“MI:0915”(physical association)	0.370
WFDC1	OCM	psi-mi:“MI:0914”(association)	0.350

BioGRID (12): WFDC1 (Affinity Capture-RNA), WFDC1 (Affinity Capture-RNA), TPP2 (Affinity Capture-MS), LRP2 (Affinity Capture-MS), KLHL8 (Affinity Capture-MS), OCM (Affinity Capture-MS), RBM14-RBM4 (Affinity Capture-MS), WFDC1 (Two-hybrid), XRCC2 (Two-hybrid), WFDC1 (Two-hybrid), WFDC1 (Two-hybrid), ZNF677 (Two-hybrid)

ESM2 similar proteins: A1L3C1, A2AWP8, A2RRU4, A6QM06, A6QNS9, E1BBQ2, F1LQY6, G3V9M2, O43189, O94827, P29372, P29590, P41155, P97260, Q01113, Q02833, Q04841, Q0P5I0, Q12770, Q13387, Q13505, Q29RM4, Q32L49, Q3V1H9, Q5MNU5, Q5R5M3, Q66T02, Q69Z89, Q6GQT6, Q6IPT2, Q6RFZ7, Q6ZN54, Q70EL4, Q7Z6G3, Q8BQB4, Q8C4U2, Q8N1F8, Q8N554, Q8WWW0, Q8WXF8

Diamond homologs: O70280, P00993, Q8JG33, Q9ESH5, Q9HC57

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	59
Likely benign	6
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1063 predictions. Top by Δscore:

Variant	Effect	Δscore
16:84295114:GT:G	donor_gain	1.0000
16:84295116:G:GG	donor_gain	1.0000
16:84313153:GGTA:G	donor_loss	1.0000
16:84313154:GTAG:G	donor_loss	1.0000
16:84295111:CCCGT:C	donor_gain	0.9900
16:84295112:CCGT:C	donor_gain	0.9900
16:84295113:CGTG:C	donor_loss	0.9900
16:84295114:GTGTA:G	donor_loss	0.9900
16:84295115:TGTAA:T	donor_loss	0.9900
16:84295116:GT:G	donor_loss	0.9900
16:84295117:TAAG:T	donor_loss	0.9900
16:84312955:CCGCA:C	acceptor_loss	0.9900
16:84312956:CGCA:C	acceptor_loss	0.9900
16:84312957:GCAG:G	acceptor_loss	0.9900
16:84312958:CAGG:C	acceptor_loss	0.9900
16:84313149:GCCAG:G	donor_gain	0.9900
16:84324458:CAGG:C	donor_loss	0.9900
16:84324459:AGG:A	donor_loss	0.9900
16:84324461:G:GG	donor_loss	0.9900
16:84324462:T:A	donor_loss	0.9900
16:84326880:A:AG	acceptor_gain	0.9900
16:84326881:G:GA	acceptor_gain	0.9900
16:84326881:GAA:G	acceptor_gain	0.9900
16:84295113:CGT:C	donor_gain	0.9800
16:84295114:GTG:G	donor_gain	0.9800
16:84295115:TGT:T	donor_gain	0.9800
16:84295118:AAGT:A	donor_loss	0.9800
16:84312959:A:AG	acceptor_gain	0.9800
16:84312960:G:GG	acceptor_gain	0.9800
16:84312960:GGCC:G	acceptor_gain	0.9800

AlphaMissense

1388 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:84318282:G:C	W116C	1.000
16:84318282:G:T	W116C	1.000
16:84318324:G:C	W130C	0.999
16:84318324:G:T	W130C	0.999
16:84319493:T:A	C162S	0.999
16:84319494:G:C	C162S	0.999
16:84319547:T:A	C180S	0.999
16:84319548:G:C	C180S	0.999
16:84318280:T:A	W116R	0.998
16:84318280:T:C	W116R	0.998
16:84319439:T:A	C144S	0.998
16:84319440:G:C	C144S	0.998
16:84319475:T:A	C156S	0.998
16:84319475:T:C	C156R	0.998
16:84319476:G:C	C156S	0.998
16:84318322:T:A	W130R	0.997
16:84318322:T:C	W130R	0.997
16:84319493:T:C	C162R	0.997
16:84319439:T:C	C144R	0.996
16:84319440:G:A	C144Y	0.996
16:84319441:C:G	C144W	0.996
16:84319477:T:G	C156W	0.996
16:84319547:T:C	C180R	0.996
16:84318306:G:C	W124C	0.995
16:84318306:G:T	W124C	0.995
16:84319442:A:C	S145R	0.995
16:84319444:C:A	S145R	0.995
16:84319444:C:G	S145R	0.995
16:84319476:G:A	C156Y	0.995
16:84319495:C:G	C162W	0.995

dbSNP variants (sampled 300 via entrez): RS1000024918 (16:84324852 C>A,G), RS1000077505 (16:84324990 T>G), RS1000102476 (16:84299093 G>A,T), RS1000148462 (16:84310004 C>CT), RS1000155762 (16:84326760 G>T), RS1000160266 (16:84295409 C>G), RS1000285527 (16:84320681 T>G), RS1000329375 (16:84316760 C>G), RS1000366392 (16:84328741 T>G), RS1000477958 (16:84298975 T>G), RS1000543098 (16:84313194 C>G,T), RS1000580360 (16:84315788 T>C,G), RS1000604088 (16:84298802 G>T), RS1000606356 (16:84309371 A>C,G), RS1000650319 (16:84309579 C>G)

Disease associations

OMIM: gene MIM:605322 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001523_23	Visceral adipose tissue adjusted for BMI	6.000000e-06
GCST002307_6	Systolic blood pressure (alcohol consumption interaction)	1.000000e-07
GCST006585_2079	Blood protein levels	6.000000e-54
GCST010483_3	Cardiovascular death, myocardial infarction or stroke in response to clopidogrel treatment	3.000000e-06
GCST011891_4	Systolic blood pressure (baseline)	2.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004329	alcohol drinking
EFO:0006335	systolic blood pressure
EFO:0006919	cardiovascular event measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases expression	2
bisphenol A	decreases methylation	1
deoxynivalenol	decreases expression	1
trimellitic anhydride	decreases expression	1
triadimefon	decreases expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
2,2’,4,4’,5-brominated diphenyl ether	increases expression	1
Temozolomide	affects response to substance	1
Decitabine	affects expression	1
Arsenic Trioxide	decreases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation	1
Carmustine	affects response to substance	1
Diazinon	increases methylation	1
Lead	decreases expression	1
Rotenone	increases expression	1
Triclosan	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	increases expression	1

Clinical trials (associated diseases)

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