WFDC12

Summary

WFDC12 (WAP four-disulfide core domain 12, HGNC:16115) is a protein-coding gene on chromosome 20q13.12, encoding WAP four-disulfide core domain protein 12 (Q8WWY7). Antibacterial protein.

This gene encodes a member of the WAP-type four-disulfide core (WFDC) domain family. The WFDC domain, or WAP signature motif, contains eight cysteines forming four disulfide bonds at the core of the protein, and functions as a protease inhibitor. Most WFDC gene members are localized to chromosome 20q12-q13 in two clusters: centromeric and telomeric. This gene belongs to the centromeric cluster.

Source: NCBI Gene 128488 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 19 total
• MANE Select transcript: NM_080869

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16115
Approved symbol	WFDC12
Name	WAP four-disulfide core domain 12
Location	20q13.12
Locus type	gene with protein product
Status	Approved
Aliases	dJ211D12.4, WAP2
Ensembl gene	ENSG00000168703
Ensembl biotype	protein_coding
OMIM	609872
Entrez	128488

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000372785

RefSeq mRNA: 1 — MANE Select: NM_080869 NM_080869

CCDS: CCDS13343

Canonical transcript exons

ENST00000372785 — 3 exons

Exon	Start	End
ENSE00001125915	45124107	45124265
ENSE00001458646	45123425	45123943
ENSE00001458647	45124369	45124465

Expression profiles

Bgee: expression breadth broad, 96 present calls, max score 93.82.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0924 / max 46.3436, expressed in 26 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
187384	0.0924	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
penis	UBERON:0000989	93.82	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.39	gold quality
mammalian vulva	UBERON:0000997	85.95	gold quality
buccal mucosa cell	CL:0002336	84.00	gold quality
nipple	UBERON:0002030	83.49	gold quality
upper leg skin	UBERON:0004262	81.59	gold quality
epithelium of nasopharynx	UBERON:0001951	79.44	gold quality
cardia of stomach	UBERON:0001162	79.24	gold quality
body of tongue	UBERON:0011876	79.19	gold quality
gingiva	UBERON:0001828	79.14	gold quality
gingival epithelium	UBERON:0001949	78.92	silver quality
skin of leg	UBERON:0001511	78.72	gold quality
tongue	UBERON:0001723	77.54	gold quality
subthalamic nucleus	UBERON:0001906	77.31	gold quality
inferior vagus X ganglion	UBERON:0005363	76.89	gold quality
vena cava	UBERON:0004087	76.59	gold quality
lower esophagus mucosa	UBERON:0035834	76.49	gold quality
zone of skin	UBERON:0000014	76.33	gold quality
dorsal plus ventral thalamus	UBERON:0001897	75.96	gold quality
pharyngeal mucosa	UBERON:0000355	75.90	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	75.83	gold quality
superficial temporal artery	UBERON:0001614	75.57	gold quality
lateral globus pallidus	UBERON:0002476	75.44	gold quality
cerebellar vermis	UBERON:0004720	75.43	gold quality
sperm	CL:0000019	75.24	gold quality
trachea	UBERON:0003126	75.01	gold quality
superior surface of tongue	UBERON:0007371	74.91	gold quality
lateral nuclear group of thalamus	UBERON:0002736	74.81	gold quality
mammary duct	UBERON:0001765	74.68	gold quality
superior vestibular nucleus	UBERON:0007227	74.58	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.48

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP63

miRNA regulators (miRDB)

35 targeting WFDC12, 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-9-5P	100.00	72.28	2361
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-422A	99.18	65.83	550
HSA-MIR-4451	98.82	68.17	1455
HSA-MIR-4260	98.78	65.37	848
HSA-MIR-4710	98.61	65.96	1048
HSA-MIR-5572	98.55	65.84	970
HSA-MIR-378A-3P	98.43	66.10	548
HSA-MIR-378B	98.43	65.36	573
HSA-MIR-378C	98.43	66.10	548
HSA-MIR-378D	98.43	66.10	548
HSA-MIR-378E	98.43	65.99	551
HSA-MIR-378F	98.43	65.66	554
HSA-MIR-378H	98.43	66.16	545
HSA-MIR-378I	98.43	66.10	548
HSA-MIR-4277	98.34	67.17	1323
HSA-MIR-615-5P	98.10	63.76	591

Literature-anchored findings (GeneRIF, showing 4)

• The size is 774 bp and it gives rise to a polypeptide of 111 amino acid residues that is homologous to elafin and similar WAP-type protease inhibitors. (PMID:11779191)
• The Whey Acidic Protein WFDC12 Is Specifically Expressed in Terminally Differentiated Keratinocytes and Regulates Epidermal Serine Protease Activity. (PMID:33157095)
• WFDC12-overexpressing contributes to the development of atopic dermatitis via accelerating ALOX12/15 metabolism and PAF accumulation. (PMID:36882395)
• Construction of a novel pyrotosis-related prognostic model of esophageal square cell carcinoma and determination of the anti-tumor effect of WFDC12. (PMID:37225895)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Wfdc12	ENSMUSG00000042845
rattus_norvegicus	Wfdc12	ENSRNOG00000032412
drosophila_melanogaster	CG5639	FBGN0039527
caenorhabditis_elegans		WBGENE00015620

Paralogs (9): PI3 (ENSG00000124102), SLPI (ENSG00000124107), WFDC3 (ENSG00000124116), WFDC13 (ENSG00000168634), WFDC5 (ENSG00000175121), WFDC11 (ENSG00000180083), WFDC9 (ENSG00000180205), WFDC10A (ENSG00000180305), WFDC10B (ENSG00000182931)

Protein

Protein identifiers

WAP four-disulfide core domain protein 12 — Q8WWY7 (reviewed: Q8WWY7)

Alternative names: Putative protease inhibitor WAP12, Whey acidic protein 2

All UniProt accessions (1): Q8WWY7

UniProt curated annotations — full annotation on UniProt →

Function. Antibacterial protein. Putative acid-stable proteinase inhibitor.

Subcellular location. Secreted.

Tissue specificity. Highly expressed in prostate, skin, lung and esophagus. Weakly expressed in skeletal muscle, epididymis, kidney, trachea, salivary gland, testis and seminal vesicle.

RefSeq proteins (1): NP_543145* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008197	WAP_dom	Domain
IPR036645	Elafin-like_sf	Homologous_superfamily

Pfam: PF00095

UniProt features (9 total): disulfide bond 4, signal peptide 1, chain 1, domain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WWY7-F1	78.44	0.46

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): 34–62, 41–66, 49–61, 55–70

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 31 (showing top): GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_HUMORAL_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_BACTERIUM, BURTON_ADIPOGENESIS_PEAK_AT_24HR, RICKMAN_HEAD_AND_NECK_CANCER_C, BURTON_ADIPOGENESIS_6, GOMF_PEPTIDASE_REGULATOR_ACTIVITY, GOMF_SERINE_TYPE_ENDOPEPTIDASE_INHIBITOR_ACTIVITY, GOMF_ENZYME_INHIBITOR_ACTIVITY, GOBP_RESPONSE_TO_BACTERIUM, GOMF_ENZYME_REGULATOR_ACTIVITY, NIKOLSKY_BREAST_CANCER_20Q12_Q13_AMPLICON, GOBP_ANTIBACTERIAL_HUMORAL_RESPONSE, AKT_UP_MTOR_DN.V1_UP

GO Biological Process (3): antibacterial humoral response (GO:0019731), defense response to bacterium (GO:0042742), innate immune response (GO:0045087)

GO Molecular Function (3): serine-type endopeptidase inhibitor activity (GO:0004867), protein binding (GO:0005515), 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
antimicrobial humoral response	1
defense response to bacterium	1
defense response	1
response to bacterium	1
immune response	1
defense response to symbiont	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

332 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WFDC12	WFDC5	Q8TCV5	967
WFDC12	SEMG2	Q02383	871
WFDC12	SEMG1	P04279	858
WFDC12	PI3	P19957	828
WFDC12	ZNF251	Q9BRH9	564
WFDC12	WFDC11	Q8NEX6	544
WFDC12	ZIK1	Q3SY52	537
WFDC12	PNMA5	Q96PV4	530
WFDC12	ZNF426	Q9BUY5	521
WFDC12	WFDC3	Q8IUB2	508
WFDC12	BPIFC	Q8NFQ6	498
WFDC12	BPIFA3	Q9BQP9	495
WFDC12	DEFB115	Q30KQ5	478
WFDC12	MATN4	O95460	476
WFDC12	DEFB128	Q7Z7B8	441

IntAct

25 interactions, top by confidence:

A	B	Type	Score
WFDC12	UBQLN2	psi-mi:“MI:0915”(physical association)	0.560
SGTA	WFDC12	psi-mi:“MI:0915”(physical association)	0.560
WFDC12	SGTB	psi-mi:“MI:0915”(physical association)	0.560
WFDC12	SLC39A7	psi-mi:“MI:0915”(physical association)	0.560
ASPH	WFDC12	psi-mi:“MI:0915”(physical association)	0.560
WFDC12	UBQLN1	psi-mi:“MI:0915”(physical association)	0.560
ATG16L1		psi-mi:“MI:0914”(association)	0.350
INSR	UBXN8	psi-mi:“MI:0914”(association)	0.350
SOX2	IGF2BP3	psi-mi:“MI:0914”(association)	0.350
WFDC12	UBQLN2	psi-mi:“MI:0915”(physical association)	0.000
WFDC12	SGTA	psi-mi:“MI:0915”(physical association)	0.000
ASPH	WFDC12	psi-mi:“MI:0915”(physical association)	0.000
UBQLN1	WFDC12	psi-mi:“MI:0915”(physical association)	0.000
UBQLN2	WFDC12	psi-mi:“MI:0915”(physical association)	0.000
WFDC12	SGTB	psi-mi:“MI:0915”(physical association)	0.000
SLC39A7	WFDC12	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (7): WFDC12 (Synthetic Lethality), WFDC12 (Two-hybrid), WFDC12 (Two-hybrid), WFDC12 (Two-hybrid), UBQLN2 (Two-hybrid), SGTB (Two-hybrid), ASPH (Two-hybrid)

ESM2 similar proteins: A4K2M6, A4K2P0, A4K2P8, A4K2Q7, A4K2R5, A4K2S3, A4K2S4, A4K2T3, A4K2U0, A4K2U1, A4K2V4, A4K2W8, A4K2X6, A4K2Y4, A7X4M7, B5G6G7, B5G6G8, B5G6G9, B5G6H0, B5G6H1, B5G6H3, B5G6H4, B5G6H5, B5KGY9, B5L5M9, B5L5N1, B5L5N2, B5L5N4, B5L5N6, B5L5P2, B5L5P3, B5L5P4, B5L5P5, B5L5P6, B5L5P7, B5L5P8, B5L5P9, B6DCY1, P01173, P01174

Diamond homologs: A4K2M6, A4K2P0, A4K2P8, A4K2R5, A4K2S4, A4K2T3, A4K2U1, A4K2V4, A4K2W8, A4K2X6, A4K2Y4, P01173, P03973, Q6IE40, Q6V9X0, Q8WWY7, Q9JHY3, P22298, Q868Z9, Q8MI69, P09837, A4K2M5, A4K2N9, A4K2P7, A4K2R4, A4K2S3, A4K2T2, A4K2U0, A4K2V3, A4K2W7, A4K2X5, A4K2Y3, O46655, P19957, Q8TCV5, A4K2Q7, A7X4M7, P16225, P23352, P33005

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	19
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

220 predictions. Top by Δscore:

Variant	Effect	Δscore
20:45124366:CA:C	donor_loss	1.0000
20:45124367:AC:A	donor_gain	1.0000
20:45124368:CC:C	donor_gain	1.0000
20:45124368:CCCT:C	donor_gain	1.0000
20:45124101:CCTTA:C	donor_loss	0.9900
20:45124102:CTTAC:C	donor_loss	0.9900
20:45124103:TTACC:T	donor_loss	0.9900
20:45124104:TA:T	donor_loss	0.9900
20:45124106:C:CA	donor_loss	0.9900
20:45124263:TAC:T	acceptor_gain	0.9900
20:45124263:TACC:T	acceptor_loss	0.9900
20:45124265:CCT:C	acceptor_loss	0.9900
20:45124267:T:A	acceptor_loss	0.9900
20:45124269:G:C	acceptor_gain	0.9900
20:45124269:G:GC	acceptor_gain	0.9900
20:45124363:GCTCA:G	donor_loss	0.9900
20:45124364:CTCA:C	donor_loss	0.9900
20:45124367:A:AC	donor_gain	0.9900
20:45124368:C:CC	donor_gain	0.9900
20:45124106:CCTT:C	donor_gain	0.9800
20:45124266:C:CC	acceptor_gain	0.9800
20:45124367:ACC:A	donor_gain	0.9800
20:45124367:ACCCT:A	donor_gain	0.9800
20:45124368:CCC:C	donor_gain	0.9800
20:45124368:CCCTC:C	donor_gain	0.9800
20:45124376:AACT:A	donor_gain	0.9800
20:45124261:TATAC:T	acceptor_gain	0.9700
20:45124265:CCTAG:C	acceptor_gain	0.9700
20:45124377:A:C	donor_gain	0.9700
20:45124105:A:AC	donor_gain	0.9600

AlphaMissense

721 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:45124199:C:G	C49S	0.991
20:45124200:A:T	C49S	0.991
20:45124165:C:A	K60N	0.984
20:45124165:C:G	K60N	0.984
20:45124136:C:G	C70S	0.983
20:45124137:A:T	C70S	0.983
20:45124163:C:G	C61S	0.978
20:45124164:A:T	C61S	0.978
20:45124244:C:G	C34S	0.977
20:45124245:A:T	C34S	0.977
20:45124190:T:A	D52V	0.975
20:45124148:C:G	C66S	0.974
20:45124149:A:T	C66S	0.974
20:45124223:C:G	C41S	0.974
20:45124224:A:T	C41S	0.974
20:45124181:C:G	C55S	0.973
20:45124182:A:T	C55S	0.973
20:45124200:A:G	C49R	0.973
20:45124160:C:G	C62S	0.971
20:45124161:A:T	C62S	0.971
20:45124137:A:G	C70R	0.967
20:45124245:A:G	C34R	0.967
20:45124167:T:C	K60E	0.959
20:45124180:A:C	C55W	0.958
20:45124224:A:G	C41R	0.958
20:45124198:A:C	C49W	0.954
20:45124191:C:G	D52H	0.953
20:45124190:T:G	D52A	0.952
20:45124245:A:C	C34G	0.952
20:45124199:C:T	C49Y	0.949

dbSNP variants (sampled 300 via entrez): RS1000800677 (20:45123894 C>T), RS1002096052 (20:45123018 C>T), RS1002763487 (20:45126055 T>C), RS1004211802 (20:45123063 A>G), RS1006727141 (20:45124925 G>A,T), RS1009659829 (20:45124891 C>G), RS1011914630 (20:45125326 G>A,T), RS1013332064 (20:45123044 G>T), RS1013343352 (20:45123342 T>C), RS1013365883 (20:45126426 C>T), RS1016115083 (20:45123076 G>A), RS1016336405 (20:45125825 G>T), RS1017138938 (20:45123649 G>A), RS1018217367 (20:45124931 T>C), RS1018607515 (20:45125312 T>C)

Disease associations

OMIM: gene MIM:609872 | 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
GCST008103_18	Bipolar disorder	1.000000e-08
GCST008103_27	Bipolar disorder	3.000000e-08
GCST012465_46	Bipolar disorder	4.000000e-11

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
Particulate Matter	increases expression	2
sodium arsenate	decreases expression, increases abundance	1
hydroquinone	increases expression	1
CGP 52608	affects binding, increases reaction	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic	increases abundance, decreases expression	1
Benzo(a)pyrene	increases methylation	1
Estradiol	increases expression	1
Folic Acid	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Testosterone	increases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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