WFDC8

Summary

WFDC8 (WAP four-disulfide core domain 8, HGNC:16163) is a protein-coding gene on chromosome 20q13.12, encoding WAP four-disulfide core domain protein 8 (Q8IUA0).

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. The encoded protein contains a Kunitz-inhibitor domain, in addition to three WFDC domains. Most WFDC genes are localized to chromosome 20q12-q13 in two clusters: centromeric and telomeric. This gene belongs to the telomeric cluster. Two alternatively spliced transcript variants have been found for this gene, and they encode the same protein.

Source: NCBI Gene 90199 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 34 total
• MANE Select transcript: NM_130896

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16163
Approved symbol	WFDC8
Name	WAP four-disulfide core domain 8
Location	20q13.12
Locus type	gene with protein product
Status	Approved
Aliases	dJ461P17.1, WAP8
Ensembl gene	ENSG00000158901
Ensembl biotype	protein_coding
Entrez	90199

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000289953, ENST00000357199

RefSeq mRNA: 2 — MANE Select: NM_130896 NM_130896, NM_181510

CCDS: CCDS13361

Canonical transcript exons

ENST00000289953 — 6 exons

Exon	Start	End
ENSE00001041886	45558852	45558992
ENSE00001041894	45555701	45555868
ENSE00001041913	45553136	45553276
ENSE00001125155	45562110	45562219
ENSE00001321878	45551762	45552165
ENSE00003899398	45579222	45579284

Expression profiles

Bgee: expression breadth broad, 31 present calls, max score 99.23.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1428 / max 228.1490, expressed in 7 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
187461	0.0659	4
187459	0.0187	2
187462	0.0180	2
187460	0.0138	3
187463	0.0124	1
187458	0.0071	1
209143	0.0070	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	99.23	gold quality
cauda epididymis	UBERON:0004360	91.65	gold quality
sperm	CL:0000019	77.41	gold quality
caput epididymis	UBERON:0004358	68.38	gold quality
oocyte	CL:0000023	66.72	gold quality
epithelium of nasopharynx	UBERON:0001951	64.71	gold quality
endometrium epithelium	UBERON:0004811	64.56	gold quality
nasal cavity epithelium	UBERON:0005384	56.71	gold quality
metanephric glomerulus	UBERON:0004736	55.97	gold quality
mammary duct	UBERON:0001765	55.89	gold quality
buccal mucosa cell	CL:0002336	55.80	gold quality
vena cava	UBERON:0004087	54.95	gold quality
skin of hip	UBERON:0001554	53.84	silver quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	53.51	gold quality
upper leg skin	UBERON:0004262	53.45	silver quality
paraflocculus	UBERON:0005351	52.36	gold quality
quadriceps femoris	UBERON:0001377	51.55	gold quality
thymus	UBERON:0002370	51.31	gold quality
seminal vesicle	UBERON:0000998	51.25	gold quality
vastus lateralis	UBERON:0001379	51.20	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.18	gold quality
cerebellar vermis	UBERON:0004720	49.25	gold quality
adult organism	UBERON:0007023	47.69	gold quality
lateral globus pallidus	UBERON:0002476	46.19	gold quality
endometrium	UBERON:0001295	46.15	gold quality
left lobe of thyroid gland	UBERON:0001120	45.73	gold quality
ventral tegmental area	UBERON:0002691	45.61	gold quality
biceps brachii	UBERON:0001507	45.02	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-38	yes	899.12
E-ANND-3	yes	3.93

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

20 targeting WFDC8, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-3682-3P	99.58	67.63	865
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-6507-3P	99.35	67.32	1059
HSA-MIR-16-2-3P	99.29	70.60	1954
HSA-MIR-195-3P	99.29	70.61	1954
HSA-MIR-580-5P	99.28	70.94	1776
HSA-MIR-3973	99.20	69.19	1990
HSA-MIR-8060	98.61	66.93	1187
HSA-MIR-5089-5P	98.45	66.06	1388
HSA-MIR-1245B-3P	98.01	68.91	1387
HSA-MIR-4670-3P	97.37	68.35	1378

Literature-anchored findings (GeneRIF, showing 1)

• We propose that the evolution of WFDC8 and SPINT4 has been shaped by complex selective scenarios due to the interdependence of variant fitness and ecological variables. (PMID:21536719)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	spint1b	ENSDARG00000012467
danio_rerio	lrp11	ENSDARG00000034076
danio_rerio	wfikkn1	ENSDARG00000101364
danio_rerio	spint1a	ENSDARG00000102332
mus_musculus	Wfdc8	ENSMUSG00000070533
rattus_norvegicus	Wfdc8	ENSRNOG00000014771
drosophila_melanogaster	CG7565	FBGN0035833
caenorhabditis_elegans		WBGENE00008449
caenorhabditis_elegans		WBGENE00009386
caenorhabditis_elegans		WBGENE00010792
caenorhabditis_elegans		WBGENE00015355
caenorhabditis_elegans		WBGENE00021939

Paralogs (13): TFPI (ENSG00000003436), EPPIN (ENSG00000101448), TFPI2 (ENSG00000105825), AMBP (ENSG00000106927), LRP11 (ENSG00000120256), WFIKKN1 (ENSG00000127578), KIAA0319 (ENSG00000137261), KIAA0319L (ENSG00000142687), SPINT4 (ENSG00000149651), SPINT1 (ENSG00000166145), SPINT2 (ENSG00000167642), WFIKKN2 (ENSG00000173714), WFDC6 (ENSG00000243543)

Protein

Protein identifiers

WAP four-disulfide core domain protein 8 — Q8IUA0 (reviewed: Q8IUA0)

Alternative names: Putative protease inhibitor WAP8

All UniProt accessions (2): Q8IUA0, A0A140VK68

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Secreted.

Tissue specificity. Expressed ubiquitously, the highest levels are found in the epididymis followed by testis and trachea.

RefSeq proteins (2): NP_570966, NP_852611 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002223	Kunitz_BPTI	Domain
IPR008197	WAP_dom	Domain
IPR020901	Prtase_inh_Kunz-CS	Conserved_site
IPR036645	Elafin-like_sf	Homologous_superfamily
IPR036880	Kunitz_BPTI_sf	Homologous_superfamily

Pfam: PF00014, PF00095

UniProt features (23 total): disulfide bond 15, domain 4, sequence variant 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IUA0-F1	86.80	0.64

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 (15): 95–145, 104–128, 120–141, 154–182, 165–186, 169–181, 175–190, 201–229, 208–232, 216–228, 222–236, 51–79, 58–83, 66–78, 72–87

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 32 (showing top): GOMF_PEPTIDASE_REGULATOR_ACTIVITY, GOMF_SERINE_TYPE_ENDOPEPTIDASE_INHIBITOR_ACTIVITY, GOMF_ENZYME_INHIBITOR_ACTIVITY, GOMF_ENZYME_REGULATOR_ACTIVITY, GOMF_ENDOPEPTIDASE_REGULATOR_ACTIVITY, JAK2_DN.V1_UP, HMGA1_TARGET_GENES, MIR182_5P, MIR580_5P, MIR5197_3P, MIR222_5P, MIR3129_5P, MIR199A_3P_MIR199B_3P, MIR5089_5P, MIR3682_3P

GO Biological Process (0):

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

432 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WFDC8	SPINT4	Q6UDR6	809
WFDC8	WFDC6	Q9BQY6	804
WFDC8	WFDC9	Q8NEX5	669
WFDC8	WFDC10A	Q9H1F0	636
WFDC8	SEMG1	P04279	607
WFDC8	SEMG2	Q02383	582
WFDC8	PATE1	Q8WXA2	547
WFDC8	WFDC3	Q8IUB2	544
WFDC8	SPINK13	Q1W4C9	519
WFDC8	EDDM3B	P56851	517
WFDC8	DEFB134	Q4QY38	506
WFDC8	WFDC5	Q8TCV5	506
WFDC8	WFDC11	Q8NEX6	491
WFDC8	DEFB131A	P59861	478
WFDC8	PI3	P19957	474

IntAct

2 interactions, top by confidence:

A	B	Type	Score
WFDC8	ACTA2	psi-mi:“MI:0914”(association)	0.350

BioGRID (4): SYCE2 (Affinity Capture-MS), ACTA2 (Affinity Capture-MS), APBB2 (Affinity Capture-MS), WFDC8 (Reconstituted Complex)

ESM2 similar proteins: A4K2M5, A4K2N9, A4K2P7, A4K2Q7, A4K2R4, A4K2S3, A4K2T2, A4K2U0, A4K2V3, A4K2W7, A4K2X5, A4K2Y3, A7X4K1, A7X4M7, B5G6G7, B5G6G8, B5G6G9, B5G6H0, B5G6H1, B5G6H2, B5G6H3, B5G6H4, B5G6H5, B5KGY9, B5L5M9, B5L5N1, B5L5N2, B5L5N3, B5L5N4, B5L5N6, B5L5P0, B5L5P2, B5L5P3, B5L5P4, B5L5P5, B5L5P6, B5L5P7, B5L5P8, B5L5P9, P01174

Diamond homologs: A4K2M5, A4K2N9, A4K2P7, A4K2Q7, A4K2R4, A4K2S3, A4K2T2, A4K2U0, A4K2U1, A4K2V3, A4K2W7, A4K2X5, A4K2X6, A4K2Y3, P03973, Q8IUA0, Q8TCV5, A0A6P8HC43, A7X3V7, A8Y7N9, B1B5I8, B2G331, B2ZBB6, B5M0W4, B6ZIW0, C0HJF3, C0HK74, C0HLB2, C0HMC7, C1IBY4, C1IC51, C1IC52, C8YJ94, C8YJ95, D4A2Z2, D8KY58, F5GTK6, F6ULY1, I2G9B4, O35536

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	27
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

907 predictions. Top by Δscore:

Variant	Effect	Δscore
20:45562108:A:AC	donor_gain	1.0000
20:45562109:C:CC	donor_gain	1.0000
20:45579220:ACCCT:A	donor_gain	1.0000
20:45579221:CCCTC:C	donor_gain	1.0000
20:45562101:TGAAC:T	donor_loss	0.9900
20:45562102:GAAC:G	donor_loss	0.9900
20:45562103:AACTC:A	donor_loss	0.9900
20:45562104:ACTCA:A	donor_loss	0.9900
20:45562105:C:G	donor_loss	0.9900
20:45562106:T:TA	donor_loss	0.9900
20:45562107:CAC:C	donor_loss	0.9900
20:45562108:A:C	donor_loss	0.9900
20:45579220:AC:A	donor_gain	0.9900
20:45579221:CC:C	donor_gain	0.9900
20:45579224:T:A	donor_gain	0.9900
20:45579258:C:A	donor_gain	0.9900
20:45562109:CGT:C	donor_gain	0.9800
20:45562218:GCC:G	acceptor_loss	0.9800
20:45579221:CCCT:C	donor_gain	0.9800
20:45562109:CG:C	donor_gain	0.9700
20:45553277:C:CC	acceptor_gain	0.9600
20:45562216:GTGC:G	acceptor_gain	0.9600
20:45562217:TGC:T	acceptor_gain	0.9600
20:45562220:C:CC	acceptor_gain	0.9600
20:45579217:CTCAC:C	donor_loss	0.9600
20:45579218:TCA:T	donor_loss	0.9600
20:45579219:CAC:C	donor_loss	0.9600
20:45579220:A:AG	donor_loss	0.9600
20:45579221:C:A	donor_loss	0.9600
20:45579228:T:TA	donor_gain	0.9600

AlphaMissense

1616 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:45555742:A:C	F135C	0.993
20:45555741:G:C	F135L	0.990
20:45555741:G:T	F135L	0.990
20:45555743:A:G	F135L	0.990
20:45555787:C:G	C120S	0.984
20:45555788:A:T	C120S	0.984
20:45553198:C:G	C175S	0.983
20:45553199:A:T	C175S	0.983
20:45552105:C:G	C216S	0.982
20:45552106:A:T	C216S	0.982
20:45553261:C:G	C154S	0.982
20:45553262:A:T	C154S	0.982
20:45555807:A:C	F113L	0.982
20:45555807:A:T	F113L	0.982
20:45555809:A:G	F113L	0.982
20:45555724:C:G	C141S	0.980
20:45555725:A:T	C141S	0.980
20:45555742:A:G	F135S	0.979
20:45552087:C:G	C222S	0.978
20:45552088:A:T	C222S	0.978
20:45555813:C:A	W111C	0.978
20:45555813:C:G	W111C	0.978
20:45553180:C:G	C181S	0.977
20:45553181:A:T	C181S	0.977
20:45553216:C:G	C169S	0.977
20:45553217:A:T	C169S	0.977
20:45555747:G:C	N133K	0.976
20:45555747:G:T	N133K	0.976
20:45555862:C:G	C95S	0.975
20:45555863:A:T	C95S	0.975

dbSNP variants (sampled 300 via entrez): RS1000202876 (20:45552584 C>A), RS1000206760 (20:45577020 C>T), RS1000253746 (20:45552943 G>C), RS1000431424 (20:45570400 A>C), RS1000841040 (20:45558508 T>C), RS1000848617 (20:45570509 G>C), RS1000850238 (20:45563449 G>A,T), RS1001042485 (20:45553272 C>G,T), RS1001125790 (20:45556852 T>A), RS1001144081 (20:45576794 T>G), RS1001168109 (20:45571897 T>C), RS1001198082 (20:45577111 A>T), RS1001426601 (20:45576554 C>A), RS1001435498 (20:45559359 G>A), RS1001489810 (20:45578158 G>A)

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

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

5 total (human), top 5 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
perfluorooctanoic acid	increases expression	1
perfluoro-n-nonanoic acid	increases expression	1
perfluorohexanesulfonic acid	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Antirheumatic Agents	decreases expression	1

Clinical trials (associated diseases)

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