KLK4

Summary

KLK4 (kallikrein related peptidase 4, HGNC:6365) is a protein-coding gene on chromosome 19q13.41, encoding Kallikrein-4 (Q9Y5K2). Has a major role in enamel formation.

Kallikreins are a subgroup of serine proteases having diverse physiological functions. Growing evidence suggests that many kallikreins are implicated in carcinogenesis and some have potential as novel cancer and other disease biomarkers. This gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. In some tissues its expression is hormonally regulated. The expression pattern of a similar mouse protein in murine developing teeth supports a role for the protein in the degradation of enamel proteins. Several transcript variants encoding different proteins have been found for this gene.

Source: NCBI Gene 9622 — RefSeq curated summary.

At a glance

• Gene–disease (curated): amelogenesis imperfecta type 2A1 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 62 total — 4 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 7
• Druggable target: yes
• MANE Select transcript: NM_004917

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6365
Approved symbol	KLK4
Name	kallikrein related peptidase 4
Location	19q13.41
Locus type	gene with protein product
Status	Approved
Aliases	EMSP, EMSP1, PSTS, KLK-L1
Ensembl gene	ENSG00000167749
Ensembl biotype	protein_coding
OMIM	603767
Entrez	9622

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 3 nonsense_mediated_decay, 2 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000324041, ENST00000431178, ENST00000593885, ENST00000596876, ENST00000597441, ENST00000598305, ENST00000599865, ENST00000602148

RefSeq mRNA: 2 — MANE Select: NM_004917 NM_001302961, NM_004917

CCDS: CCDS12809

Canonical transcript exons

ENST00000324041 — 6 exons

Exon	Start	End
ENSE00001265771	50906351	50907086
ENSE00002229072	50909252	50909414
ENSE00003476601	50908579	50908829
ENSE00003550124	50908359	50908495
ENSE00003928904	50911339	50911395
ENSE00003932269	50910678	50910749

Expression profiles

Bgee: expression breadth ubiquitous, 160 present calls, max score 94.87.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.6019 / max 161.7025, expressed in 127 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
182289	0.3670	94
182288	0.0994	28
182287	0.0696	27
182290	0.0658	31

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
prostate gland	UBERON:0002367	94.87	gold quality
lower esophagus mucosa	UBERON:0035834	91.20	gold quality
kidney epithelium	UBERON:0004819	89.02	gold quality
mucosa of transverse colon	UBERON:0004991	88.35	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.48	gold quality
esophagus mucosa	UBERON:0002469	87.29	gold quality
cardiac muscle of right atrium	UBERON:0003379	86.07	gold quality
left ventricle myocardium	UBERON:0006566	85.28	gold quality
skin of leg	UBERON:0001511	84.91	gold quality
skin of abdomen	UBERON:0001416	84.67	gold quality
epithelial cell of pancreas	CL:0000083	83.68	gold quality
zone of skin	UBERON:0000014	81.71	gold quality
mucosa of paranasal sinus	UBERON:0005030	81.71	gold quality
upper arm skin	UBERON:0004263	81.29	gold quality
nasal cavity epithelium	UBERON:0005384	81.02	gold quality
vastus lateralis	UBERON:0001379	80.40	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	80.38	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	79.80	gold quality
quadriceps femoris	UBERON:0001377	79.74	gold quality
myocardium	UBERON:0002349	79.04	gold quality
superficial temporal artery	UBERON:0001614	78.99	gold quality
transverse colon	UBERON:0001157	78.86	gold quality
buccal mucosa cell	CL:0002336	77.87	gold quality
saliva-secreting gland	UBERON:0001044	76.78	gold quality
minor salivary gland	UBERON:0001830	76.40	gold quality
secondary oocyte	CL:0000655	76.21	silver quality
left lobe of thyroid gland	UBERON:0001120	76.13	gold quality
endocervix	UBERON:0000458	76.11	gold quality
biceps brachii	UBERON:0001507	75.89	gold quality
epithelium of nasopharynx	UBERON:0001951	75.39	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.79

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, DLX3, PGR, RUNX2

miRNA regulators (miRDB)

73 targeting KLK4, 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-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-6861-3P	99.60	68.46	444
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-3171	99.49	69.06	776
HSA-MIR-4498	99.47	67.42	2360

Literature-anchored findings (GeneRIF, showing 40)

• The demonstration that KLK4-specific CD4 T cells exist in the peripheral circulation of normal male donors supports the use of KLK4 in whole gene-, protein-, or peptide-based vaccine strategies against prostate cancer. (PMID:12077288)
• KLK4 has a unique structure and function compared with other members of the KLK family and may have a role in the biology and characterization of prostate cancer. (PMID:15059887)
• A novel human kallikrein mutation associated with a rare autosomal recessive form of amelogenesis imperfecta. (PMID:15235027)
• Human kallikrein 4, in particular, and prostate specific antigen, have a functional role in the progression of prostate cancer through their promotion of tumour cell migration. (PMID:16172196)
• There are two major isoforms of hK4 (KLK4-254/hK4-254 and KLK4-205/hK4-205) expressed in prostate cancer with different regulatory and expression profiles that imply both secreted and novel nuclear roles. (PMID:16322328)
• Here we demonstrate uPAR is a target for tissue kallikrein 4[hK4], cleaved in the D1-D2 linker and D3 domain. hK4 may modulate tumor-associated uPA/uPAR activity by activating the pro-enzyme form of uPA or cleaving the cell surface-associated uPA receptor (PMID:16497155)
• Design of serpin fragments as highly specific inhibitors of human kallikrein 14. (PMID:16704423)
• an investigation of its enzymatic properties regarding substrate preference, degradation of extracellular matrix proteins, and its inhibition by various inhibitors (PMID:16800736)
• hK4 expression and interaction with both tumor cells and osteoblasts suggests a role for hK4 in prostate cancer bone metastasis (PMID:17221837)
• KLK4 protein is significantly overexpressed in malignant prostate compared with normal prostate. KLK4 expression is predominantly in the nucleus of basal cells in the prostate epithelium in keeping with its distribution in prostate cancer cells in vitro. (PMID:17545602)
• KLK4 and KLK5 activate pro-HGFA. (PMID:18221492)
• These data provide insight into KLK4-mediated cell signaling and suggest that signals induced by this enzyme via protease-activated receptors may be important in prostate cancer. (PMID:18308730)
• Recombinant hK4 activates ERK1/2 signaling of prostate cancer cell lines, which express both PAR1 and PAR2. (PMID:18567807)
• KLK4 may be associated with the development and progression of breast cancer and suggest its potential use in breast cancer monitoring. (PMID:18687310)
• A total of 463 individuals from 54 families were evaluated and mutations in the AMEL, ENAM and KLK4 genes were identified. (PMID:18714142)
• KLK4 gene expression may be used as a new potential biomarker in breast cancer. (PMID:19190825)
• Prostate cancer cells exhibit a novel double-paracrine mechanism whereby cancer epithelium produces KLK4 to activate PAR-1 in the surrounding stroma, in-turn releasing cytokines that stimulate cancer cells to proliferate & increase production of KLKs. (PMID:19795418)
• In a family with a hypomaturation-type enamel defect, mutational and haplotype analyses revealed no mutations in the KLK4 gene. (PMID:19966041)
• Kallikrein 4 overexpression is associated with endometrial carcinoma. (PMID:20009893)
• KLK4 signaling via PAR1 may represent a novel pathway in colon tumorigenesis. (PMID:20056842)
• KLK4 is upregulated in early-stage but not late-stage prostate cancer. (PMID:20180634)
• Complex gene expression at the KLK4 locus that might be a hallmark of cis sense-antisense chimeric transcription in prostate cancer cells. (PMID:20406994)
• signal peptide induces cytotoxic T cell responses in healthy donors and prostate cancer patients (PMID:21874303)
• findings provide suggestive evidence of a role for genetic variation in the KLK4 locus in prostate cancer predisposition (PMID:22970239)
• Survival analysis demonstrated that KLK4 mRNA expression constitutes an unfavorable prognostic biomarker in colorectal adenocarcinoma, predicting poor disease-free survival (DFS), independently of the nodal status and tumor size. (PMID:23201139)
• amelogenesis imperfecta-causing mutations were identified in three of the probands: 1) a novel single-nucleotide deletion in both KLK4 alleles (g.6930delG; c.245delG; p.Gly82Alafs*87) that shifted the reading frame. (PMID:23355523)
• These results demonstrate that the activities of AR and mTOR pathways are maintained by KLK4, which may thus be a viable target for therapy (PMID:23798432)
• The variant rs1722561 of Kallikreins might reduce the risk of sporadic intracranial aneurysms among individuals of Chinese Han ethnicity. (PMID:24405067)
• KLK4 mRNA positivity could be regarded as a novel independent indicator of favorable prognosis for the disease-free survival of laryngeal squamous cell carcinoma patients. (PMID:24854539)
• miR-378 was predicted to target both KLK2 and KLK4 and downregulated levels detected in prostate cancer patients. (PMID:25153390)
• The differential regulation of alternative transcripts (using KLK2, KLK3 and KLK4 as models) by androgens and anti-androgens as an indicator of prostate cancers, was investigated. (PMID:25153393)
• secreted into the extracellular microenvironment by neutrophils stimulated with bioactive mediators (PMID:25563717)
• Human ephrin-B2 is poorly cleaved by KLK4 while the homologous mouse is not. (PMID:25724897)
• this study provides supportive evidence in favor of a prognostic value for KLK4 in OSCC and suggests that KLK4 could serve as a potential therapeutic target in patients with oral cancer. (PMID:25862839)
• Novel homozygous mutations in the KLK4 (c.620_621delCT, p.Ser207Trpfs*38) were identified in amelogenesis imperfecta consanguinity. Mutant KLK4 was degraded intracellularly and became inactive. (PMID:26124219)
• Studied a 70-kb region surrounding KLK4 in East Asian population; found within combined unusual low levels of diversity, high frequency variants with significant levels of population differentiation. (PMID:26420451)
• Low KLK4 expression is associated with lupus nephritis. (PMID:26546590)
• Results show that AMTN and KLK4 are not essential for biological processes outside of the dentition or during the secretory stage of amelogenesis. Both KLK4 and AMTN proved to be essential for the maturation of dental enamel, a process that requires the removal of extracellularmatrix proteins and the deposition of ions on the sides of enamel crystallites. (PMID:26620968)
• KLK4 as a potential multifunctional regulator of prostate cancer progression. (PMID:27378148)
• structural analysis of mechanism of KLK4 inhibition (PMID:27767076)

Cross-species orthologs

13 orthologs

Organism	Symbol	Gene ID
mus_musculus	Klk4	ENSMUSG00000006948
rattus_norvegicus	Klk4	ENSRNOG00000018864
drosophila_melanogaster	CG9673	FBGN0030775
drosophila_melanogaster	CG4477	FBGN0035971
drosophila_melanogaster	CG17404	FBGN0038001
drosophila_melanogaster	CG12256	FBGN0038002
drosophila_melanogaster	CG3916	FBGN0038003
drosophila_melanogaster	CG17477	FBGN0038479
drosophila_melanogaster	CG4053	FBGN0038482
drosophila_melanogaster	CG31269	FBGN0051269
drosophila_melanogaster	CG32808	FBGN0052808
drosophila_melanogaster	Phae2	FBGN0263235
drosophila_melanogaster	Send2	FBGN0264253

Paralogs (12): PRSS54 (ENSG00000103023), KLK14 (ENSG00000129437), KLK8 (ENSG00000129455), TMPRSS4 (ENSG00000137648), KLK3 (ENSG00000142515), KLK1 (ENSG00000167748), KLK2 (ENSG00000167751), KLK5 (ENSG00000167754), KLK11 (ENSG00000167757), KLK7 (ENSG00000169035), KLK12 (ENSG00000186474), PRSS58 (ENSG00000258223)

Protein

Protein identifiers

Kallikrein-4 — Q9Y5K2 (reviewed: Q9Y5K2)

Alternative names: Enamel matrix serine proteinase 1, Kallikrein-like protein 1, Prostase, Serine protease 17

All UniProt accessions (4): Q9Y5K2, A0A0C4DFQ5, M0QYN5, Q5BQA0

UniProt curated annotations — full annotation on UniProt →

Function. Has a major role in enamel formation. Required during the maturation stage of tooth development for clearance of enamel proteins and normal structural patterning of the crystalline matrix.

Subcellular location. Secreted.

Tissue specificity. Expressed in prostate.

Post-translational modifications. N-glycosylated. The N-glycan structures are of complex diantennary or triantennary type, which may be further modified with up to 2 sialic acid residues.

Disease relevance. Amelogenesis imperfecta, hypomaturation type, 2A1 (AI2A1) [MIM:204700] A defect of enamel formation. The disorder involves both primary and secondary dentitions. The teeth have a shiny agar jelly appearance and the enamel is softer than normal. Brown pigment is present in middle layers of enamel. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the peptidase S1 family. Kallikrein subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y5K2-1	1	yes
Q9Y5K2-2	2

RefSeq proteins (2): NP_001289890, NP_004908* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001254	Trypsin_dom	Domain
IPR001314	Peptidase_S1A	Family
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR018114	TRYPSIN_HIS	Active_site
IPR033116	TRYPSIN_SER	Active_site
IPR043504

Pfam: PF00089

Enzyme classification (BRENDA):

• EC 3.4.21.B12 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

UniProt features (44 total): strand 16, disulfide bond 6, helix 5, sequence variant 3, active site 3, splice variant 2, turn 2, binding site 2, signal peptide 1, propeptide 1, chain 1, domain 1, glycosylation site 1

Structure

Experimental structures (PDB)

18 structures.

PDB	Method	Resolution (Å)
4K8Y	X-RAY DIFFRACTION	1
4KEL	X-RAY DIFFRACTION	1.15
6O21	X-RAY DIFFRACTION	1.15
4K1E	X-RAY DIFFRACTION	1.3
7JOD	X-RAY DIFFRACTION	1.33
7JQK	X-RAY DIFFRACTION	1.33
7JQN	X-RAY DIFFRACTION	1.5
7JQO	X-RAY DIFFRACTION	1.6
6NVB	X-RAY DIFFRACTION	1.64
7JOW	X-RAY DIFFRACTION	1.91
2BDG	X-RAY DIFFRACTION	1.95
6KBR	X-RAY DIFFRACTION	2
7JOS	X-RAY DIFFRACTION	2.1
7JQV	X-RAY DIFFRACTION	2.1
4KGA	X-RAY DIFFRACTION	2.32
7JOE	X-RAY DIFFRACTION	2.6
2BDH	X-RAY DIFFRACTION	3
2BDI	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5K2-F1	90.60	0.84

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 (3): 71 (charge relay system); 116 (charge relay system); 207 (charge relay system)

Ligand- & substrate-binding residues (2): 40; 91

Disulfide bonds (6): 37–167, 56–72, 141–241, 148–213, 178–192, 203–228

Glycosylation sites (1): 169

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 109 (showing top): BENPORATH_ES_WITH_H3K27ME3, GOCC_SECRETORY_GRANULE, GCANCTGNY_MYOD_Q6, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_PROTEIN_MATURATION, NELSON_RESPONSE_TO_ANDROGEN_UP, GOBP_AMELOGENESIS, GOBP_EXTRACELLULAR_MATRIX_DISASSEMBLY, GOBP_ODONTOGENESIS_OF_DENTIN_CONTAINING_TOOTH, MODULE_48, MODULE_95, GOBP_ODONTOGENESIS, GOCC_SECRETORY_VESICLE, PID_UPA_UPAR_PATHWAY, GOBP_PROTEOLYSIS

GO Biological Process (6): proteolysis (GO:0006508), extracellular matrix disassembly (GO:0022617), biomineral tissue development (GO:0031214), protein maturation (GO:0051604), amelogenesis (GO:0097186), protein catabolic process (GO:0030163)

GO Molecular Function (6): serine-type endopeptidase activity (GO:0004252), serine-type peptidase activity (GO:0008236), metal ion binding (GO:0046872), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (3): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), secretory granule (GO:0030141)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	3
cellular component disassembly	1
extracellular matrix organization	1
tissue development	1
animal organ development	1
gene expression	1
odontogenesis of dentin-containing tooth	1
anatomical structure formation involved in morphogenesis	1
macromolecule catabolic process	1
endopeptidase activity	1
serine-type peptidase activity	1
peptidase activity	1
serine hydrolase activity	1
cation binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
cellular anatomical structure	1
endomembrane system	1
secretory vesicle	1

Protein interactions and networks

STRING

1610 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLK4	SERPING1	P05155	998
KLK4	KNG1	P01042	997
KLK4	A2M	P01023	993
KLK4	MMP20	O60882	963
KLK4	SERPINC1	P01008	864
KLK4	WDR72	Q3MJ13	862
KLK4	SPINK5	Q9NQ38	862
KLK4	BDKRB2	P30411	849
KLK4	SERPINA4	P29622	847
KLK4	ACE	P12821	843
KLK4	ENAM	Q9NRM1	836
KLK4	BDKRB1	P46663	832
KLK4	AMBN	Q9NP70	825
KLK4	REN	P00797	819
KLK4	MMP25	Q9NPA2	804

IntAct

11 interactions, top by confidence:

A	B	Type	Score
HLA-DRA	HLA-DRB1	psi-mi:“MI:0914”(association)	0.880
TYRO3	KLK4	psi-mi:“MI:0915”(physical association)	0.560
KLK4	TYRO3	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
KLK4	KCNIP4	psi-mi:“MI:0915”(physical association)	0.400
KLK4	SERPINA1	psi-mi:“MI:0914”(association)	0.350

BioGRID (11): KLK4 (Two-hybrid), KLK4 (Affinity Capture-MS), KLK4 (Affinity Capture-MS), KCNIP4 (Affinity Capture-MS), KLK4 (Affinity Capture-RNA), KCNIP4 (Affinity Capture-MS), BCL2L12 (Affinity Capture-MS), SERPINA1 (Affinity Capture-MS), KLK4 (Affinity Capture-Western), KLK4 (Negative Genetic), KLK4 (Two-hybrid)

ESM2 similar proteins: A7WPL7, O43240, O46683, O60259, O88780, P07288, P08311, P09650, P10144, P15944, P17977, P19236, P20151, P20718, P21842, P21844, P23946, P24158, P28293, P33619, P49862, P50339, P50341, P50342, P51124, P52195, P56435, P79204, P80219, P80931, P97592, Q07276, Q28773, Q61096, Q61955, Q6DT45, Q7JIG6, Q8CGR5, Q92876, Q9BZJ3

Diamond homologs: O18783, O35164, O35205, O46683, O60259, O88780, P00746, P00747, P00752, P00756, P00758, P00759, P00760, P00761, P00762, P00763, P00764, P00770, P03953, P04187, P07146, P07288, P08311, P08426, P08882, P08883, P09582, P09650, P10144, P11032, P11034, P12323, P12544, P12545, P15119, P15946, P15949, P18291, P19799, P20151

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PGR	“up-regulates quantity by expression”	KLK4	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	3
Uncertain significance	29
Likely benign	4
Benign	21

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
1327588	NM_004917.5(KLK4):c.637T>C (p.Cys213Arg)	Pathogenic
1327589	NM_004917.5(KLK4):c.170C>A (p.Ser57Ter)	Pathogenic
189294	NM_004917.5(KLK4):c.245del (p.Gly82fs)	Pathogenic
288110	NM_004917.5(KLK4):c.632del (p.Leu211fs)	Pathogenic
1299354	NM_004917.5(KLK4):c.620_621del (p.Ser207fs)	Likely pathogenic
3065689	NM_004917.5(KLK4):c.224+2T>C	Likely pathogenic
6079	NM_004917.5(KLK4):c.458G>A (p.Trp153Ter)	Likely pathogenic

SpliceAI

830 predictions. Top by Δscore:

Variant	Effect	Δscore
19:50908357:A:AC	donor_gain	1.0000
19:50908358:C:CC	donor_gain	1.0000
19:50908369:T:TA	donor_gain	1.0000
19:50908825:AGGAG:A	acceptor_gain	1.0000
19:50908826:GGAG:G	acceptor_gain	1.0000
19:50908827:GAG:G	acceptor_gain	1.0000
19:50908827:GAGC:G	acceptor_loss	1.0000
19:50908829:GCTGT:G	acceptor_loss	1.0000
19:50908830:C:CC	acceptor_gain	1.0000
19:50908830:CTGT:C	acceptor_loss	1.0000
19:50909250:A:AC	donor_gain	1.0000
19:50909251:C:CC	donor_gain	1.0000
19:50909251:CTT:C	donor_gain	1.0000
19:50907085:CC:C	acceptor_gain	0.9900
19:50907086:CC:C	acceptor_gain	0.9900
19:50908341:C:A	donor_gain	0.9900
19:50908346:T:A	donor_gain	0.9900
19:50908348:C:A	donor_gain	0.9900
19:50908358:CGTTG:C	donor_gain	0.9900
19:50908572:AGCTC:A	donor_loss	0.9900
19:50908573:GCTCA:G	donor_loss	0.9900
19:50908574:CT:C	donor_loss	0.9900
19:50908575:TCA:T	donor_loss	0.9900
19:50908576:CACCG:C	donor_loss	0.9900
19:50908577:A:AT	donor_loss	0.9900
19:50908828:AG:A	acceptor_gain	0.9900
19:50908838:C:CT	acceptor_gain	0.9900
19:50908838:C:T	acceptor_gain	0.9900
19:50909253:T:TA	donor_gain	0.9900
19:50908353:TCTCA:T	donor_loss	0.9800

AlphaMissense

1659 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:50908595:C:A	W153C	0.998
19:50908595:C:G	W153C	0.998
19:50906961:C:A	W246C	0.997
19:50906961:C:G	W246C	0.997
19:50908707:T:A	D116V	0.996
19:50908707:T:G	D116A	0.996
19:50908396:C:G	C192S	0.994
19:50908397:A:T	C192S	0.994
19:50908707:T:C	D116G	0.993
19:50906963:A:G	W246R	0.992
19:50906963:A:T	W246R	0.992
19:50908438:C:G	C178S	0.992
19:50908439:A:T	C178S	0.992
19:50909344:C:A	W44C	0.991
19:50909344:C:G	W44C	0.991
19:50908396:C:T	C192Y	0.990
19:50909281:C:A	W65C	0.990
19:50909281:C:G	W65C	0.990
19:50909283:A:G	W65R	0.990
19:50909283:A:T	W65R	0.990
19:50907077:C:A	G208W	0.989
19:50908594:C:A	G154C	0.989
19:50908698:A:G	L119P	0.989
19:50908704:A:G	L117P	0.989
19:50909260:A:C	C72W	0.989
19:50909261:C:T	C72Y	0.989
19:50906970:G:C	F243L	0.988
19:50906970:G:T	F243L	0.988
19:50906972:A:G	F243L	0.988
19:50907076:C:A	G208V	0.988

dbSNP variants (sampled 300 via entrez): RS1000610122 (19:50912395 G>A,C,T), RS1000811119 (19:50911196 C>T), RS1001575604 (19:50906846 A>AG), RS1002212509 (19:50912413 G>A), RS1002581740 (19:50908153 C>G,T), RS1004718399 (19:50910383 C>A,T), RS1004771647 (19:50910634 G>A,T), RS1005065630 (19:50906447 C>T), RS1005160533 (19:50906130 C>T), RS1005500772 (19:50911719 CTTCT>C), RS1006165179 (19:50907854 A>G), RS1006474492 (19:50907938 C>A), RS1006655047 (19:50907361 G>A,T), RS1006767087 (19:50912785 G>C,T), RS1006814782 (19:50913332 C>G)

Disease associations

OMIM: gene MIM:603767 | disease phenotypes: MIM:204700, MIM:104500

GenCC curated gene-disease

Disease	Classification	Inheritance
amelogenesis imperfecta type 2A1	Strong	Autosomal recessive
amelogenesis imperfecta type 2	Supportive	Autosomal recessive

Mondo (4): amelogenesis imperfecta type 2A1 (MONDO:0008772), amelogenesis imperfecta (MONDO:0019507), male infertility (MONDO:0005372), amelogenesis imperfecta type 2 (MONDO:0015048)

Orphanet (1): Amelogenesis imperfecta (Orphanet:88661)

HPO phenotypes

7 total (7 of 7 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000670	Carious teeth
HP:0000705	Amelogenesis imperfecta
HP:0003593	Infantile onset
HP:0006285	Enamel hypomineralization
HP:0006286	Yellow-brown discoloration of the teeth
HP:0009102	Anterior open-bite malocclusion

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001762_935	Obesity-related traits	2.000000e-06
GCST002112_14	Celiac disease	6.000000e-06
GCST009268_6	Dental caries (decayed, missing and filled tooth surfaces)	3.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005116	urinary metabolite measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D000567	Amelogenesis Imperfecta	C07.650.800.295.250; C07.793.700.295.250; C16.131.850.800.295.250
D007248	Infertility, Male	C12.100.500.430; C12.100.750.700; C12.200.294.430
C536606	Amelogenesis Imperfecta hypomaturation type (supp.)
C567146	Amelogenesis Imperfecta, Hypomaturation Type, Iia1 (supp.)
C538242	Amelogenesis imperfecta pigmented hypomaturation type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4446 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — S1: Chymotrypsin

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
compound 32 [PMID: 31675166]	Inhibition	6.8	pIC50
compound 33 [PMID: 19908842]	Inhibition	5.01	pIC50

ChEMBL bioactivities

18 potent at pChembl≥5 of 19 total, top 18 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.00	Ki	0.1	nM	CHEMBL4564063
9.89	Ki	0.13	nM	CHEMBL4543437
9.52	Ki	0.3	nM	CHEMBL4566258
9.36	Ki	0.44	nM	CHEMBL4531700
8.89	Ki	1.3	nM	CHEMBL4452574
8.80	Ki	1.6	nM	CHEMBL4530379
8.74	Ki	1.8	nM	CHEMBL4443340
8.47	IC50	3.4	nM	CHEMBL1184949
8.05	Ki	9	nM	CHEMBL3623790
7.92	IC50	12	nM	CHEMBL239535
7.82	IC50	15	nM	CHEMBL238913
7.70	Ki	19.9	nM	CHEMBL3623791
7.40	IC50	40	nM	CHEMBL239331
7.39	IC50	41	nM	CHEMBL238707
7.10	IC50	80	nM	CHEMBL3770794
6.60	IC50	250	nM	CHEMBL3771081
5.01	IC50	9772	nM	CHEMBL578159
5.00	IC50	1e+04	nM	GRASSYSTATIN A

PubChem BioAssay actives

11 with measured affinity, of 35 total; 11 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(aR,1R,3aS,4S,10S,16R,19S,22S,25S,28S,31S,34R,37S,40S,43S,46S,49S,52S,55R,58S,67S,70S,76S,82R,85S,91S,97S)-37,40,49-tris(4-aminobutyl)-91-(2-amino-2-oxoethyl)-52-(3-amino-3-oxopropyl)-3a,46-bis[(2S)-butan-2-yl]-28,31,97-tris(3-carbamimidamidopropyl)-19,67-bis(carboxymethyl)-22,70,76-tris(hydroxymethyl)-85-[(4-hydroxyphenyl)methyl]-4-methyl-43-(2-methylpropyl)-2a,3,5a,6,9,15,18,21,24,27,30,33,36,39,42,45,48,51,54,57,60,63,66,69,72,75,78,81,84,87,90,93,96,99-tetratriacontaoxo-58-propan-2-yl-7a,8a,11a,12a,15a,16a-hexathia-1a,2,4a,5,8,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71,74,77,80,83,86,89,92,95,98-tetratriacontazapentacyclo[53.50.4.416,82.434,100.010,14]heptadecahectan-25-yl]acetic acid	1533291: Inhibition of KLK4 (unknown origin) expressed in sf9 cells using Ac-FVQR-pNA as substrate preincubated for 30 mins followed by substrate addition and measured for 7 mins by spectrophotometric method	ki	0.0001	uM
2-[(aR,1R,3aS,4S,10S,16R,19S,22S,25S,28S,31S,34R,37S,40S,43S,46S,49S,52S,55R,58S,67S,70S,76S,82R,85S,91S,97S)-37,40-bis(4-aminobutyl)-91-(2-amino-2-oxoethyl)-52-(3-amino-3-oxopropyl)-58-benzyl-3a,46-bis[(2S)-butan-2-yl]-28,31,49,97-tetrakis(3-carbamimidamidopropyl)-19,67-bis(carboxymethyl)-22,70,76-tris(hydroxymethyl)-85-[(4-hydroxyphenyl)methyl]-4-methyl-43-(2-methylpropyl)-2a,3,5a,6,9,15,18,21,24,27,30,33,36,39,42,45,48,51,54,57,60,63,66,69,72,75,78,81,84,87,90,93,96,99-tetratriacontaoxo-7a,8a,11a,12a,15a,16a-hexathia-1a,2,4a,5,8,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71,74,77,80,83,86,89,92,95,98-tetratriacontazapentacyclo[53.50.4.416,82.434,100.010,14]heptadecahectan-25-yl]acetic acid	1533291: Inhibition of KLK4 (unknown origin) expressed in sf9 cells using Ac-FVQR-pNA as substrate preincubated for 30 mins followed by substrate addition and measured for 7 mins by spectrophotometric method	ki	0.0001	uM
2-[(1R,6aS,7S,10S,13S,16S,19S,22S,25R,28S,31S,34S,37S,40S,43R,49S,55S,58R,61S,64R,67S,73S,79S,82R,88S,94S,97S)-19,22-bis(4-aminobutyl)-73-(2-amino-2-oxoethyl)-13,61-bis[(2S)-butan-2-yl]-10,28,31,67-tetrakis(3-carbamimidamidopropyl)-40,97-bis(carboxymethyl)-37,88,94-tris(hydroxymethyl)-79-[(4-hydroxyphenyl)methyl]-55-methyl-16-(2-methylpropyl)-1a,2,4a,7a,8,11,14,17,20,23,26,29,32,35,38,41,44,50,53,56,59,62,65,68,71,74,77,80,83,86,89,92,95,98-tetratriacontaoxo-6a-propan-2-yl-10a,11a,14a,15a,18a,19a-hexathia-2a,3,5a,8a,9,12,15,18,21,24,27,30,33,36,39,42,45,51,54,57,60,63,66,69,72,75,78,81,84,87,90,93,96,99-tetratriacontazahexacyclo[56.50.4.425,64.443,82.03,7.045,49]icosahectan-34-yl]acetic acid	1533291: Inhibition of KLK4 (unknown origin) expressed in sf9 cells using Ac-FVQR-pNA as substrate preincubated for 30 mins followed by substrate addition and measured for 7 mins by spectrophotometric method	ki	0.0003	uM
2-[(aR,1R,3aS,4S,10S,16R,19S,22S,25S,28S,31S,34R,37S,40S,43S,46S,49S,52S,55R,58S,67S,70S,76S,82R,85S,91S,97S)-97-(4-aminobutyl)-91-(2-amino-2-oxoethyl)-28,31,37,40,52-pentakis(3-amino-3-oxopropyl)-58-benzyl-3a,46-bis[(2S)-butan-2-yl]-49-(3-carbamimidamidopropyl)-19,67-bis(carboxymethyl)-22,70,76-tris(hydroxymethyl)-85-[(4-hydroxyphenyl)methyl]-4-methyl-43-(2-methylpropyl)-2a,3,5a,6,9,15,18,21,24,27,30,33,36,39,42,45,48,51,54,57,60,63,66,69,72,75,78,81,84,87,90,93,96,99-tetratriacontaoxo-7a,8a,11a,12a,15a,16a-hexathia-1a,2,4a,5,8,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71,74,77,80,83,86,89,92,95,98-tetratriacontazapentacyclo[53.50.4.416,82.434,100.010,14]heptadecahectan-25-yl]acetic acid	1533291: Inhibition of KLK4 (unknown origin) expressed in sf9 cells using Ac-FVQR-pNA as substrate preincubated for 30 mins followed by substrate addition and measured for 7 mins by spectrophotometric method	ki	0.0004	uM
2-[(1R,6aS,7S,10S,13S,16S,19S,22S,25R,28S,31S,34S,37S,40S,43R,49S,55S,58R,61S,64R,67S,73S,79S,82R,88S,94S,97S)-10,19,22-tris(4-aminobutyl)-73-(2-amino-2-oxoethyl)-6a-benzyl-13,61-bis[(2S)-butan-2-yl]-28,31,67-tris(3-carbamimidamidopropyl)-40,97-bis(carboxymethyl)-37,88,94-tris(hydroxymethyl)-79-[(4-hydroxyphenyl)methyl]-55-methyl-16-(2-methylpropyl)-1a,2,4a,7a,8,11,14,17,20,23,26,29,32,35,38,41,44,50,53,56,59,62,65,68,71,74,77,80,83,86,89,92,95,98-tetratriacontaoxo-10a,11a,14a,15a,18a,19a-hexathia-2a,3,5a,8a,9,12,15,18,21,24,27,30,33,36,39,42,45,51,54,57,60,63,66,69,72,75,78,81,84,87,90,93,96,99-tetratriacontazahexacyclo[56.50.4.425,64.443,82.03,7.045,49]icosahectan-34-yl]acetic acid	1533291: Inhibition of KLK4 (unknown origin) expressed in sf9 cells using Ac-FVQR-pNA as substrate preincubated for 30 mins followed by substrate addition and measured for 7 mins by spectrophotometric method	ki	0.0013	uM
2-[(1R,3aS,7S,10S,13S,16S,19S,22S,25R,28S,31S,34S,37S,40S,43R,49S,55S,58R,61S,64R,67S,73S,79S,82R,88S,94S,97S)-10,19,22-tris(4-aminobutyl)-73-(2-amino-2-oxoethyl)-13,61-bis[(2S)-butan-2-yl]-28,31,67-tris(3-carbamimidamidopropyl)-40,97-bis(carboxymethyl)-37,88,94-tris(hydroxymethyl)-79-[(4-hydroxyphenyl)methyl]-55-methyl-16-(2-methylpropyl)-1a,2,4a,8,11,14,17,20,23,26,29,32,35,38,41,44,50,53,56,59,62,65,68,71,74,77,80,83,86,89,92,95,98-tritriacontaoxo-3a-propan-2-yl-7a,8a,11a,12a,15a,16a-hexathia-2a,3,5a,9,12,15,18,21,24,27,30,33,36,39,42,45,51,54,57,60,63,66,69,72,75,78,81,84,87,90,93,96,99-tritriacontazahexacyclo[56.47.4.425,64.443,82.03,7.045,49]heptadecahectan-34-yl]acetic acid	1533291: Inhibition of KLK4 (unknown origin) expressed in sf9 cells using Ac-FVQR-pNA as substrate preincubated for 30 mins followed by substrate addition and measured for 7 mins by spectrophotometric method	ki	0.0016	uM
2-[(1R,6aS,7S,10S,13S,16S,19S,22S,25R,28S,31S,34S,37S,40S,43R,49S,55S,58R,61S,64R,67S,73S,79S,82R,88S,94S,97S)-67-(4-aminobutyl)-73-(2-amino-2-oxoethyl)-19,22,28,31-tetrakis(3-amino-3-oxopropyl)-13,61-bis[(2S)-butan-2-yl]-10-(3-carbamimidamidopropyl)-40,97-bis(carboxymethyl)-37,88,94-tris(hydroxymethyl)-79-[(4-hydroxyphenyl)methyl]-55-methyl-16-(2-methylpropyl)-1a,2,4a,7a,8,11,14,17,20,23,26,29,32,35,38,41,44,50,53,56,59,62,65,68,71,74,77,80,83,86,89,92,95,98-tetratriacontaoxo-6a-propan-2-yl-10a,11a,14a,15a,18a,19a-hexathia-2a,3,5a,8a,9,12,15,18,21,24,27,30,33,36,39,42,45,51,54,57,60,63,66,69,72,75,78,81,84,87,90,93,96,99-tetratriacontazahexacyclo[56.50.4.425,64.443,82.03,7.045,49]icosahectan-34-yl]acetic acid	1533291: Inhibition of KLK4 (unknown origin) expressed in sf9 cells using Ac-FVQR-pNA as substrate preincubated for 30 mins followed by substrate addition and measured for 7 mins by spectrophotometric method	ki	0.0018	uM
2-[(1R,4S,7S,13S,19S,22S,25S,28S,31R,34S,40S,43S,49S)-49-(2-amino-2-oxoethyl)-4,19,28-tris[(2S)-butan-2-yl]-25-[3-(diaminomethylideneamino)propyl]-22-(hydroxymethyl)-34-(1H-indol-3-ylmethyl)-3,6,12,18,21,24,27,30,33,36,39,42,48,51-tetradecaoxo-53,54-dithia-2,5,11,17,20,23,26,29,32,35,38,41,47,50-tetradecazapentacyclo[29.20.4.07,11.013,17.043,47]pentapentacontan-40-yl]acetamide	1251578: Inhibition of KLK4 (unknown origin) expressed in Sf9 cells using FVQRpNA substrate by spectrophotometry method	ki	0.0090	uM
2-[(1R,4S,7S,13S,19S,22S,25S,28S,31R,34S,40S,43S,49S)-19-(4-aminobutyl)-49-(2-amino-2-oxoethyl)-4,28-bis[(2S)-butan-2-yl]-25-[3-(diaminomethylideneamino)propyl]-22-(hydroxymethyl)-34-(1H-indol-3-ylmethyl)-3,6,12,18,21,24,27,30,33,36,39,42,48,51-tetradecaoxo-53,54-dithia-2,5,11,17,20,23,26,29,32,35,38,41,47,50-tetradecazapentacyclo[29.20.4.07,11.013,17.043,47]pentapentacontan-40-yl]acetamide	1251578: Inhibition of KLK4 (unknown origin) expressed in Sf9 cells using FVQRpNA substrate by spectrophotometry method	ki	0.0199	uM
6-(3,5-difluoroanilino)-9-(2,2-difluoroethyl)purine-2-carbonitrile	444745: Inhibition of human Kallikrein 4	ic50	9.7724	uM
methyl (2S)-1-[(2R)-2-[[(2S)-2-[[(2S,3R)-2-[[(3S,4S)-4-[[(2S)-4-amino-2-[[(2S)-2-[[(2R)-2-[(2S)-2-[(2S)-2-(dimethylamino)-3-methylbutanoyl]oxy-3-methylbutanoyl]oxy-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-3-hydroxy-6-methylheptanoyl]amino]-3-hydroxybutanoyl]amino]propanoyl]-methylamino]-3-phenylpropanoyl]pyrrolidine-2-carboxylate	448889: Inhibition of kallikrein 4 after 10 to 15 mins by fluorescence assay	ic50	10.0000	uM

CTD chemical–gene interactions

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases methylation	2
ICG 001	decreases expression	1
abrine	increases expression	1
Arsenic	affects methylation	1
Cisplatin	affects response to substance	1
Diethylhexyl Phthalate	decreases expression	1
Mercuric Chloride	increases expression	1
Dihydrotestosterone	increases expression	1

ChEMBL screening assays

13 unique, capped per target: 13 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1039260	Binding	Inhibition of kallikrein 4 after 10 to 15 mins by fluorescence assay	Grassystatins A-C from marine cyanobacteria, potent cathepsin E inhibitors that reduce antigen presentation. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02202382	PHASE4	COMPLETED	Effects of Korean Red Ginseng on Male Infertility
NCT02204826	PHASE4	COMPLETED	Effects of Korean Red Ginseng on Semen Parameters in Male Infertility Patients: a Randomized, Placebo-controlled, Double-blind Clinical Study
NCT03802864	PHASE4	COMPLETED	Post-operative Pain Control of Testicular Sperm Extraction Using Liposomal Bupivacaine
NCT06100432	PHASE4	ACTIVE_NOT_RECRUITING	Effect of Eurycoma Longifolia (DLBS5055) and Multivitamins (Vitamin C+Vitamin E+ β-carotene) for Infertile Males
NCT07523022	PHASE4	ENROLLING_BY_INVITATION	Comparison of the Effect of Gonadotropin and Clomiphene Citrate Treatment on Sperm Parameters and the Outcome of Assisted Reproductive Procedures in Subfertile Men Based on the APHRODITE Groups
NCT00975117	PHASE3	COMPLETED	Spermotrend in the Treatment of Male Infertility
NCT01407432	PHASE3	COMPLETED	Impact of Folates in the Care of the Male Infertility
NCT01895816	PHASE3	COMPLETED	Herbal Tonic Fertile Supplement(ZO2C5)
NCT02605070	PHASE3	TERMINATED	Pilot Study on the Effects of FSH Treatment on the Epigenetic Characteristics of Spermatozoa in Infertile Patients With Severe Oligozoospermia
NCT07402759	PHASE3	ACTIVE_NOT_RECRUITING	Impact of tdrd9 Gene Mutations in the Therapeutic Response to L-carnitine in Oligoasthenozoospermic Men
NCT01880086	PHASE2	COMPLETED	Clomiphene Citrate for the Treatment of Low Testosterone Associated With Chronic Opioid Pain Medication Administration
NCT02061384	PHASE2	COMPLETED	RA-2 13-cis Retinoic Acid (Isotretinoin)
NCT02421887	PHASE2	COMPLETED	Males, Antioxidants, and Infertility Trial
NCT05200663	PHASE2	UNKNOWN	Efficacy Comparison of Tamoxifen and Tamoxifen With Antioxidants on Semen Quality of Male With Idiopathic Infertility
NCT05290558	PHASE2	ACTIVE_NOT_RECRUITING	The Therapeutic Effects of Bu Shen Yi Jing Pill on Semen Quality in Sub Fertile Males: a Randomized Controlled Trial
NCT06091969	PHASE2	NOT_YET_RECRUITING	Supplementation for Male Subfertility
NCT01595308	PHASE1	COMPLETED	A Pilot Study to Evaluate the Effect of Pomegranate Juice on Semen Parameters in Healthy Male Volunteers
NCT02122211	PHASE1	COMPLETED	Choline Dehydrogenase and Sperm Function: Effects of Betaine
NCT02575924	PHASE1	UNKNOWN	Influence of Culture Media on Clinical Outcomes in Poor Responders or Severe Male Infertility
NCT01746121	Not specified	TERMINATED	Amelogenesis Imperfecta
NCT02994862	Not specified	UNKNOWN	E. Max Laminate Veneers With and Without Using Galla Chinnesis as Natural Cross Linking and Remineralizing Agent
NCT03810859	Not specified	UNKNOWN	Non-syndromic Inherited Anomalies of Mineralized Tooth Tissues: a Whole Exome Study to Identify New Pathogenic Variants
NCT04704089	Not specified	RECRUITING	Colorimetric, Ultra-structural and Elemental Comparison of Dental Enamel Defects
NCT04897724	Not specified	UNKNOWN	Clinical Performance of Composites in Patients With Amelogenesis Imperfecta
NCT04927962	Not specified	COMPLETED	Psycho-social Impact of Amelogenesis and Dentinogenesis Imperfecta
NCT05343247	Not specified	COMPLETED	Dental Age Estimation by Different Methods in Patients With Amelogenesis Imperfecta
NCT07250906	Not specified	RECRUITING	Oral Health Related Quality of Life of Children With Amelogenesis Imperfecta
NCT01304927	PHASE2/PHASE3	COMPLETED	Vitamin D Supplementation and Male Infertility: The CBG-study a Randomized Clinical Trial
NCT02349945	PHASE2/PHASE3	COMPLETED	FSH Receptor Polymorphism p.N680S and Efficacy of FSH Therapy
NCT05222841	PHASE2/PHASE3	COMPLETED	The Effectiveness of Spermotrend Food Supplement in the Treatment of Male Infertility
NCT05616598	PHASE2/PHASE3	COMPLETED	Effect of New Oral Treatment for Hepatitis C Virus on Seminal Parameters
NCT02025270	PHASE1/PHASE2	COMPLETED	MSCs For Treatment of Azoospermic Patients
NCT04541459	EARLY_PHASE1	UNKNOWN	Validation of New Devices Against Ambient Electromagnetic Radiation
NCT05792813	EARLY_PHASE1	UNKNOWN	Efficacy and Safety of Linggui Yangyuan Paste in Patients With Male Infertility
NCT06188936	EARLY_PHASE1	COMPLETED	Home Semen Analysis Tests As a Screening Tool for Fertility Patients
NCT00012480	Not specified	COMPLETED	Effect of Environmental Exposures on the Egg Fertilizing Ability of Human Sperm
NCT00044369	Not specified	COMPLETED	Role of the Toxic Metal Cadmium in the Mechanism Producing Infertility With a Varicocele
NCT00119925	Not specified	UNKNOWN	‘SPRING’-Study: Subfertility Guidelines: Patient Related Implementation in the Netherlands Among Gynaecologists
NCT00178516	Not specified	COMPLETED	Vitamin E and Male Infertility
NCT00315029	Not specified	COMPLETED	Patient-Centered Implementation Trial for Single Embryo Transfer