LOXL4

Summary

LOXL4 (lysyl oxidase like 4, HGNC:17171) is a protein-coding gene on chromosome 10q24.2, encoding Lysyl oxidase homolog 4 (Q96JB6). Catalyzes the oxidative deamination of lysine and hydroxylysine residues in collagen and elastin, resulting in the formation of covalent cross-linkages, and the stabilization of collagen and elastin fibers.

This gene encodes a member of the lysyl oxidase gene family. The prototypic member of the family is essential to the biogenesis of connective tissue, encoding an extracellular copper-dependent amine oxidase that catalyses the first step in the formation of crosslinks in collagens and elastin. A highly conserved amino acid sequence at the C-terminus end appears to be sufficient for amine oxidase activity, suggesting that each family member may retain this function. The N-terminus is poorly conserved and may impart additional roles in developmental regulation, senescence, tumor suppression, cell growth control, and chemotaxis to each member of the family.

Source: NCBI Gene 84171 — RefSeq curated summary.

At a glance

• Gene–disease (curated): skeletal dysplasia (Limited, GenCC)
• GWAS associations: 5
• Clinical variants (ClinVar): 167 total
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_032211

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17171
Approved symbol	LOXL4
Name	lysyl oxidase like 4
Location	10q24.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ21889, LOXC
Ensembl gene	ENSG00000138131
Ensembl biotype	protein_coding
OMIM	607318
Entrez	84171

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 14 protein_coding

ENST00000260702, ENST00000905878, ENST00000905879, ENST00000905880, ENST00000905881, ENST00000905882, ENST00000905883, ENST00000905884, ENST00000905885, ENST00000905886, ENST00000905887, ENST00000958236, ENST00000958237, ENST00000958239

RefSeq mRNA: 1 — MANE Select: NM_032211 NM_032211

CCDS: CCDS7473

Canonical transcript exons

ENST00000260702 — 15 exons

Exon	Start	End
ENSE00000933115	98247690	98248991
ENSE00000933116	98251065	98251176
ENSE00000933117	98251566	98251702
ENSE00000933118	98252353	98252468
ENSE00000933119	98253553	98253796
ENSE00000933120	98255577	98255739
ENSE00000933122	98257650	98257804
ENSE00000987329	98260922	98261127
ENSE00000987330	98257981	98258164
ENSE00000987332	98262743	98263051
ENSE00000987337	98256780	98256947
ENSE00001020051	98259009	98259228
ENSE00001020054	98262035	98262213
ENSE00001020058	98259391	98259429
ENSE00001382904	98268132	98268194

Expression profiles

Bgee: expression breadth ubiquitous, 194 present calls, max score 96.85.

FANTOM5 (CAGE): breadth broad, TPM avg 4.6188 / max 407.4960, expressed in 639 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
110961	4.6188	639

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	96.85	gold quality
islet of Langerhans	UBERON:0000006	94.51	gold quality
cartilage tissue	UBERON:0002418	93.11	gold quality
tibialis anterior	UBERON:0001385	90.76	gold quality
epithelial cell of pancreas	CL:0000083	90.55	silver quality
tendon of biceps brachii	UBERON:0008188	89.53	gold quality
pancreatic ductal cell	CL:0002079	86.92	silver quality
olfactory segment of nasal mucosa	UBERON:0005386	85.51	gold quality
nasal cavity epithelium	UBERON:0005384	85.04	silver quality
stromal cell of endometrium	CL:0002255	84.69	gold quality
parotid gland	UBERON:0001831	84.37	gold quality
minor salivary gland	UBERON:0001830	84.14	gold quality
tendon	UBERON:0000043	83.07	gold quality
saliva-secreting gland	UBERON:0001044	83.03	gold quality
ileal mucosa	UBERON:0000331	82.97	gold quality
ascending aorta	UBERON:0001496	82.40	gold quality
calcaneal tendon	UBERON:0003701	82.40	gold quality
thoracic aorta	UBERON:0001515	82.38	gold quality
deltoid	UBERON:0001476	81.37	silver quality
descending thoracic aorta	UBERON:0002345	81.17	gold quality
pancreas	UBERON:0001264	80.30	gold quality
mouth mucosa	UBERON:0003729	80.25	gold quality
kidney epithelium	UBERON:0004819	79.99	gold quality
nasal cavity mucosa	UBERON:0001826	79.74	gold quality
endocervix	UBERON:0000458	79.20	gold quality
muscle layer of sigmoid colon	UBERON:0035805	79.18	gold quality
aorta	UBERON:0000947	78.95	gold quality
upper arm skin	UBERON:0004263	78.56	gold quality
smooth muscle tissue	UBERON:0001135	78.38	gold quality
metanephros cortex	UBERON:0010533	78.20	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	2131.88
E-GEOD-83139	yes	717.82
E-ENAD-27	yes	610.59
E-GEOD-81608	yes	546.55
E-HCAD-31	yes	28.35
E-ANND-3	yes	5.41

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, FOS, JUN, SP1

miRNA regulators (miRDB)

86 targeting LOXL4, 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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-574-5P	100.00	66.01	989
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-4500	99.99	72.72	2367
HSA-MIR-4531	99.99	69.70	3181
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-MIR-98-5P	99.98	72.33	1787
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-7978	99.86	66.90	856
HSA-MIR-202-3P	99.84	71.41	1290
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-518A-5P	99.70	69.01	2209

Literature-anchored findings (GeneRIF, showing 34)

• The data presented in this work might emphasize the involvement of LOXL4 in molecular processes of the genesis or progression of head and neck carcinomas. (PMID:12894545)
• LOXL4, with the four scavenger receptor cysteine rich domains, may also function as an active amine oxidase (PMID:14551188)
• Up-regulation of lysyl oxidase mRNA and protein expression is associated with oral squamous cell carcinoma (PMID:17671119)
• LOXL4-DC stimulated T cells produce higher IFN-gamma secretion compared to unstimulated T cells and T cells stimulated with untransfected DCs, in the presence of the pan-DR-epitope (PADRE) (PMID:18202753)
• These results suggest that LOXL4 may function as a negative feedback regulator of TGF-beta1 in cell invasion by inhibiting the metabolism of extracellular matrix (ECM) components. (PMID:18586005)
• Functional analysis of the 5’ flanking domain of the LOXL4 gene in head and neck squamous cell carcinoma cells. (PMID:18949373)
• In breast carcinoma, LOXL4 was expressed only in the effusion samples. In malignant mesothelioma, LOXL4 and its splice variants were expressed at all sites. (PMID:19015874)
• Overexpression of the lysyl oxidase-like 4 gene is associated with metastatic head/neck carcinoma. (PMID:21115907)
• SNPs in the lysyl oxidase-like protein 4 and complement component 3 genes are associated with increased risk for endometriosis and endometriosis-associated infertility in a Puerto Rican population. (PMID:21733505)
• The human lysyl oxidase-like 4 gene does not confer increased genotypic risk for adolescent idiopathic scoliosis. (PMID:21740577)
• Alternatively spliced lysyl oxidase-like 4 isoforms have a pro-metastatic role in cancer. (PMID:22806361)
• TGF-beta1 induced injured MCL to express more LOXs than injured ACL (up to 1.85-fold in LOX, 2.21-fold in LOXL-1, 1.71-fold in LOXL-2, 2.52-fold in LOXL-3 and 3.32-fold in LOXL-4). (PMID:23357697)
• data suggest that abnormal expression of LOXL4 of KCOT may enhance angiogenesis in KCOT, which may help to promote the locally aggressive biological behavior of KCOT. (PMID:24357854)
• High Lysyl oxidase-like 4 promotes proliferation and metastasis of gastric cancer via FAK/Src pathway. (PMID:25216702)
• These results provide a set of the essential genes in this newly identified miR-193a-3p/LOXL4/Oxidative Stress axis. (PMID:25311867)
• In hepatocellular carcinoma, low LOXL4 expression was associated with lower overall survival rates and higher cumulative recurrence rates. (PMID:26097573)
• Although expression of LOXL4 is not statistically associated with neck metastases, we showed that LOXL4 expression significantly increased in laryngeal cancer. (PMID:26138381)
• study describes for the first time a direct link between a retinoic-induced gene and protein, LOXL4, and its general clinical pro-healing properties in ECM dynamics (PMID:27597564)
• trans-suppression of host CDH3 and LOXL4 genes in cultured human intestinal epithelial cells following C. parvum infection involves nuclear delivery of parasite Cdg7_FLc_1000 RNA (PMID:29438669)
• Our study suggests lack of association between DNA polymorphisms rs2236479 of COL18A1 and rs2862296 of LOXL-4 with advanced POP [pelvic organ prolapse] in this population [Brazil]. (PMID:29532123)
• LOXL1, LOXL3, and LOXL4 expressions are associated with distant metastasis of gastric cancer. (PMID:30045039)
• we confirmed that LOXL4 could serve as a downstream target of miR-210 and miR-210 promoted lung cancer progression via targeting LOXL4. In A549 and H1650 cells, knockdown of LOXL4 dramatically repressed lung cancer cell proliferation, migration, and invasion. (PMID:30633357)
• The data demonstrate a novel function of LOXL4 in tumor metastasis mediated by exosomes through regulation of the FAK/Src pathway and angiogenesis in hepatocellular carcinoma. (PMID:30704479)
• Derepression of LOXL4 inhibits liver cancer growth by reactivating compromised p53. (PMID:30728460)
• High LOXL4 expression is associated with esophageal squamous cell carcinoma. (PMID:30900087)
• This study revealed miR-135a-5p might be indicated as a perspective for lung cancer via targeting LOXL4. (PMID:30993701)
• Neutrophils expressing lysyl oxidase-like 4 protein are present in colorectal cancer liver metastases resistant to anti-angiogenic therapy. (PMID:32297656)
• Lysyl Oxidase-Like 4 Fosters an Immunosuppressive Microenvironment During Hepatocarcinogenesis. (PMID:33068461)
• Lysyl Oxidase Like-4 (LOXL4) as a tumor marker and prognosticator in advanced stage laryngeal cancer. (PMID:33757755)
• LOXL4 Abrogation Does Not Exaggerate Angiotensin II-Induced Thoracic or Abdominal Aortic Aneurysm in Mice. (PMID:33807332)
• LAMA2 and LOXL4 are candidate FSGS genes. (PMID:34565340)
• LOXL4, but not LOXL2, is the critical determinant of pathological collagen cross-linking and fibrosis in the lung. (PMID:37235663)
• The possibilities of LOXL4 as a prognostic marker for carcinomas. (PMID:37814029)
• LOXL4 Shuttled by Tumor Cells-derived Extracellular Vesicles Promotes Immune Escape in Hepatocellular Carcinoma by Activating the STAT1/PD-L1 Axis. (PMID:38047403)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	loxl4	ENSDARG00000025089
danio_rerio	LOXL4	ENSDARG00000105442
mus_musculus	Loxl4	ENSMUSG00000025185
rattus_norvegicus	Loxl4	ENSRNOG00000015727

Paralogs (15): CD6 (ENSG00000013725), CD5L (ENSG00000073754), LGALS3BP (ENSG00000108679), CD5 (ENSG00000110448), LOX (ENSG00000113083), LOXL3 (ENSG00000115318), LOXL1 (ENSG00000129038), LOXL2 (ENSG00000134013), SSC4D (ENSG00000146700), PRSS12 (ENSG00000164099), CD163 (ENSG00000177575), CD163L1 (ENSG00000177675), SSC5D (ENSG00000179954), DMBT1 (ENSG00000187908), SCART1 (ENSG00000214279)

Protein

Protein identifiers

Lysyl oxidase homolog 4 — Q96JB6 (reviewed: Q96JB6)

Alternative names: Lysyl oxidase-like protein 4, Lysyl oxidase-related protein C

All UniProt accessions (1): Q96JB6

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the oxidative deamination of lysine and hydroxylysine residues in collagen and elastin, resulting in the formation of covalent cross-linkages, and the stabilization of collagen and elastin fibers.

Subcellular location. Secreted. Extracellular space.

Tissue specificity. Expressed in many tissues, the highest levels among the tissues studied being in the skeletal muscle, testis and pancreas. Expressed in cartilage.

Post-translational modifications. The lysine tyrosylquinone cross-link (LTQ) is generated by condensation of the epsilon-amino group of a lysine with a topaquinone produced by oxidation of tyrosine. May be proteolytically cleaved by BMP1.

Activity regulation. Inhibited by beta-aminopropionitrile (BAPN).

Cofactor. Contains 1 lysine tyrosylquinone.

Similarity. Belongs to the lysyl oxidase family.

RefSeq proteins (1): NP_115587* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001190	SRCR	Domain
IPR001695	Lysyl_oxidase	Family
IPR019828	Lysyl_oxidase_CS	Conserved_site
IPR036772	SRCR-like_dom_sf	Homologous_superfamily
IPR050912

Pfam: PF00530, PF01186

Catalyzed reactions (Rhea), 1 shown:

• L-lysyl-[protein] + O2 + H2O = (S)-2-amino-6-oxohexanoyl-[protein] + H2O2 + NH4(+) (RHEA:24544)

UniProt features (41 total): disulfide bond 17, sequence conflict 6, domain 4, sequence variant 3, binding site 3, glycosylation site 2, signal peptide 1, chain 1, site 1, modified residue 1, cross-link 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96JB6-F1	86.43	0.62

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 (1): 569–570 (cleavage; by bmp1)

Ligand- & substrate-binding residues (3): 611; 613; 615

Post-translational modifications (2): 674, 638–674

Disulfide bonds (17): 58–122, 71–132, 102–112, 191–276, 204–286, 251–261, 336–400, 349–410, 380–390, 450–515, 463–528, 497–507, 558–564, 610–658, 642–648, 670–680, 717–731

Glycosylation sites (2): 198, 629

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-1566948	Elastic fibre formation
R-HSA-2243919	Crosslinking of collagen fibrils
R-HSA-1474244	Extracellular matrix organization
R-HSA-1474290	Collagen formation
R-HSA-2022090	Assembly of collagen fibrils and other multimeric structures

MSigDB gene sets: 121 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, MYOGENIN_Q6, GOBP_COLLAGEN_FIBRIL_ORGANIZATION, ATACCTC_MIR202, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_DN, AP4_Q6, CAGCTG_AP4_Q5, SP1_Q2_01, SENESE_HDAC1_AND_HDAC2_TARGETS_DN, TGANTCA_AP1_C, NRF2_Q4, YYCATTCAWW_UNKNOWN, CTAWWWATA_RSRFC4_Q2

GO Biological Process (1): collagen fibril organization (GO:0030199)

GO Molecular Function (6): protein-lysine 6-oxidase activity (GO:0004720), copper ion binding (GO:0005507), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on the CH-NH2 group of donors, oxygen as acceptor (GO:0016641), metal ion binding (GO:0046872)

GO Cellular Component (5): obsolete extracellular space (GO:0005615), membrane (GO:0016020), signaling receptor complex (GO:0043235), extracellular exosome (GO:0070062), extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Extracellular matrix organization	2
Assembly of collagen fibrils and other multimeric structures	1
Collagen formation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
extracellular matrix organization	1
oxidoreductase activity, acting on the CH-NH2 group of donors, oxygen as acceptor	1
catalytic activity, acting on a protein	1
transition metal ion binding	1
binding	1
catalytic activity	1
oxidoreductase activity, acting on the CH-NH2 group of donors	1
cation binding	1
protein-containing complex	1
extracellular vesicle	1

Protein interactions and networks

STRING

1042 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LOXL4	ELN	P15502	623
LOXL4	FBLN5	Q9UBX5	600
LOXL4	HOXC9	P31274	499
LOXL4	ING5	Q8WYH8	495
LOXL4	PLOD2	O00469	460
LOXL4	SRSF2	Q01130	447
LOXL4	PSEN1	P49768	434
LOXL4	PLOD1	Q02809	432
LOXL4	BMP1	P13497	415
LOXL4	CHCHD1	Q96BP2	412
LOXL4	ERBB4	Q15303	393
LOXL4	FAM90A7	A6NKC0	375
LOXL4	PLOD3	O60568	374
LOXL4	RAB27B	O00194	360
LOXL4	MAX	P25912	353
LOXL4	CASP2	P42575	353

IntAct

79 interactions, top by confidence:

A	B	Type	Score
TRIP13	LOXL4	psi-mi:“MI:0915”(physical association)	0.760
LOXL4	TRIP13	psi-mi:“MI:0915”(physical association)	0.760
LOXL4	CCT6B	psi-mi:“MI:0915”(physical association)	0.620
CASP6	LOXL4	psi-mi:“MI:0915”(physical association)	0.560
CRYAA	LOXL4	psi-mi:“MI:0915”(physical association)	0.560
LOXL4	ATN1	psi-mi:“MI:0915”(physical association)	0.560
LOXL4	FGFR3	psi-mi:“MI:0915”(physical association)	0.560
GRN	LOXL4	psi-mi:“MI:0915”(physical association)	0.560
GRIN2C	LOXL4	psi-mi:“MI:0915”(physical association)	0.560
LOXL4	GSN	psi-mi:“MI:0915”(physical association)	0.560
LOXL4	HSPB1	psi-mi:“MI:0915”(physical association)	0.560
LAMP2	LOXL4	psi-mi:“MI:0915”(physical association)	0.560
KLK6	LOXL4	psi-mi:“MI:0915”(physical association)	0.560
LOXL4	WFS1	psi-mi:“MI:0915”(physical association)	0.560
KLF11	LOXL4	psi-mi:“MI:0915”(physical association)	0.560
DNAJB6	LOXL4	psi-mi:“MI:0915”(physical association)	0.560
LOXL4	KIF1B	psi-mi:“MI:0915”(physical association)	0.560
RNF11	LOXL4	psi-mi:“MI:0915”(physical association)	0.560
LOXL4	SPRED1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (108): LOXL4 (Two-hybrid), CCT6B (Affinity Capture-MS), SEPHS2 (Affinity Capture-MS), LOXL4 (Two-hybrid), SEPHS2 (Affinity Capture-MS), CCT6B (Affinity Capture-MS), CCT6A (Affinity Capture-MS), LOXL4 (Affinity Capture-MS), LOXL4 (Protein-RNA), LOXL4 (Affinity Capture-MS), LOXL4 (Affinity Capture-MS), LOXL4 (Affinity Capture-MS), LOXL4 (Affinity Capture-RNA), LOXL4 (Affinity Capture-RNA), CCT6B (Affinity Capture-MS)

ESM2 similar proteins: A1L0T3, A1L4H1, D3ZTE0, G3V801, O08762, O43866, O75636, O95428, O97507, P00748, P22457, P56730, P58215, P69525, P69526, P85521, P98140, Q02853, Q04756, Q04962, Q24K22, Q2VL90, Q2VLG4, Q2VLG6, Q2VLH6, Q499S5, Q4G0T1, Q5G265, Q5G268, Q5G269, Q5G270, Q5G271, Q5IJ48, Q6QNF4, Q70UZ7, Q769J6, Q76LX8, Q7Z410, Q80YA8, Q80YC5

Diamond homologs: A1L0T3, A1L1V4, A1L4H1, A5PJQ2, A6H737, A7E3W2, B4F6N6, B5DF27, B8A4W9, E1C3U7, F1QQC3, F1RD85, F7J220, G3V801, M9NDE3, O08762, O43866, O70513, P21757, P21758, P30203, P30204, P30205, P56730, P58022, P58215, P70117, P85521, Q05585, Q07797, Q08380, Q08B63, Q14DK5, Q24JV9, Q2VL90, Q2VLG4, Q2VLG6, Q2VLH6, Q4A3R3, Q4G0T1

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 45 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
protein folding	7	16.1×	1e-04
protein stabilization	6	8.9×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	152
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2578 predictions. Top by Δscore:

Variant	Effect	Δscore
10:98248988:TTCC:T	acceptor_gain	1.0000
10:98248989:TCC:T	acceptor_gain	1.0000
10:98248990:CC:C	acceptor_gain	1.0000
10:98248990:CCC:C	acceptor_gain	1.0000
10:98248991:CC:C	acceptor_gain	1.0000
10:98248992:C:CC	acceptor_gain	1.0000
10:98248993:T:A	acceptor_loss	1.0000
10:98251060:GTTA:G	donor_loss	1.0000
10:98251062:TAC:T	donor_loss	1.0000
10:98251063:A:C	donor_loss	1.0000
10:98251064:CCT:C	donor_loss	1.0000
10:98251173:TCAC:T	acceptor_gain	1.0000
10:98251173:TCACC:T	acceptor_loss	1.0000
10:98251174:CAC:C	acceptor_gain	1.0000
10:98251174:CACC:C	acceptor_gain	1.0000
10:98251177:C:CC	acceptor_gain	1.0000
10:98251177:CTA:C	acceptor_loss	1.0000
10:98251178:T:G	acceptor_loss	1.0000
10:98251561:CTTAC:C	donor_loss	1.0000
10:98251563:TACC:T	donor_loss	1.0000
10:98251564:A:AC	donor_gain	1.0000
10:98251564:A:AG	donor_loss	1.0000
10:98251565:C:CC	donor_gain	1.0000
10:98251698:CAGTC:C	acceptor_gain	1.0000
10:98251699:AGTC:A	acceptor_gain	1.0000
10:98251700:GTC:G	acceptor_gain	1.0000
10:98251701:TC:T	acceptor_gain	1.0000
10:98251702:CC:C	acceptor_gain	1.0000
10:98251702:CCT:C	acceptor_loss	1.0000
10:98251703:C:CC	acceptor_gain	1.0000

AlphaMissense

4964 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:98251608:C:A	W682C	0.999
10:98251608:C:G	W682C	0.999
10:98258066:C:A	W340C	0.998
10:98258066:C:G	W340C	0.998
10:98252378:A:C	C642W	0.997
10:98252379:C:G	C642S	0.997
10:98252380:A:T	C642S	0.997
10:98255678:C:G	C497S	0.997
10:98255679:A:T	C497S	0.997
10:98256846:C:A	W454C	0.997
10:98256846:C:G	W454C	0.997
10:98252380:A:G	C642R	0.996
10:98252382:A:C	F641C	0.996
10:98252430:A:G	L625P	0.996
10:98252445:A:C	F620C	0.996
10:98253573:C:A	W605C	0.996
10:98253573:C:G	W605C	0.996
10:98253666:C:A	W574C	0.996
10:98253666:C:G	W574C	0.996
10:98260999:C:A	W195C	0.996
10:98260999:C:G	W195C	0.996
10:98251610:A:G	W682R	0.995
10:98251610:A:T	W682R	0.995
10:98251614:G:C	C680W	0.995
10:98252404:C:G	A634P	0.995
10:98253567:C:A	W607C	0.995
10:98253567:C:G	W607C	0.995
10:98256819:G:C	C463W	0.995
10:98256820:C:T	C463Y	0.995
10:98256870:C:A	W446C	0.995

dbSNP variants (sampled 300 via entrez): RS1000041988 (10:98263654 T>C), RS1000136499 (10:98263921 C>T), RS1000304674 (10:98252727 G>A), RS1000306616 (10:98260436 G>A), RS1000351716 (10:98252948 T>C), RS1000358562 (10:98260616 A>G), RS1000366683 (10:98253161 A>G), RS1000689675 (10:98254114 T>G), RS1000802907 (10:98247639 A>G), RS1000946870 (10:98269586 C>G,T), RS1001367994 (10:98251785 A>G), RS1001466091 (10:98250156 C>T), RS1001916891 (10:98260957 G>A), RS1001969143 (10:98261249 G>C,T), RS1002097239 (10:98266843 A>G,T)

Disease associations

OMIM: gene MIM:607318 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
skeletal dysplasia	Limited	Autosomal dominant

Mondo (1): skeletal dysplasia (MONDO:0018230)

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST003784_13	Multiple system atrophy	4.000000e-06
GCST008129_21	Body mass index	8.000000e-16
GCST008476_29	Emphysema annual change measurement in smokers (percent low attenuation area)	6.000000e-06
GCST008839_44	Height	2.000000e-08
GCST012020_414	Serum metabolite levels	4.000000e-62

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0007626	emphysema imaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295926 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 133,533 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1356238	PYRITHIONE	4	15,582
CHEMBL964	DISULFIRAM	4	38,611
CHEMBL120563	THIRAM	2	79,340

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

ChEMBL bioactivities

5 potent at pChembl≥5 of 7 total, top 5 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.23	IC50	59	nM	DISULFIRAM
6.75	IC50	180	nM	THIRAM
6.55	IC50	280	nM	CHEMBL4457578
5.68	IC50	2100	nM	CHEMBL4245637
5.48	IC50	3300	nM	CHEMBL4251179

PubChem BioAssay actives

5 with measured affinity, of 29 total; 5 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
Disulfiram	1399352: Inhibition of recombinant human LOXL4 expressed in baculovirus infected insect cells using diaminopentane as substrate preincubated for 30 mins followed by substrate addition measured after 1 hr by fluorimetric method	ic50	0.0590	uM
dimethylcarbamothioylsulfanyl N,N-dimethylcarbamodithioate	1399352: Inhibition of recombinant human LOXL4 expressed in baculovirus infected insect cells using diaminopentane as substrate preincubated for 30 mins followed by substrate addition measured after 1 hr by fluorimetric method	ic50	0.1800	uM
1-[(Z)-4-amino-2-fluorobut-2-enyl]-3-[3-(dimethylsulfamoyl)phenyl]-2-methylindole-5-carboxylic acid;hydrochloride	1526685: Inhibition of recombinant human LOXL4 using putrescine as substrate preincubated with enzyme for 30 mins followed by substrate addition and measured every 2.5 mins for 30 mins by Amplex-Red oxidation assay	ic50	0.2800	uM
4,5-dimethyl-2-phenyl-4H-pyrazol-3-one	1399352: Inhibition of recombinant human LOXL4 expressed in baculovirus infected insect cells using diaminopentane as substrate preincubated for 30 mins followed by substrate addition measured after 1 hr by fluorimetric method	ic50	2.1000	uM
diethyl 5-[(5-amino-3-oxo-2-phenyl-1H-pyrazol-4-yl)diazenyl]-3-methylthiophene-2,4-dicarboxylate	1399352: Inhibition of recombinant human LOXL4 expressed in baculovirus infected insect cells using diaminopentane as substrate preincubated for 30 mins followed by substrate addition measured after 1 hr by fluorimetric method	ic50	3.3000	uM

CTD chemical–gene interactions

46 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects cotreatment, decreases expression, increases expression, decreases reaction	4
Cyclosporine	decreases expression, increases expression, affects expression	4
bisphenol A	affects expression, decreases expression, decreases methylation	3
Progesterone	decreases reaction, affects cotreatment, decreases expression, increases expression	3
sodium arsenite	increases expression	2
Doxorubicin	decreases expression, increases expression	2
Tobacco Smoke Pollution	affects expression	2
Valproic Acid	decreases expression, increases expression	2
Aflatoxin B1	increases expression, increases methylation	2
bisphenol F	affects cotreatment, decreases expression	1
propionaldehyde	increases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
zinc chromate	decreases expression, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
diallyl trisulfide	decreases reaction, increases expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
3-(5’-hydroxymethyl-2’-furyl)-1-benzylindazole	decreases reaction, increases expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
nutlin 3	affects cotreatment, increases expression	1
ICG 001	increases expression	1
abrine	increases expression	1
bisphenol S	decreases expression	1
bisphenol AF	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Decitabine	increases expression	1
Sunitinib	decreases expression	1
Benzo(a)pyrene	affects methylation	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4235822	Binding	Inhibition of recombinant human LOXL4 expressed in baculovirus infected insect cells using diaminopentane as substrate preincubated for 30 mins followed by substrate addition measured after 1 hr by fluorimetric method	Inhibition of the LOX enzyme family members with old and new ligands. Selectivity analysis revisited. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00001754	Not specified	COMPLETED	Study of Skeletal Disorders and Short Stature
NCT02762318	Not specified	TERMINATED	Identification and Characterization of Bone-related Genetic Variants in Families
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT05247645	Not specified	RECRUITING	Data Collection of Patients With Rare Bone Diseases
NCT05876416	Not specified	RECRUITING	Decoding the Genetic Landscape of Skeletal Diseases
NCT05991609	Not specified	ACTIVE_NOT_RECRUITING	Extreme Morphology and Metabolic Health
NCT06002373	Not specified	UNKNOWN	Assessment of Artificial Intelligence for Treatment Decision Recommendation of Adult Skeletal Class III Patients