MMP15

Summary

MMP15 (matrix metallopeptidase 15, HGNC:7161) is a protein-coding gene on chromosome 16q21, encoding Matrix metalloproteinase-15 (P51511). Endopeptidase that degrades various components of the extracellular matrix.

This gene encodes a member of the peptidase M10 family and membrane-type subfamily of matrix metalloproteinases (MMPs). Proteins in this family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. Members of this subfamily contain a transmembrane domain suggesting that these proteins are expressed at the cell surface rather than secreted. The encoded preproprotein is proteolytically processed to generate the mature protease. This protein may play a role in cancer progression.

Source: NCBI Gene 4324 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Alagille syndrome (Moderate, GenCC)
• GWAS associations: 19
• Clinical variants (ClinVar): 145 total — 1 pathogenic
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002428

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7161
Approved symbol	MMP15
Name	matrix metallopeptidase 15
Location	16q21
Locus type	gene with protein product
Status	Approved
Aliases	MT2-MMP, MTMMP2, SMCP-2
Ensembl gene	ENSG00000102996
Ensembl biotype	protein_coding
OMIM	602261
Entrez	4324

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 9 protein_coding

ENST00000219271, ENST00000570065, ENST00000907592, ENST00000907593, ENST00000907594, ENST00000907595, ENST00000930620, ENST00000930621, ENST00000966677

RefSeq mRNA: 1 — MANE Select: NM_002428 NM_002428

CCDS: CCDS10792

Canonical transcript exons

ENST00000219271 — 10 exons

Exon	Start	End
ENSE00000685581	58043512	58043627
ENSE00000685586	58043210	58043360
ENSE00000685590	58042231	58042369
ENSE00000685593	58041617	58041870
ENSE00000685598	58039875	58040182
ENSE00000685601	58038266	58038394
ENSE00000685603	58037472	58037620
ENSE00000852984	58045007	58046901
ENSE00001290805	58025754	58026512
ENSE00001603001	58040537	58040698

Expression profiles

Bgee: expression breadth ubiquitous, 189 present calls, max score 95.53.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.1200 / max 94.8763, expressed in 1345 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154434	7.7858	1337
154433	0.3342	219

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	95.53	gold quality
apex of heart	UBERON:0002098	94.17	gold quality
right lobe of thyroid gland	UBERON:0001119	92.82	gold quality
left lobe of thyroid gland	UBERON:0001120	92.06	gold quality
thyroid gland	UBERON:0002046	91.66	gold quality
right lobe of liver	UBERON:0001114	90.87	gold quality
heart left ventricle	UBERON:0002084	89.38	gold quality
right testis	UBERON:0004534	89.24	gold quality
left testis	UBERON:0004533	89.05	gold quality
right atrium auricular region	UBERON:0006631	88.84	gold quality
cardiac ventricle	UBERON:0002082	88.75	gold quality
transverse colon	UBERON:0001157	88.56	gold quality
endometrium epithelium	UBERON:0004811	88.48	gold quality
body of stomach	UBERON:0001161	87.92	gold quality
cardiac atrium	UBERON:0002081	87.67	gold quality
testis	UBERON:0000473	87.51	gold quality
paraflocculus	UBERON:0005351	86.59	gold quality
ileal mucosa	UBERON:0000331	86.55	gold quality
frontal pole	UBERON:0002795	86.27	gold quality
ventricular zone	UBERON:0003053	86.19	gold quality
ganglionic eminence	UBERON:0004023	85.70	gold quality
heart	UBERON:0000948	85.65	gold quality
stomach	UBERON:0000945	85.60	gold quality
middle frontal gyrus	UBERON:0002702	85.52	gold quality
small intestine Peyer’s patch	UBERON:0003454	85.13	gold quality
nerve	UBERON:0001021	85.07	gold quality
tibial nerve	UBERON:0001323	85.07	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.75	gold quality
Brodmann (1909) area 10	UBERON:0013541	84.70	gold quality
small intestine	UBERON:0002108	84.51	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.99

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, FOXC1, HIF1A, SNAI1

miRNA regulators (miRDB)

101 targeting MMP15, 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-5196-5P	100.00	67.98	2761
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4510	100.00	66.60	2050
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-1252-5P	100.00	69.80	2774
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6756-5P	99.82	67.97	2466

Literature-anchored findings (GeneRIF, showing 24)

• down-regulation of most MT-MMPs is typical for prostate carcinoma; seems to occur mainly in epithelial cells (PMID:12661033)
• Data show that the MT2-MMP catalytic domain has a higher propensity than that of MT1-MMP to initiate cleavage of the MMP-2 prodomain in the absence of TIMP-2. (PMID:16825197)
• Type-2 metalloproteinases, are identified as the triggering agents that independently confer cancer cells with the ability to proteolytically efface the BM scaffolding, initiate the assembly of invasive pseudopodia, and propagate transmigration. (PMID:16983145)
• Data show that MMP15 may be relevant with carcinogenesis, development and metastasis of adenoid cystic carcinoma, and different metastasis potential may result from different subtype of MMPs gene family. (PMID:17029196)
• These results indicate MT2-MMP might be involved in the cancer progression more than or equal to MT1-MMP independently of MMP-2 and MT1-MMP. (PMID:20117087)
• MMP2 activity is associated with an increase in MT2-MMP expression and with lymph node metastasis. (PMID:20586027)
• The intensity of immunochemical staining of MT2-MMP was significantly positively correlated to the intratumoral angiogenesis of esophageal cancer tissues. (PMID:21036765)
• Data show that MT2-MMP was a novel hypoxia-responsive gene and was upregulated by HIF-1alpha under hypoxia. (PMID:21751260)
• MMP-15 and MMP-19 are upregulated during colorectal tumorigenesis (PMID:22576687)
• MMP-15 is up-regulated in preeclampsia, but does not cleave endoglin to produce soluble endoglin. (PMID:22768148)
• HLA-G expression involved in tumor invasiveness or metastasis may rely on the NK cytotoxicity inhibition and induction of MMP-15 expression in ovarian cancer. (PMID:23228395)
• our data suggest that MT2-MMP expression positively involves in non-small cell lung cancer and might play an important role in promoting the tumor progression and intra-tumoral angiogenesis (PMID:25031779)
• In conclusion, MT2-MMP is involved in gastric cancer invasion and metastasis and may serve as an independent prognostic factor for gastric cancer patients. (PMID:25973093)
• TCF-4 is a co-activator of NF-kappaB p65 that promotes MMP-15 transcription and potentiate the migration activity of the lung cancer cells (PMID:27046058)
• Results suggest that MT2-MMP degrades adherens and tight junction proteins and results in EMT, making it a potential mediator of EMT in carcinomas. (PMID:27374080)
• identify an MT2-MMP-E-cadherin axis that functions as a novel regulator of epithelial cell homeostasis in vivo (PMID:29061881)
• Over-expression of MAFG-AS1 significantly decreased the level of miR-339-5p in NSCLC cell. Moreover, the matrix metalloproteinase 15 (MMP15) was identified to be a target of miR-339-5p. (PMID:30599080)
• Up-regulation of MMP15 expression in the acute myeloid leukemia.High expression of MMP15 predicted poor prognosis in the acute myeloid leukemia. (PMID:30809850)
• content decreases in high-grade bladder cancer (PMID:32049862)
• Effect of indole-3-carbinol on transcriptional profiling of wound-healing genes in macrophages of systemic lupus erythematosus patients: an RNA sequencing assay. (PMID:32517571)
• Bi-allelic null variant in matrix metalloproteinase-15, causes congenital cardiac defect, cholestasis jaundice, and failure to thrive. (PMID:34988996)
• MT2-MMP is differentially expressed in multiple myeloma cells and mediates their growth and progression. (PMID:35041985)
• Changes in the expression of membrane type-matrix metalloproteinases genes (MMP14, MMP15, MMP16, MMP24) during treatment and their potential impact on the survival of patients with non-small cell lung cancer (NSCLC). (PMID:35062057)
• MMP-14 Exhibits Greater Expression, Content and Activity Compared to MMP-15 in Human Renal Carcinoma. (PMID:39125675)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	mmp15b	ENSDARG00000013072
danio_rerio	mmp15a	ENSDARG00000051962
mus_musculus	Mmp15	ENSMUSG00000031790
rattus_norvegicus	Mmp15	ENSRNOG00000012622
caenorhabditis_elegans		WBGENE00010524
caenorhabditis_elegans		WBGENE00012185
caenorhabditis_elegans		WBGENE00012364
caenorhabditis_elegans		WBGENE00016283
caenorhabditis_elegans		WBGENE00194737

Paralogs (23): MMP25 (ENSG00000008516), MMP2 (ENSG00000087245), MMP11 (ENSG00000099953), MMP9 (ENSG00000100985), HPX (ENSG00000110169), MMP8 (ENSG00000118113), MMP19 (ENSG00000123342), MMP24 (ENSG00000125966), MMP7 (ENSG00000137673), MMP20 (ENSG00000137674), MMP27 (ENSG00000137675), MMP13 (ENSG00000137745), MMP3 (ENSG00000149968), MMP21 (ENSG00000154485), MMP16 (ENSG00000156103), MMP14 (ENSG00000157227), MMP10 (ENSG00000166670), MMP26 (ENSG00000167346), MMP23B (ENSG00000189409), MMP1 (ENSG00000196611), MMP17 (ENSG00000198598), MMP12 (ENSG00000262406), MMP28 (ENSG00000271447)

Protein

Protein identifiers

Matrix metalloproteinase-15 — P51511 (reviewed: P51511)

Alternative names: Membrane-type matrix metalloproteinase 2, Membrane-type-2 matrix metalloproteinase, SMCP-2

All UniProt accessions (2): P51511, H3BT97

UniProt curated annotations — full annotation on UniProt →

Function. Endopeptidase that degrades various components of the extracellular matrix. May activate progelatinase A.

Subcellular location. Membrane.

Tissue specificity. Appeared to be synthesized preferentially in liver, placenta, testis, colon and intestine. Substantial amounts are also detected in pancreas, kidney, lung, heart and skeletal muscle.

Post-translational modifications. The precursor is cleaved by a furin endopeptidase.

Cofactor. Binds 1 zinc ion per subunit.

Domain organisation. The conserved cysteine present in the cysteine-switch motif binds the catalytic zinc ion, thus inhibiting the enzyme. The dissociation of the cysteine from the zinc ion upon the activation-peptide release activates the enzyme.

Similarity. Belongs to the peptidase M10A family.

RefSeq proteins (1): NP_002419* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000585	Hemopexin-like_dom	Domain
IPR001818	Pept_M10_metallopeptidase	Domain
IPR002477	Peptidoglycan-bd-like	Domain
IPR006026	Peptidase_Metallo	Domain
IPR018486	Hemopexin_CS	Conserved_site
IPR018487	Hemopexin-like_repeat	Repeat
IPR021158	Pept_M10A_Zn_BS	Binding_site
IPR021190	Pept_M10A	Family
IPR021805	Pept_M10A_metallopeptidase_C	Domain
IPR024079	MetalloPept_cat_dom_sf	Homologous_superfamily
IPR033739	M10A_MMP	Domain
IPR036365	PGBD-like_sf	Homologous_superfamily
IPR036375	Hemopexin-like_dom_sf	Homologous_superfamily

Pfam: PF00045, PF00413, PF01471, PF11857

Enzyme classification (BRENDA):

• EC 3.4.24.B5 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

UniProt features (28 total): sequence variant 5, binding site 4, repeat 4, region of interest 2, compositionally biased region 2, topological domain 2, signal peptide 1, propeptide 1, short sequence motif 1, active site 1, chain 1, modified residue 1, glycosylation site 1, disulfide bond 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51511-F1	74.82	0.44

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): 260

Ligand- & substrate-binding residues (4): 111 (in inhibited form); 259; 263; 269

Post-translational modifications (1): 589

Disulfide bonds (1): 370–559

Glycosylation sites (1): 150

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1442490	Collagen degradation
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-1592389	Activation of Matrix Metalloproteinases
R-HSA-1474244	Extracellular matrix organization

MSigDB gene sets: 169 (showing top): MODULE_172, GOBP_RESPONSE_TO_ESTRADIOL, GOMF_METALLOPEPTIDASE_ACTIVITY, DORN_ADENOVIRUS_INFECTION_12HR_UP, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, GCANCTGNY_MYOD_Q6, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, MODULE_16, RODRIGUES_NTN1_TARGETS_DN, MISSIAGLIA_REGULATED_BY_METHYLATION_UP, BILD_E2F3_ONCOGENIC_SIGNATURE, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_GASTRULATION, GOBP_ENDODERM_DEVELOPMENT

GO Biological Process (7): proteolysis (GO:0006508), extracellular matrix disassembly (GO:0022617), extracellular matrix organization (GO:0030198), collagen catabolic process (GO:0030574), response to estradiol (GO:0032355), endodermal cell differentiation (GO:0035987), protein modification process (GO:0036211)

GO Molecular Function (9): metalloendopeptidase activity (GO:0004222), enzyme activator activity (GO:0008047), zinc ion binding (GO:0008270), metalloaminopeptidase activity (GO:0070006), protein binding (GO:0005515), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (4): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), extracellular matrix (GO:0031012), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Degradation of the extracellular matrix	2
Extracellular matrix organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	2
catalytic activity	2
cellular component disassembly	1
extracellular matrix organization	1
extracellular structure organization	1
external encapsulating structure organization	1
catabolic process	1
collagen metabolic process	1
response to lipid	1
response to oxygen-containing compound	1
endoderm formation	1
cell differentiation	1
macromolecule modification	1
endopeptidase activity	1
metallopeptidase activity	1
enzyme regulator activity	1
molecular function activator activity	1
transition metal ion binding	1
aminopeptidase activity	1
metalloexopeptidase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
cation binding	1
membrane	1
cell periphery	1
external encapsulating structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

980 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MMP15	TIMP3	P35625	684
MMP15	TIMP2	P16035	656
MMP15	TIMP1	P01033	613
MMP15	TIMP4	Q99727	565
MMP15	CD44	P16070	536
MMP15	OBSL1	O75147	496
MMP15	FURIN	P09958	453
MMP15	FBN1	P35555	452
MMP15	MMP9	P14780	448
MMP15	FN1	P02751	447
MMP15	HPX	P02790	420
MMP15	MMP16	P51512	403
MMP15	ADAMTS8	Q9UP79	401
MMP15	MMP14	P50281	400
MMP15	ADAMTS1	Q9UHI8	400

IntAct

37 interactions, top by confidence:

A	B	Type	Score
MMP15	PROC	psi-mi:“MI:0915”(physical association)	0.400
PROC	MMP15	psi-mi:“MI:0915”(physical association)	0.400
MMP15	Gorasp2	psi-mi:“MI:0915”(physical association)	0.370
	SHTN1	psi-mi:“MI:0914”(association)	0.350
	TMEM223	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
CCL3	KRBA1	psi-mi:“MI:0914”(association)	0.350
TMEM59	GPR89A	psi-mi:“MI:0914”(association)	0.350
TRPV3	MMP15	psi-mi:“MI:0914”(association)	0.350
PCDHB3	ESYT2	psi-mi:“MI:0914”(association)	0.350
RTN3	ESYT2	psi-mi:“MI:0914”(association)	0.350
UPK2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SFTPC	TMEM131L	psi-mi:“MI:0914”(association)	0.350
GPR45	VWA8	psi-mi:“MI:0914”(association)	0.350
DKKL1	VWA8	psi-mi:“MI:0914”(association)	0.350
IL5RA	POTEF	psi-mi:“MI:0914”(association)	0.350
NCR3	POTEF	psi-mi:“MI:0914”(association)	0.350
PI15		psi-mi:“MI:0914”(association)	0.350
AQP3	UBXN8	psi-mi:“MI:0914”(association)	0.350
MFAP4	QSOX1	psi-mi:“MI:0914”(association)	0.350
PRG2	QSOX1	psi-mi:“MI:0914”(association)	0.350
LYZL1	MAN2B1	psi-mi:“MI:0914”(association)	0.350
SIRPD	ADAM10	psi-mi:“MI:0914”(association)	0.350
MOG	SCAMP2	psi-mi:“MI:0914”(association)	0.350
TMED7	SMPD2	psi-mi:“MI:0914”(association)	0.350
GORASP2	MMP15	psi-mi:“MI:0914”(association)	0.350
AFG2A	ESYT2	psi-mi:“MI:0914”(association)	0.350
MMP14	BIN1	psi-mi:“MI:0914”(association)	0.350
UPK2	IFT56	psi-mi:“MI:0914”(association)	0.350
SLC22A11	CNOT1	psi-mi:“MI:0914”(association)	0.350

BioGRID (38): MMP15 (Proximity Label-MS), MMP15 (Positive Genetic), MMP15 (Affinity Capture-MS), MMP15 (Affinity Capture-MS), MMP15 (Affinity Capture-MS), MMP15 (Affinity Capture-MS), MMP15 (Affinity Capture-MS), MMP15 (Affinity Capture-MS), MMP15 (Affinity Capture-MS), MMP15 (Affinity Capture-MS), MMP15 (Affinity Capture-MS), MMP15 (Affinity Capture-MS), MMP15 (Affinity Capture-MS), MMP15 (Affinity Capture-MS), MMP15 (Affinity Capture-MS)

ESM2 similar proteins: A0A0C5PRQ1, A6H737, A8Q2D1, D5FM34, D5FM37, E1C3U7, K7Z9Q9, O17264, O35548, O43897, O54732, O57460, O77636, P25723, P50281, P51511, P51512, P55114, P98060, P98069, P98070, Q10739, Q11005, Q18206, Q19204, Q20459, Q20942, Q20958, Q22396, Q22710, Q5RES1, Q5W7F4, Q61EX6, Q62381, Q7Z0M7, Q8JI28, Q8MPP3, Q93243, Q93542, Q94316

Diamond homologs: A0A0N9E2K8, D0EM77, G5EBU3, O04529, O54732, O55761, O75900, O88272, O88676, O93470, P04004, P22458, P22757, P41245, P48819, P50280, P51511, P53690, P55032, Q02853, Q10739, Q196W5, Q2TBM7, Q499S5, Q5XF51, Q8K3F2, Q8N119, Q90YC2, Q99542, Q9NRE1, O13065, O18733, O18767, O18927, O23507, O35548, O44836, O55123, O60882, O62806

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
MMP15	up-regulates	ECM_disassembly
MMP15	down-regulates	ECM

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	123
Likely benign	6
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3384009	NM_002428.4(MMP15):c.1058del (p.Pro353fs)	Pathogenic

SpliceAI

1617 predictions. Top by Δscore:

Variant	Effect	Δscore
16:58026511:AGGT:A	donor_loss	1.0000
16:58026512:GGTA:G	donor_loss	1.0000
16:58026513:GT:G	donor_loss	1.0000
16:58026514:T:A	donor_loss	1.0000
16:58037466:TTGCA:T	acceptor_loss	1.0000
16:58037467:TGCA:T	acceptor_loss	1.0000
16:58037469:CA:C	acceptor_loss	1.0000
16:58037470:A:AG	acceptor_gain	1.0000
16:58037471:G:GG	acceptor_gain	1.0000
16:58037471:GA:G	acceptor_gain	1.0000
16:58037471:GAACT:G	acceptor_gain	1.0000
16:58037616:AAGGA:A	donor_gain	1.0000
16:58037617:AGGA:A	donor_gain	1.0000
16:58037618:G:GT	donor_gain	1.0000
16:58037618:GGA:G	donor_gain	1.0000
16:58037619:GA:G	donor_gain	1.0000
16:58037619:GAG:G	donor_gain	1.0000
16:58037619:GAGTG:G	donor_loss	1.0000
16:58037620:A:T	donor_gain	1.0000
16:58037621:G:C	donor_loss	1.0000
16:58037621:G:GG	donor_gain	1.0000
16:58038261:CCCAG:C	acceptor_loss	1.0000
16:58038262:CCAGG:C	acceptor_loss	1.0000
16:58038263:CAG:C	acceptor_loss	1.0000
16:58038365:G:GT	donor_gain	1.0000
16:58039873:A:AG	acceptor_gain	1.0000
16:58039874:G:GG	acceptor_gain	1.0000
16:58039874:GC:G	acceptor_gain	1.0000
16:58040147:A:G	donor_gain	1.0000
16:58040178:GCATG:G	donor_gain	1.0000

AlphaMissense

4358 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:58038285:T:C	C111R	0.999
16:58038286:G:A	C111Y	0.999
16:58039945:T:A	W171R	0.999
16:58039945:T:C	W171R	0.999
16:58040068:T:C	F212L	0.999
16:58040069:T:G	F212C	0.999
16:58040070:T:A	F212L	0.999
16:58040070:T:G	F212L	0.999
16:58040138:T:C	F235S	0.999
16:58040155:T:A	W241R	0.999
16:58040155:T:C	W241R	0.999
16:58040157:G:C	W241C	0.999
16:58040157:G:T	W241C	0.999
16:58040557:G:C	A257P	0.999
16:58040588:T:C	L267P	0.999
16:58042243:T:A	W393R	0.999
16:58042243:T:C	W393R	0.999
16:58042300:T:A	W412R	0.999
16:58042300:T:C	W412R	0.999
16:58037479:T:C	L57P	0.998
16:58038282:C:A	R110S	0.998
16:58038285:T:A	C111S	0.998
16:58038286:G:C	C111S	0.998
16:58038286:G:T	C111F	0.998
16:58038287:T:G	C111W	0.998
16:58038371:G:C	W139C	0.998
16:58038371:G:T	W139C	0.998
16:58039947:G:C	W171C	0.998
16:58039947:G:T	W171C	0.998
16:58040050:C:G	H206D	0.998

dbSNP variants (sampled 300 via entrez): RS1000024926 (16:58025830 T>C), RS1000070635 (16:58032660 G>A), RS1000301917 (16:58031640 A>G), RS1000338266 (16:58032983 A>G), RS1000466740 (16:58036674 G>C), RS1000631275 (16:58031464 A>C,G), RS1000771056 (16:58036699 AGCCTGGATGG>A), RS1000777524 (16:58043426 A>G), RS1000777901 (16:58047264 C>T), RS1000943731 (16:58034187 G>A), RS1001026437 (16:58026997 C>A,G,T), RS1001236471 (16:58039614 C>T), RS1001244430 (16:58025651 T>A,C,G), RS1001378572 (16:58044803 C>G), RS1001791587 (16:58029876 G>A,C,T)

Disease associations

OMIM: gene MIM:602261 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
Alagille syndrome	Moderate	Autosomal recessive

Mondo (1): Alagille syndrome (MONDO:0007318)

Orphanet (0):

HPO phenotypes

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

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST001248_15	Pulmonary function	4.000000e-08
GCST001784_8	Pulmonary function (smoking interaction)	4.000000e-08
GCST007430_129	Peak expiratory flow	1.000000e-06
GCST007431_127	Lung function (FEV1/FVC)	1.000000e-38
GCST007692_39	Chronic obstructive pulmonary disease	4.000000e-08
GCST010796_3499	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-09
GCST010796_3500	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-08
GCST010796_3601	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_3602	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-08
GCST010796_3603	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_3604	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08
GCST010796_3605	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08
GCST010796_3606	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_3607	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_3608	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST90011898_45	Alanine aminotransferase levels	1.000000e-10
GCST90013407_130	Liver enzyme levels (gamma-glutamyl transferase)	2.000000e-40
GCST90013663_80	Alanine aminotransferase levels	8.000000e-15
GCST90013664_76	Aspartate aminotransferase levels	2.000000e-09

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0003892	pulmonary function measurement
EFO:0004713	FEV/FVC ratio
EFO:0009718	peak expiratory flow
EFO:0004327	electrocardiography
EFO:0004532	serum gamma-glutamyl transferase measurement
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D016738	Alagille Syndrome	C06.130.120.135.250.125; C06.552.150.125; C14.240.400.044; C16.131.077.065; C16.131.240.400.044; C16.320.051

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2963 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 41,512 (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
CHEMBL279785	MARIMASTAT	3	29,447
CHEMBL19611	ILOMASTAT	2	12,065

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — M10: Matrix metallopeptidase

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

Ligand	Action	Affinity	Parameter
ilomastat	Inhibition	8.1	pIC50
SL422	Inhibition	7.7	pKi

ChEMBL bioactivities

22 potent at pChembl≥5 of 24 total, top 19 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.40	IC50	4	nM	CHEMBL358539
8.22	IC50	6	nM	ILOMASTAT
8.22	IC50	6	nM	CHEMBL148214
7.77	IC50	17	nM	CHEMBL147881
7.72	IC50	19	nM	CHEMBL147882
7.70	Ki	20	nM	CHEMBL88520
7.54	IC50	29	nM	CHEMBL148171
7.36	IC50	44	nM	CHEMBL146718
7.15	Ki	71	nM	CHEMBL91636
6.90	IC50	126	nM	CHEMBL147489
6.66	IC50	218	nM	CHEMBL146289
6.42	IC50	385	nM	CHEMBL148406
6.21	IC50	621	nM	CHEMBL356124
5.77	Ki	1700	nM	CHEMBL495502
5.75	IC50	1789	nM	CHEMBL424130
5.70	Ki	2000	nM	CHEMBL325163
5.40	Ki	3997	nM	CHEMBL148169
5.14	IC50	7303	nM	CHEMBL147604
5.00	IC50	1e+04	nM	MARIMASTAT

PubChem BioAssay actives

22 with measured affinity, of 52 total; 19 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
N-hydroxy-2-(4-methoxyphenyl)sulfonyl-6-phenylmethoxy-3,4-dihydro-1H-isoquinoline-1-carboxamide	109571: Inhibition of matrix metalloprotease-15 (MMP-15)	ic50	0.0040	uM
(2R)-N’-hydroxy-N-[(2S)-3-(1H-indol-3-yl)-1-(methylamino)-1-oxopropan-2-yl]-2-(2-methylpropyl)butanediamide	109571: Inhibition of matrix metalloprotease-15 (MMP-15)	ic50	0.0060	uM
N,6-dihydroxy-7-methoxy-2-(4-methoxyphenyl)sulfonyl-3,4-dihydro-1H-isoquinoline-1-carboxamide	109571: Inhibition of matrix metalloprotease-15 (MMP-15)	ic50	0.0060	uM
2-(benzenesulfonyl)-N-hydroxy-6-phenylmethoxy-3,4-dihydro-1H-isoquinoline-1-carboxamide	109571: Inhibition of matrix metalloprotease-15 (MMP-15)	ic50	0.0170	uM
N,6-dihydroxy-2-(4-methylphenyl)sulfonyl-3,4-dihydro-1H-isoquinoline-1-carboxamide	109571: Inhibition of matrix metalloprotease-15 (MMP-15)	ic50	0.0190	uM
(6S,7R,10S)-6-N-hydroxy-10-N-[2-(methylamino)-2-oxoethyl]-7-(2-methylpropyl)-8-oxo-2-oxa-9-azabicyclo[10.2.2]hexadeca-1(14),12,15-triene-6,10-dicarboxamide	109569: Inhibition of matrix metalloprotease-15	ki	0.0200	uM
2-(benzenesulfonyl)-N,6-dihydroxy-7-methoxy-3,4-dihydro-1H-isoquinoline-1-carboxamide	109571: Inhibition of matrix metalloprotease-15 (MMP-15)	ic50	0.0290	uM
N-hydroxy-2-(4-methylphenyl)sulfonyl-6-phenylmethoxy-3,4-dihydro-1H-isoquinoline-1-carboxamide	109571: Inhibition of matrix metalloprotease-15 (MMP-15)	ic50	0.0440	uM
(8S,11R,12S)-12-N-hydroxy-11-(2-methylpropyl)-8-N-(2-morpholin-4-yl-2-oxoethyl)-2,10-dioxo-1-oxa-3,9-diazacyclopentadecane-8,12-dicarboxamide	109569: Inhibition of matrix metalloprotease-15	ki	0.0710	uM
N,6-dihydroxy-2-(4-nitrophenyl)sulfonyl-3,4-dihydro-1H-isoquinoline-1-carboxamide	109571: Inhibition of matrix metalloprotease-15 (MMP-15)	ic50	0.1260	uM
2-(benzenesulfonyl)-N,6-dihydroxy-3,4-dihydro-1H-isoquinoline-1-carboxamide	109571: Inhibition of matrix metalloprotease-15 (MMP-15)	ic50	0.2180	uM
2-(4-aminophenyl)sulfonyl-N,6-dihydroxy-3,4-dihydro-1H-isoquinoline-1-carboxamide	109571: Inhibition of matrix metalloprotease-15 (MMP-15)	ic50	0.3850	uM
N,6-dihydroxy-2-(4-methoxyphenyl)sulfonyl-3,4-dihydro-1H-isoquinoline-1-carboxamide	109571: Inhibition of matrix metalloprotease-15 (MMP-15)	ic50	0.6210	uM
N-[(2S,6R)-4-[2-(hydroxyamino)-2-oxoethyl]-2,6-dimethylpiperidin-4-yl]-4-[(2-methylquinolin-4-yl)methoxy]benzamide	349415: Inhibition of MMP15	ki	1.7000	uM
2-(2,5-dichlorophenyl)sulfonyl-N,6-dihydroxy-3,4-dihydro-1H-isoquinoline-1-carboxamide	109571: Inhibition of matrix metalloprotease-15 (MMP-15)	ic50	1.7890	uM
(8S,11R,12S)-12-N-hydroxy-8-N-(2-morpholin-4-yl-2-oxoethyl)-2,10-dioxo-11-[[4-[2-(trifluoromethyl)phenyl]phenyl]methyl]-1-oxa-3,9-diazacyclopentadecane-8,12-dicarboxamide	109570: Inhibition of matrix metalloprotease-15	ki	2.0000	uM
(2R)-N-hydroxy-2-[(3S)-3-methyl-3-[4-[(2-methylquinolin-4-yl)methoxy]phenyl]-2-oxopyrrolidin-1-yl]propanamide	109568: Affinity for Matrix metalloprotease-15 (MMP-15)	ki	3.9970	uM
2-(2,5-dichlorophenyl)sulfonyl-N-hydroxy-6-phenylmethoxy-3,4-dihydro-1H-isoquinoline-1-carboxamide	109571: Inhibition of matrix metalloprotease-15 (MMP-15)	ic50	7.3030	uM
(2R,3S)-N-[(2S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]-N’,3-dihydroxy-2-(2-methylpropyl)butanediamide	1274672: Inhibition of MMP15 (unknown origin) catalytic domain using MCA-Arg-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-Glu-Arg-NH2 as substrate preincubated for 60 mins followed by substrate addition by fluorescence assay	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Cisplatin	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	increases expression, decreases expression	2
Aflatoxin B1	increases methylation	2
Cadmium Chloride	decreases expression, increases expression	2
FR900359	increases phosphorylation	1
propionaldehyde	increases expression	1
bisphenol A	decreases methylation	1
afimoxifene	decreases expression	1
butyraldehyde	increases expression	1
aflatoxin B2	decreases methylation	1
cupric oxide	increases expression	1
hydroquinone	affects expression	1
pentanal	increases expression	1
abrine	decreases expression	1
jinfukang	increases expression, affects cotreatment	1
(+)-JQ1 compound	increases 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	decreases expression	1
Sunitinib	decreases expression	1
Fulvestrant	increases expression	1
Air Pollutants	increases abundance, decreases expression	1
Aldehydes	increases expression	1
Arsenates	affects cotreatment, increases expression	1
Arsenic	increases methylation	1
Atrazine	affects cotreatment, increases expression	1
Cadmium	decreases expression	1
Caffeine	increases phosphorylation	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Diazinon	increases methylation	1

ChEMBL screening assays

19 unique, capped per target: 19 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1005438	Binding	Inhibition of MMP15	Specific targeting of metzincin family members with small-molecule inhibitors: progress toward a multifarious challenge. — Bioorg Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SY60	HAP1 MMP15 (-) 1	Cancer cell line	Male
CVCL_SY61	HAP1 MMP15 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05488067	PHASE4	COMPLETED	Atorvastatin Therapy on Xanthoma in Alagille Syndrome
NCT07290257	PHASE4	RECRUITING	Long-Term Low-Intervention SafEty and Clinical Outcomes Clinical Study of LivmArli® in Patients With Alagille Syndrome in the European Union (LEAP-EU)
NCT04674761	PHASE3	COMPLETED	Efficacy and Safety of Odevixibat in Patients With Alagille Syndrome
NCT05035030	PHASE3	RECRUITING	Long-term Safety and Efficacy of Odevixibat in Patients With Alagille Syndrome
NCT05543174	PHASE3	COMPLETED	A Study of TAK-625 for the Treatment of Alagille Syndrome (ALGS)
NCT01903460	PHASE2	COMPLETED	Safety and Efficacy Study of LUM001 in the Treatment of Cholestatic Liver Disease in Patients With Alagille Syndrome
NCT02047318	PHASE2	COMPLETED	An Extension Study to Evaluate the Long-Term Safety and Durability of Effect of LUM001 in the Treatment of Cholestatic Liver Disease in Subjects With Alagille Syndrome (ALGS)
NCT02057692	PHASE2	COMPLETED	Evaluation of LUM001 in the Reduction of Pruritus in Alagille Syndrome
NCT02117713	PHASE2	COMPLETED	An Extension Study to Evaluate the Long-Term Safety and Durability of Effect of LUM001 in the Treatment of Cholestatic Liver Disease in Pediatric Subjects With Alagille Syndrome
NCT02160782	PHASE2	COMPLETED	Safety and Efficacy Study of LUM001 (Maralixibat) With a Drug Withdrawal Period in Participants With Alagille Syndrome (ALGS)
NCT04729751	PHASE2	COMPLETED	A Study to Evaluate the Safety and Tolerability of Maralixibat in Infant Participants With Cholestatic Liver Diseases Including Progressive Familial Intrahepatic Cholestasis (PFIC) and Alagille Syndrome (ALGS).
NCT02963077	PHASE1	COMPLETED	A Safety and Pharmakokinetic Study of A4250 Alone or in Combination With A3384
NCT03082937	PHASE1	COMPLETED	An Open Label, Single-dose, Single Period ADME Study of A4250 in Healthy Subjects
NCT00001642	Not specified	COMPLETED	Positional Cloning of the Gene(s) Responsible for Alagille Syndrome
NCT00007033	Not specified	COMPLETED	Study of Magnesium Sulfate in Children With Reduced Bone Density Secondary to Chronic Cholestatic Liver Disease
NCT00571272	Not specified	SUSPENDED	Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC)
NCT01515631	Not specified	COMPLETED	Characterization of Pulmonary Artery Stenoses in Alagille Syndrome - a Medical Record Review
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02131623	Not specified	COMPLETED	Validation of the Itch Reported Outcome (ItchRO) Diaries in Pediatric Cholestatic Liver Disease
NCT02922751	Not specified	COMPLETED	FibroScan™ in Pediatric Cholestatic Liver Disease (FORCE)
NCT04530994	Not specified	APPROVED_FOR_MARKETING	A Maralixibat Expanded Access Program for Patients With Cholestatic Pruritus Associated With Alagille Syndrome (ALGS)
NCT05846854	Not specified	UNKNOWN	Decreasing Hemorrhage Risk in Children With Alagille Syndrome
NCT06193928	Not specified	RECRUITING	Long-Term SafEty and Clinical Outcomes of LivmArli in Patients in the United States (LEAP-US)
NCT06850038	Not specified	RECRUITING	A Study Observing the Long-term, Effectiveness and Safety of Odevixibat (Bylvay) in Patients With Alagille Syndrome (ALGS) Who Are Receiving Ongoing Treatment
NCT07293897	Not specified	RECRUITING	A Database Study of Maralixibat (TAK-625) in Participants With Alagille Syndrome (ALGS) and Progressive Familial Intrahepatic Cholestasis (PFIC)
NCT07411716	Not specified	RECRUITING	Pediatric Evaluation and Registry for Liver Cholestasis in Canada
NCT07585097	Not specified	NOT_YET_RECRUITING	A Study to Observe the Long-term Safety of Odevixibat in Patients With Alagille Syndrome (ALGS) Who Are Receiving Ongoing Treatment