ADAMTS18

Summary

ADAMTS18 (ADAM metallopeptidase with thrombospondin type 1 motif 18, HGNC:17110) is a protein-coding gene on chromosome 16q23.1, encoding A disintegrin and metalloproteinase with thrombospondin motifs 18 (Q8TE60).

This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. ADAMTS family members share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The encoded preproprotein is proteolytically processed to generate the mature protein, which may regulate hemostatic balance and function as a tumor suppressor. Mutations in this gene may be associated with microcornea, myopic chorioretinal atrophy, and telecanthus (MMCAT) and cone-rod dystrophy in human patients.

Source: NCBI Gene 170692 — RefSeq curated summary.

At a glance

• Gene–disease (curated): microcornea-myopic chorioretinal atrophy (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 21
• Clinical variants (ClinVar): 1,350 total — 53 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 9
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_199355

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17110
Approved symbol	ADAMTS18
Name	ADAM metallopeptidase with thrombospondin type 1 motif 18
Location	16q23.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000140873
Ensembl biotype	protein_coding
OMIM	607512
Entrez	170692

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 3 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000282849, ENST00000449265, ENST00000562332, ENST00000562345, ENST00000564369, ENST00000567121, ENST00000567914, ENST00000568393, ENST00000569309

RefSeq mRNA: 2 — MANE Select: NM_199355 NM_001326358, NM_199355

CCDS: CCDS10926

Canonical transcript exons

ENST00000282849 — 23 exons

Exon	Start	End
ENSE00001892625	77282128	77284071
ENSE00002203993	77300263	77300404
ENSE00002210053	77353733	77353886
ENSE00002212384	77322336	77322466
ENSE00002213644	77355940	77356077
ENSE00002217791	77321079	77321202
ENSE00002234432	77297289	77297415
ENSE00002242966	77434418	77434505
ENSE00002253050	77434606	77435034
ENSE00002259614	77294923	77295127
ENSE00002271287	77341704	77341799
ENSE00002288132	77293076	77293258
ENSE00002297917	77367441	77367723
ENSE00002304108	77325866	77326038
ENSE00002305849	77362105	77362264
ENSE00002308246	77289264	77289411
ENSE00002320230	77291266	77291478
ENSE00002323319	77335756	77335904
ENSE00003524861	77359318	77359423
ENSE00003550648	77319849	77320093
ENSE00003597304	77363802	77363885
ENSE00003634534	77364188	77364381
ENSE00003671998	77431295	77431611

Expression profiles

Bgee: expression breadth ubiquitous, 152 present calls, max score 87.70.

FANTOM5 (CAGE): breadth broad, TPM avg 1.9413 / max 126.3419, expressed in 372 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
158193	1.5772	335
158194	0.1822	94
158192	0.0952	54
158191	0.0636	42
158190	0.0231	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar vermis	UBERON:0004720	87.70	gold quality
secondary oocyte	CL:0000655	87.46	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.26	gold quality
cerebellum	UBERON:0002037	82.61	gold quality
cerebellar cortex	UBERON:0002129	82.52	gold quality
cerebellar hemisphere	UBERON:0002245	82.44	gold quality
placenta	UBERON:0001987	81.54	gold quality
buccal mucosa cell	CL:0002336	81.33	silver quality
right hemisphere of cerebellum	UBERON:0014890	80.99	gold quality
oocyte	CL:0000023	79.55	gold quality
germinal epithelium of ovary	UBERON:0001304	71.57	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	69.46	gold quality
corpus callosum	UBERON:0002336	68.05	gold quality
adipose tissue	UBERON:0001013	67.54	gold quality
Brodmann (1909) area 46	UBERON:0006483	66.28	gold quality
tibialis anterior	UBERON:0001385	64.64	silver quality
adipose tissue of abdominal region	UBERON:0007808	63.82	gold quality
omental fat pad	UBERON:0010414	63.53	gold quality
peritoneum	UBERON:0002358	63.50	gold quality
pancreatic ductal cell	CL:0002079	63.38	silver quality
subcutaneous adipose tissue	UBERON:0002190	63.28	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	62.85	gold quality
ileal mucosa	UBERON:0000331	62.64	silver quality
spinal cord	UBERON:0002240	62.29	gold quality
smooth muscle tissue	UBERON:0001135	62.07	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	61.89	gold quality
inferior vagus X ganglion	UBERON:0005363	60.45	gold quality
subthalamic nucleus	UBERON:0001906	59.72	gold quality
deltoid	UBERON:0001476	59.30	gold quality
decidua	UBERON:0002450	58.89	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.84

Regulation

Is transcription factor: no

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 19)

• comparison of the effects of C-terminal truncation on the GAG-binding properties and aggrecanase activity of ADAMTS-5 relative to three other ADAMTS family members, ADAMTS-9, ADAMTS-16 and ADAMTS-18 (PMID:16507336)
• Functional epigenetics show ADAMTS18 to be a novel functional tumor suppressor, being frequently inactivated epigenetically in multiple carcinomas. (PMID:17546048)
• ADAMTS18 and TGFBR3 might underlie BMD determination in the major human ethnic groups. (PMID:19249006)
• ADAMTS18 gene methylation in 3 types of cancers was significantly higher than normal tissues. No significant association was found between methylation status & TNM staging. Epigenetic regulation of ADAMTS18 was associated with carcinogenesis. (PMID:19806480)
• ADAMTS18 mutations promote growth, migration, and metastasis in melanoma (PMID:21047771)
• the study identified ADAMTS18 as the only gene carrying a homozygous protein altering mutation. (PMID:21862674)
• study reveals that mutations in the ADAMTS18 gene can cause a broad phenotypic spectrum of eye disorders and contribute to shed further light on the complexity of retinal diseases (PMID:23356391)
• Results suggest that ADAMTS18 plays an essential role in early eye development and that mutations therein cause a distinct eye phenotype that is mainly characterized by microcornea and myopia. (PMID:23818446)
• Novel homozygous mutations in ADAMTS18 were identified, consisting of c.1067T>A [p.L356*] in the first proband, c.2159G>C [p.C720S] in the 2 affected brothers (PMID:24874986)
• Studies suggest that ADAM metallopeptidase with thrombospondin type 1 motif, 18 protein (ADAMTS-18) as a promising diagnostic and therapeutic target. (PMID:24896365)
• study suggests that ADAMTS18 is downregulated in cervical cancer and ADAMTS18 may serve as a potential prognostic biomarker for cervical cancer. (PMID:28362704)
• In summary, we demonstrate that ADAMTS18 silencing in breast cancer is significantly correlated with promoter CpG methylation. ADAMTS18 acts as an antagonist of AKT and NF-kappaB signaling, further suppressing EMT and metastasis of breast cancer cells. (PMID:28503860)
• This study showed that ADAMTS1, 8, and 18 are highly expressed in GC and its nodal metastases, suggesting important roles of these proteases in carcinogenesis and lymphatic metastasis. The findings from the present study indicate that these proteases may be promising candidates for novel and alternative treatments in GC (gastric cancer) (PMID:28814085)
• ADAMTS18 promoter methylation is a potential epigenetic biomarker. (PMID:30417422)
• Adamts18 links luminal hormone receptor signaling to basement membrane remodeling and stem cell activation. (PMID:32218432)
• Aberrant methylation of the 16q23.1 tumor suppressor gene ADAMTS18 promotes tumorigenesis and progression of clear cell renal cell carcinoma. (PMID:33469885)
• Characterization of a functional endothelial super-enhancer that regulates ADAMTS18 and angiogenesis. (PMID:34320216)
• Secreted protease ADAMTS18 in development and disease. (PMID:36632911)
• [A family with developmental glaucoma and microcornea due to novel ADAMTS18 gene mutations]. (PMID:38199772)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	adamts18	ENSDARG00000001999
mus_musculus	Adamts18	ENSMUSG00000053399
rattus_norvegicus	Adamts18	ENSRNOG00000011575

Paralogs (25): ADAMTS6 (ENSG00000049192), ADAMTS2 (ENSG00000087116), PAPLN (ENSG00000100767), ADAMTS8 (ENSG00000134917), ADAMTS7 (ENSG00000136378), ADAMTS14 (ENSG00000138316), ADAMTS17 (ENSG00000140470), ADAMTS10 (ENSG00000142303), ADAMTSL4 (ENSG00000143382), ADAMTS16 (ENSG00000145536), ADAMTS19 (ENSG00000145808), ADAMTS12 (ENSG00000151388), ADAMTS1 (ENSG00000154734), ADAMTS5 (ENSG00000154736), ADAMTS3 (ENSG00000156140), ADAMTSL3 (ENSG00000156218), ADAMTS4 (ENSG00000158859), ADAMTS13 (ENSG00000160323), ADAMTS9 (ENSG00000163638), ADAMTS15 (ENSG00000166106), ADAMTS20 (ENSG00000173157), ADAMTSL1 (ENSG00000178031), ADAMTSL5 (ENSG00000185761), THSD4 (ENSG00000187720), ADAMTSL2 (ENSG00000197859)

Protein

Protein identifiers

A disintegrin and metalloproteinase with thrombospondin motifs 18 — Q8TE60 (reviewed: Q8TE60)

All UniProt accessions (4): Q8TE60, B4DEX3, H3BMG1, H3BTZ3

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Expressed in fetal lung, liver, and kidney and in adult brain, prostate, submaxillary gland, and endothelium.

Post-translational modifications. The precursor is cleaved by a furin endopeptidase. Glycosylated. Can be O-fucosylated by POFUT2 on a serine or a threonine residue found within the consensus sequence C1-X(2)-(S/T)-C2-G of the TSP type-1 repeat domains where C1 and C2 are the first and second cysteine residue of the repeat, respectively. Fucosylated repeats can then be further glycosylated by the addition of a beta-1,3-glucose residue by the glucosyltransferase, B3GALTL. Fucosylation mediates the efficient secretion of ADAMTS family members. Can also be C-glycosylated with one or two mannose molecules on tryptophan residues within the consensus sequence W-X-X-W of the TPRs, and N-glycosylated. These other glycosylations can also facilitate secretion.

Disease relevance. Microcornea, myopic chorioretinal atrophy, and telecanthus (MMCAT) [MIM:615458] A ocular syndrome characterized by microcornea and myopic chorioretinal atrophy. Microcornea is defined by a corneal diameter inferior to 10 mm in both meridians in an otherwise normal eye. In addition to ocular findings, some patients have telecanthus and posteriorly rotated ears. The disease is caused by variants affecting the gene represented in this entry.

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.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8TE60-1	1	yes
Q8TE60-2	2

RefSeq proteins (2): NP_001313287, NP_955387* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000884	TSP1_rpt	Repeat
IPR001590	Peptidase_M12B	Domain
IPR002870	Peptidase_M12B_N	Domain
IPR010294	ADAMTS_spacer1	Domain
IPR010909	PLAC	Domain
IPR013273	ADAMTS/ADAMTS-like	Family
IPR024079	MetalloPept_cat_dom_sf	Homologous_superfamily
IPR036383	TSP1_rpt_sf	Homologous_superfamily
IPR041645	ADAMTS_CR_2	Domain
IPR045371	ADAMTS_CR_3	Domain
IPR050439	ADAMTS_ADAMTS-like	Family

Pfam: PF00090, PF01421, PF01562, PF05986, PF08686, PF17771, PF19030, PF19236

UniProt features (51 total): disulfide bond 11, sequence variant 11, domain 8, glycosylation site 6, binding site 4, region of interest 2, splice variant 2, signal peptide 1, propeptide 1, short sequence motif 1, compositionally biased region 1, active site 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TE60-F1	73.83	0.13

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): 437

Ligand- & substrate-binding residues (4): 254 (in inhibited form); 436; 440; 446

Disulfide bonds (11): 369–420, 395–402, 414–493, 453–477, 521–546, 532–553, 541–572, 566–577, 601–638, 605–643, 616–628

Glycosylation sites (6): 151, 190, 313, 745, 838, 909

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-5083635	Defective B3GALTL causes PpS
R-HSA-5173214	O-glycosylation of TSR domain-containing proteins
R-HSA-1474244	Extracellular matrix organization
R-HSA-1643685	Disease
R-HSA-3781865	Diseases of glycosylation
R-HSA-3906995	Diseases associated with O-glycosylation of proteins
R-HSA-392499	Metabolism of proteins
R-HSA-5173105	O-linked glycosylation
R-HSA-5668914	Diseases of metabolism
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 143 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_REGULATION_OF_CELL_ACTIVATION, BENPORATH_ES_WITH_H3K27ME3, GOBP_REGULATION_OF_WOUND_HEALING, GOMF_METALLOPEPTIDASE_ACTIVITY, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_REGULATION_OF_COAGULATION, GOBP_NEGATIVE_REGULATION_OF_PLATELET_ACTIVATION, GOBP_PLATELET_ACTIVATION, GOBP_NEGATIVE_REGULATION_OF_CELL_CELL_ADHESION, GOBP_NEGATIVE_REGULATION_OF_COAGULATION, GOBP_WOUND_HEALING, GOBP_CELL_CELL_ADHESION, GOBP_REGULATION_OF_PLATELET_AGGREGATION, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS

GO Biological Process (5): eye development (GO:0001654), proteolysis (GO:0006508), extracellular matrix organization (GO:0030198), negative regulation of platelet aggregation (GO:0090331), integrin-mediated signaling pathway (GO:0007229)

GO Molecular Function (5): metalloendopeptidase activity (GO:0004222), metal ion binding (GO:0046872), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787)

GO Cellular Component (2): extracellular matrix (GO:0031012), extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Extracellular matrix organization	1
Diseases associated with O-glycosylation of proteins	1
O-linked glycosylation	1
Diseases of metabolism	1
Diseases of glycosylation	1
Post-translational protein modification	1
Disease	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
sensory organ development	1
visual system development	1
protein metabolic process	1
extracellular structure organization	1
external encapsulating structure organization	1
negative regulation of platelet activation	1
negative regulation of homotypic cell-cell adhesion	1
platelet aggregation	1
regulation of platelet aggregation	1
cell surface receptor signaling pathway	1
endopeptidase activity	1
metallopeptidase activity	1
cation binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
external encapsulating structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1024 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADAMTS18	FAM218A	Q96MZ4	534
ADAMTS18	ANKRD45	Q5TZF3	515
ADAMTS18	KIF25	Q9UIL4	491
ADAMTS18	RAB9B	Q9NP90	474
ADAMTS18	SRPK2	P78362	474
ADAMTS18	ATP8A2	Q9NTI2	444
ADAMTS18	HIVEP3	Q5T1R4	428
ADAMTS18	CHD7	Q9P2D1	427
ADAMTS18	USH2A	O75445	402
ADAMTS18	IRX3	P78415	397
ADAMTS18	ARID4B	Q4LE39	396
ADAMTS18	GPR31	O00270	395
ADAMTS18	CHRM5	P08912	388
ADAMTS18	GPR84	Q9NQS5	386
ADAMTS18	LRP5	O75197	384

IntAct

4 interactions, top by confidence:

A	B	Type	Score
ADAMTS18	ALB	psi-mi:“MI:0914”(association)	0.530
ADAMTS18	IGKC	psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350

BioGRID (12): ADAMTS18 (Biochemical Activity), B3GALTL (Affinity Capture-MS), IGKC (Affinity Capture-MS), HSPA5 (Affinity Capture-MS), ALB (Affinity Capture-MS), ADAMTS18 (Synthetic Lethality), ELAVL4 (Affinity Capture-MS), HSPA5 (Affinity Capture-MS), ALB (Affinity Capture-MS), B3GALTL (Affinity Capture-MS), ADAMTS18 (Affinity Capture-MS), ADAMTS18 (Affinity Capture-MS)

ESM2 similar proteins: A1A547, A6QPN6, D2GZV9, E1BPW0, O18956, O75356, O75594, O93295, P10852, P15396, P22413, P49961, P55772, P57110, P70665, P82450, P97535, P97687, Q0V8L2, Q0VB07, Q53H76, Q58CQ9, Q5E9H0, Q5R5M5, Q5RBQ5, Q5RFU0, Q67BJ4, Q6P6S9, Q6YGZ1, Q71RP1, Q794F9, Q8K0L2, Q8TE60, Q8VI78, Q95194, Q96LB8, Q96LB9, Q99JP7, Q99MZ4, Q9HAT2

Diamond homologs: A7MBS7, A8WGB1, B3EWY9, B3EWZ3, B3EWZ8, C0HL12, C5IAW9, D3YXG0, D3ZTD8, F1LW30, G5ECS8, O08721, O08722, O08747, O14514, O15072, O60241, O60242, O95185, O95450, P07996, P10643, P11680, P27590, P27918, P35440, P35441, P35442, P35446, P35447, P35448, P57110, P58397, P59384, P59509, P59510, P59511, P79331, Q03350, Q19204

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1350 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	53
Likely pathogenic	15
Uncertain significance	681
Likely benign	503
Benign	56

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068709	NM_199355.4(ADAMTS18):c.2813del (p.Gly938fs)	Pathogenic
1068894	NM_199355.4(ADAMTS18):c.3334C>T (p.Arg1112Ter)	Pathogenic
1069405	NM_199355.4(ADAMTS18):c.3454C>T (p.Gln1152Ter)	Pathogenic
1069791	NM_199355.4(ADAMTS18):c.736C>T (p.Arg246Ter)	Pathogenic
1071878	NM_199355.4(ADAMTS18):c.1998G>A (p.Trp666Ter)	Pathogenic
1072777	NM_199355.4(ADAMTS18):c.916del (p.Val306fs)	Pathogenic
1076416	NM_199355.4(ADAMTS18):c.589dup (p.His197fs)	Pathogenic
1354967	NM_199355.4(ADAMTS18):c.1252C>T (p.Arg418Ter)	Pathogenic
1361816	NM_199355.4(ADAMTS18):c.3025C>T (p.Arg1009Ter)	Pathogenic
1399985	NM_199355.4(ADAMTS18):c.3067del (p.Ala1023fs)	Pathogenic
1408100	NM_199355.4(ADAMTS18):c.3105del (p.Arg1036fs)	Pathogenic
1419416	NM_199355.4(ADAMTS18):c.2374C>T (p.Arg792Ter)	Pathogenic
1434732	NM_199355.4(ADAMTS18):c.654del (p.Gly219fs)	Pathogenic
1452511	NM_199355.4(ADAMTS18):c.230C>G (p.Ser77Ter)	Pathogenic
1454085	NM_199355.4(ADAMTS18):c.3244A>T (p.Lys1082Ter)	Pathogenic
1456719	NM_199355.4(ADAMTS18):c.3139C>T (p.Arg1047Ter)	Pathogenic
1456807	NM_199355.4(ADAMTS18):c.766C>T (p.Arg256Ter)	Pathogenic
1460298	NC_000016.9:g.(?77331166)(77331332_?)del	Pathogenic
1460454	NC_000016.9:g.(?77325143)(77359955_?)del	Pathogenic
146126	GRCh38/hg38 16q23.1(chr16:75541502-79154140)x1	Pathogenic
1909312	NM_199355.4(ADAMTS18):c.1642C>T (p.Arg548Ter)	Pathogenic
1936348	NM_199355.4(ADAMTS18):c.262C>T (p.Arg88Ter)	Pathogenic
2025896	NM_199355.4(ADAMTS18):c.622G>T (p.Glu208Ter)	Pathogenic
2026248	NM_199355.4(ADAMTS18):c.2204C>G (p.Ser735Ter)	Pathogenic
2095701	NM_199355.4(ADAMTS18):c.934G>T (p.Gly312Ter)	Pathogenic
2099755	NM_199355.4(ADAMTS18):c.2364C>G (p.Tyr788Ter)	Pathogenic
2129361	NM_199355.4(ADAMTS18):c.2435del (p.Phe812fs)	Pathogenic
2143485	NM_199355.4(ADAMTS18):c.3280C>T (p.Arg1094Ter)	Pathogenic
2684813	GRCh37/hg19 16q22.1-23.2(chr16:70607067-81561138)x3	Pathogenic
2693505	NM_199355.4(ADAMTS18):c.3082G>T (p.Glu1028Ter)	Pathogenic

SpliceAI

4445 predictions. Top by Δscore:

Variant	Effect	Δscore
16:77293260:T:C	acceptor_gain	1.0000
16:77319842:GGCTT:G	donor_loss	1.0000
16:77319843:GCTT:G	donor_loss	1.0000
16:77319844:CTTA:C	donor_loss	1.0000
16:77319845:TTA:T	donor_loss	1.0000
16:77319847:A:AC	donor_gain	1.0000
16:77319848:C:CT	donor_gain	1.0000
16:77319848:C:G	donor_loss	1.0000
16:77319848:CT:C	donor_gain	1.0000
16:77319848:CTT:C	donor_gain	1.0000
16:77319850:T:TA	donor_gain	1.0000
16:77320089:ATATT:A	acceptor_gain	1.0000
16:77320090:TATT:T	acceptor_gain	1.0000
16:77320091:ATT:A	acceptor_gain	1.0000
16:77320092:TT:T	acceptor_gain	1.0000
16:77320094:C:CC	acceptor_gain	1.0000
16:77320095:T:C	acceptor_loss	1.0000
16:77322334:A:AC	donor_gain	1.0000
16:77322335:C:CC	donor_gain	1.0000
16:77335754:A:AC	donor_gain	1.0000
16:77335755:C:CC	donor_gain	1.0000
16:77341711:AAG:A	donor_gain	1.0000
16:77353728:CATA:C	donor_loss	1.0000
16:77353729:ATACC:A	donor_loss	1.0000
16:77353730:TAC:T	donor_loss	1.0000
16:77353731:ACC:A	donor_loss	1.0000
16:77353882:GTGTG:G	acceptor_gain	1.0000
16:77353883:TGTG:T	acceptor_gain	1.0000
16:77353884:GTG:G	acceptor_gain	1.0000
16:77353885:TG:T	acceptor_gain	1.0000

AlphaMissense

7982 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:77322355:C:G	C715S	1.000
16:77322356:A:T	C715S	1.000
16:77322441:G:C	C686W	1.000
16:77325888:C:A	W670C	1.000
16:77325888:C:G	W670C	1.000
16:77325890:A:G	W670R	1.000
16:77325890:A:T	W670R	1.000
16:77353785:C:G	C521S	1.000
16:77353786:A:T	C521S	1.000
16:77355966:G:C	S478R	1.000
16:77355966:G:T	S478R	1.000
16:77355968:T:G	S478R	1.000
16:77355978:C:A	W474C	1.000
16:77355978:C:G	W474C	1.000
16:77355980:A:G	W474R	1.000
16:77355980:A:T	W474R	1.000
16:77356062:G:C	H446Q	1.000
16:77356062:G:T	H446Q	1.000
16:77356064:G:C	H446D	1.000
16:77359322:G:C	H440D	1.000
16:77359329:C:A	E437D	1.000
16:77359329:C:G	E437D	1.000
16:77359330:T:A	E437V	1.000
16:77359333:T:G	H436P	1.000
16:77359334:G:C	H436D	1.000
16:77359380:A:C	C420W	1.000
16:77359381:C:T	C420Y	1.000
16:77359382:A:G	C420R	1.000
16:77359398:G:C	C414W	1.000
16:77359399:C:G	C414S	1.000

dbSNP variants (sampled 300 via entrez): RS1000032791 (16:77307108 T>G), RS1000044634 (16:77294774 T>C), RS1000050386 (16:77395222 G>C), RS1000076494 (16:77350668 ACTGT>A), RS1000109377 (16:77358141 G>C,T), RS1000123069 (16:77383348 A>C,G,T), RS1000127293 (16:77403074 T>C), RS1000146012 (16:77391620 G>A), RS1000191169 (16:77380513 G>C,T), RS1000200171 (16:77320493 G>T), RS1000203843 (16:77284158 T>C), RS1000208909 (16:77427898 C>T), RS1000209726 (16:77397781 C>A,T), RS1000217045 (16:77372584 G>T), RS1000242328 (16:77368491 C>T)

Disease associations

OMIM: gene MIM:607512 | disease phenotypes: MIM:615458, MIM:267750, MIM:204000, MIM:268000

GenCC curated gene-disease

Disease	Classification	Inheritance
microcornea-myopic chorioretinal atrophy	Definitive	Autosomal recessive
inherited retinal dystrophy	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
microcornea-myopic chorioretinal atrophy	Definitive	AR

Mondo (6): microcornea-myopic chorioretinal atrophy (MONDO:0014195), retinal disorder (MONDO:0005283), inherited retinal dystrophy (MONDO:0019118), Knobloch syndrome (MONDO:0800166), Leber congenital amaurosis (MONDO:0018998), retinitis pigmentosa (MONDO:0019200)

Orphanet (5): Microcornea-myopic chorioretinal atrophy-telecanthus syndrome (Orphanet:369970), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Knobloch syndrome (Orphanet:1571), Leber congenital amaurosis (Orphanet:65), Retinitis pigmentosa (Orphanet:791)

HPO phenotypes

9 total (10 of 9 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000358	Posteriorly rotated ears
HP:0000445	Wide nose
HP:0000455	Broad nasal tip
HP:0000482	Microcornea
HP:0000506	Telecanthus
HP:0000533	Chorioretinal atrophy
HP:0000545	Myopia
HP:0007787	Posterior subcapsular cataract
HP:0000556	Retinal dystrophy

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST000347_1	Bone mineral density	2.000000e-08
GCST001446_1	White matter integrity	2.000000e-06
GCST002001_8	Adverse response to chemotherapy (neutropenia/leucopenia) (all antimicrotubule drugs)	4.000000e-06
GCST002337_159	Amyotrophic lateral sclerosis (sporadic)	4.000000e-06
GCST003501_4	Asparaginase-induced acute pancreatitis in acute lymphoblastic leukemia (onset time)	4.000000e-10
GCST003654_18	Bone mineral density (Ward’s triangle area)	2.000000e-06
GCST004125_24	Type 2 diabetes (age of onset)	6.000000e-06
GCST005170_34	Intraocular pressure	3.000000e-14
GCST005580_124	Intraocular pressure	2.000000e-27
GCST005580_204	Intraocular pressure	1.000000e-25
GCST006365_2	Upper eyelid sagging severity	3.000000e-07
GCST006394_101	Intraocular pressure	7.000000e-13
GCST007001_10	Cerebrospinal AB1-42 levels in normal cognition	2.000000e-07
GCST009725_32	Intraocular pressure	3.000000e-13
GCST010703_237	Brain morphology (MOSTest)	3.000000e-12
GCST010796_2075	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08
GCST010796_2101	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-08
GCST010796_2102	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_2103	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_2104	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-08
GCST90011770_75	Glaucoma (primary open-angle)	7.000000e-13

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004641	white matter integrity
EFO:0005260	response to antimicrotubule agent
EFO:1001507	asparaginase-induced acute pancreatitis
EFO:0007785	femoral neck bone mineral density
EFO:0004695	intraocular pressure measurement
EFO:0004670	beta-amyloid 1-42 measurement
EFO:0004346	neuroimaging measurement
EFO:0004327	electrocardiography

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D057130	Leber Congenital Amaurosis	C11.270.516; C11.768.364
D012164	Retinal Diseases	C11.768
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1346563	Toxicity	3	sorafenib	Hypertension

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1346563	ADAMTS18	3	3.00	1	sorafenib

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — M12: Astacin/Adamalysin

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases expression	4
Tretinoin	increases expression, decreases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
methylmercuric chloride	decreases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
benzo(e)pyrene	increases methylation	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	decreases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Fulvestrant	affects cotreatment, decreases methylation	1
Troglitazone	increases expression	1
Vehicle Emissions	decreases methylation	1
Benzo(a)pyrene	affects methylation	1
Cadmium	decreases expression, increases abundance	1
Endosulfan	increases expression	1
Estradiol	decreases expression	1
Methapyrilene	increases methylation	1
Phenylmercuric Acetate	affects cotreatment, increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Antirheumatic Agents	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01955135	PHASE4	COMPLETED	Anesthesia for Retinopathy of Prematurity
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT00999609	PHASE3	ACTIVE_NOT_RECRUITING	Safety and Efficacy Study in Subjects With Leber Congenital Amaurosis
NCT06891443	PHASE3	RECRUITING	Study to Evaluate Sepofarsen in Subjects With Leber Congenital Amaurosis (LCA) Type 10 (HYPERION)
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT01373476	PHASE2	COMPLETED	Multicentre, Randomized, Controlled Trial of Qideng Mingmu Capsule in The Treatment of Diabetic Retinopathy
NCT01793090	PHASE2	COMPLETED	EPI-743 in Cobalamin C Defect: Effects on Visual and Neurological Impairment
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa
NCT05392179	PHASE2	COMPLETED	A Study in Subjects With Retinitis Pigmentosa
NCT06627179	PHASE2	RECRUITING	Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene