ADAMTSL2

Summary

ADAMTSL2 (ADAMTS like 2, HGNC:14631) is a protein-coding gene on chromosome 9q34.2, encoding ADAMTS-like protein 2 (Q86TH1).

This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) and ADAMTS-like protein family. Members of the family 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 protein encoded by this gene lacks the protease domain, and is therefore of a member of the the ADAMTS-like protein subfamily. It is a secreted glycoprotein that binds the cell surface and extracellular matrix; it also interacts with latent transforming growth factor beta binding protein 1. Mutations in this gene have been associated with geleophysic dysplasia.

Source: NCBI Gene 9719 — RefSeq curated summary.

At a glance

• Gene–disease (curated): geleophysic dysplasia 1 (Definitive, GenCC) — +2 more curated relationships
• Clinical variants (ClinVar): 332 total — 7 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 109
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_014694

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14631
Approved symbol	ADAMTSL2
Name	ADAMTS like 2
Location	9q34.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0605
Ensembl gene	ENSG00000197859
Ensembl biotype	protein_coding
OMIM	612277
Entrez	9719

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 16 protein_coding

ENST00000354484, ENST00000393060, ENST00000393061, ENST00000651351, ENST00000857364, ENST00000857365, ENST00000857366, ENST00000952998, ENST00000952999, ENST00000953000, ENST00000953001, ENST00000953002, ENST00000953003, ENST00000953004, ENST00000953005, ENST00000953006

RefSeq mRNA: 2 — MANE Select: NM_014694 NM_001145320, NM_014694

CCDS: CCDS6976

Canonical transcript exons

ENST00000651351 — 19 exons

Exon	Start	End
ENSE00003849624	133534704	133534917
ENSE00003888969	133537405	133537547
ENSE00003889214	133561198	133561295
ENSE00003889399	133569408	133569578
ENSE00003890524	133544470	133544550
ENSE00003890606	133539771	133539873
ENSE00003890720	133568273	133568486
ENSE00003892835	133570331	133570507
ENSE00003893288	133540598	133540743
ENSE00003893310	133536563	133536802
ENSE00003893570	133566936	133567062
ENSE00003893806	133573843	133573987
ENSE00003894192	133568603	133568758
ENSE00003894311	133540878	133541001
ENSE00003894502	133555558	133555930
ENSE00003894826	133547038	133547213
ENSE00003896014	133554357	133554693
ENSE00003896195	133538349	133538424
ENSE00003901982	133574746	133575519

Expression profiles

Bgee: expression breadth ubiquitous, 159 present calls, max score 93.82.

FANTOM5 (CAGE): breadth broad, TPM avg 1.2320 / max 43.5612, expressed in 312 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
99282	0.6831	235
99281	0.3860	159
99283	0.1628	99

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right atrium auricular region	UBERON:0006631	93.82	gold quality
metanephros cortex	UBERON:0010533	91.64	gold quality
cardiac atrium	UBERON:0002081	91.20	gold quality
apex of heart	UBERON:0002098	88.12	gold quality
right adrenal gland	UBERON:0001233	88.00	gold quality
left adrenal gland cortex	UBERON:0035825	87.95	gold quality
left adrenal gland	UBERON:0001234	87.71	gold quality
right adrenal gland cortex	UBERON:0035827	87.58	gold quality
right lobe of liver	UBERON:0001114	87.20	gold quality
right lung	UBERON:0002167	86.79	gold quality
adrenal cortex	UBERON:0001235	86.63	gold quality
upper lobe of left lung	UBERON:0008952	85.34	gold quality
adrenal gland	UBERON:0002369	83.76	gold quality
adenohypophysis	UBERON:0002196	82.45	gold quality
upper lobe of lung	UBERON:0008948	82.07	gold quality
right lobe of thyroid gland	UBERON:0001119	81.27	gold quality
tibial nerve	UBERON:0001323	80.39	gold quality
pituitary gland	UBERON:0000007	80.33	gold quality
left lobe of thyroid gland	UBERON:0001120	79.46	gold quality
prefrontal cortex	UBERON:0000451	78.54	gold quality
right frontal lobe	UBERON:0002810	77.96	gold quality
heart	UBERON:0000948	77.81	gold quality
cingulate cortex	UBERON:0003027	77.80	gold quality
anterior cingulate cortex	UBERON:0009835	77.64	gold quality
thyroid gland	UBERON:0002046	77.52	gold quality
right coronary artery	UBERON:0001625	77.50	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	76.97	gold quality
islet of Langerhans	UBERON:0000006	76.68	gold quality
left coronary artery	UBERON:0001626	76.32	gold quality
right hemisphere of cerebellum	UBERON:0014890	76.17	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.86

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

15 targeting ADAMTSL2, 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-185-3P	99.95	67.01	1743
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-3960	99.41	66.11	96
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-760	98.81	66.65	1392
HSA-MIR-6827-5P	98.46	64.88	1256
HSA-MIR-8072	98.27	66.24	83
HSA-MIR-1913	97.07	66.20	1417

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 15)

• These data suggest that ADAMTSL2 mutations may lead to a dysregulation of TGF-beta signaling and may be the underlying mechanism of geleophysic dysplasia. (PMID:18677313)
• Molecular screening of ADAMTSL2 gene in 33 patients reveals the genetic heterogeneity of geleophysic dysplasia. (PMID:21415077)
• Two novel homozygous missense mutations in the ADAMTSL2 gene underlie geleophysic dysplasia in two consanguineous families from the United Arab Emirates. (PMID:24014090)
• A novel mutation in ADAMTSL2 (p. Gly421Ser) gene was identified in individuals with Ehlers-Danlos Syndrome. (PMID:26879370)
• CpG-specific DNA methylation of ADAMTSL2 and BTN3A2 at rheumatoid arthritis diagnosis can serve as a marker of treatment response. (PMID:28447857)
• Two compound heterozygous mutations were confirmed in the ADAMTSL2 gene of the patient with geleophysic dysplasia. (PMID:28917829)
• Upon investigating the interaction between LOX and ADAMTSL2 we found that the absence or inhibition of Lox affected ADAMTSL2 molecular forms and reduced its tissue levels. Thus, ADAMTSL2 stability and inter-molecular complexes may depend on the activity of lysyl oxidases. (PMID:29758265)
• Findings postulate that abnormal fibrillin microfibril assembly is the general molecular basis of geleophysic dysplasia, and the specific role of ADAMTSL2 may be to inhibit microfibril assembly, whether it be assembly of FBN2 fibrils in the embryonic period or FBN1 fibrils in tendons during the postnatal period. (PMID:30738849)
• ADAMTSL2 gene variant in patients with features of autosomal dominant connective tissue disorders. (PMID:33369194)
• ADAMTSL2 protein and a soluble biomarker signature identify at-risk non-alcoholic steatohepatitis and fibrosis in adults with NAFLD. (PMID:34600973)
• The extracellular matrix glycoprotein ADAMTSL2 is increased in heart failure and inhibits TGFbeta signalling in cardiac fibroblasts. (PMID:34611183)
• The relationship of ADAMTSL2 and LRPAP1 gene methylation level with rheumatoid arthritis activity. (PMID:34936547)
• Aberrant interaction between mutated ADAMTSL2 and LTBP4 is associated with adolescent idiopathic scoliosis. (PMID:34958866)
• Al-Gazali Skeletal Dysplasia Constitutes the Lethal End of ADAMTSL2-Related Disorders. (PMID:36896612)
• Secreted ADAMTS-like 2 promotes myoblast differentiation by potentiating WNT signaling. (PMID:37187448)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	adamtsl2	ENSDARG00000074033
mus_musculus	Adamtsl2	ENSMUSG00000036040
rattus_norvegicus	Adamtsl2	ENSRNOG00000027742

Paralogs (25): ADAMTS6 (ENSG00000049192), ADAMTS2 (ENSG00000087116), PAPLN (ENSG00000100767), ADAMTS8 (ENSG00000134917), ADAMTS7 (ENSG00000136378), ADAMTS14 (ENSG00000138316), ADAMTS17 (ENSG00000140470), ADAMTS18 (ENSG00000140873), 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)

Protein

Protein identifiers

ADAMTS-like protein 2 — Q86TH1 (reviewed: Q86TH1)

All UniProt accessions (2): B1B0D4, Q86TH1

UniProt curated annotations — full annotation on UniProt →

Subunit / interactions. Interacts with LTBP1.

Subcellular location. Secreted.

Post-translational modifications. 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. Geleophysic dysplasia 1 (GPHYSD1) [MIM:231050] An autosomal recessive disorder characterized by severe short stature, short hands and feet, joint limitations, and skin thickening. Radiologic features include delayed bone age, cone-shaped epiphyses, shortened long tubular bones, and ovoid vertebral bodies. Affected individuals have characteristic facial features including a ‘happy’ face with full cheeks, shortened nose, hypertelorism, long and flat philtrum, and thin upper lip. Other distinctive features include progressive cardiac valvular thickening often leading to an early death, toe walking, tracheal stenosis, respiratory insufficiency, and lysosomal-like storage vacuoles in various tissues. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. There is a significant increase in total and active TGFB1 in the culture medium as well as nuclear localization of phosphorylated SMAD2 in fibroblasts from individuals with geleophysic dysplasia.

RefSeq proteins (2): NP_001138792, NP_055509* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000884	TSP1_rpt	Repeat
IPR010294	ADAMTS_spacer1	Domain
IPR010909	PLAC	Domain
IPR013273	ADAMTS/ADAMTS-like	Family
IPR036383	TSP1_rpt_sf	Homologous_superfamily
IPR045371	ADAMTS_CR_3	Domain
IPR050439	ADAMTS_ADAMTS-like	Family

Pfam: PF00090, PF05986, PF08686, PF19030, PF19236

UniProt features (44 total): sequence variant 16, glycosylation site 10, domain 8, disulfide bond 3, region of interest 2, compositionally biased region 2, signal peptide 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86TH1-F1	67.10	0.12

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (3): 59–100, 63–105, 74–90

Glycosylation sites (10): 87, 367, 428, 475, 511, 524, 533, 544, 731, 807

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-5083635	Defective B3GALTL causes PpS
R-HSA-5173214	O-glycosylation of TSR domain-containing proteins
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: 384 (showing top): MORF_RAGE, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EPITHELIUM_DEVELOPMENT, CAR_TNFRSF25, GOBP_LUNG_EPITHELIUM_DEVELOPMENT, GOMF_METALLOPEPTIDASE_ACTIVITY, GCANCTGNY_MYOD_Q6, CAGCTG_AP4_Q5, GOBP_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY, GOBP_RESPONSE_TO_TRANSFORMING_GROWTH_FACTOR_BETA, MORF_FANCG, ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_DN, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_TRANSFORMING_GROWTH_FACTOR_BETA_STIMULUS, MYOD_Q6

GO Biological Process (3): extracellular matrix organization (GO:0030198), negative regulation of transforming growth factor beta receptor signaling pathway (GO:0030512), lobar bronchus epithelium development (GO:0060481)

GO Molecular Function (2): microfibril binding (GO:0050436), protein binding (GO:0005515)

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

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
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
extracellular structure organization	1
external encapsulating structure organization	1
transforming growth factor beta receptor signaling pathway	1
regulation of transforming growth factor beta receptor signaling pathway	1
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
lung epithelium development	1
lobar bronchus development	1
extracellular matrix binding	1
binding	1
cellular anatomical structure	1
external encapsulating structure	1

Protein interactions and networks

STRING

588 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADAMTSL2	LTBP1	P22064	956
ADAMTSL2	FBN1	P35555	787
ADAMTSL2	ADAMTS10	Q9H324	630
ADAMTSL2	ADAMTS2	O95450	617
ADAMTSL2	TBRG1	Q3YBR2	599
ADAMTSL2	SLC8A2	Q9UPR5	577
ADAMTSL2	FBN2	P35556	552
ADAMTSL2	SMAD2	Q15796	544
ADAMTSL2	POFUT2	Q9Y2G5	543
ADAMTSL2	COL8A2	P25067	536
ADAMTSL2	COL16A1	Q07092	516
ADAMTSL2	LTBP3	Q9NS15	509
ADAMTSL2	COL6A1	P12109	506
ADAMTSL2	ADAMTS4	O75173	502
ADAMTSL2	MFAP4	P55083	492

IntAct

10 interactions, top by confidence:

A	B	Type	Score
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
ADAMTSL2	HOXA1	psi-mi:“MI:0915”(physical association)	0.370
FBLN1	ADAMTSL2	psi-mi:“MI:0915”(physical association)	0.370
NECAB2	ADAMTSL2	psi-mi:“MI:0915”(physical association)	0.370
AURKB	VWA8	psi-mi:“MI:0914”(association)	0.350
GPR17	C1QTNF9B	psi-mi:“MI:0914”(association)	0.350
HPN	DDX39A	psi-mi:“MI:0914”(association)	0.350
P2RY8	CIT	psi-mi:“MI:0914”(association)	0.350
PIM1	IDH3B	psi-mi:“MI:0914”(association)	0.350

BioGRID (2): ADAMTSL2 (Two-hybrid), FBLN1 (Two-hybrid)

ESM2 similar proteins: A7MBS7, D3YXF5, F1LW30, O89103, P10643, P11680, P27918, P35446, P82987, P90884, Q29RQ1, Q2I0M5, Q2MKA7, Q3UPR9, Q3UTY6, Q4R7Z5, Q5M7L6, Q5RAD0, Q5RBP1, Q5RBP8, Q5UE90, Q64181, Q66PY1, Q69ZU6, Q6NZL8, Q6P4U0, Q6UXX9, Q6ZMP0, Q7T3Q2, Q7TSK7, Q80YN4, Q86TH1, Q8BFU0, Q8BJ73, Q8BLI0, Q8IUX8, Q8IWY4, Q8IX30, Q8N6G6, Q8VCC9

Diamond homologs: A2VEC9, B3EWY9, B3EWZ3, B3EWZ8, C0HL12, C5IAW9, D3YXF5, D3YXG0, D3Z7H8, D3ZTD8, E9Q6D8, F1LW30, G1FC92, G5ECS8, O08721, O08722, O08747, O14514, O15072, O60241, O60242, O95185, O95450, P07358, P07996, P10643, P11680, P13671, P27918, P35440, P35441, P35442, P35448, P48960, P55314, P57110, P58397, P59384, P61134, P61135

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	15
Uncertain significance	199
Likely benign	36
Benign	46

Top pathogenic / likely-pathogenic (22)

Variant ID	HGVS	Classification
30945	NM_014694.4(ADAMTSL2):c.661C>T (p.Arg221Cys)	Pathogenic
427943	NM_014694.4(ADAMTSL2):c.234-2A>G	Pathogenic
624558	NM_014694.4(ADAMTSL2):c.499G>A (p.Asp167Asn)	Pathogenic
693	NM_014694.4(ADAMTSL2):c.440C>T (p.Pro147Leu)	Pathogenic
696	NM_014694.4(ADAMTSL2):c.2431G>A (p.Gly811Arg)	Pathogenic
697	NM_014694.4(ADAMTSL2):c.2586G>A (p.Trp862Ter)	Pathogenic
915302	NM_014694.4(ADAMTSL2):c.529C>T (p.Arg177Ter)	Pathogenic
1162207	NM_014694.4(ADAMTSL2):c.2737+1G>T	Likely pathogenic
1164089	NM_014694.4(ADAMTSL2):c.337C>T (p.Arg113Cys)	Likely pathogenic
1224440	NM_014694.4(ADAMTSL2):c.538del (p.Cys180fs)	Likely pathogenic
1326007	NM_014694.4(ADAMTSL2):c.1851C>A (p.Cys617Ter)	Likely pathogenic
1326072	NM_014694.4(ADAMTSL2):c.338G>T (p.Arg113Leu)	Likely pathogenic
1710157	NM_014694.4(ADAMTSL2):c.1061del (p.Gly354fs)	Likely pathogenic
1710160	NM_014694.4(ADAMTSL2):c.502G>A (p.Gly168Ser)	Likely pathogenic
1710162	NM_014694.4(ADAMTSL2):c.229C>T (p.Gln77Ter)	Likely pathogenic
1710163	NM_014694.4(ADAMTSL2):c.800G>T (p.Gly267Val)	Likely pathogenic
1710164	NM_014694.4(ADAMTSL2):c.496C>T (p.Arg166Cys)	Likely pathogenic
1710165	NM_014694.4(ADAMTSL2):c.718C>T (p.Arg240Ter)	Likely pathogenic
2633504	NM_014694.4(ADAMTSL2):c.1773T>A (p.Cys591Ter)	Likely pathogenic
30944	NM_014694.4(ADAMTSL2):c.215G>A (p.Arg72Gln)	Likely pathogenic
3596752	NM_014694.4(ADAMTSL2):c.799G>A (p.Gly267Ser)	Likely pathogenic
694	NM_014694.4(ADAMTSL2):c.338G>A (p.Arg113His)	Likely pathogenic

SpliceAI

3736 predictions. Top by Δscore:

Variant	Effect	Δscore
9:133539857:G:GT	donor_gain	1.0000
9:133539905:G:GT	donor_gain	1.0000
9:133540594:CCA:C	acceptor_loss	1.0000
9:133540596:A:AG	acceptor_gain	1.0000
9:133540596:AGAT:A	acceptor_gain	1.0000
9:133540596:AGATG:A	acceptor_loss	1.0000
9:133540597:G:GA	acceptor_loss	1.0000
9:133540597:G:GG	acceptor_gain	1.0000
9:133540597:GAT:G	acceptor_gain	1.0000
9:133540597:GATG:G	acceptor_gain	1.0000
9:133540718:GGGTT:G	donor_gain	1.0000
9:133540719:GGTT:G	donor_gain	1.0000
9:133540998:CTTGG:C	donor_loss	1.0000
9:133540999:TTGG:T	donor_loss	1.0000
9:133541001:GGTAA:G	donor_loss	1.0000
9:133541002:G:A	donor_loss	1.0000
9:133541003:TAAG:T	donor_loss	1.0000
9:133544464:CTCCA:C	acceptor_loss	1.0000
9:133544465:TCCAG:T	acceptor_loss	1.0000
9:133544466:CCAGG:C	acceptor_loss	1.0000
9:133544467:CAGG:C	acceptor_loss	1.0000
9:133544468:A:AG	acceptor_gain	1.0000
9:133544468:AGGTT:A	acceptor_loss	1.0000
9:133544469:G:GG	acceptor_gain	1.0000
9:133547036:A:AC	acceptor_loss	1.0000
9:133547036:A:AG	acceptor_gain	1.0000
9:133547037:G:GT	acceptor_gain	1.0000
9:133547037:GC:G	acceptor_gain	1.0000
9:133547037:GCT:G	acceptor_gain	1.0000
9:133547037:GCTC:G	acceptor_gain	1.0000

AlphaMissense

6272 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:133561250:T:A	W568R	1.000
9:133561250:T:C	W568R	1.000
9:133561252:G:C	W568C	1.000
9:133561252:G:T	W568C	1.000
9:133568465:G:C	W689C	1.000
9:133568465:G:T	W689C	1.000
9:133570484:T:A	W857R	1.000
9:133570484:T:C	W857R	1.000
9:133570486:G:C	W857C	1.000
9:133570486:G:T	W857C	1.000
9:133570501:G:C	W862C	1.000
9:133570501:G:T	W862C	1.000
9:133573888:T:C	C880R	1.000
9:133537473:G:C	W53C	0.999
9:133537473:G:T	W53C	0.999
9:133539857:G:C	W132C	0.999
9:133539857:G:T	W132C	0.999
9:133540639:T:A	C152S	0.999
9:133540639:T:C	C152R	0.999
9:133540640:G:C	C152S	0.999
9:133540641:T:G	C152W	0.999
9:133540723:T:C	C180R	0.999
9:133547130:T:G	Y286D	0.999
9:133554399:T:G	Y328D	0.999
9:133566959:T:A	C591S	0.999
9:133566959:T:C	C591R	0.999
9:133566960:G:A	C591Y	0.999
9:133566960:G:C	C591S	0.999
9:133566961:T:G	C591W	0.999
9:133566998:T:A	C604S	0.999

dbSNP variants (sampled 300 via entrez): RS1000029018 (9:133543926 T>C), RS1000098328 (9:133550163 C>T), RS1000128646 (9:133534566 G>A,C), RS1000182196 (9:133569307 C>T), RS1000235950 (9:133569638 A>G), RS1000264488 (9:133536521 G>A,T), RS1000357560 (9:133545096 C>G), RS1000386709 (9:133539958 C>T), RS1000402191 (9:133555377 C>T), RS1000473690 (9:133574363 A>G), RS1000516152 (9:133570495 C>T), RS1000522950 (9:133546872 C>T), RS1000565512 (9:133570691 C>T), RS1000602352 (9:133554250 G>A,T), RS1000755846 (9:133541133 A>G)

Disease associations

OMIM: gene MIM:612277 | disease phenotypes: MIM:231050, MIM:601356

GenCC curated gene-disease

Disease	Classification	Inheritance
geleophysic dysplasia 1	Definitive	Autosomal recessive
Ehlers-Danlos syndrome, dermatosparaxis type	Moderate	Autosomal dominant
Ehlers-Danlos syndrome	Limited	Autosomal dominant

Mondo (5): geleophysic dysplasia 1 (MONDO:0009269), lethal short-limb skeletal dysplasia, Al Gazali type (MONDO:0011051), geleophysic dysplasia (MONDO:0000127), Ehlers-Danlos syndrome (MONDO:0020066), Ehlers-Danlos syndrome, dermatosparaxis type (MONDO:0009161)

Orphanet (2): Geleophysic dysplasia (Orphanet:2623), Dysplastic cortical hyperostosis, Al-Gazali type (Orphanet:646136)

HPO phenotypes

109 total (30 of 109 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000154	Wide mouth
HP:0000219	Thin upper lip vermilion
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000311	Round face
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000391	Thickened helices
HP:0000405	Conductive hearing impairment
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000483	Astigmatism
HP:0000501	Glaucoma
HP:0000540	Hypermetropia
HP:0000545	Myopia
HP:0000582	Upslanted palpebral fissure
HP:0000767	Pectus excavatum
HP:0000821	Hypothyroidism
HP:0000926	Platyspondyly
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0000963	Thin skin
HP:0000974	Hyperextensible skin
HP:0001001	Abnormality of subcutaneous fat tissue
HP:0001072	Thickened skin
HP:0001156	Brachydactyly

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D004535	Ehlers-Danlos Syndrome	C14.907.454.240; C15.378.463.515.240; C16.131.831.428; C16.320.850.260; C17.300.200.310; C17.800.804.428; C17.800.827.260
C567527	Ehlers-Danlos Syndrome, Type VII, Autosomal Recessive (supp.)
C537598	Short limb dwarfism Al Gazali type (supp.)

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
rs756770	Efficacy	3	buprenorphine	Opioid-Related Disorders

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs756770	ADAMTSL2	3	0.00	1	buprenorphine

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation	2
ethyl-p-hydroxybenzoate	decreases expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	increases expression	1
sodium arsenite	decreases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	increases expression	1
perfluorooctanoic acid	increases expression	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
obeticholic acid	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	affects methylation	1
Doxorubicin	decreases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Phthalic Acids	increases methylation	1
Tobacco Smoke Pollution	decreases expression	1
Toluene	decreases expression, increases methylation	1
Tretinoin	decreases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	decreases methylation	1
Particulate Matter	increases abundance, increases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D2ZZ	GM28074	Transformed cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04890431	PHASE4	UNKNOWN	Impact of Oxygen Therapy on Fatigue in Patients With Hypermobile-type Ehlers-Danlos Syndrome
NCT05603741	PHASE4	ACTIVE_NOT_RECRUITING	Local Anesthetic Response in Ehlers-Danlos Syndrome (EDS) and Healthy Volunteers
NCT05279937	PHASE3	NOT_YET_RECRUITING	The Ultrasound-Guided Dextrose Prolotherapy in Ehlers-Danlos Syndrome Patients
NCT00001966	PHASE2	COMPLETED	Mind-Body Therapy for Pain in Ehlers-Danlos Syndrome
NCT03686748	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Two Point Discrimination
NCT00001641	Not specified	COMPLETED	Study of Heritable Connective Tissue Disorders
NCT00270686	Not specified	COMPLETED	Studies of Heritable Disorders of Connective Tissue
NCT01322165	Not specified	COMPLETED	National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions
NCT01356134	Not specified	COMPLETED	Vascular Fundus Changes in Patients With High Probability of Chronic Cerebrospinal Venous Insufficiency (CCSVI)
NCT01367977	Not specified	COMPLETED	Head Circumference Growth in Children With Ehlers-Danlos Syndrome Who Develop Dysautonomia Later in Life
NCT02050113	Not specified	RECRUITING	Complex Aortic Aneurysm Repair Using Physician Modified Endografts and Custom Made Devices
NCT02435745	Not specified	COMPLETED	Obstructive Sleep Apnoea in Ehlers-Danlos Syndrome
NCT02721797	Not specified	UNKNOWN	Origins and Impact of EDS in Connective Tissues and Skin
NCT02985710	Not specified	COMPLETED	Assessment of Small Fiber Neuropathy in Rare Diseases Using Sudoscan
NCT03093493	Not specified	COMPLETED	Genetics of Ehlers-Danlos Syndrome
NCT03330977	Not specified	UNKNOWN	Efficiency Clinical Study of NOVATEX MEDICAL Compression Garments in Patients With Ehlers-Danlos Syndrome
NCT03575182	Not specified	UNKNOWN	Gait Retraining in Patients With Joint Hypermobility Syndrome/Hypermobile Ehlers Danlos Syndrome
NCT03596437	Not specified	UNKNOWN	Study of Arterial Properties by Ultra-high Frequency Ultrasound in Fibromuscular Dysplasia and Vascular Ehlers-Danlos Syndrome
NCT03602482	Not specified	COMPLETED	Standing Cognition and Co-morbidities of POTS Evaluation
NCT03681080	Not specified	COMPLETED	Concentration and Attentional Deficits in POTS and Other Autonomic Neuropathies
NCT03986229	Not specified	COMPLETED	Evaluation of the Effect of Custom Compression Garments on Standing Static Balance in Ehlers Danlos Syndrome
NCT04036305	Not specified	ACTIVE_NOT_RECRUITING	Local Anesthetic Response in Ehlers-Danlos Syndrome (EDS) and Healthy Volunteers
NCT04133272	Not specified	RECRUITING	Registry of Ehlers-Danlos Syndrome
NCT04437589	Not specified	COMPLETED	Opioid-Free Anesthesia for Patients With Joint Hypermobility Syndrome Undergoing Craneo-Cervical Fixation: A Case-series
NCT04680793	Not specified	COMPLETED	Effects of a Multidisciplinary Outpatient Rehabilitation Program in Patients With Ehlers-Danlos Syndrome.
NCT04734041	Not specified	COMPLETED	Integrative Medicine for Hypermobility Spectrum Disorder and Ehlers-Danlos Syndromes (IMforHSDandEDS)
NCT04742803	Not specified	COMPLETED	Straberi Epistamp Needling Treatment For Skin Rejuvenation
NCT04806620	Not specified	RECRUITING	Unhide® Project: A Digital Health Platform to Collect Lifestyle Data for Brain Inflammation Research
NCT05137379	Not specified	COMPLETED	Evaluation of a Cohort of Patients With Ehlers-Danlos Syndrome Treated With Orthopedic Surgery (SED-eval)
NCT05366114	Not specified	UNKNOWN	Vision-based Assessment of Joint Extensibility in Ehlers Danlos Syndrome
NCT05389865	Not specified	ACTIVE_NOT_RECRUITING	Proximal Aortopathy in Scotland - Epidemiology and Surgical Outcomes
NCT05429996	Not specified	UNKNOWN	Ultrastructural Collagen Markers in Ehlers Danlos Syndromes
NCT05434728	Not specified	UNKNOWN	Characterization of Bleeding Disorders in EDS
NCT05516043	Not specified	COMPLETED	Safety and Performance of POLYTHESE® Vascular Prosthesis
NCT05561270	Not specified	RECRUITING	Light Exposure on Pain in Hypermobile Ehlers-Danlos Syndrome
NCT05720923	Not specified	ACTIVE_NOT_RECRUITING	Analysis of Muscular Properties in Patients With MFS and EDS
NCT05871216	Not specified	RECRUITING	Functional Instability in Patients Suffering From Collagen Disease and Joint Hypermobility
NCT05945784	Not specified	COMPLETED	Exploring Accessible Beauty for Individuals With Upper Extremity Deficits
NCT06074276	Not specified	RECRUITING	The Effects of Almond on Facial Skin Collagen and Wrinkles
NCT06105541	Not specified	COMPLETED	Hypermobile Ehlers-Danlos Syndrome - Transcutaneous Auricular Neuromodulation