DSE

Summary

DSE (dermatan sulfate epimerase, HGNC:21144) is a protein-coding gene on chromosome 6q22.1, encoding Dermatan-sulfate epimerase (Q9UL01). Converts D-glucuronic acid to L-iduronic acid (IdoUA) residues.

The protein encoded by this gene is a tumor-rejection antigen. It is localized to the endoplasmic reticulum and functions to convert D-glucuronic acid to L-iduronic acid during the biosynthesis of dermatan sulfate. This antigen possesses tumor epitopes capable of inducing HLA-A24-restricted and tumor-specific cytotoxic T lymphocytes in cancer patients and may be useful for specific immunotherapy. Mutations in this gene cause inmusculocontractural Ehlers-Danlos syndrome. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 9, and a paralogous gene exists on chromosome 18.

Source: NCBI Gene 29940 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Ehlers-Danlos syndrome, musculocontractural type 2 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 11
• Clinical variants (ClinVar): 582 total — 8 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 88
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_013352

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21144
Approved symbol	DSE
Name	dermatan sulfate epimerase
Location	6q22.1
Locus type	gene with protein product
Status	Approved
Aliases	DSEPI, DS-Epi1
Ensembl gene	ENSG00000111817
Ensembl biotype	protein_coding
OMIM	605942
Entrez	29940

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 18 protein_coding, 6 protein_coding_CDS_not_defined, 3 retained_intron

ENST00000331677, ENST00000359564, ENST00000430252, ENST00000448740, ENST00000449314, ENST00000452085, ENST00000453463, ENST00000606265, ENST00000606712, ENST00000607094, ENST00000642434, ENST00000643175, ENST00000644252, ENST00000645959, ENST00000645988, ENST00000646710, ENST00000647046, ENST00000647244, ENST00000891542, ENST00000891543, ENST00000891544, ENST00000931461, ENST00000950996, ENST00000950997, ENST00000950998, ENST00000950999, ENST00000951000

RefSeq mRNA: 12 — MANE Select: NM_013352 NM_001080976, NM_001322937, NM_001322938, NM_001322939, NM_001322940, NM_001322941, NM_001322943, NM_001322944, NM_001374520, NM_001374521, NM_001374522, NM_013352

CCDS: CCDS5107, CCDS87432, CCDS87433

Canonical transcript exons

ENST00000644252 — 6 exons

Exon	Start	End
ENSE00000762626	116426574	116426827
ENSE00000762628	116430954	116431193
ENSE00000762640	116433343	116433550
ENSE00001512292	116370947	116371121
ENSE00003459633	116399198	116399666
ENSE00003819206	116435587	116444861

Expression profiles

Bgee: expression breadth ubiquitous, 275 present calls, max score 97.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 56.3506 / max 1864.7973, expressed in 1798 samples.

FANTOM5 promoters (15 alternative TSS)

Promoter ID	TPM avg	Samples expressed
69412	48.9882	1627
69398	2.4443	1065
69402	1.0210	657
69403	1.0132	580
69405	0.7640	388
69407	0.6239	114
69406	0.4594	222
69404	0.2353	84
69399	0.2184	71
69410	0.1594	61

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
parietal pleura	UBERON:0002400	97.60	gold quality
calcaneal tendon	UBERON:0003701	97.58	gold quality
germinal epithelium of ovary	UBERON:0001304	97.51	gold quality
cartilage tissue	UBERON:0002418	97.06	gold quality
pleura	UBERON:0000977	96.55	gold quality
pericardium	UBERON:0002407	95.76	gold quality
synovial joint	UBERON:0002217	95.27	gold quality
visceral pleura	UBERON:0002401	94.60	gold quality
layer of synovial tissue	UBERON:0007616	94.47	gold quality
tendon	UBERON:0000043	94.12	gold quality
choroid plexus epithelium	UBERON:0003911	93.88	gold quality
right lung	UBERON:0002167	93.87	gold quality
skin of hip	UBERON:0001554	93.77	gold quality
gingival epithelium	UBERON:0001949	92.92	gold quality
adipose tissue	UBERON:0001013	92.89	gold quality
gingiva	UBERON:0001828	92.74	gold quality
connective tissue	UBERON:0002384	92.74	gold quality
tibia	UBERON:0000979	92.70	gold quality
subcutaneous adipose tissue	UBERON:0002190	92.66	gold quality
stromal cell of endometrium	CL:0002255	92.57	gold quality
palpebral conjunctiva	UBERON:0001812	92.43	gold quality
adipose tissue of abdominal region	UBERON:0007808	92.26	gold quality
omental fat pad	UBERON:0010414	92.22	gold quality
peritoneum	UBERON:0002358	92.21	gold quality
esophagus squamous epithelium	UBERON:0006920	92.13	gold quality
lower lobe of lung	UBERON:0008949	92.12	gold quality
tibial nerve	UBERON:0001323	91.98	gold quality
decidua	UBERON:0002450	91.83	gold quality
monocyte	CL:0000576	91.66	gold quality
mononuclear cell	CL:0000842	91.31	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-9543	yes	22.60
E-CURD-112	yes	5.42
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

56 targeting DSE, 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-9-5P	100.00	72.28	2361
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-8076	99.78	68.52	1170
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-141-5P	99.57	67.86	897
HSA-MIR-7159-3P	99.51	70.17	1920

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 6)

• Identification of the active site of DS-epimerase 1 and requirement of N-glycosylation for enzyme function. (PMID:19004833)
• Dermatan sulfate epimerase 1 was highly upregulated in esophagus squamous cell carcinoma (PMID:22350411)
• study identified a homozygous DSE missense mutation (c.803C>T, p.S268L) in a male child with musculocontractural type of Ehlers-Danlos syndrome; data indicate mutation affects the epimerase activity, resulting in reduced dermatan sulfate (DS) biosynthesis and an increased synthesis or an accumulation or reduced conversion of chondroitin sulfate (PMID:23704329)
• Study showed that DSE is frequently upregulated in human glioma tissue and cell lines and associated with a worse tumor grade and poor overall survival. Its knockdown suppresses malignant phenotypes, whereas DSE overexpression enhances glioma cell malignancy, both in vitro and in vivo. Mechanically, DSE modulates HB-EGF-induced EGFR/ErbB2 activity and downstream signaling. (PMID:29864158)
• DS-epi1, DS-epi2, and D4ST1 form homomers and are all part of a hetero-oligomeric complex where D4ST1 directly interacts with DS-epi1, but not with DS-epi2. The cooperation of DS-epi1 with D4ST1 may therefore explain the processive mode of the formation of iduronic acid blocks. (PMID:29976758)
• Dermatan sulfate epimerase 1 expression and mislocalization may interfere with dermatan sulfate synthesis and breast cancer cell growth. (PMID:31972438)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	dse	ENSDARG00000017988
mus_musculus	Dse	ENSMUSG00000039497
rattus_norvegicus	Dse	ENSRNOG00000000824

Paralogs (1): DSEL (ENSG00000171451)

Protein

Protein identifiers

Dermatan-sulfate epimerase — Q9UL01 (reviewed: Q9UL01)

Alternative names: Chondroitin-glucuronate 5-epimerase, Squamous cell carcinoma antigen recognized by T-cells 2

All UniProt accessions (6): Q9UL01, A0A2R8Y4N7, A0A2R8Y6Y4, A0A2R8YE23, A0A2U3TZJ0, X6REM1

UniProt curated annotations — full annotation on UniProt →

Function. Converts D-glucuronic acid to L-iduronic acid (IdoUA) residues. Plays an important role in the biosynthesis of the glycosaminoglycan/mucopolysaccharide dermatan sulfate.

Subcellular location. Endoplasmic reticulum membrane. Golgi apparatus membrane. Cytoplasmic vesicle membrane. Microsome membrane.

Tissue specificity. Ubiquitously expressed with higher expression in kidney and ovary and lower expression in brain, colon and thymus. Also expressed in renal cell carcinomas, brain tumors, and in a part of melanomas and adenocarcinomas from organs other than the breast. Expressed in squamous cell carcinomas (SCC), glioma, and some adenocarcinoma cell lines, but not in breast cancer cell lines or any normal tissues (at protein level).

Post-translational modifications. N-glycosylated (PubMed:19004833, Ref.7). Glycosylation is important for enzymatic activity.

Disease relevance. Ehlers-Danlos syndrome, musculocontractural type 2 (EDSMC2) [MIM:615539] A form of Ehlers-Danlos syndrome characterized by progressive multisystem manifestations, including joint dislocations and deformities, skin hyperextensibility, skin bruisability and fragility with recurrent large subcutaneous hematomas, cardiac valvular, respiratory, gastrointestinal, and ophthalmologic complications. Motor developmental delay is associated with muscle hypoplasia, muscle weakness, and an abnormal muscle fiber pattern in histology in adulthood. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Also has weak activity in the presence of Mg(2+) or Ca(2+) ions.

Pathway. Glycan metabolism; chondroitin sulfate biosynthesis. Glycan metabolism; heparan sulfate biosynthesis.

Similarity. Belongs to the dermatan-sulfate isomerase family.

RefSeq proteins (12): NP_001074445, NP_001309866, NP_001309867, NP_001309868, NP_001309869, NP_001309870, NP_001309872, NP_001309873, NP_001361449, NP_001361450, NP_001361451, NP_037484* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008929	Chondroitin_lyas	Homologous_superfamily
IPR052447	Dermatan-Sulfate_Isomerase	Family

Enzyme classification (BRENDA):

• EC 5.1.3.19 — chondroitin-glucuronate 5-epimerase (BRENDA: 5 organisms, 18 substrates, 0 inhibitors, 8 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

3 substrates with measured Km, best-characterized 3. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
D-GLUCURONATE	0.0049–0.024	5
D-GLUCURONOSYL RESIDUES	0.067–0.37	2
CHONDROITIN D-GLUCURONOSYL RESIDUE	0.12	1

Catalyzed reactions (Rhea), 1 shown:

• chondroitin 4’-sulfate = dermatan 4’-sulfate (RHEA:21084)

UniProt features (93 total): helix 28, strand 25, mutagenesis site 12, glycosylation site 5, turn 5, sequence variant 4, binding site 3, topological domain 3, active site 3, transmembrane region 2, signal peptide 1, chain 1, site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6HZN	X-RAY DIFFRACTION	2.41

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UL01-F1	86.59	0.70

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 (4): 450 (critical for catalysis); 205 (proton donor); 261; 473

Ligand- & substrate-binding residues (3): 452; 470; 481

Glycosylation sites (5): 183, 336, 411, 642, 648

Mutagenesis-validated functional residues (12):

Position	Phenotype
98	severely impairs catalytic activity.
147	impairs catalytic activity.
203	severely impairs catalytic activity.
205	abolishes catalytic activity.
256	moderately reduced catalytic activity.
261	abolishes catalytic activity.
331	no significant effect on catalytic activity.
383	very low levels of protein expression and no detectable catalytic activity.
450	abolishes catalytic activity.
452	abolishes catalytic activity.
470	abolishes catalytic activity.
473	abolishes catalytic activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2022923	DS-GAG biosynthesis

MSigDB gene sets: 473 (showing top): WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, VERHAAK_AML_WITH_NPM1_MUTATED_DN, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_HEPARAN_SULFATE_PROTEOGLYCAN_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, HELLER_HDAC_TARGETS_SILENCED_BY_METHYLATION_UP, CHARAFE_BREAST_CANCER_LUMINAL_VS_BASAL_DN, MARIADASON_REGULATED_BY_HISTONE_ACETYLATION_UP, GOBP_CHONDROITIN_SULFATE_PROTEOGLYCAN_METABOLIC_PROCESS, GOBP_PROTEIN_O_LINKED_GLYCOSYLATION, GOBP_GLYCOPROTEIN_METABOLIC_PROCESS, SENESE_HDAC3_TARGETS_DN, REACTOME_METABOLISM_OF_CARBOHYDRATES_AND_CARBOHYDRATE_DERIVATIVES

GO Biological Process (4): heparan sulfate proteoglycan biosynthetic process (GO:0015012), dermatan sulfate proteoglycan biosynthetic process (GO:0050651), chondroitin sulfate proteoglycan metabolic process (GO:0050654), dermatan sulfate proteoglycan metabolic process (GO:0050655)

GO Molecular Function (3): metal ion binding (GO:0046872), chondroitin-glucuronate 5-epimerase activity (GO:0047757), isomerase activity (GO:0016853)

GO Cellular Component (7): Golgi membrane (GO:0000139), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), cytoplasmic vesicle membrane (GO:0030659), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Chondroitin sulfate/dermatan sulfate metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
proteoglycan biosynthetic process	2
protein O-linked glycosylation via xylose	2
proteoglycan metabolic process	2
endomembrane system	2
intracellular membrane-bounded organelle	2
heparan sulfate proteoglycan metabolic process	1
dermatan sulfate proteoglycan metabolic process	1
cation binding	1
racemase and epimerase activity, acting on carbohydrates and derivatives	1
catalytic activity	1
Golgi apparatus	1
bounding membrane of organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
vesicle membrane	1
cytoplasmic vesicle	1
cellular anatomical structure	1
intracellular vesicle	1

Protein interactions and networks

STRING

378 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DSE	SART1	O43290	884
DSE	MAGEC1	O60732	828
DSE	SLC39A7	Q92504	761
DSE	CHST14	Q8NCH0	731
DSE	B3GALT6	Q96L58	621
DSE	SART3	Q15020	609
DSE	CHST15	Q7LFX5	581
DSE	UST	Q9Y2C2	580
DSE	CHST12	Q9NRB3	571
DSE	NELFA	Q9H3P2	542
DSE	HS2ST1	Q7LGA3	535
DSE	CHSY1	Q86X52	515
DSE	CHST11	Q9NPF2	514
DSE	CHST13	Q8NET6	507
DSE	CHPF	Q8IZ52	505
DSE	CHST3	Q7LGC8	505

IntAct

40 interactions, top by confidence:

A	B	Type	Score
MGAT4C	GXYLT2	psi-mi:“MI:0914”(association)	0.530
PICK1	ILVBL	psi-mi:“MI:0914”(association)	0.530
HLA-DPA1	TYW5	psi-mi:“MI:0914”(association)	0.530
NRBP1	TBC1D4	psi-mi:“MI:0914”(association)	0.530
ACSL4	DSE	psi-mi:“MI:0915”(physical association)	0.370
INTS11	DSE	psi-mi:“MI:0915”(physical association)	0.370
NEK4	E2F8	psi-mi:“MI:0914”(association)	0.350
CHRNA3	TMEM223	psi-mi:“MI:0914”(association)	0.350
HLA-DPA1	GXYLT2	psi-mi:“MI:0914”(association)	0.350
NRG1	HS6ST1	psi-mi:“MI:0914”(association)	0.350
CD79B	GOLIM4	psi-mi:“MI:0914”(association)	0.350
SYNE4	GOLIM4	psi-mi:“MI:0914”(association)	0.350
HTR3A	GPAA1	psi-mi:“MI:0914”(association)	0.350
HLA-DRA	TMEM223	psi-mi:“MI:0914”(association)	0.350
HLA-DQA1	TMEM223	psi-mi:“MI:0914”(association)	0.350
CLEC12B	GXYLT2	psi-mi:“MI:0914”(association)	0.350
SLC7A14	TMEM120B	psi-mi:“MI:0914”(association)	0.350
CHRNB2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SIDT2	KLRG2	psi-mi:“MI:0914”(association)	0.350
MCOLN2	POTEF	psi-mi:“MI:0914”(association)	0.350
FAXC	METTL15	psi-mi:“MI:0914”(association)	0.350
SCGB2A2	RTL8C	psi-mi:“MI:0914”(association)	0.350
C1orf54	AGRN	psi-mi:“MI:0914”(association)	0.350
CD1E	ADAM10	psi-mi:“MI:0914”(association)	0.350
NRG1	CHST10	psi-mi:“MI:0914”(association)	0.350

BioGRID (49): DSE (Affinity Capture-MS), DSE (Affinity Capture-MS), DSE (Affinity Capture-MS), DSE (Affinity Capture-MS), DSE (Affinity Capture-MS), DSE (Affinity Capture-MS), DSE (Affinity Capture-MS), DSE (Affinity Capture-MS), DSE (Affinity Capture-MS), DSE (Affinity Capture-MS), DSE (Affinity Capture-MS), DSE (Affinity Capture-MS), DSE (Affinity Capture-MS), DSE (Affinity Capture-RNA), DSE (Synthetic Lethality)

ESM2 similar proteins: A0A0E0S977, A0A1U8QQU5, A2QRA0, A6NHR9, B1WB39, E9EFH8, F4JSE7, G2WS43, G2X5A0, G4N553, I1RE72, O17482, O45380, P03271, P03272, P03273, P0C2H4, P12540, P13563, P48752, P49021, P78746, Q03720, Q08460, Q12791, Q21029, Q3B8G4, Q5BKX6, Q5K2C1, Q5K2C4, Q5YLM1, Q60649, Q62976, Q6P5D8, Q6WQJ1, Q803Z2, Q8BLI4, Q8CDG3, Q8CF97, Q91YE9

Diamond homologs: P0C2H4, Q0VBN2, Q8BLI4, Q8IZU8, Q9UL01, Q80WV3, Q9Y4C5

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 51 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
adaptive immune response	6	11.8×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	6
Uncertain significance	318
Likely benign	192
Benign	23

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
2119102	NM_013352.4(DSE):c.480del (p.Ala161fs)	Pathogenic
3773661	NM_013352.4(DSE):c.874C>T (p.Gln292Ter)	Pathogenic
446171	NM_013352.4(DSE):c.799A>G (p.Arg267Gly)	Pathogenic
4807721	NM_013352.4(DSE):c.406C>T (p.Gln136Ter)	Pathogenic
4809221	NM_013352.4(DSE):c.811del (p.Gln271fs)	Pathogenic
5385	NM_003309.4(TSPYL1):c.460dup (p.Glu154fs)	Pathogenic
88848	NM_013352.4(DSE):c.803C>T (p.Ser268Leu)	Pathogenic
985873	NM_013352.4(DSE):c.387del (p.Asp128_Tyr129insTer)	Pathogenic
1690440	NM_013352.4(DSE):c.2538_2541del (p.Lys846fs)	Likely pathogenic
1708660	NM_013352.4(DSE):c.416+1G>A	Likely pathogenic
2503345	NM_013352.4(DSE):c.22dup (p.Ala8fs)	Likely pathogenic
2572748	NM_013352.4(DSE):c.2428C>T (p.Arg810Ter)	Likely pathogenic
2576809	NM_013352.4(DSE):c.2091C>G (p.Tyr697Ter)	Likely pathogenic
3592992	NM_013352.4(DSE):c.2097G>A (p.Trp699Ter)	Likely pathogenic

SpliceAI

2154 predictions. Top by Δscore:

Variant	Effect	Δscore
6:116399658:GCCTA:G	donor_gain	1.0000
6:116399663:G:GG	donor_gain	1.0000
6:116426572:AGGTT:A	acceptor_gain	1.0000
6:116426573:GGTTG:G	acceptor_gain	1.0000
6:116426682:G:GT	donor_gain	1.0000
6:116426692:G:GT	donor_gain	1.0000
6:116426714:GGTA:G	donor_gain	1.0000
6:116431028:G:T	donor_gain	1.0000
6:116431056:GAGT:G	donor_gain	1.0000
6:116431059:T:G	donor_gain	1.0000
6:116280258:A:T	donor_gain	0.9900
6:116399187:A:AG	acceptor_gain	0.9900
6:116399188:T:G	acceptor_gain	0.9900
6:116399193:C:G	acceptor_gain	0.9900
6:116399195:TA:T	acceptor_loss	0.9900
6:116399196:A:AG	acceptor_gain	0.9900
6:116399196:A:G	acceptor_loss	0.9900
6:116399196:AG:A	acceptor_gain	0.9900
6:116399197:G:GC	acceptor_gain	0.9900
6:116399197:GG:G	acceptor_gain	0.9900
6:116403265:AACAG:A	donor_gain	0.9900
6:116403266:ACAGA:A	donor_gain	0.9900
6:116426568:TTACA:T	acceptor_loss	0.9900
6:116426569:TACA:T	acceptor_loss	0.9900
6:116426571:CA:C	acceptor_loss	0.9900
6:116426572:A:AG	acceptor_gain	0.9900
6:116426572:AG:A	acceptor_gain	0.9900
6:116426573:G:GG	acceptor_gain	0.9900
6:116426573:GG:G	acceptor_gain	0.9900
6:116426573:GGTT:G	acceptor_gain	0.9900

AlphaMissense

6344 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:116399542:T:A	W98R	1.000
6:116399542:T:C	W98R	1.000
6:116399544:G:C	W98C	1.000
6:116399544:G:T	W98C	1.000
6:116399665:T:A	W139R	1.000
6:116399665:T:C	W139R	1.000
6:116426596:G:C	D147H	1.000
6:116426597:A:T	D147V	1.000
6:116426746:T:A	W197R	1.000
6:116426746:T:C	W197R	1.000
6:116426748:G:C	W197C	1.000
6:116426748:G:T	W197C	1.000
6:116426769:T:A	N204K	1.000
6:116426769:T:G	N204K	1.000
6:116426770:C:G	H205D	1.000
6:116431053:A:T	E257V	1.000
6:116431055:G:A	G258R	1.000
6:116431055:G:C	G258R	1.000
6:116431064:T:C	Y261H	1.000
6:116433370:A:T	D313V	1.000
6:116433387:T:C	F319L	1.000
6:116433389:T:A	F319L	1.000
6:116433389:T:G	F319L	1.000
6:116435816:C:G	H450D	1.000
6:116435818:T:A	H450Q	1.000
6:116435818:T:G	H450Q	1.000
6:116435996:T:A	W510R	1.000
6:116435996:T:C	W510R	1.000
6:116435998:G:C	W510C	1.000
6:116435998:G:T	W510C	1.000

dbSNP variants (sampled 300 via entrez): RS1000010164 (6:116336439 A>G), RS1000044427 (6:116254783 A>G), RS1000058852 (6:116440954 G>A), RS1000086549 (6:116283248 A>G), RS1000092094 (6:116392621 C>G), RS1000093781 (6:116423909 T>C), RS1000111339 (6:116273974 C>T), RS1000130295 (6:116347972 A>G), RS1000165523 (6:116405455 C>T), RS1000226630 (6:116371855 G>T), RS1000228776 (6:116385207 C>T), RS1000234604 (6:116353539 T>C), RS1000243923 (6:116397633 T>C), RS1000282649 (6:116329780 G>A), RS1000291670 (6:116411134 C>T)

Disease associations

OMIM: gene MIM:605942 | disease phenotypes: MIM:615539, MIM:130000, MIM:608800

GenCC curated gene-disease

Disease	Classification	Inheritance
Ehlers-Danlos syndrome, musculocontractural type 2	Definitive	Autosomal recessive
Ehlers-Danlos syndrome, musculocontractural type	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Ehlers-Danlos syndrome, musculocontractural type 2	Definitive	AR

Mondo (4): Ehlers-Danlos syndrome, musculocontractural type 2 (MONDO:0014236), Ehlers-Danlos syndrome (MONDO:0020066), sudden infant death-dysgenesis of the testes syndrome (MONDO:0012124), Ehlers-Danlos syndrome, musculocontractural type (MONDO:0011142)

Orphanet (3): Musculocontractural Ehlers-Danlos syndrome (Orphanet:2953), Ehlers-Danlos syndrome (Orphanet:98249), Sudden infant death-dysgenesis of the testes syndrome (Orphanet:168593)

HPO phenotypes

88 total (30 of 88 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000009	Functional abnormality of the bladder
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000085	Horseshoe kidney
HP:0000126	Hydronephrosis
HP:0000160	Narrow mouth
HP:0000175	Cleft palate
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000239	Large fontanelles
HP:0000248	Brachycephaly
HP:0000297	Facial hypotonia
HP:0000308	Microretrognathia
HP:0000316	Hypertelorism
HP:0000343	Long philtrum
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000377	Abnormal pinna morphology
HP:0000400	Macrotia
HP:0000411	Protruding ear
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000501	Glaucoma
HP:0000506	Telecanthus
HP:0000541	Retinal detachment
HP:0000545	Myopia
HP:0000592	Blue sclerae
HP:0000678	Dental crowding

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST002579_31	Heschl’s gyrus morphology	5.000000e-06
GCST003902_3	Fast beta electroencephalogram	3.000000e-08
GCST008163_51	Height	5.000000e-06
GCST010002_333	Refractive error	2.000000e-36
GCST011096_34	Systemic lupus erythematosus	6.000000e-06
GCST011956_21	Systemic lupus erythematosus	1.000000e-08
GCST012227_81	Hip circumference adjusted for BMI	1.000000e-09
GCST90002395_485	Mean platelet volume	8.000000e-13
GCST90002402_704	Platelet count	2.000000e-14
GCST90011866_14	Systemic lupus erythematosus	3.000000e-08
GCST90020028_541	Hip circumference adjusted for BMI	3.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004357	electroencephalogram measurement
EFO:0007835	alcohol dependence measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0004309	platelet count

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
C000600608	Ehlers-Danlos Syndrome, musculocontractural type 1 (supp.)
C563856	Sudden Infant Death with Dysgenesis of the Testes Syndrome (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
rs3828743	Efficacy	3	abiraterone;prednisolone	Prostatic Neoplasms

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3828743	DSE, TSPYL1	3	4.50	1	abiraterone;prednisolone

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases expression, affects expression	5
Aflatoxin B1	affects expression, decreases methylation, increases expression	3
Acetaminophen	increases expression	2
Cisplatin	increases expression	2
Valproic Acid	affects expression, increases expression	2
aristolochic acid I	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
sodium arsenite	decreases expression	1
doxifluridine	decreases response to substance	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
nickel sulfate	decreases expression	1
1-UFT protocol	decreases response to substance	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
perfluorooctane sulfonic acid	decreases expression	1
S 1 (combination)	decreases response to substance	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
bisphenol S	decreases methylation	1
Capecitabine	decreases response to substance	1
Zoledronic Acid	increases expression	1
Carbamazepine	affects expression	1
Copper	affects binding, increases expression	1
Diethylhexyl Phthalate	increases abundance, increases methylation	1
Dinitrochlorobenzene	decreases expression	1
Disulfiram	affects binding, increases expression	1
Estradiol	affects expression	1
Formaldehyde	increases expression	1
Oxazolone	decreases expression	1

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