ECEL1

Summary

ECEL1 (endothelin converting enzyme like 1, HGNC:3147) is a protein-coding gene on chromosome 2q37.1, encoding Endothelin-converting enzyme-like 1 (O95672). May contribute to the degradation of peptide hormones and be involved in the inactivation of neuronal peptides.

This gene encodes a member of the M13 family of endopeptidases. Members of this family are zinc-containing type II integral-membrane proteins that are important regulators of neuropeptide and peptide hormone activity. Mutations in this gene are associated with autosomal recessive distal arthrogryposis, type 5D. This gene has multiple pseudogenes on chromosome 2. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 9427 — RefSeq curated summary.

At a glance

• Gene–disease (curated): distal arthrogryposis type 5D (Definitive, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 298 total — 32 pathogenic, 30 likely-pathogenic
• Phenotypes (HPO): 30
• MANE Select transcript: NM_004826

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3147
Approved symbol	ECEL1
Name	endothelin converting enzyme like 1
Location	2q37.1
Locus type	gene with protein product
Status	Approved
Aliases	XCE, DINE
Ensembl gene	ENSG00000171551
Ensembl biotype	protein_coding
OMIM	605896
Entrez	9427

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 10 protein_coding, 1 retained_intron

ENST00000304546, ENST00000409941, ENST00000411860, ENST00000482346, ENST00000862796, ENST00000931991, ENST00000931992, ENST00000931993, ENST00000931994, ENST00000931995, ENST00000950077

RefSeq mRNA: 2 — MANE Select: NM_004826 NM_001290787, NM_004826

CCDS: CCDS2493, CCDS77540

Canonical transcript exons

ENST00000304546 — 18 exons

Exon	Start	End
ENSE00001145892	232484981	232485091
ENSE00001145909	232487719	232487834
ENSE00002477688	232485199	232485267
ENSE00003465775	232484001	232484223
ENSE00003480311	232485868	232486754
ENSE00003486526	232481506	232481630
ENSE00003552625	232482418	232482469
ENSE00003578625	232481782	232481849
ENSE00003591519	232482550	232482608
ENSE00003608458	232480399	232480475
ENSE00003612032	232479827	232480252
ENSE00003612482	232484801	232484893
ENSE00003624697	232482851	232482954
ENSE00003655857	232481091	232481156
ENSE00003669974	232483416	232483514
ENSE00003683536	232480718	232480813
ENSE00003684923	232483105	232483179
ENSE00003686488	232484472	232484596

Expression profiles

Bgee: expression breadth ubiquitous, 152 present calls, max score 94.02.

FANTOM5 (CAGE): breadth broad, TPM avg 0.6981 / max 194.7437, expressed in 227 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
34560	0.4944	159
34561	0.0857	31
34559	0.0804	30
34562	0.0376	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ovary	UBERON:0002119	94.02	gold quality
right ovary	UBERON:0002118	90.71	gold quality
adenohypophysis	UBERON:0002196	86.85	gold quality
hypothalamus	UBERON:0001898	85.87	gold quality
ovary	UBERON:0000992	85.86	gold quality
pituitary gland	UBERON:0000007	84.34	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.92	gold quality
right adrenal gland cortex	UBERON:0035827	80.50	gold quality
type B pancreatic cell	CL:0000169	78.55	gold quality
right adrenal gland	UBERON:0001233	78.55	gold quality
olfactory bulb	UBERON:0002264	77.46	gold quality
putamen	UBERON:0001874	75.14	gold quality
hair follicle	UBERON:0002073	75.07	gold quality
adrenal cortex	UBERON:0001235	75.04	gold quality
left adrenal gland	UBERON:0001234	74.98	gold quality
left adrenal gland cortex	UBERON:0035825	74.97	gold quality
diaphragm	UBERON:0001103	74.50	gold quality
caudate nucleus	UBERON:0001873	74.02	gold quality
gluteal muscle	UBERON:0002000	73.82	gold quality
islet of Langerhans	UBERON:0000006	73.74	gold quality
adrenal gland	UBERON:0002369	73.36	gold quality
triceps brachii	UBERON:0001509	73.15	gold quality
left uterine tube	UBERON:0001303	71.53	gold quality
secondary oocyte	CL:0000655	68.95	gold quality
nucleus accumbens	UBERON:0001882	67.63	gold quality
vastus lateralis	UBERON:0001379	67.31	gold quality
epithelial cell of pancreas	CL:0000083	67.01	gold quality
quadriceps femoris	UBERON:0001377	66.97	gold quality
endothelial cell	CL:0000115	66.01	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	65.92	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-9154	yes	967.25
E-MTAB-7303	no	1251.18
E-ANND-3	no	1.28

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF3, JUN, SP1, STAT3

miRNA regulators (miRDB)

16 targeting ECEL1, 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-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-7854-3P	99.08	66.26	1117
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-4763-5P	98.75	63.89	854
HSA-MIR-423-5P	98.69	67.48	1522
HSA-MIR-4700-5P	98.63	67.43	1915
HSA-MIR-3184-5P	98.56	67.13	1491
HSA-MIR-3144-5P	97.64	65.45	646
HSA-MIR-6858-3P	96.37	64.41	771

Literature-anchored findings (GeneRIF, showing 10)

• Sp1 recruits ATF3, c-Jun, and STAT3 to obtain the requisite synergistic effect in neuronal injury through DINE neuronal injury-inducible gene (PMID:18192274)
• We described a new and homogenous phenotype of DA associated with ECEL1 that resulted in symptoms involving rather the peripheral than the central nervous system and suggesting a developmental dysfunction (PMID:23236030)
• Mutations in ECEL1 cause distal arthrogryposis type 5D. (PMID:23261301)
• A novel missense c.1819G>A mutation (G607S) in the ECEL1 gene has been identified in a consanguineous pedigree of Turkish origin presenting with congenital contracture syndromes. (PMID:23808592)
• Three novel ECEL1 mutations have been identified in consanguineous pedigrees of Saudi Arabian origin presenting with distal arthrogryposis type 5D. (PMID:23829171)
• Our clinical findings are consistent with recessive ECEL1 mutations causing variably penetrant orbital dysinnervation phenotypes (ptosis and/or complex strabismus with abnormal synkinesis) (PMID:25173900)
• Mutation of a conserved residue in ECEL1 is linked with fetal arthrogryposis multiplex congenita. (PMID:25708584)
• A novel ECEL1 homozygote mutation in the patient with distal arthrogryposis multiplex congenita type 5D to include pretibial vertical skin creases. (PMID:29663639)
• Distal arthrogryposis type 5D in a South Indian family caused by novel deletion in ECEL1 gene. (PMID:33491998)
• ECEL1 related distal arthrogryposis 5D in an Indian cohort-Report of recognizable musculoskeletal phenotype and a possible founder variant. (PMID:38568023)

Cross-species orthologs

25 orthologs

Organism	Symbol	Gene ID
danio_rerio	ecel1	ENSDARG00000060549
mus_musculus	Ecel1	ENSMUSG00000026247
rattus_norvegicus	Ecel1	ENSRNOG00000019447
drosophila_melanogaster	Nepl21	FBGN0027578
drosophila_melanogaster	Nep3	FBGN0031081
drosophila_melanogaster	Nepl3	FBGN0031678
drosophila_melanogaster	Nepl12	FBGN0037727
drosophila_melanogaster	Nep4	FBGN0038818
drosophila_melanogaster	Nepl15	FBGN0039024
drosophila_melanogaster	Nep7	FBGN0039564
drosophila_melanogaster	Nepl18	FBGN0039611
drosophila_melanogaster	Nepl19	FBGN0039612
drosophila_melanogaster	Nepl20	FBGN0039613
caenorhabditis_elegans		WBGENE00013785
caenorhabditis_elegans		WBGENE00013786
caenorhabditis_elegans		WBGENE00013926
caenorhabditis_elegans		WBGENE00016778
caenorhabditis_elegans		WBGENE00016896
caenorhabditis_elegans		WBGENE00017550
caenorhabditis_elegans		WBGENE00017553
caenorhabditis_elegans		WBGENE00017554
caenorhabditis_elegans		WBGENE00017555
caenorhabditis_elegans		WBGENE00018196
caenorhabditis_elegans		WBGENE00018227
caenorhabditis_elegans		WBGENE00020293

Paralogs (6): PHEX (ENSG00000102174), ECE1 (ENSG00000117298), MMEL1 (ENSG00000142606), ECE2 (ENSG00000145194), MME (ENSG00000196549), KEL (ENSG00000197993)

Protein

Protein identifiers

Endothelin-converting enzyme-like 1 — O95672 (reviewed: O95672)

Alternative names: Xce protein

All UniProt accessions (3): O95672, A0A6F7YIA8, H7C3M0

UniProt curated annotations — full annotation on UniProt →

Function. May contribute to the degradation of peptide hormones and be involved in the inactivation of neuronal peptides.

Subcellular location. Membrane.

Tissue specificity. Highly expressed in the CNS, in particular in putamen, spinal cord, medulla and subthalamic nucleus. A strong signal was also detected in uterine subepithelial cells and around renal blood vessels. Detected at lower levels in amygdala, caudate, thalamus, pancreas and skeletal muscle. Detected at very low levels in substantia nigra, cerebellum, cortex, corpus callosum and hippocampus.

Post-translational modifications. N-glycosylated.

Disease relevance. Arthrogryposis, distal, 5D (DA5D) [MIM:615065] An autosomal recessive form of distal arthrogryposis, a disease characterized by congenital joint contractures that mainly involve two or more distal parts of the limbs, in the absence of a primary neurological or muscle disease. DA5D is characterized by severe camptodactyly of the hands, mild camptodactyly of the toes, clubfoot and/or a calcaneovalgus deformity, extension contractures of the knee, unilateral ptosis or ptosis that is more severe on one side, a round-shaped face, arched eyebrows, a bulbous upturned nose, and micrognathia. Patients do not have ophthalmoplegia. The disease is caused by variants affecting the gene represented in this entry. ECEL1 mutations have also been found in patients with arthrogryposis, significant ophthalmoplegia, and refractive errors.

Cofactor. Binds 1 zinc ion.

Similarity. Belongs to the peptidase M13 family.

Isoforms (2)

UniProt ID	Names	Canonical?
O95672-1	1	yes
O95672-2	2

RefSeq proteins (2): NP_001277716, NP_004817* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000718	Peptidase_M13	Family
IPR008753	Peptidase_M13_N	Domain
IPR018497	Peptidase_M13_C	Domain
IPR024079	MetalloPept_cat_dom_sf	Homologous_superfamily
IPR042089	Peptidase_M13_dom_2	Homologous_superfamily

Pfam: PF01431, PF05649

UniProt features (34 total): sequence conflict 10, sequence variant 6, disulfide bond 4, glycosylation site 3, binding site 3, topological domain 2, active site 2, chain 1, splice variant 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95672-F1	88.62	0.77

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 (2): 613; 676 (proton donor)

Ligand- & substrate-binding residues (3): 612; 616; 672

Disulfide bonds (4): 123–760, 131–720, 187–441, 649–772

Glycosylation sites (3): 255, 322, 656

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 176 (showing top): GOBP_RESPIRATORY_GASEOUS_EXCHANGE_BY_RESPIRATORY_SYSTEM, BENPORATH_ES_WITH_H3K27ME3, GOMF_METALLOPEPTIDASE_ACTIVITY, GOBP_RESPIRATORY_SYSTEM_PROCESS, MODULE_331, IRF7_01, GOBP_PROTEIN_MATURATION, MODULE_289, AFP1_Q6, YY1_01, MODULE_207, TTCNRGNNNNTTC_HSF_Q6, TGGAAA_NFAT_Q4_01, SPZ1_01, GOBP_PROTEOLYSIS

GO Biological Process (4): respiratory system process (GO:0003016), neuropeptide signaling pathway (GO:0007218), protein processing (GO:0016485), proteolysis (GO:0006508)

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

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
system process	1
respiratory gaseous exchange by respiratory system	1
G protein-coupled receptor signaling pathway	1
proteolysis	1
protein maturation	1
protein metabolic process	1
endopeptidase activity	1
metallopeptidase activity	1
peptidase activity	1
cation binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1018 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ECEL1	CHRND	Q07001	616
ECEL1	RPS12	P25398	548
ECEL1	PIEZO2	Q9H5I5	503
ECEL1	EED	O75530	463
ECEL1	CHRNG	P07510	455
ECEL1	EIF4E2	O60573	444
ECEL1	CTCF	P49711	440
ECEL1	NANOG	Q9H9S0	438
ECEL1	DICER1	Q9UPY3	431
ECEL1	BRCC3	P46736	428
ECEL1	F8	P00451	427
ECEL1	PHKA1	P46020	427
ECEL1	YY1	P25490	425
ECEL1	PGK1	P00558	425
ECEL1	TNNI2	P48788	423

IntAct

32 interactions, top by confidence:

A	B	Type	Score
BTNL3	FAM171A2	psi-mi:“MI:0914”(association)	0.530
CD1B	TOR1B	psi-mi:“MI:0914”(association)	0.530
CLGN	NPC1	psi-mi:“MI:0914”(association)	0.530
ECEL1	CANX	psi-mi:“MI:0914”(association)	0.530
ECEL1	CLGN	psi-mi:“MI:0914”(association)	0.530
ECEL1	OCIAD2	psi-mi:“MI:0915”(physical association)	0.400
Npc1	ESYT2	psi-mi:“MI:0914”(association)	0.350
CACNA1C	CACNB4	psi-mi:“MI:0914”(association)	0.350
CACNA1C	DISP2	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
HLA-DRA	TMEM223	psi-mi:“MI:0914”(association)	0.350
TLR10	TMEM223	psi-mi:“MI:0914”(association)	0.350
HLA-DQA1	TMEM223	psi-mi:“MI:0914”(association)	0.350
LDLRAD1	GXYLT2	psi-mi:“MI:0914”(association)	0.350
CLEC12B	GXYLT2	psi-mi:“MI:0914”(association)	0.350
CLEC2D	TMEM120B	psi-mi:“MI:0914”(association)	0.350
ZDHHC12	NBAS	psi-mi:“MI:0914”(association)	0.350
MPPE1	FAM234B	psi-mi:“MI:0914”(association)	0.350
SCGB2A1	RAP1BL	psi-mi:“MI:0914”(association)	0.350
RLN1	RTL8C	psi-mi:“MI:0914”(association)	0.350
SCGB2A2	RTL8C	psi-mi:“MI:0914”(association)	0.350
CEACAM8	PRRT4	psi-mi:“MI:0914”(association)	0.350
GPIHBP1	SAC3D1	psi-mi:“MI:0914”(association)	0.350
HFE	PODXL	psi-mi:“MI:0914”(association)	0.350
SPX	ERI3	psi-mi:“MI:0914”(association)	0.350
CD1A	EXTL3	psi-mi:“MI:0914”(association)	0.350
ECEL1	DNAJB6	psi-mi:“MI:0914”(association)	0.350
TSPAN16	ENDOD1	psi-mi:“MI:0914”(association)	0.350
HLA-E	ECEL1	psi-mi:“MI:0914”(association)	0.350
RNASE4	ECEL1	psi-mi:“MI:0914”(association)	0.350

BioGRID (144): ECEL1 (Affinity Capture-MS), ECEL1 (Affinity Capture-MS), ECEL1 (Affinity Capture-MS), ECEL1 (Affinity Capture-MS), ECEL1 (Affinity Capture-MS), ECEL1 (Affinity Capture-MS), ECEL1 (Affinity Capture-MS), ECEL1 (Affinity Capture-MS), ECEL1 (Affinity Capture-MS), ECEL1 (Affinity Capture-MS), OCIAD2 (Proximity Label-MS), ECEL1 (Affinity Capture-MS), ECEL1 (Positive Genetic), ECEL1 (Affinity Capture-MS), ECEL1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0B4K692, A5HUI5, B2RQR8, D3UW23, F1N476, O16796, O44857, O95672, P07861, P08049, P08473, P0C1T0, P0DPD6, P0DPD9, P15144, P15145, P15684, P16406, P42891, P42892, P42893, P50123, P97739, Q07075, Q10715, Q10751, Q18673, Q22523, Q32LQ0, Q495T6, Q4PZA2, Q56H28, Q56NL1, Q58DD0, Q5EGZ1, Q5RE69, Q5RFN1, Q61391, Q6Q4G4, Q8IS64

Diamond homologs: A0A0B4K692, B2RQR8, F1N476, O16796, O44857, O95672, P07861, P08049, P08473, P0C1T0, P0DPD6, P0DPD8, P0DPD9, P0DPE2, P42891, P42892, P42893, P70669, P78562, P97739, Q18673, Q22523, Q495T6, Q4PZA2, Q5RE69, Q61391, Q8IS64, Q8T062, Q9JHL3, Q9JLI3, Q9JMI0, Q9W436, Q9W5Y0, W4VS99, P23276, Q9EQF2, P19621, A5PK19, A5WVX1, P0DPD7

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 49 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	5	10.3×	7e-03
immune response	7	8.0×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	32
Likely pathogenic	30
Uncertain significance	131
Likely benign	46
Benign	31

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
100650	NM_004826.4(ECEL1):c.2278T>C (p.Cys760Arg)	Pathogenic
100651	NM_004826.4(ECEL1):c.1649C>G (p.Ser550Ter)	Pathogenic
100652	NM_004826.4(ECEL1):c.1685+1G>T	Pathogenic
1048794	NM_004826.4(ECEL1):c.2151+1G>T	Pathogenic
1254652	NM_004826.4(ECEL1):c.1185-2A>G	Pathogenic
1300733	NM_004826.4(ECEL1):c.1802_1803del (p.Leu601fs)	Pathogenic
161451	NM_004826.4(ECEL1):c.2023G>A (p.Ala675Thr)	Pathogenic
1706601	NM_004826.4(ECEL1):c.1672del (p.Val558fs)	Pathogenic
1803196	NM_004826.4(ECEL1):c.2069G>A (p.Trp690Ter)	Pathogenic
210910	NM_004826.4(ECEL1):c.997C>T (p.Arg333Ter)	Pathogenic
242402	NM_004826.4(ECEL1):c.797_801delinsGCT (p.Asp266fs)	Pathogenic
242403	NM_004826.4(ECEL1):c.869A>G (p.Tyr290Cys)	Pathogenic
2444189	NM_004826.4(ECEL1):c.1042del (p.Gln348fs)	Pathogenic
2506362	NM_004826.4(ECEL1):c.1059+1G>A	Pathogenic
2506368	NM_004826.4(ECEL1):c.1685+1G>A	Pathogenic
2572395	NM_004826.4(ECEL1):c.1702C>T (p.Gln568Ter)	Pathogenic
3340907	NM_004826.4(ECEL1):c.69C>A (p.Cys23Ter)	Pathogenic
373060	NM_004826.4(ECEL1):c.4G>T (p.Glu2Ter)	Pathogenic
374305	NM_004826.4(ECEL1):c.1470G>A (p.Trp490Ter)	Pathogenic
3770938	NM_004826.4(ECEL1):c.966+1G>A	Pathogenic
3772465	NM_004826.4(ECEL1):c.1469G>A (p.Trp490Ter)	Pathogenic
39488	NM_004826.4(ECEL1):c.716dup (p.Tyr239Ter)	Pathogenic
39489	NM_004826.4(ECEL1):c.344_355del (p.Asn115_Ala118del)	Pathogenic
39490	NM_004826.4(ECEL1):c.1252C>A (p.Arg418Ser)	Pathogenic
39491	NM_004826.4(ECEL1):c.1184+3A>T	Pathogenic
435023	NM_004826.4(ECEL1):c.509del (p.Gly170fs)	Pathogenic
435024	NM_004826.4(ECEL1):c.110_155del (p.Phe37fs)	Pathogenic
488495	NM_004826.4(ECEL1):c.2151+2T>A	Pathogenic
816799	NM_004826.4(ECEL1):c.505_529del (p.Gly169fs)	Pathogenic
816827	NM_004826.4(ECEL1):c.1147C>T (p.Gln383Ter)	Pathogenic

SpliceAI

2554 predictions. Top by Δscore:

Variant	Effect	Δscore
2:232480483:C:CT	acceptor_gain	1.0000
2:232480483:C:T	acceptor_gain	1.0000
2:232480484:A:T	acceptor_gain	1.0000
2:232480489:C:CT	acceptor_gain	1.0000
2:232480490:G:T	acceptor_gain	1.0000
2:232480493:G:C	acceptor_gain	1.0000
2:232480493:G:GC	acceptor_gain	1.0000
2:232481021:C:A	donor_gain	1.0000
2:232481027:T:C	donor_gain	1.0000
2:232481051:C:A	donor_gain	1.0000
2:232481054:T:TA	donor_gain	1.0000
2:232481089:A:AC	donor_gain	1.0000
2:232481090:C:CC	donor_gain	1.0000
2:232481502:TCA:T	donor_loss	1.0000
2:232481503:CA:C	donor_loss	1.0000
2:232481504:A:AC	donor_gain	1.0000
2:232481504:AC:A	donor_gain	1.0000
2:232481505:C:CA	donor_loss	1.0000
2:232481505:C:CC	donor_gain	1.0000
2:232481505:CC:C	donor_gain	1.0000
2:232481505:CCCG:C	donor_gain	1.0000
2:232481626:GCCCC:G	acceptor_gain	1.0000
2:232481627:CCCC:C	acceptor_gain	1.0000
2:232481627:CCCCC:C	acceptor_gain	1.0000
2:232481628:CCC:C	acceptor_gain	1.0000
2:232481628:CCCC:C	acceptor_gain	1.0000
2:232481629:CC:C	acceptor_gain	1.0000
2:232481629:CCC:C	acceptor_gain	1.0000
2:232481630:CC:C	acceptor_gain	1.0000
2:232481631:C:CC	acceptor_gain	1.0000

AlphaMissense

5035 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:232480399:C:A	R743M	1.000
2:232482451:A:G	L588P	1.000
2:232484038:A:C	F457C	1.000
2:232486262:C:T	C131Y	1.000
2:232480399:C:G	R743T	0.999
2:232480418:G:C	H737D	0.999
2:232480467:G:C	C720W	0.999
2:232480468:C:G	C720S	0.999
2:232480468:C:T	C720Y	0.999
2:232480469:A:G	C720R	0.999
2:232480469:A:T	C720S	0.999
2:232480722:G:T	A716D	0.999
2:232481120:C:G	D676H	0.999
2:232481127:G:C	N673K	0.999
2:232481127:G:T	N673K	0.999
2:232481131:T:A	E672V	0.999
2:232481609:C:A	G629V	0.999
2:232481609:C:T	G629E	0.999
2:232481610:C:A	G629W	0.999
2:232481800:G:C	H616D	0.999
2:232481805:A:G	L614P	0.999
2:232481807:C:A	E613D	0.999
2:232481807:C:G	E613D	0.999
2:232481808:T:A	E613V	0.999
2:232481810:A:C	H612Q	0.999
2:232481810:A:T	H612Q	0.999
2:232481811:T:G	H612P	0.999
2:232481812:G:C	H612D	0.999
2:232481814:C:T	G611E	0.999
2:232481826:C:T	G607D	0.999

dbSNP variants (sampled 300 via entrez): RS1000027670 (2:232483232 C>A,G,T), RS1000028912 (2:232486750 C>G), RS1000051849 (2:232480453 G>A), RS1000161339 (2:232485706 C>A,T), RS1000277741 (2:232481975 G>A,C,T), RS1001540722 (2:232480915 G>A), RS1001880234 (2:232487341 C>T), RS1001955124 (2:232484593 G>A), RS1002141270 (2:232484816 C>G,T), RS1002271287 (2:232479961 C>G,T), RS1002947300 (2:232488153 G>A), RS1002947573 (2:232481976 T>C), RS1003273014 (2:232479717 G>A), RS1003379745 (2:232484327 C>T), RS1003630017 (2:232480010 G>A)

Disease associations

OMIM: gene MIM:605896 | disease phenotypes: MIM:615065, MIM:108120, MIM:617468

GenCC curated gene-disease

Disease	Classification	Inheritance
distal arthrogryposis type 5D	Definitive	Autosomal recessive

Mondo (4): distal arthrogryposis type 5D (MONDO:0014028), arthrogryposis (MONDO:0008779), distal arthrogryposis (MONDO:0019942), arthrogryposis multiplex congenita (MONDO:0015168)

Orphanet (3): Distal arthrogryposis type 5D (Orphanet:329457), Distal arthrogryposis (Orphanet:97120), Arthrogryposis multiplex congenita (Orphanet:1037)

HPO phenotypes

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

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000059	Hypoplastic labia majora
HP:0000160	Narrow mouth
HP:0000175	Cleft palate
HP:0000194	Open mouth
HP:0000221	Furrowed tongue
HP:0000311	Round face
HP:0000347	Micrognathia
HP:0000414	Bulbous nose
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000508	Ptosis
HP:0001181	Adducted thumb
HP:0001374	Congenital hip dislocation
HP:0001762	Talipes equinovarus
HP:0001848	Calcaneovalgus deformity
HP:0002553	Highly arched eyebrow
HP:0002650	Scoliosis
HP:0002987	Elbow flexion contracture
HP:0002996	Limited elbow movement
HP:0003199	Decreased muscle mass
HP:0003307	Hyperlordosis
HP:0003577	Congenital onset
HP:0004322	Short stature
HP:0006201	Hypermobility of distal interphalangeal joints
HP:0006389	Limited knee flexion
HP:0006467	Limited shoulder movement
HP:0012385	Camptodactyly
HP:0012473	Tongue atrophy
HP:0030001	Lagophthalmos

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010002_411	Refractive error	1.000000e-123

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D001176	Arthrogryposis	C05.550.150; C05.651.102; C05.660.077; C16.131.621.077

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases methylation	2
arsenite	increases methylation	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Diethylhexyl Phthalate	decreases expression	1
Folic Acid	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Rotenone	increases expression	1
Silicon Dioxide	decreases expression	1
Tretinoin	increases expression	1
1-Methyl-4-phenylpyridinium	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01028833	PHASE2	COMPLETED	Effects of Power Mobility on Young Children With Severe Motor Impairments
NCT01144741	Not specified	TERMINATED	Survey Study and Records Review of Treatment Outcomes in Freeman-Sheldon Syndrome
NCT01306994	Not specified	WITHDRAWN	Study of Resting and Exercising Body Functioning in Freeman-Sheldon Syndrome and Related Conditions
NCT01307475	Not specified	TERMINATED	Study of Quality of Life in Freeman-Sheldon Syndrome and Related Conditions
NCT02218593	Not specified	COMPLETED	WREX Outcome Study
NCT04789746	Not specified	UNKNOWN	Ready, Set, Go! A Physical Fitness Intervention for Children With Mobility Challenges
NCT04798378	Not specified	ACTIVE_NOT_RECRUITING	NuroSleeve Powered Brace & Stimulation System to Restore Arm Function
NCT06192134	Not specified	NOT_YET_RECRUITING	Continuous Passive Motion Device for Children With Arthrogryposis
NCT07429188	Not specified	RECRUITING	Impact Study on Users of Upper Limb Assistive Devices
NCT05137756	Not specified	COMPLETED	Mercuri Analysis Contribution on Handicap Evaluation in ArthrogypOsis, a Congenital Neuromuscular Disease
NCT05393375	Not specified	COMPLETED	Arthrogryposis Multiplex Congenita in Pediatric Age: Correlation Between MUScular MRI and Functional Evaluation
NCT05673265	Not specified	UNKNOWN	Pediatric and Adult Registry for Patients With ARThrogryposis
NCT06130592	Not specified	UNKNOWN	Technical Feasibility Study of Ultrasound Muscle Imaging in Antenatal Ultrasound
NCT07360574	Not specified	NOT_YET_RECRUITING	Piezo2-related Arthrogryposis & physiopathOLOgy 3