COL25A1

Summary

COL25A1 (collagen type XXV alpha 1 chain, HGNC:18603) is a protein-coding gene on chromosome 4q25, encoding Collagen alpha-1(XXV) chain (Q9BXS0). Inhibits fibrillization of amyloid-beta peptide during the elongation phase.

This gene encodes a brain-specific membrane associated collagen. A product of proteolytic processing of the encoded protein, CLAC (collagenous Alzheimer amyloid plaque component), binds to amyloid beta-peptides found in Alzheimer amyloid plaques but CLAC inhibits rather than facilitates amyloid fibril elongation (PMID: 16300410). A study of over-expression of this collagen in mice, however, found changes in pathology and behavior suggesting that the encoded protein may promote amyloid plaque formation (PMID: 19548013). Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 84570 — RefSeq curated summary.

At a glance

• Gene–disease (curated): fibrosis of extraocular muscles, congenital, 5 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 7
• Clinical variants (ClinVar): 165 total — 5 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 71
• MANE Select transcript: NM_198721

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18603
Approved symbol	COL25A1
Name	collagen type XXV alpha 1 chain
Location	4q25
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000188517
Ensembl biotype	protein_coding
OMIM	610004
Entrez	84570

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 6 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000399126, ENST00000399127, ENST00000399132, ENST00000494183, ENST00000505377, ENST00000505591, ENST00000512961, ENST00000642955

RefSeq mRNA: 3 — MANE Select: NM_198721 NM_001256074, NM_032518, NM_198721

CCDS: CCDS43258, CCDS43259, CCDS58922

Canonical transcript exons

ENST00000399132 — 38 exons

Exon	Start	End
ENSE00001290995	109300583	109300652
ENSE00001365339	108848759	108848803
ENSE00001366043	108852902	108852925
ENSE00001367061	108852236	108852280
ENSE00001368366	108889701	108889733
ENSE00001370641	108896667	108896711
ENSE00001371185	108884178	108884222
ENSE00001374581	108889221	108889256
ENSE00001375017	108869088	108869150
ENSE00001377473	108860927	108860971
ENSE00001381018	108862501	108862545
ENSE00001382094	108863319	108863387
ENSE00001382622	108859656	108859733
ENSE00001388170	108918172	108918216
ENSE00001388595	108901119	108901172
ENSE00001401402	108974533	108974559
ENSE00001407871	108846139	108846219
ENSE00001408991	108941366	108941437
ENSE00001409928	108819252	108819329
ENSE00001413010	108974367	108974393
ENSE00001420488	108937808	108937843
ENSE00001421511	108899154	108899180
ENSE00001424638	108940539	108940646
ENSE00001430390	109050135	109050179
ENSE00001432904	108920578	108920604
ENSE00002170772	109301723	109302075
ENSE00002495149	109048168	109048175
ENSE00002501574	109010358	109010375
ENSE00003527730	108832380	108832433
ENSE00003559382	108827135	108827188
ENSE00003598741	108817397	108817435
ENSE00003626277	108825196	108825222
ENSE00003628633	108841695	108841721
ENSE00003659602	108844519	108844569
ENSE00003667429	108845189	108845251
ENSE00003689459	108824174	108824227
ENSE00003816979	108808725	108813929
ENSE00003841651	109302169	109302658

Expression profiles

Bgee: expression breadth ubiquitous, 163 present calls, max score 88.58.

FANTOM5 (CAGE): breadth broad, TPM avg 1.7954 / max 353.5949, expressed in 471 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
53596	1.4120	378
53597	0.3783	225
53595	0.0052	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	88.58	gold quality
left testis	UBERON:0004533	84.55	gold quality
right testis	UBERON:0004534	84.41	gold quality
jejunal mucosa	UBERON:0000399	83.78	gold quality
testis	UBERON:0000473	81.81	gold quality
buccal mucosa cell	CL:0002336	81.66	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.20	gold quality
pancreatic ductal cell	CL:0002079	76.83	silver quality
omental fat pad	UBERON:0010414	76.50	gold quality
peritoneum	UBERON:0002358	76.40	gold quality
cortical plate	UBERON:0005343	76.33	gold quality
adipose tissue of abdominal region	UBERON:0007808	74.62	gold quality
calcaneal tendon	UBERON:0003701	74.32	gold quality
subcutaneous adipose tissue	UBERON:0002190	74.21	gold quality
adenohypophysis	UBERON:0002196	73.77	gold quality
metanephros cortex	UBERON:0010533	73.36	gold quality
sural nerve	UBERON:0015488	72.89	gold quality
ileal mucosa	UBERON:0000331	70.84	gold quality
left lobe of thyroid gland	UBERON:0001120	69.61	gold quality
right lobe of thyroid gland	UBERON:0001119	69.24	gold quality
thyroid gland	UBERON:0002046	68.69	gold quality
gall bladder	UBERON:0002110	68.22	gold quality
ventricular zone	UBERON:0003053	67.84	gold quality
adipose tissue	UBERON:0001013	67.81	gold quality
cartilage tissue	UBERON:0002418	67.23	silver quality
pituitary gland	UBERON:0000007	66.50	gold quality
hypothalamus	UBERON:0001898	65.93	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	64.82	gold quality
adrenal tissue	UBERON:0018303	64.57	gold quality
jejunum	UBERON:0002115	64.35	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	16.60
E-ANND-3	yes	7.75
E-MTAB-7303	no	140.14

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

31 targeting COL25A1, 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-4692	100.00	67.32	2066
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-548G-3P	99.48	68.67	2159
HSA-MIR-12131	99.48	68.72	1673
HSA-MIR-145-3P	99.33	67.66	764
HSA-MIR-4711-5P	98.89	68.00	965
HSA-MIR-501-5P	98.77	68.88	1328
HSA-MIR-4755-3P	98.77	65.59	1915
HSA-MIR-500A-5P	98.76	69.13	1241
HSA-MIR-1183	98.75	67.10	1116
HSA-MIR-4299	98.28	66.96	850
HSA-MIR-7111-3P	97.80	66.75	1467
HSA-MIR-4723-3P	97.67	65.91	1017
HSA-MIR-938	97.41	68.28	656
HSA-MIR-6769B-3P	97.41	65.53	1036
HSA-MIR-3183	97.40	65.68	978
HSA-MIR-3137	97.26	66.78	761

Literature-anchored findings (GeneRIF, showing 13)

• CLAC displays features characteristic of a collagen protein, ie. it forms a partly protease-resistant triple-helical structure, exhibits an intermediate affinity for heparin, and is glycosylated; binding domain between CLAC and amyloid beta-peptide (PMID:15522881)
• CLACbinds to amyloid beta peptides through the positively charged amino acid cluster within the collagenous domain 1 and inhibits formation of amyloid fibrils (PMID:15615705)
• Results show that collagenous Alzheimer amyloid plaque component (CLAC) assembles amyloid-beta fibrils into fibril bundles that have an increased resistance to proteases. (PMID:15853808)
• suggest that CLAC becomes involved at an intermediate stage in the pathogenesis of Alzheimer’s disease by binding to Abeta fibrils, including fibrils formed from peptides with truncated N- or C-termini, and thereby slows their growth (PMID:16300410)
• provides genetic evidence of association between COL25A1 and risk for Alzheimer’s disease (PMID:18501477)
• COL25A1 leads to Alzheimer’s disease-like pathology in vivo (PMID:19548013)
• The next best locus for gene x gender interactions for age at onset was in COL25A1 gene at 4q25 (PMID:21688384)
• The COL25A1 single nucleotide polymorphism rs13134663 was significantly associated with antisocial personality disorder, especially in subjects with comorbid substance dependence. (PMID:22297151)
• COL25A1 methylation correlates with severity of cervical intraepithelial neoplasia (PMID:23018867)
• We identified COL25A1 mutations as a cause of autosomal-recessive congenital cranial dysinnervation disorder. (PMID:25500261)
• We highlight phenotypes of the 4 affected children from the 2 reported families: isolated congenital ptosis (one unilateral, one bilateral) and Duane syndrome (one unilateral, one bilateral) with synergistic divergence. (PMID:26486031)
• Collagenous Alzheimer amyloid plaque component impacts on the compaction of amyloid-beta plaques. (PMID:33287899)
• Recessive variants in COL25A1 gene as novel cause of arthrogryposis multiplex congenita with ocular congenital cranial dysinnervation disorder. (PMID:35077597)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Col25a1	ENSMUSG00000058897
rattus_norvegicus	Col25a1	ENSRNOG00000050706

Paralogs (37): COL9A2 (ENSG00000049089), COL23A1 (ENSG00000050767), COL11A1 (ENSG00000060718), COL17A1 (ENSG00000065618), COL5A3 (ENSG00000080573), COL4A4 (ENSG00000081052), COL16A1 (ENSG00000084636), COL9A3 (ENSG00000092758), COL20A1 (ENSG00000101203), COL1A1 (ENSG00000108821), COL9A1 (ENSG00000112280), COL7A1 (ENSG00000114270), COL21A1 (ENSG00000124749), COL5A1 (ENSG00000130635), COL4A2 (ENSG00000134871), COL2A1 (ENSG00000139219), COL6A1 (ENSG00000142156), COL6A2 (ENSG00000142173), EDA (ENSG00000158813), COL26A1 (ENSG00000160963), COL1A2 (ENSG00000164692), COL3A1 (ENSG00000168542), COL4A3 (ENSG00000169031), COL22A1 (ENSG00000169436), COL24A1 (ENSG00000171502), COL18A1 (ENSG00000182871), EMID1 (ENSG00000186998), COL4A1 (ENSG00000187498), COL4A5 (ENSG00000188153), COL27A1 (ENSG00000196739), COL13A1 (ENSG00000197467), COL4A6 (ENSG00000197565), COL11A2 (ENSG00000204248), COL5A2 (ENSG00000204262), COL15A1 (ENSG00000204291), COLQ (ENSG00000206561), COL28A1 (ENSG00000215018)

Protein

Protein identifiers

Collagen alpha-1(XXV) chain — Q9BXS0 (reviewed: Q9BXS0)

Alternative names: Alzheimer disease amyloid-associated protein, CLAC-P

All UniProt accessions (6): Q9BXS0, A0A2R8Y760, A8MWQ5, D6R8Y2, E9PNV9, H0YAE1

UniProt curated annotations — full annotation on UniProt →

Function. Inhibits fibrillization of amyloid-beta peptide during the elongation phase. Has also been shown to assemble amyloid fibrils into protease-resistant aggregates. Binds heparin.

Subunit / interactions. Forms homodimers and homotrimers. Binds to the fibrillized forms of amyloid-beta protein 40 (beta-APP40) and amyloid-beta protein 42 (beta-APP42). Found associated with beta-APP42 more frequently than with beta-APP40.

Subcellular location. Membrane.

Tissue specificity. Expressed predominantly in brain. Deposited preferentially in primitive or neuritic amyloid plaques which are typical of Alzheimer disease.

Post-translational modifications. Undergoes proteolytic cleavage by furin protease to yield the soluble collagen-like Alzheimer amyloid plaque component. Glycosylated. Hydroxylated on 11% of proline residues and 49% of lysine residues.

Disease relevance. Fibrosis of extraocular muscles, congenital, 5 (CFEOM5) [MIM:616219] An ocular motility disorder characterized by congenital dysinnervation of various cranial nerves to ocular muscles. Clinical features are ophthalmoplegia, anchoring of the eyes in downward gaze, ptosis, and backward tilt of the head. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9BXS0-1	1	yes
Q9BXS0-2	2
Q9BXS0-3	3

RefSeq proteins (3): NP_001243003, NP_115907, NP_942014* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008160	Collagen	Repeat
IPR050938	Collagen_Structural_Proteins	Family

Pfam: PF01391

UniProt features (42 total): compositionally biased region 12, domain 7, region of interest 5, splice variant 4, mutagenesis site 4, chain 2, topological domain 2, sequence conflict 2, site 1, transmembrane region 1, modified residue 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BXS0-F1	57.23	0.02

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): 112–113 (cleavage; by furin)

Post-translational modifications (1): 113

Mutagenesis-validated functional residues (4):

Position	Phenotype
109	not secreted.
112	not secreted.
181–188	reduces binding to amyloid-beta peptide.
181–188	abolishes binding to amyloid-beta peptide.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1442490	Collagen degradation
R-HSA-1650814	Collagen biosynthesis and modifying enzymes
R-HSA-8948216	Collagen chain trimerization

MSigDB gene sets: 325 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_UP, chr4q25, BENPORATH_ES_WITH_H3K27ME3, GOCC_COLLAGEN_TRIMER, GOBP_NEUROGENESIS, CEBPB_01, GOMF_EXTRACELLULAR_MATRIX_STRUCTURAL_CONSTITUENT, GOBP_NERVE_DEVELOPMENT, GOMF_GLYCOSAMINOGLYCAN_BINDING, AACTTT_UNKNOWN, POU3F2_02, ZHANG_BREAST_CANCER_PROGENITORS_UP, GOBP_CELL_PROJECTION_ORGANIZATION, CUI_TCF21_TARGETS_2_DN, OCT1_B

GO Biological Process (1): axonogenesis involved in innervation (GO:0060385)

GO Molecular Function (4): amyloid-beta binding (GO:0001540), heparin binding (GO:0008201), identical protein binding (GO:0042802), extracellular matrix structural constituent conferring tensile strength (GO:0030020)

GO Cellular Component (7): extracellular region (GO:0005576), collagen trimer (GO:0005581), obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788), plasma membrane (GO:0005886), membrane (GO:0016020), extracellular matrix (GO:0031012)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Degradation of the extracellular matrix	1
Collagen formation	1
Collagen biosynthesis and modifying enzymes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
axonogenesis	1
innervation	1
peptide binding	1
glycosaminoglycan binding	1
sulfur compound binding	1
protein binding	1
extracellular matrix structural constituent	1
protein-containing complex	1
endoplasmic reticulum	1
intracellular organelle lumen	1
membrane	1
cell periphery	1
external encapsulating structure	1

Protein interactions and networks

STRING

1086 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COL25A1	BACE1	P56817	595
COL25A1	CDK5R1	Q15078	582
COL25A1	SYP	P08247	548
COL25A1	CCBE1	Q6UXH8	536
COL25A1	SNCA	P37840	507
COL25A1	BACE2	Q9Y5Z0	502
COL25A1	CDK5	Q00535	495
COL25A1	COLEC10	Q9Y6Z7	476
COL25A1	CTHRC1	Q96CG8	456
COL25A1	C1QL1	O75973	449
COL25A1	C1QL4	Q86Z23	448
COL25A1	TOGARAM2	Q6ZUX3	447
COL25A1	SOAT1	P35610	441
COL25A1	IAPP	P10997	426
COL25A1	FURIN	P09958	425

IntAct

3 interactions, top by confidence:

A	B	Type	Score
PLOD1	PLK4	psi-mi:“MI:0914”(association)	0.350
SLC10A5	STXBP3	psi-mi:“MI:0914”(association)	0.350

BioGRID (15): COL25A1 (Affinity Capture-MS), COL25A1 (Synthetic Lethality), COL25A1 (Reconstituted Complex), APP (Co-localization), COL25A1 (Affinity Capture-RNA), COL25A1 (Affinity Capture-MS), COL25A1 (Affinity Capture-MS), COL25A1 (Cross-Linking-MS (XL-MS)), COL25A1 (Cross-Linking-MS (XL-MS)), TFRC (Cross-Linking-MS (XL-MS)), YBX3 (Cross-Linking-MS (XL-MS)), COL25A1 (Affinity Capture-MS), COL25A1 (Reconstituted Complex), APP (Reconstituted Complex), COL25A1 (Protein-peptide)

ESM2 similar proteins: A0A060WQA3, A0MSJ1, A5PN28, A6NHN0, A8WGB1, A8WR59, B2RNN3, C7DZK3, O35167, O35348, O88207, P0C862, P12106, P12107, P13942, P20849, P20908, P20909, P23805, P25940, P83371, P98085, Q03637, Q05722, Q07092, Q0II24, Q0VF58, Q14993, Q17RW2, Q30D77, Q32S24, Q3MI99, Q4ZJM7, Q4ZJN1, Q60467, Q61245, Q641F3, Q64739, Q69DL0, Q6UXH8

Diamond homologs: Q810Y4, Q86Y22, Q8K4G2, Q99MQ5, Q9BXS0, Q9R1N9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	6
Uncertain significance	95
Likely benign	34
Benign	9

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
180690	NM_198721.4(COL25A1):c.1144G>A (p.Gly382Arg)	Pathogenic
180691	NM_198721.4(COL25A1):c.1489G>T (p.Gly497Ter)	Pathogenic
180692	NM_198721.4:c.368-5122_708+6063del	Pathogenic
2067909	NM_198721.4(COL25A1):c.920C>G (p.Ser307Ter)	Pathogenic
2501778	NM_198721.4(COL25A1):c.1598del (p.Pro533fs)	Pathogenic
1324108	NM_198721.4(COL25A1):c.382C>T (p.Arg128Ter)	Likely pathogenic
1698993	NM_198721.4(COL25A1):c.672+1G>A	Likely pathogenic
1699063	NM_198721.4(COL25A1):c.672+1del	Likely pathogenic
4056089	NM_198721.4(COL25A1):c.836G>C (p.Gly279Ala)	Likely pathogenic
4688029	NM_198721.4(COL25A1):c.1198G>A (p.Gly400Arg)	Likely pathogenic
4849374	NM_198721.4(COL25A1):c.780+1G>A	Likely pathogenic

SpliceAI

7708 predictions. Top by Δscore:

Variant	Effect	Δscore
4:108832378:A:AC	donor_gain	1.0000
4:108832379:C:CC	donor_gain	1.0000
4:108832379:CT:C	donor_gain	1.0000
4:108834423:G:C	acceptor_gain	1.0000
4:108834423:G:GC	acceptor_gain	1.0000
4:108834429:C:CT	acceptor_gain	1.0000
4:108834431:C:CT	acceptor_gain	1.0000
4:108845187:A:AC	donor_gain	1.0000
4:108845188:C:CC	donor_gain	1.0000
4:108846134:CATA:C	donor_loss	1.0000
4:108846135:ATAC:A	donor_loss	1.0000
4:108846137:A:AC	donor_gain	1.0000
4:108846137:AC:A	donor_gain	1.0000
4:108846137:ACCG:A	donor_loss	1.0000
4:108846138:C:CT	donor_gain	1.0000
4:108846138:CC:C	donor_gain	1.0000
4:108846216:GTCC:G	acceptor_gain	1.0000
4:108846217:TCC:T	acceptor_gain	1.0000
4:108846217:TCCC:T	acceptor_loss	1.0000
4:108846218:CC:C	acceptor_gain	1.0000
4:108846218:CCC:C	acceptor_gain	1.0000
4:108846219:CC:C	acceptor_gain	1.0000
4:108846220:C:CC	acceptor_gain	1.0000
4:108846220:CTAA:C	acceptor_loss	1.0000
4:108846221:T:C	acceptor_loss	1.0000
4:108860977:CCCGT:C	acceptor_gain	1.0000
4:108860978:CCGT:C	acceptor_gain	1.0000
4:108860979:C:T	acceptor_gain	1.0000
4:108860979:CGT:C	acceptor_gain	1.0000
4:108860981:T:C	acceptor_gain	1.0000

AlphaMissense

4114 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:108869131:C:T	G347D	0.999
4:108869150:C:G	G341R	0.999
4:108869150:C:T	G341R	0.999
4:108884185:C:T	G338E	0.999
4:108940600:C:T	G204D	0.999
4:108940609:C:T	G201D	0.999
4:108940618:C:T	G198E	0.999
4:108941408:A:C	F174L	0.999
4:108941408:A:T	F174L	0.999
4:108941410:A:G	F174L	0.999
4:108817408:A:G	C651R	0.998
4:108869095:C:T	G359E	0.998
4:108869104:C:T	G356D	0.998
4:108869113:C:T	G353D	0.998
4:108869140:C:T	G344D	0.998
4:108869149:C:T	G341E	0.998
4:108884186:C:A	G338W	0.998
4:108884194:C:T	G335E	0.998
4:108884203:C:T	G332E	0.998
4:108940573:C:T	G213E	0.998
4:108940582:C:T	G210E	0.998
4:108940591:C:T	G207E	0.998
4:108940627:C:T	G195E	0.998
4:108940628:C:A	G195W	0.998
4:108940646:C:G	G189R	0.998
4:108941397:T:A	D178V	0.998
4:108817407:C:G	C651S	0.997
4:108817408:A:T	C651S	0.997
4:108819258:G:C	C639W	0.997
4:108819259:C:T	C639Y	0.997

dbSNP variants (sampled 300 via entrez): RS1000000688 (4:108888767 T>C), RS1000010569 (4:108977599 T>A,G), RS1000013768 (4:109059171 C>G,T), RS1000027778 (4:109143361 T>C), RS1000035140 (4:108878080 A>G), RS1000039500 (4:108934281 C>A), RS1000040453 (4:109269718 G>C), RS1000041715 (4:108977809 C>T), RS1000073675 (4:109230102 T>A), RS1000089141 (4:109266005 A>G), RS1000094711 (4:109144762 G>A), RS1000095866 (4:109093788 C>T), RS1000097385 (4:109010024 G>C), RS1000102505 (4:108833924 C>T), RS10001049 (4:108988646 A>C,G,T)

Disease associations

OMIM: gene MIM:610004 | disease phenotypes: MIM:616219, MIM:617468

GenCC curated gene-disease

Disease	Classification	Inheritance
fibrosis of extraocular muscles, congenital, 5	Strong	Autosomal recessive
congenital ptosis	Supportive	Autosomal dominant

Mondo (4): arthrogryposis (MONDO:0008779), fibrosis of extraocular muscles, congenital, 5 (MONDO:0014538), arthrogryposis multiplex congenita (MONDO:0015168), congenital ptosis (MONDO:0008340)

Orphanet (3): Duane retraction syndrome (Orphanet:233), Congenital ptosis (Orphanet:91411), Arthrogryposis multiplex congenita (Orphanet:1037)

HPO phenotypes

71 total (30 of 71 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000044	Hypogonadotropic hypogonadism
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000473	Torticollis
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000512	Abnormal electroretinogram
HP:0000518	Cataract
HP:0000539	Abnormality of refraction
HP:0000542	Impaired ocular adduction
HP:0000565	Esotropia
HP:0000577	Exotropia
HP:0000609	Optic nerve hypoplasia
HP:0000616	Miosis
HP:0000646	Amblyopia
HP:0001239	Wrist flexion contracture
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001284	Areflexia
HP:0001357	Plagiocephaly
HP:0001371	Flexion contracture
HP:0001477	Compensatory chin elevation
HP:0001491	Congenital fibrosis of extraocular muscles
HP:0001558	Decreased fetal movement
HP:0001562	Oligohydramnios
HP:0001623	Breech presentation
HP:0001627	Abnormal heart morphology
HP:0001838	Rocker bottom foot
HP:0002013	Vomiting

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST000996_17	Systemic lupus erythematosus	1.000000e-06
GCST001115_1	Schizophrenia (age at onset)	4.000000e-06
GCST002571_3	Body mass index	5.000000e-07
GCST003815_68	Late-onset Alzheimer’s disease	8.000000e-07
GCST004162_21	Carotid plaque burden	1.000000e-06
GCST005182_10	Common carotid intima-media thickness in HIV negative individuals	9.000000e-07
GCST008163_432	Height	3.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004847	age at onset
EFO:0004340	body mass index
EFO:1001870	late-onset Alzheimers disease
EFO:0006501	carotid plaque build

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D001176	Arthrogryposis	C05.550.150; C05.651.102; C05.660.077; C16.131.621.077
C566737	Ptosis, Hereditary Congenital 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression	2
Aflatoxin B1	decreases methylation	2
geldanamycin	increases expression	1
bisphenol A	affects cotreatment, increases methylation	1
sodium arsenite	affects splicing, decreases expression	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
CGP 52608	affects binding, increases reaction	1
Resveratrol	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	decreases expression, increases abundance	1
Vehicle Emissions	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	1
Copper	affects cotreatment, decreases expression	1
Lead	affects expression	1
Lipopolysaccharides	increases expression, affects response to substance	1
Tretinoin	increases expression	1
Antirheumatic Agents	increases expression	1
Particulate Matter	increases expression, decreases expression, increases abundance	1

Clinical trials (associated diseases)

18 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
NCT03240107	Not specified	COMPLETED	Levator Resection with3 Point Fixation Versus 2 Point Fixation Tucking for Congenital Ptosis
NCT04537169	Not specified	UNKNOWN	Clinical Significance of Whitnall Ligament Structure
NCT05895695	Not specified	UNKNOWN	Levator Muscle Reaction for Unilateral Congenital Ptosis Repair as Compared to Levator Plication
NCT07078552	Not specified	COMPLETED	Research on Precision Diagnosis and Treatment Decision of Common Eye Diseases Based on Artificial Intelligence
NCT07466706	Not specified	NOT_YET_RECRUITING	Levator Muscle and Its Aponeurotic Maldevelopment in Congenital Ptosis
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
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