SPARCL1

Summary

SPARCL1 (SPARC like 1, HGNC:11220) is a protein-coding gene on chromosome 4q22.1, encoding SPARC-like protein 1 (Q14515).

Predicted to enable calcium ion binding activity; collagen binding activity; and extracellular matrix binding activity. Predicted to be involved in regulation of synapse organization. Located in extracellular space.

Source: NCBI Gene 8404 — RefSeq curated summary.

At a glance

• Gene–disease (curated): stromal corneal dystrophy (Limited, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 118 total — 1 pathogenic
• MANE Select transcript: NM_004684

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11220
Approved symbol	SPARCL1
Name	SPARC like 1
Location	4q22.1
Locus type	gene with protein product
Status	Approved
Aliases	MAST9
Ensembl gene	ENSG00000152583
Ensembl biotype	protein_coding
OMIM	606041
Entrez	8404

Gene structure

Transcript identifiers

Ensembl transcripts: 41 — 41 protein_coding

ENST00000282470, ENST00000418378, ENST00000434434, ENST00000458304, ENST00000503414, ENST00000509407, ENST00000512317, ENST00000535835, ENST00000541496, ENST00000543631, ENST00000880787, ENST00000880788, ENST00000880789, ENST00000880790, ENST00000880791, ENST00000880792, ENST00000880793, ENST00000880794, ENST00000880795, ENST00000880796, ENST00000880797, ENST00000880798, ENST00000880799, ENST00000880800, ENST00000880801, ENST00000880802, ENST00000880803, ENST00000946052, ENST00000946053, ENST00000946054, ENST00000946055, ENST00000946056, ENST00000946057, ENST00000946058, ENST00000946059, ENST00000946060, ENST00000946061, ENST00000946062, ENST00000946063, ENST00000946064, ENST00000946065

RefSeq mRNA: 4 — MANE Select: NM_004684 NM_001128310, NM_001291976, NM_001291977, NM_004684

CCDS: CCDS3622, CCDS77939

Canonical transcript exons

ENST00000282470 — 11 exons

Exon	Start	End
ENSE00001006053	87491618	87491690
ENSE00001006057	87490760	87490878
ENSE00001175672	87479430	87479578
ENSE00001175678	87480372	87480520
ENSE00001175684	87482424	87482560
ENSE00001175691	87490273	87490393
ENSE00001914146	87473335	87473803
ENSE00001942085	87529045	87529376
ENSE00003592507	87499521	87499585
ENSE00003602905	87494981	87495127
ENSE00003651115	87493582	87494598

Expression profiles

Bgee: expression breadth ubiquitous, 303 present calls, max score 99.97.

FANTOM5 (CAGE): breadth broad, TPM avg 107.7865 / max 22822.2467, expressed in 363 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
53049	28.7295	295
53045	28.0148	290
53046	23.0313	281
53050	9.8474	252
53044	7.0529	208
53051	4.7693	195
53048	2.3578	185
53052	1.6451	162
53047	1.4177	177
53042	0.7814	133

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	99.97	gold quality
blood vessel layer	UBERON:0004797	99.94	gold quality
postcentral gyrus	UBERON:0002581	99.93	gold quality
superior frontal gyrus	UBERON:0002661	99.93	gold quality
parietal lobe	UBERON:0001872	99.92	gold quality
lateral globus pallidus	UBERON:0002476	99.92	gold quality
orbitofrontal cortex	UBERON:0004167	99.92	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.92	gold quality
CA1 field of hippocampus	UBERON:0003881	99.91	gold quality
occipital lobe	UBERON:0002021	99.90	gold quality
primary visual cortex	UBERON:0002436	99.89	gold quality
entorhinal cortex	UBERON:0002728	99.89	gold quality
Brodmann (1909) area 46	UBERON:0006483	99.89	gold quality
parietal pleura	UBERON:0002400	99.88	gold quality
frontal pole	UBERON:0002795	99.88	gold quality
Brodmann (1909) area 10	UBERON:0013541	99.88	gold quality
descending thoracic aorta	UBERON:0002345	99.87	gold quality
vena cava	UBERON:0004087	99.87	gold quality
urethra	UBERON:0000057	99.86	gold quality
pleura	UBERON:0000977	99.86	gold quality
seminal vesicle	UBERON:0000998	99.86	gold quality
right coronary artery	UBERON:0001625	99.85	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	99.85	gold quality
ascending aorta	UBERON:0001496	99.84	gold quality
thoracic aorta	UBERON:0001515	99.84	gold quality
visceral pleura	UBERON:0002401	99.84	gold quality
pericardium	UBERON:0002407	99.84	gold quality
cauda epididymis	UBERON:0004360	99.84	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.84	gold quality
caudate nucleus	UBERON:0001873	99.83	gold quality

Single-cell (SCXA)

Detected in 48 experiment(s), a significant marker in 46.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	13429.70
E-GEOD-134144	yes	10205.93
E-GEOD-124263	yes	9619.17
E-HCAD-23	yes	8063.81
E-HCAD-35	yes	6594.69
E-MTAB-6308	yes	6378.86
E-MTAB-10287	yes	5662.13
E-MTAB-8322	yes	5051.68
E-GEOD-130148	yes	5008.63
E-MTAB-8381	yes	4810.10
E-GEOD-135922	yes	4784.73
E-HCAD-36	yes	4595.35
E-HCAD-15	yes	4434.49
E-HCAD-1	yes	4230.08
E-MTAB-9435	yes	4174.95

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFIX

miRNA regulators (miRDB)

37 targeting SPARCL1, 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-5692A	100.00	74.40	6850
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-144-3P	99.94	73.98	2698
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-497-3P	99.61	69.71	1990
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-3616-5P	99.55	67.02	989
HSA-MIR-573	99.55	67.44	955
HSA-MIR-5004-3P	99.54	68.27	1371
HSA-MIR-105-5P	99.54	69.24	2060
HSA-MIR-7853-5P	99.54	69.30	2055
HSA-MIR-140-5P	99.44	67.20	792
HSA-MIR-3182	99.40	68.15	2454
HSA-MIR-3678-3P	99.31	67.10	1432
HSA-MIR-5589-3P	99.29	68.30	1443
HSA-MIR-4795-5P	99.11	66.90	876
HSA-MIR-511-5P	98.97	70.94	2268
HSA-MIR-153-3P	98.96	72.51	1644
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-548Q	98.71	65.35	563
HSA-MIR-6755-3P	98.61	66.90	834

Literature-anchored findings (GeneRIF, showing 40)

• Overall, these results suggested that the C-t of hevin contains important determinants for interaction with myocilin. (PMID:16316624)
• hevin can modulate the structure of dermal extracellular matrix, specifically by its regulation of decorin levels and collagen fibril assembly (PMID:16844696)
• Despite proteomic studies in CSF from MS patients suggested an important role for SPARCL1 in the development of the disease, SPARCL1 gene does not appear to act as susceptibility factor for MS in the population investigated here. (PMID:17825989)
• A transgenic mouse model in which SPARCL1 is expressed in radial glia provides a novel in vivo system for evaluating the role of SPARCL1 in brain development and function. (PMID:18381651)
• Data suggest that SPARCL1, Shp2, MSH2, E-cadherin, p53, ADCY-2 and MAPK are potential prognostic markers in colorectal cancer. (PMID:21528083)
• Data suggest that the expression of SPARCL1 protein might be a valuable biomarker for early diagnosis in colorectal cancers and further predicting patients’ prognosis. (PMID:21887554)
• Down-regulated SPARCL1 is associated with gastric cancer. (PMID:22161898)
• SPARCL1 functions as a tumor suppressor promoting differentiation possibly via MET, which inhibits the aggressiveness of colorectal cancers (PMID:22891198)
• Sparc-like protein 1 expression correlates with glioma grade, suggesting the possible role for this protein in the progression of this malignancy. (PMID:22909274)
• SPARCL1 is a potent regulator of cell migration/invasion and its loss is independently associated with prostate cancer recurrence. (PMID:22927397)
• SPARCL1 expression did not inhibit tumor cell proliferation in vitro. By contrast, SPARCL1 did suppress tumor cell migration and invasiveness in vitro and tumor metastatic growth in vivo, conferring improved survival in xenograft mouse models (PMID:23916135)
• radiotherapy causes an increase in SPARCL1 expression; SPARCL1 may have a role in survival in rectal cancer patients (PMID:24661672)
• Androgen-Regulated SPARCL1 in the Tumor Microenvironment Inhibits Metastatic Progression (PMID:26294211)
• SPARCL1 is involved in the tumorigenesis of hilar cholangiocarcinoma and may serve as a novel molecular biomarker for patients’ outcome. (PMID:26490986)
• This study demonstrated the SPARCL1-containing neurons in the human brainstem and sensory ganglion. (PMID:27357901)
• tumor endothelial cells heterogeneity is regulated by SPARCL1, which promotes the cell quiescence and vessel homeostasis contributing to the favorable prognoses associated with Th1-tumor microenvironments colorectal carcinomas. (PMID:27721236)
• The expression of SPARCL-1 by brain endothelial cells in chronic multiple sclerosis lesions together with its regulation by inflammatory mediators in vitro suggest a role for SPARCL-1 in MS neuropathology, possibly at the brain vascular level. (PMID:28543098)
• The present study demonstrated that the expression of SPARCL1 was downregulated in renal cell carcinoma (RCC) cells and tissues, however, the overexpression of SPARCL1 inhibited RCC cell migration and invasion. (PMID:28944877)
• Low SPARCL1 expression promotes lung metastasis in osteosarcoma. (PMID:29084211)
• SC1 levels were independently associated with ischemic stroke severity evaluated by the NIHSS. (PMID:29102542)
• The results of this study suggest that the SPARCL1 accelerates Alzheimer’s Disease pathogenesis and thus link neuroinflammation with widespread changes in brain structure and function during aging. (PMID:29154276)
• sTBI patients had an increase of serum SPARCL1 concentrations, and that there is an association between high serum SPARCL1 concentrations and sTBI mortality or trauma severity. (PMID:30639238)
• This study demonstrated that the hevin-expressing cells in the adult brain reveals prominent expression in astrocytes and parvalbumin neurons. (PMID:30656447)
• Both Hevin and SPARC proteins were detected in postmortem Alzheimer’s disease brain and confirmed significant alterations in transcript expression. (PMID:30883351)
• MiR-539-3p promotes the progression of epithelial ovarian cancer by targeting SPARCL1. (PMID:30964161)
• SPARCL1 was the most significantly hypermethylated gene in upper urinary tract urothelial carcinoma tissues. (PMID:30987093)
• SLIT3 and SPARCL1 can be regulated by DNA methylation and down-regulated in lung adenocarcinoma (PMID:31154721)
• SPARCL1 impedes trophoblast migration and invasion by down-regulating ERK phosphorylation and AP-1 production and altering EMT-related molecule expression. (PMID:31675488)
• Enhanced SPARCL1 expression in cancer stem cells improves preclinical modeling of glioblastoma by promoting both tumor infiltration and angiogenesis. (PMID:31830525)
• SPARCL1 as a biomarker of maladaptive right ventricular remodelling in pulmonary hypertension. (PMID:32248722)
• Species-, organ- and cell-type-dependent expression of SPARCL1 in human and mouse tissues. (PMID:32437418)
• Interplay between hevin, SPARC, and MDGAs: Modulators of neurexin-neuroligin transsynaptic bridges. (PMID:33535026)
• Characterization of Hevin (SPARCL1) Immunoreactivity in Postmortem Human Brain Homogenates. (PMID:34033869)
• SPARCL1 exhibits different expressions in left- and right-sided colon cancer and is downregulated via DNA methylation. (PMID:34435512)
• Association of Tumor Suppressor Sparcl1 with Clinical Staging and Prognosis of NSCLC. (PMID:34921028)
• SPARCL1 Is a Novel Prognostic Biomarker and Correlates with Tumor Microenvironment in Colorectal Cancer. (PMID:35111844)
• The KDM6A-SPARCL1 axis blocks metastasis and regulates the tumour microenvironment of gastrointestinal stromal tumours by inhibiting the nuclear translocation of p65. (PMID:35136209)
• Circular_0086414 induces SPARC like 1 (SPARCL1) production to inhibit esophageal cancer cell proliferation, invasion and glycolysis and induce cell apoptosis by sponging miR-1290. (PMID:35549806)
• The Matricellular Protein Hevin Is Involved in Alcohol Use Disorder. (PMID:36830603)
• Identifying liver metastasis-related hub genes in breast cancer and characterizing SPARCL1 as a potential prognostic biomarker. (PMID:37180578)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	sparcl1	ENSDARG00000074989
mus_musculus	Sparcl1	ENSMUSG00000029309
rattus_norvegicus	Sparcl1	ENSRNOG00000015093
drosophila_melanogaster	SPARC	FBGN0026562
caenorhabditis_elegans		WBGENE00003893

Paralogs (1): SPARC (ENSG00000113140)

Protein

Protein identifiers

SPARC-like protein 1 — Q14515 (reviewed: Q14515)

Alternative names: High endothelial venule protein, MAST 9

All UniProt accessions (8): C9JJR8, D6RA29, E7EU82, E9PC64, Q14515, F5H1Y9, F5H331, F5H4Y3

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Highly expressed in lymph node, brain, heart, lung, skeletal muscle, ovary, small intestine, and colon, with lower levels in placenta, pancreas, testis, spleen, and thymus, and no expression in kidney, liver, and peripheral blood leukocytes.

Post-translational modifications. N- and O-glycosylated. O-glycosylated with a core 1 or possibly core 8 glycan.

Similarity. Belongs to the SPARC family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q14515-1	1	yes
Q14515-2	2

RefSeq proteins (4): NP_001121782, NP_001278905, NP_001278906, NP_004675* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001999	Osteonectin_CS	Conserved_site
IPR002048	EF_hand_dom	Domain
IPR002350	Kazal_dom	Domain
IPR003645	Fol_N	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR015369	Follistatin/Osteonectin_EGF	Domain
IPR016359	SPARC-like_p1	Family
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR019577	SPARC/Testican_Ca-bd-dom	Domain
IPR036058	Kazal_dom_sf	Homologous_superfamily

Pfam: PF07648, PF09289, PF10591

UniProt features (87 total): helix 15, compositionally biased region 13, glycosylation site 12, modified residue 8, disulfide bond 7, strand 6, binding site 5, turn 5, sequence conflict 4, domain 3, region of interest 3, sequence variant 3, signal peptide 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
7KBU	X-RAY DIFFRACTION	2.27

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14515-F1	59.92	0.32

Functional residue map

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

Ligand- & substrate-binding residues (5): 635; 637; 639; 641; 646

Post-translational modifications (8): 76, 84, 92, 171, 272, 358, 365, 420

Disulfide bonds (7): 433–444, 438–454, 456–490, 462–483, 472–509, 515–626, 634–650

Glycosylation sites (12): 31, 40, 44, 116, 169, 176, 196, 280, 331, 398, 412, 476

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-8957275	Post-translational protein phosphorylation
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 192 (showing top): KAAB_FAILED_HEART_ATRIUM_DN, XU_GH1_AUTOCRINE_TARGETS_UP, STOSSI_RESPONSE_TO_ESTRADIOL, TERAMOTO_OPN_TARGETS_CLUSTER_6, MODULE_66, GOBP_CELL_CELL_ADHESION, PICCALUGA_ANGIOIMMUNOBLASTIC_LYMPHOMA_UP, JOHANSSON_BRAIN_CANCER_EARLY_VS_LATE_DN, GOBP_CELL_JUNCTION_ORGANIZATION, ONKEN_UVEAL_MELANOMA_UP, BOQUEST_STEM_CELL_CULTURED_VS_FRESH_DN, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, KINSEY_TARGETS_OF_EWSR1_FLII_FUSION_DN, WTGAAAT_UNKNOWN, TCF11_01

GO Biological Process (3): signal transduction (GO:0007165), regulation of synapse organization (GO:0050807), synaptic membrane adhesion (GO:0099560)

GO Molecular Function (5): calcium ion binding (GO:0005509), collagen binding (GO:0005518), extracellular matrix binding (GO:0050840), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788), glutamatergic synapse (GO:0098978), obsolete collagen-containing extracellular matrix (GO:0062023)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of proteins	2
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
synapse organization	2
binding	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
regulation of synapse structure or activity	1
regulation of cellular component organization	1
cell-cell adhesion	1
metal ion binding	1
protein-containing complex binding	1
cation binding	1
cellular anatomical structure	1
endoplasmic reticulum	1
intracellular organelle lumen	1
synapse	1

Protein interactions and networks

STRING

2316 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPARCL1	MYOC	Q99972	814
SPARCL1	NLGN1	Q8N2Q7	724
SPARCL1	PTN	P21246	699
SPARCL1	NRXN1	Q9ULB1	677
SPARCL1	AMBN	Q9NP70	580
SPARCL1	ENAM	Q9NRM1	572
SPARCL1	GPC4	O75487	558
SPARCL1	MEGF10	Q96KG7	542
SPARCL1	COL4A1	P02462	513
SPARCL1	GAPDH	P00354	511
SPARCL1	THBS2	P35442	506
SPARCL1	MEPE	Q9NQ76	501
SPARCL1	COL5A1	P20908	480
SPARCL1	IBSP	P21815	467
SPARCL1	SMOC2	Q9H3U7	464
SPARCL1	GPC6	Q9Y625	464

IntAct

19 interactions, top by confidence:

A	B	Type	Score
SPARCL1	MYOC	psi-mi:“MI:0915”(physical association)	0.530
SPARCL1	MYOC	psi-mi:“MI:0407”(direct interaction)	0.530
FAM20C	SPARCL1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
EGFR	SPARCL1	psi-mi:“MI:0915”(physical association)	0.370
SPARCL1	MYCBP2	psi-mi:“MI:0915”(physical association)	0.370
SPG11	SPARCL1	psi-mi:“MI:0915”(physical association)	0.370
SPARCL1	PDGFRL	psi-mi:“MI:0915”(physical association)	0.370
SPARCL1	DUSP14	psi-mi:“MI:0914”(association)	0.350
CLU	SPARCL1	psi-mi:“MI:0915”(physical association)	0.000
DISC1	SPARCL1	psi-mi:“MI:0915”(physical association)	0.000
SPARCL1	TNF	psi-mi:“MI:0915”(physical association)	0.000
SPARCL1	CBFB	psi-mi:“MI:0915”(physical association)	0.000
RCAN1	SPARCL1	psi-mi:“MI:0915”(physical association)	0.000
BTG3	SPARCL1	psi-mi:“MI:0915”(physical association)	0.000
DSCR9	SPARCL1	psi-mi:“MI:0915”(physical association)	0.000
HUNK	SPARCL1	psi-mi:“MI:0915”(physical association)	0.000
TTC3	SPARCL1	psi-mi:“MI:0915”(physical association)	0.000
LCOR	SPARCL1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (19): SPARCL1 (Two-hybrid), SPARCL1 (Two-hybrid), DUSP14 (Affinity Capture-MS), VSIG8 (Affinity Capture-MS), DSG4 (Affinity Capture-MS), PADI3 (Affinity Capture-MS), AIM1 (Affinity Capture-MS), FNDC8 (Affinity Capture-MS), SPARCL1 (Two-hybrid), SPARCL1 (Two-hybrid), SPARCL1 (Two-hybrid), SPARCL1 (Two-hybrid), SPARCL1 (Two-hybrid), SPARCL1 (Two-hybrid), SPARCL1 (Affinity Capture-MS)

ESM2 similar proteins: A2BDC9, A6NM62, E9Q793, O08999, O35806, O55233, O95813, P13207, P22389, P23499, P23943, P24054, P29560, P35054, P70041, P86275, Q07G34, Q14515, Q17R60, Q2Q0I9, Q3UU94, Q3V1M1, Q4V9H3, Q4ZHG4, Q5K027, Q5NRP8, Q5NRP9, Q5NRQ1, Q5QQ37, Q68CR7, Q6WRH9, Q6WRI0, Q701R2, Q701R3, Q701R4, Q76K27, Q8CG19, Q8JIR8, Q8JZQ0, Q8R1W8

Diamond homologs: A2ASQ1, A5YT95, G4V4G1, O00468, O35679, O60575, O62650, O93390, O95633, P07214, P09486, P0DKM8, P0DKT1, P10184, P10669, P13213, P16895, P16975, P19883, P20112, P21674, P23499, P25304, P31514, P31515, P31696, P36233, P36377, P36378, P37109, P47931, P50291, Q12841, Q14515, Q1LZB9, Q58D84, Q5R767, Q5R9Y1, Q62356, Q62632

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	83
Likely benign	8
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3257740	NM_004684.6(SPARCL1):c.334G>A (p.Glu112Lys)	Pathogenic

SpliceAI

1870 predictions. Top by Δscore:

Variant	Effect	Δscore
4:87479429:CCTT:C	donor_gain	1.0000
4:87479479:AT:A	donor_gain	1.0000
4:87479574:AGACT:A	acceptor_gain	1.0000
4:87479575:GACT:G	acceptor_gain	1.0000
4:87479576:ACT:A	acceptor_gain	1.0000
4:87479577:CT:C	acceptor_gain	1.0000
4:87479577:CTC:C	acceptor_gain	1.0000
4:87479578:TCT:T	acceptor_gain	1.0000
4:87479579:C:CC	acceptor_gain	1.0000
4:87479579:CTG:C	acceptor_loss	1.0000
4:87479580:T:C	acceptor_loss	1.0000
4:87480366:TCTTA:T	donor_loss	1.0000
4:87480367:CTTAC:C	donor_loss	1.0000
4:87480368:TTAC:T	donor_loss	1.0000
4:87480369:TACCT:T	donor_loss	1.0000
4:87480370:A:AC	donor_gain	1.0000
4:87480371:C:CC	donor_gain	1.0000
4:87480371:C:CG	donor_loss	1.0000
4:87480371:CCTAT:C	donor_gain	1.0000
4:87480521:C:CG	acceptor_loss	1.0000
4:87480522:T:A	acceptor_loss	1.0000
4:87480527:T:TC	acceptor_gain	1.0000
4:87490271:A:AC	donor_gain	1.0000
4:87490272:C:CC	donor_gain	1.0000
4:87491612:ACTC:A	donor_loss	1.0000
4:87491614:TCA:T	donor_loss	1.0000
4:87491616:AC:A	donor_gain	1.0000
4:87491617:CC:C	donor_gain	1.0000
4:87491617:CCCA:C	donor_gain	1.0000
4:87491689:GC:G	acceptor_gain	1.0000

AlphaMissense

4507 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:87479455:C:A	W647C	0.999
4:87479455:C:G	W647C	0.999
4:87479457:A:G	W647R	0.999
4:87479457:A:T	W647R	0.999
4:87479518:G:C	C626W	0.999
4:87479519:C:T	C626Y	0.999
4:87479520:A:G	C626R	0.999
4:87482500:A:G	L531P	0.999
4:87482502:C:A	W530C	0.999
4:87482502:C:G	W530C	0.999
4:87482524:A:C	F523C	0.999
4:87482547:A:C	C515W	0.999
4:87479446:G:C	C650W	0.998
4:87479447:C:T	C650Y	0.998
4:87479448:A:G	C650R	0.998
4:87479494:A:C	C634W	0.998
4:87479495:C:T	C634Y	0.998
4:87479496:A:G	C634R	0.998
4:87479519:C:A	C626F	0.998
4:87479519:C:G	C626S	0.998
4:87479520:A:T	C626S	0.998
4:87479558:A:G	L613P	0.998
4:87480393:A:G	L599P	0.998
4:87480401:A:C	F596L	0.998
4:87480401:A:T	F596L	0.998
4:87480402:A:C	F596C	0.998
4:87480402:A:G	F596S	0.998
4:87480403:A:G	F596L	0.998
4:87480407:C:A	W594C	0.998
4:87480407:C:G	W594C	0.998

dbSNP variants (sampled 300 via entrez): RS1000005938 (4:87512495 G>C,T), RS1000040777 (4:87506977 C>CT), RS10001608 (4:87516558 T>A,C), RS1000242060 (4:87506229 C>A,T), RS1000303332 (4:87499632 A>G), RS1000340603 (4:87526159 C>A,T), RS10003497 (4:87508607 A>G,T), RS1000356868 (4:87499342 T>G), RS1000429891 (4:87505042 T>G), RS10004408 (4:87517178 T>C), RS1000519852 (4:87519529 T>C), RS1000563066 (4:87510899 T>G), RS1000639912 (4:87517636 G>A), RS1000696214 (4:87524612 C>T), RS1000786282 (4:87474546 A>G)

Disease associations

OMIM: gene MIM:606041 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
stromal corneal dystrophy	Limited	Autosomal dominant
corneal dystrophy	Limited	Autosomal dominant

Mondo (2): stromal corneal dystrophy (MONDO:0020213), corneal dystrophy (MONDO:0018102)

Orphanet (1): Stromal corneal dystrophy (Orphanet:98626)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST005588_24	Idiopathic dilated cardiomyopathy	3.000000e-06
GCST006585_1807	Blood protein levels	1.000000e-78
GCST006585_345	Blood protein levels	9.000000e-15
GCST008972_35	Urate levels	4.000000e-12

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009094	idiopathic dilated cardiomyopathy
EFO:0004531	urate measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D003317	Corneal Dystrophies, Hereditary	C11.204.236; C11.270.162; C16.320.290.162

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	affects expression, decreases expression	4
Benzo(a)pyrene	increases methylation, decreases expression	3
Estradiol	decreases expression, affects cotreatment, increases expression	3
Progesterone	affects cotreatment, increases expression	3
Valproic Acid	increases expression, affects expression, decreases expression	3
sodium arsenite	increases expression, decreases expression, affects cotreatment	2
Tetrachlorodibenzodioxin	affects expression, decreases expression	2
aristolochic acid I	increases expression	1
methylmercuric chloride	increases expression	1
lasiocarpine	decreases expression	1
methyleugenol	decreases expression	1
pirinixic acid	increases activity, affects binding, decreases expression	1
bisphenol A	increases expression, affects cotreatment	1
lead acetate	affects cotreatment, increases expression	1
cordycepin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	affects expression	1
2,2’,4,4’,5-brominated diphenyl ether	decreases expression	1
Rosiglitazone	decreases expression	1
Troglitazone	decreases expression	1
Arsenic	affects methylation	1
Calcitriol	increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Lead	affects expression	1
Methyl Methanesulfonate	increases expression	1
Tobacco Smoke Pollution	affects expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05279157	PHASE2	COMPLETED	Autologous Adipose-Derived Adult Stem Cell Implantation for Corneal Diseases (ADASCs-CT-CD)
NCT04484402	PHASE1/PHASE2	COMPLETED	Treatment of Patients With Inflammatory-dystrophic Diseases of the Cornea Using Autologous Stem Cells
NCT02932852	EARLY_PHASE1	UNKNOWN	Autologous Adipose-Derived Adult Stem Cell Transplantation for Corneal Diseases
NCT01084850	Not specified	UNKNOWN	Corneal Endothelium Morphology and Central Thickness in Type II Diabetes Mellitus and Normal Subjects
NCT02173847	Not specified	COMPLETED	Laser Assisted Procedures in Penetrating Keratoplasty
NCT02736877	Not specified	UNKNOWN	Corneal Transplantation Guided by OCT RESCAN
NCT02746055	Not specified	UNKNOWN	Study of the Prevalence of TGFBI Corneal Dystrophies
NCT03461991	Not specified	COMPLETED	Correlation Between In-vivo Anatomy of Corneal Dystrophies as Assessed by High- Resolution Optical Coherence Tomography (OCT) Measurement and Histological Examination
NCT03504800	Not specified	RECRUITING	OCT in Diagnosis of Irregular Corneas
NCT04129021	Not specified	RECRUITING	High Resolution, High-speed Multimodal Ophthalmic Imaging
NCT04164407	Not specified	UNKNOWN	Keratoconus, Corneal Diseases and Transplant Registry
NCT04384094	Not specified	UNKNOWN	Defining the Operating Parameters for a Rebound-esthesiometer
NCT04424550	Not specified	COMPLETED	Comparative Results After DSAEK, UT-DSAEK and DMEK for Fuchs Endothelial Corneal Dystophy
NCT05742321	Not specified	RECRUITING	Analysis of the Genotype/Phenotype Relationship in the Fuchs’ Corneal Endothelial Dystrophy in France
NCT05891106	Not specified	COMPLETED	AONDA Therapeutic Indication Study I
NCT05927740	Not specified	COMPLETED	The Efficacy of Hyperemesis Gravidarum on Macular Thickness, Corneal Thickness and Intraocular Pressure in Pregnancy
NCT05956535	Not specified	COMPLETED	Air Optix® Night and Day® Aqua Therapeutic Wear
NCT06491615	Not specified	RECRUITING	National Ophthalmic Genotyping and Phenotyping Network (eyeGENE (Registered Trademark)), Stage 3 - Expansion of DNA and Data Repositories for Rare Inherited Ophthalmic Diseases
NCT06844123	Not specified	RECRUITING	Microsurgical Robot-assisted Corneal Transplant
NCT06881771	Not specified	RECRUITING	FECD-TRACE: Fuchs’ Endothelial Corneal Dystrophy TRAjectory and Correlation With Genotype in the United Kingdom