MYOC

Summary

MYOC (myocilin, HGNC:7610) is a protein-coding gene on chromosome 1q24.3, encoding Myocilin (Q99972). Secreted glycoprotein regulating the activation of different signaling pathways in adjacent cells to control different processes including cell adhesion, cell-matrix adhesion, cytoskeleton organization and cell migration.

MYOC encodes the protein myocilin, which is believed to have a role in cytoskeletal function. MYOC is expressed in many occular tissues, including the trabecular meshwork, and was revealed to be the trabecular meshwork glucocorticoid-inducible response protein (TIGR). The trabecular meshwork is a specialized eye tissue essential in regulating intraocular pressure, and mutations in MYOC have been identified as the cause of hereditary juvenile-onset open-angle glaucoma.

Source: NCBI Gene 4653 — RefSeq curated summary.

At a glance

• Gene–disease (curated): open-angle glaucoma (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 336 total — 16 pathogenic, 35 likely-pathogenic
• Phenotypes (HPO): 35
• Druggable target: yes
• MANE Select transcript: NM_000261

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7610
Approved symbol	MYOC
Name	myocilin
Location	1q24.3
Locus type	gene with protein product
Status	Approved
Aliases	TIGR, JOAG1
Ensembl gene	ENSG00000034971
Ensembl biotype	protein_coding
OMIM	601652
Entrez	4653

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 nonsense_mediated_decay

ENST00000037502, ENST00000638471, ENST00000877923, ENST00000971579

RefSeq mRNA: 1 — MANE Select: NM_000261 NM_000261

CCDS: CCDS1297

Canonical transcript exons

ENST00000037502 — 3 exons

Exon	Start	End
ENSE00000789785	171638597	171638722
ENSE00001369365	171652008	171652688
ENSE00001852498	171635417	171636709

Expression profiles

Bgee: expression breadth ubiquitous, 201 present calls, max score 99.57.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 2.6517 / max 609.7639, expressed in 118 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
15894	2.6308	117
201816	0.0210	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	99.57	gold quality
mucosa of stomach	UBERON:0001199	99.53	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.17	gold quality
synovial joint	UBERON:0002217	96.22	gold quality
tibial nerve	UBERON:0001323	95.91	gold quality
popliteal artery	UBERON:0002250	95.34	gold quality
tibial artery	UBERON:0007610	95.31	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.29	gold quality
lower esophagus	UBERON:0013473	95.11	gold quality
gluteal muscle	UBERON:0002000	94.64	gold quality
tendon	UBERON:0000043	94.27	gold quality
aorta	UBERON:0000947	92.74	gold quality
right coronary artery	UBERON:0001625	92.54	gold quality
trachea	UBERON:0003126	92.44	gold quality
tendon of biceps brachii	UBERON:0008188	92.25	gold quality
fundus of stomach	UBERON:0001160	91.79	gold quality
descending thoracic aorta	UBERON:0002345	91.76	gold quality
triceps brachii	UBERON:0001509	91.15	gold quality
eye trabecular meshwork	UBERON:0005969	90.47	gold quality
left coronary artery	UBERON:0001626	89.62	gold quality
coronary artery	UBERON:0001621	89.55	gold quality
thoracic aorta	UBERON:0001515	89.46	gold quality
ascending aorta	UBERON:0001496	89.36	gold quality
subcutaneous adipose tissue	UBERON:0002190	87.79	gold quality
muscle of leg	UBERON:0001383	87.38	gold quality
adipose tissue	UBERON:0001013	86.90	gold quality
gastrocnemius	UBERON:0001388	86.78	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	86.72	gold quality
connective tissue	UBERON:0002384	86.28	gold quality
muscle organ	UBERON:0001630	86.17	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): USF1

miRNA regulators (miRDB)

27 targeting MYOC, 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-513B-5P	99.99	69.96	2150
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-3660	99.68	67.33	1149
HSA-MIR-516A-3P	99.46	67.96	1378
HSA-MIR-516B-3P	99.46	67.96	1378
HSA-MIR-7162-5P	99.46	68.08	1368
HSA-MIR-3140-5P	99.39	69.04	1136
HSA-MIR-5580-5P	99.38	66.96	1139
HSA-MIR-4786-3P	99.36	68.35	1390
HSA-MIR-20B-3P	99.29	67.05	784
HSA-MIR-1237-3P	98.55	67.65	1423
HSA-MIR-628-5P	98.36	67.74	844
HSA-MIR-4782-5P	98.35	69.33	1474
HSA-MIR-5706	98.35	69.33	1463
HSA-MIR-9851-5P	97.57	67.49	1067
HSA-MIR-6514-3P	97.52	66.50	808
HSA-MIR-630	97.50	66.38	921
HSA-MIR-890	97.47	68.67	982
HSA-MIR-5699-5P	97.36	67.03	1014
HSA-MIR-335-5P	97.10	68.12	1022
HSA-MIR-4474-3P	96.97	65.87	870
HSA-MIR-6839-5P	96.74	68.29	1088
HSA-MIR-378J	96.44	66.20	1020
HSA-MIR-591	96.29	68.16	611
HSA-MIR-555	95.92	65.25	564

Literature-anchored findings (GeneRIF, showing 40)

• Myocilin is shown here to undergo a post-transcriptional modification event, giving rise to deletion forms, their upregulation by dexamethasone provide support for a possible role in steroid-induced glaucoma. (PMID:11738824)
• digenic inheritance of early-onset glaucoma: CYP1B1, a potential modifier gene, and MYOC mutational analysis (PMID:11774072)
• Mutation in the myocilin gene is not the common cause for glaucoma in Uganda (PMID:11910561)
• Apolipoprotein E-promoter single-nucleotide polymorphisms affect the phenotype of primary open-angle glaucoma and demonstrate interaction with the myocilin gene (PMID:11992263)
• Optimedin and myocilin interact with each other in vitro (PMID:12019210)
• results indicate an age independence, argue thus against a direct role of myocilin and reiterate the involvement of additional factors in the pathogenesis of glaucoma (PMID:12060848)
• A total of 4.4% of patients with POAG have novel disease-associated mutations in myocilin. (PMID:12362081)
• Five novel mutations, namely Gly434Ser, Asn450Asp, Val251Ala, Ile345Met and Ser393Asn, could be identified as cause of preperimetric POAG, JOAG, normal tension POAG and POAG. (PMID:12442283)
• Two single nucleotide polymorphisms (SNPs) were identified in MYOC gene of Indian primary open angle glaucoma patients. (PMID:12447164)
• Myocilin mutations are associated with 3-4% of POAG in patient populations worldwide. (PMID:12504739)
• Q368STOP mutation of myocilin is associated with primary open-angle glaucoma in Australia (PMID:12522550)
• the olfactomedin-domain of myocilin contains a single disulphide-bond connecting Cys-245 and Cys-433 residues; secondary structure predictions and circular dichroism studies indicate that it consists primarily of beta-strands (PMID:12615070)
• A family with a myocilin (MYOC) gene mutation ascertained on the basis of the phenotype of the 71-year-old proband with juvenile-onset primary open-angle glaucoma (JOAG). (PMID:12671462)
• The Cys433Arg mutation in this pedigree was associated with a phenotype characterized by early-onset open-angle glaucoma (PMID:12671463)
• Carriers of the myocilin Thr377Met mutation have reduced outflow facility, which may be detected prior to developing glaucoma. (PMID:12782842)
• APOE interacts at a highly significant level with a single nucleotide polymorphism of MYOC, a known glaucoma-causing gene. (PMID:12817590)
• We identified a previously unreported GGT right curved arrow GAT transition at codon 451 in exon 3, resulting in a glycine to asparagine substitution in one POAG patient. (PMID:12851728)
• Mutations in the myocilin gene in families with primary open-angle glaucoma and juvenile open-angle glaucoma. (PMID:12860809)
• polymorphisms in myocilin gene is associated with primary open-angle glaucoma (PMID:12868033)
• Four novel MYOC missense mutations in French Primary open-angle glaucoma patients which are associated with increased intraocular pressure. (PMID:12872267)
• The GLC1A Thr377Met mutation is associated with POAG (primary open-angle glaucoma) (PMID:12912696)
• Therefore, our results support the statement that gain of function rather than haploinsufficiency is a critical mechanism for primary open-angle glaucoma in individuals with mutations on MYOC. (PMID:14680806)
• Definitive evidence of MYOC variants associated with NTG (normal tension glaucoma) was not found (PMID:14688426)
• Many groups worldwide have confirmed the presence of probable disease-causing mutations in the coding region of the (TIGR/MYOC) gene associated with glaucoma. (PMID:14740993)
• The polymorphisms of the MYOC gene may be related to primary open-angle glaucoma. (PMID:14767915)
• A novel mutation in exon 1 (144 G–>Alpha) resulting in Gln48His substitution was observed in 2% of the patients; this mutation was found to alter the secondary structure in the glycosaminoglycan initiation site of the protein (PMID:15025728)
• Extracellular myocilin affects activity of trabecular meshwork cells. (PMID:15137056)
• When the myocilin expression was increased, the transfectants showed a dramatic loss of actin stress fibers and focal adhesions. Cell adhesion to fibronectin and spreading were also compromised. (PMID:15194423)
• This study reports a novel missense mutation in a four-generation Indian family with all but one member affected with J-POAG (juvenile-onset primary open-angle glaucoma). (PMID:15255110)
• in Chinese, polymorphisms in MYOC promoter are not related to risk of primary open-angle glaucoma (POAG). No association between MYOC.mt1 promoter polymorphism with severity of POAG. (PMID:15354075)
• five primary open angle glaucoma patients with sequence variants in the consensus region of the promoter. These sequence variants might be involved in the altered association between the consensus region and the corresponding transcription factor. (PMID:15483649)
• Mutations in the MYOC gene were demonstrated chromatographically in 2.9% of our Japanese primary open-angle glaucoma patients. (PMID:15534471)
• Myocilin impaired focal adhesion formation and specifically blocked the incorporation of paxillin, but not vinculin, into focal adhesions. (PMID:15652337)
• The myocilin mutation, Gln48His, represents an allelic condition involving a spectrum of glaucoma phenotypes in Indian populations. (PMID:15723004)
• observations suggest a possible role of MYOC in primary congenital glaucoma, which might be mediated via digenic interaction with CYP1B1 and/or an yet unidentified locus associated with the disease (PMID:15733270)
• endoproteolytic processing might regulate the activity of myocilin; the inhibition of the processing by pathogenic mutations impairs the normal role of myocilin (PMID:15795224)
• Our results further support the evidence that the Thr377Met mutation in MYOC may represent a susceptibility allele for glaucoma. (PMID:15823921)
• The findings in the current study provide further evidence that MYOC and OPTN gene variants are rare causes of NTG (normal tension glaucoma). (PMID:15851979)
• MYOC appears in the extracellular space of trabecular meshwork cells by an unconventional mechanism, likely associated with exosome-like vesicles (PMID:15944158)
• The alteration of the interaction by mutations in MYOC might be a key factor of the pathogenesis of POAG (PMID:16198165)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	myoc	ENSDARG00000021789
mus_musculus	Myoc	ENSMUSG00000026697
rattus_norvegicus	Myoc	ENSRNOG00000003221

Paralogs (9): OLFM4 (ENSG00000102837), OLFM2 (ENSG00000105088), OLFML3 (ENSG00000116774), OLFM3 (ENSG00000118733), OLFM1 (ENSG00000130558), OLFML2B (ENSG00000162745), OLFML1 (ENSG00000183801), OLFML2A (ENSG00000185585), GLDN (ENSG00000186417)

Protein

Protein identifiers

Myocilin — Q99972 (reviewed: Q99972)

Alternative names: Myocilin 55 kDa subunit, Trabecular meshwork-induced glucocorticoid response protein

All UniProt accessions (3): A0A0S2Z421, A0A1W2PP09, Q99972

UniProt curated annotations — full annotation on UniProt →

Function. Secreted glycoprotein regulating the activation of different signaling pathways in adjacent cells to control different processes including cell adhesion, cell-matrix adhesion, cytoskeleton organization and cell migration. Promotes substrate adhesion, spreading and formation of focal contacts. Negatively regulates cell-matrix adhesion and stress fiber assembly through Rho protein signal transduction. Modulates the organization of actin cytoskeleton by stimulating the formation of stress fibers through interactions with components of Wnt signaling pathways. Promotes cell migration through activation of PTK2 and the downstream phosphatidylinositol 3-kinase signaling. Plays a role in bone formation and promotes osteoblast differentiation in a dose-dependent manner through mitogen-activated protein kinase signaling. Mediates myelination in the peripheral nervous system through ERBB2/ERBB3 signaling. Plays a role as a regulator of muscle hypertrophy through the components of dystrophin-associated protein complex. Involved in positive regulation of mitochondrial depolarization. Plays a role in neurite outgrowth. May participate in the obstruction of fluid outflow in the trabecular meshwork.

Subunit / interactions. Homodimer (via N-terminus). Can also form higher oligomers. Interacts with OLFM3, FN1, NRCAM, GLDN and NFASC. Interacts (via N-terminus) with MYL2. Interacts with SFRP1, FRZB, FZD7, FZD10, FZD1 and WIF1; regulates Wnt signaling. Interacts with SNTA1; regulates muscle hypertrophy. Interacts with ERBB2 and ERBB3; activates ERBB2-ERBB3 signaling pathway. Interacts with SNCG; affects its secretion and its aggregation.

Subcellular location. Secreted. Golgi apparatus. Cytoplasmic vesicle. Extracellular space. Extracellular matrix. Extracellular exosome. Mitochondrion. Mitochondrion intermembrane space. Mitochondrion inner membrane. Mitochondrion outer membrane. Rough endoplasmic reticulum. Cell projection. Cilium Secreted Endoplasmic reticulum.

Tissue specificity. Detected in aqueous humor. Detected in the eye (at protein level). Widely expressed. Highly expressed in various types of muscle, ciliary body, papillary sphincter, skeletal muscle, heart, and bone marrow-derived mesenchymal stem cells. Expressed predominantly in the retina. In normal eyes, found in the inner uveal meshwork region and the anterior portion of the meshwork. In contrast, in many glaucomatous eyes, it is found in more regions of the meshwork and seems to be expressed at higher levels than in normal eyes, regardless of the type or clinical severity of glaucoma. The myocilin 35 kDa fragment is detected in aqueous humor and to a lesser extent in iris and ciliary body.

Post-translational modifications. Different isoforms may arise by post-translational modifications. Glycosylated. Palmitoylated. Undergoes a calcium-dependent proteolytic cleavage at Arg-226 by CAPN2 in the endoplasmic reticulum. The result is the production of two fragments, one of 35 kDa containing the C-terminal olfactomedin-like domain, and another of 20 kDa containing the N-terminal leucine zipper-like domain.

Disease relevance. Glaucoma 1, open angle, A (GLC1A) [MIM:137750] A form of primary open angle glaucoma (POAG). POAG is characterized by a specific pattern of optic nerve and visual field defects. The angle of the anterior chamber of the eye is open, and usually the intraocular pressure is increased. However, glaucoma can occur at any intraocular pressure. The disease is generally asymptomatic until the late stages, by which time significant and irreversible optic nerve damage has already taken place. The disease is caused by variants affecting the gene represented in this entry. Glaucoma 3, primary congenital, A (GLC3A) [MIM:231300] An autosomal recessive form of primary congenital glaucoma (PCG). PCG is characterized by marked increase of intraocular pressure at birth or early childhood, large ocular globes (buphthalmos) and corneal edema. It results from developmental defects of the trabecular meshwork and anterior chamber angle of the eye that prevent adequate drainage of aqueous humor. The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. MYOC mutations may contribute to GLC3A via digenic inheritance with CYP1B1 and/or another locus associated with the disease.

Induction. Up-regulated by dexamethasone, a glucocorticoid.

RefSeq proteins (1): NP_000252* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003112	Olfac-like_dom	Domain
IPR050605	Olfactomedin-like_domain	Family

Pfam: PF02191

UniProt features (149 total): sequence variant 90, strand 26, mutagenesis site 6, turn 6, binding site 5, chain 3, helix 3, region of interest 2, signal peptide 1, site 1, glycosylation site 1, disulfide bond 1, domain 1, coiled-coil region 1, short sequence motif 1, compositionally biased region 1

Structure

Experimental structures (PDB)

24 structures.

PDB	Method	Resolution (Å)
7SKE	X-RAY DIFFRACTION	1.24
8FRR	X-RAY DIFFRACTION	1.27
7SKF	X-RAY DIFFRACTION	1.28
7SKG	X-RAY DIFFRACTION	1.33
7SJW	X-RAY DIFFRACTION	1.38
7T8D	X-RAY DIFFRACTION	1.38
7SJV	X-RAY DIFFRACTION	1.39
7SJU	X-RAY DIFFRACTION	1.39
9DRW	X-RAY DIFFRACTION	1.45
9DOZ	X-RAY DIFFRACTION	1.45
6PKF	X-RAY DIFFRACTION	1.48
7SIJ	X-RAY DIFFRACTION	1.54
7SJT	X-RAY DIFFRACTION	1.54
7SKD	X-RAY DIFFRACTION	1.71
7SIB	X-RAY DIFFRACTION	1.78
6OU3	X-RAY DIFFRACTION	1.8
6OU0	X-RAY DIFFRACTION	1.8
6OU1	X-RAY DIFFRACTION	1.88
6PKE	X-RAY DIFFRACTION	1.88
4WXS	X-RAY DIFFRACTION	1.9
6PKD	X-RAY DIFFRACTION	1.9
6OU2	X-RAY DIFFRACTION	1.96
4WXU	X-RAY DIFFRACTION	2.09
4WXQ	X-RAY DIFFRACTION	2.15

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99972-F1	79.40	0.53

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): 226–227 (cleavage; by capn2)

Ligand- & substrate-binding residues (5): 380; 428; 429; 477; 478

Disulfide bonds (1): 245–433

Glycosylation sites (1): 57

Mutagenesis-validated functional residues (6):

Position	Phenotype
226–230	impairs endoproteolytic processing.
226	reduced processing. impairs endoproteolytic processing; when associated with a-229 or a-230. completely processed after
226	slightly increases endoproteolytic processing.
227	reduced processing.
229	completely blocks endoproteolytic processing; when associated with a-226. completely processed after 6 days of expressio
230	impairs endoproteolytic processing; when associated with a-226. completely processed after 6 days of expression, and rel

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 278 (showing top): GOBP_MEMBRANE_DEPOLARIZATION, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_SKELETAL_MUSCLE_ADAPTATION, GOBP_NEURON_MATURATION, GOBP_NON_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_FOCAL_ADHESION_ASSEMBLY, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_GLIAL_CELL_DEVELOPMENT, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_OSTEOBLAST_DIFFERENTIATION, GOBP_NEUROGENESIS

GO Biological Process (20): osteoblast differentiation (GO:0001649), negative regulation of cell-matrix adhesion (GO:0001953), signal transduction (GO:0007165), skeletal muscle hypertrophy (GO:0014734), myelination in peripheral nervous system (GO:0022011), positive regulation of cell migration (GO:0030335), neuron projection development (GO:0031175), negative regulation of Rho protein signal transduction (GO:0035024), non-canonical Wnt signaling pathway (GO:0035567), ERBB2-ERBB3 signaling pathway (GO:0038133), regulation of MAPK cascade (GO:0043408), clustering of voltage-gated sodium channels (GO:0045162), positive regulation of JNK cascade (GO:0046330), positive regulation of stress fiber assembly (GO:0051496), negative regulation of stress fiber assembly (GO:0051497), positive regulation of focal adhesion assembly (GO:0051894), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), positive regulation of mitochondrial depolarization (GO:0051901), bone development (GO:0060348), positive regulation of substrate adhesion-dependent cell spreading (GO:1900026)

GO Molecular Function (6): fibronectin binding (GO:0001968), frizzled binding (GO:0005109), receptor tyrosine kinase binding (GO:0030971), myosin light chain binding (GO:0032027), metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (15): obsolete extracellular space (GO:0005615), mitochondrial outer membrane (GO:0005741), mitochondrial inner membrane (GO:0005743), mitochondrial intermembrane space (GO:0005758), endoplasmic reticulum (GO:0005783), rough endoplasmic reticulum (GO:0005791), Golgi apparatus (GO:0005794), cilium (GO:0005929), cytoplasmic vesicle (GO:0031410), node of Ranvier (GO:0033268), extracellular exosome (GO:0070062), extracellular region (GO:0005576), mitochondrion (GO:0005739), membrane (GO:0016020), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	4
cellular anatomical structure	4
intracellular membrane-bounded organelle	3
stress fiber assembly	2
regulation of stress fiber assembly	2
mitochondrial membrane	2
endomembrane system	2
ossification	1
cell differentiation	1
regulation of cell-matrix adhesion	1
cell-matrix adhesion	1
negative regulation of cell-substrate adhesion	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
striated muscle hypertrophy	1
skeletal muscle adaptation	1
Schwann cell development	1
peripheral nervous system axon ensheathment	1
myelination	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
neuron development	1
plasma membrane bounded cell projection organization	1
Rho protein signal transduction	1
regulation of Rho protein signal transduction	1
negative regulation of small GTPase mediated signal transduction	1
Wnt signaling pathway	1
ERBB2 signaling pathway	1
ERBB3 signaling pathway	1
MAPK cascade	1
regulation of intracellular signal transduction	1
neuronal ion channel clustering	1
JNK cascade	1
positive regulation of MAPK cascade	1
regulation of JNK cascade	1
positive regulation of actin filament bundle assembly	1

Protein interactions and networks

STRING

1204 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MYOC	WDR36	Q8NI36	970
MYOC	OPTN	Q96CV9	951
MYOC	OLFM3	Q96PB7	950
MYOC	CYP1B1	Q16678	944
MYOC	FLOT1	O75955	898
MYOC	FBN1	P35555	871
MYOC	ASB10	Q8WXI3	857
MYOC	SPARCL1	Q14515	814
MYOC	PEX5	P50542	753
MYOC	SNCG	O76070	729
MYOC	NTF4	P34130	702
MYOC	FN1	P02751	698
MYOC	TMCO1	Q9UM00	697
MYOC	CRYBB1	P53674	696
MYOC	LINGO1	Q96FE5	695

IntAct

18 interactions, top by confidence:

A	B	Type	Score
MYL2	MYOC	psi-mi:“MI:0915”(physical association)	0.620
MYOC	MYL2	psi-mi:“MI:0915”(physical association)	0.620
MYL2	MYOC	psi-mi:“MI:0403”(colocalization)	0.620
SGTA	MYOC	psi-mi:“MI:0915”(physical association)	0.560
SPARC	MYOC	psi-mi:“MI:0915”(physical association)	0.530
SPARCL1	MYOC	psi-mi:“MI:0915”(physical association)	0.530
SPARCL1	MYOC	psi-mi:“MI:0407”(direct interaction)	0.530
SPARC	MYOC	psi-mi:“MI:0407”(direct interaction)	0.530
MYOC	MYOC	psi-mi:“MI:0915”(physical association)	0.370
SGTA	MYOC	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (50): SGTA (Two-hybrid), MYOC (Reconstituted Complex), OLFM3 (Reconstituted Complex), MYOC (Far Western), OLFM3 (Far Western), MYOC (Affinity Capture-MS), FBN1 (Reconstituted Complex), FN1 (Reconstituted Complex), MYOC (Two-hybrid), SERPINF1 (Two-hybrid), ACTA2 (Two-hybrid), GAPDH (Two-hybrid), FTL (Two-hybrid), ACTB (Two-hybrid), ACTG1 (Two-hybrid)

ESM2 similar proteins: A2A699, A2BD09, A4IIT5, A5D7T4, A6QLD2, A8MVW0, O35764, O43278, O70624, O95502, O95897, P35054, P51693, Q03157, Q2PT31, Q3UPI1, Q3UZZ4, Q3V1G4, Q568Y7, Q594P2, Q5QQ37, Q66H86, Q68BL7, Q68BL8, Q6AYE5, Q6P7B4, Q6UWH4, Q6UWY5, Q6ZMI3, Q701R2, Q701R3, Q701R4, Q766D5, Q76KP1, Q80WL1, Q863A3, Q866N2, Q86VZ4, Q8BHP7, Q8BM13

Diamond homologs: A2BD09, A4IIT5, A6QLD2, B0BNI5, B5MFE9, O70624, O88917, O88923, O88998, O94910, O95490, O95897, O97817, O97827, O97831, P63056, P63057, Q0P3W2, Q0V9V5, Q0VCP3, Q25C36, Q2PT31, Q3UZZ4, Q3V1G4, Q568Y7, Q594P2, Q62609, Q66H86, Q68BL7, Q68BL8, Q6UWY5, Q6UX06, Q80TR1, Q80TS3, Q863A3, Q866N2, Q8BHP7, Q8BK62, Q8BM13, Q8JZZ7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	16
Likely pathogenic	35
Uncertain significance	208
Likely benign	51
Benign	26

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1342196	NM_000261.2(MYOC):c.752T>C (p.Val251Ala)	Pathogenic
1342202	NM_000261.2(MYOC):c.1130C>T (p.Thr377Met)	Pathogenic
1342203	NM_000261.2(MYOC):c.1139A>C (p.Asp380Ala)	Pathogenic
1367461	NC_000001.10:g.(?171605065)(173962123_?)del	Pathogenic
1439558	NM_000261.2(MYOC):c.1021T>C (p.Ser341Pro)	Pathogenic
1686785	NM_000261.2(MYOC):c.1440C>G (p.Asn480Lys)	Pathogenic
3026189	NM_000261.2(MYOC):c.565C>T (p.Arg189Ter)	Pathogenic
7946	NM_000261.2(MYOC):c.1309T>C (p.Tyr437His)	Pathogenic
7947	NM_000261.2(MYOC):c.1091G>T (p.Gly364Val)	Pathogenic
7948	NM_000261.2(MYOC):c.1109C>T (p.Pro370Leu)	Pathogenic
7949	NM_000261.2(MYOC):c.1102C>T (p.Gln368Ter)	Pathogenic
7951	NM_000261.2(MYOC):c.1440C>A (p.Asn480Lys)	Pathogenic
7952	NM_000261.2(MYOC):c.1099G>A (p.Gly367Arg)	Pathogenic
7954	NM_000261.2(MYOC):c.1267A>G (p.Lys423Glu)	Pathogenic
7956	NM_000261.2(MYOC):c.1297T>C (p.Cys433Arg)	Pathogenic
7960	NM_000261.2(MYOC):c.754G>A (p.Gly252Arg)	Pathogenic
1173106	NM_000261.2(MYOC):c.1435T>C (p.Tyr479His)	Likely pathogenic
1342197	NM_000261.2(MYOC):c.856T>C (p.Trp286Arg)	Likely pathogenic
1342198	NM_000261.2(MYOC):c.976G>C (p.Gly326Arg)	Likely pathogenic
1342205	NM_000261.2(MYOC):c.1150G>A (p.Asp384Asn)	Likely pathogenic
1342210	NM_000261.2(MYOC):c.736G>A (p.Gly246Arg)	Likely pathogenic
1342962	NM_000261.2(MYOC):c.1087G>A (p.Ala363Thr)	Likely pathogenic
1342963	NM_000261.2(MYOC):c.1100_1103delinsT (p.Gly367_Gln368delinsVal)	Likely pathogenic
1342964	NM_000261.2(MYOC):c.1139A>G (p.Asp380Gly)	Likely pathogenic
1342965	NM_000261.2(MYOC):c.1138G>T (p.Asp380Tyr)	Likely pathogenic
1342967	NM_000261.2(MYOC):c.761C>T (p.Pro254Leu)	Likely pathogenic
1342969	NM_000261.2(MYOC):c.967G>A (p.Glu323Lys)	Likely pathogenic
1686782	NM_000261.2(MYOC):c.1276G>T (p.Val426Phe)	Likely pathogenic
1686788	NM_000261.2(MYOC):c.814C>G (p.Arg272Gly)	Likely pathogenic
1686789	NM_000261.2(MYOC):c.1442C>T (p.Pro481Leu)	Likely pathogenic

SpliceAI

413 predictions. Top by Δscore:

Variant	Effect	Δscore
1:171636720:C:CT	acceptor_gain	1.0000
1:171636721:A:T	acceptor_gain	1.0000
1:171638587:A:AC	donor_gain	1.0000
1:171638588:A:C	donor_gain	1.0000
1:171638595:A:AC	donor_gain	1.0000
1:171638596:C:CC	donor_gain	1.0000
1:171638718:AGAAA:A	acceptor_gain	1.0000
1:171638719:GAAA:G	acceptor_gain	1.0000
1:171638720:AAA:A	acceptor_gain	1.0000
1:171638721:AA:A	acceptor_gain	1.0000
1:171638722:ACTG:A	acceptor_loss	1.0000
1:171638723:C:CC	acceptor_gain	1.0000
1:171638723:CTGC:C	acceptor_loss	1.0000
1:171638724:T:C	acceptor_loss	1.0000
1:171638728:T:C	acceptor_gain	1.0000
1:171638728:T:TC	acceptor_gain	1.0000
1:171636709:CCTGG:C	acceptor_gain	0.9900
1:171638591:TCATA:T	donor_loss	0.9900
1:171638592:CATA:C	donor_loss	0.9900
1:171638593:AT:A	donor_loss	0.9900
1:171638594:TAC:T	donor_loss	0.9900
1:171638605:C:CA	donor_gain	0.9900
1:171638638:T:A	donor_gain	0.9900
1:171638726:C:CT	acceptor_gain	0.9900
1:171638727:A:C	acceptor_gain	0.9900
1:171638727:A:T	acceptor_gain	0.9900
1:171650029:T:TA	donor_gain	0.9900
1:171652002:TCTTA:T	donor_loss	0.9900
1:171652003:CTTA:C	donor_loss	0.9900
1:171652004:TTA:T	donor_loss	0.9900

AlphaMissense

3285 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:171636632:A:G	W270R	0.991
1:171636632:A:T	W270R	0.991
1:171636171:C:A	K423N	0.988
1:171636171:C:G	K423N	0.988
1:171636468:G:C	S324R	0.987
1:171636468:G:T	S324R	0.987
1:171636470:T:G	S324R	0.987
1:171635975:A:G	W489R	0.986
1:171635975:A:T	W489R	0.986
1:171636094:A:T	V449D	0.985
1:171636630:C:A	W270C	0.984
1:171636630:C:G	W270C	0.984
1:171635973:C:A	W489C	0.983
1:171635973:C:G	W489C	0.983
1:171635972:C:G	D490H	0.982
1:171636323:A:G	W373R	0.982
1:171636323:A:T	W373R	0.982
1:171636584:A:G	W286R	0.982
1:171636584:A:T	W286R	0.982
1:171636150:G:C	F430L	0.981
1:171636150:G:T	F430L	0.981
1:171636152:A:G	F430L	0.981
1:171636261:G:C	S393R	0.980
1:171636261:G:T	S393R	0.980
1:171636263:T:G	S393R	0.980
1:171636131:A:C	Y437D	0.978
1:171636015:G:C	S475R	0.977
1:171636015:G:T	S475R	0.977
1:171636017:T:G	S475R	0.977
1:171636637:C:T	G268D	0.977

dbSNP variants (sampled 300 via entrez): RS1000017079 (1:171639880 G>A,T), RS1000051182 (1:171639543 G>A,T), RS1000059587 (1:171641095 C>T), RS1000848871 (1:171647849 A>G), RS1000950154 (1:171647225 A>C), RS1001060600 (1:171641117 T>C), RS1001221280 (1:171652123 A>G), RS1001327386 (1:171645783 T>A,C), RS1001338257 (1:171648088 C>G,T), RS1001400466 (1:171645475 G>C), RS1001424455 (1:171634919 A>G), RS1001651472 (1:171651851 G>A), RS1001908923 (1:171641015 C>T), RS1002252495 (1:171653113 A>G), RS1002282994 (1:171641532 AG>A)

Disease associations

OMIM: gene MIM:601652 | disease phenotypes: MIM:137750, MIM:601859, MIM:613839, MIM:137760

GenCC curated gene-disease

Disease	Classification	Inheritance
glaucoma 1, open angle, A	Definitive	Autosomal dominant
juvenile open angle glaucoma	Definitive	Autosomal dominant
congenital glaucoma	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
open-angle glaucoma	Definitive	AD

Mondo (8): open-angle glaucoma (MONDO:0005338), glaucoma 1, open angle, A (MONDO:0007664), autoimmune lymphoproliferative syndrome type 1 (MONDO:0011158), constitutional megaloblastic anemia with severe neurologic disease (MONDO:0013456), glaucoma (MONDO:0005041), OPTN-related open angle glaucoma (MONDO:0100553), congenital glaucoma (MONDO:0020366), juvenile open angle glaucoma (MONDO:0020367)

Orphanet (3): Juvenile glaucoma (Orphanet:98977), Autoimmune lymphoproliferative syndrome (Orphanet:3261), Constitutional megaloblastic anemia with severe neurologic disease (Orphanet:319651)

HPO phenotypes

35 total (30 of 35 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000485	Megalocornea
HP:0000501	Glaucoma
HP:0000505	Visual impairment
HP:0000525	Abnormality iris morphology
HP:0000545	Myopia
HP:0000557	Buphthalmos
HP:0000572	Visual loss
HP:0000587	Abnormal optic nerve morphology
HP:0000593	Abnormal anterior chamber morphology
HP:0000603	Central scotoma
HP:0000613	Photophobia
HP:0000643	Blepharospasm
HP:0000646	Amblyopia
HP:0001089	Iris atrophy
HP:0001138	Optic neuropathy
HP:0007663	Reduced visual acuity
HP:0007765	Deep anterior chamber
HP:0007854	Glaucomatous visual field defect
HP:0007905	Abnormal iris vasculature
HP:0007906	Ocular hypertension
HP:0007957	Corneal opacity
HP:0007994	Peripheral visual field loss
HP:0009926	Epiphora
HP:0011003	High myopia
HP:0011490	Abnormal Descemet membrane morphology
HP:0012040	Corneal stromal edema
HP:0012108	Open angle glaucoma
HP:0012511	Temporal optic disc pallor
HP:0012636	Retinal venous occlusion

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST003075_102	Cognitive decline rate in late mild cognitive impairment	1.000000e-07
GCST003075_8	Cognitive decline rate in late mild cognitive impairment	2.000000e-07
GCST008759_30	Intake of total sugars	6.000000e-06
GCST90011766_7	Glaucoma (primary open-angle)	5.000000e-33
GCST90011770_33	Glaucoma (primary open-angle)	1.000000e-42

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007710	cognitive decline measurement
EFO:0010158	sugar consumption measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D005901	Glaucoma	C11.525.381
D005902	Glaucoma, Open-Angle	C11.525.381.407
D006871	Hydrophthalmos	C11.250.480; C11.525.381.407.480; C16.131.384.480; C16.614.438
C564234	Glaucoma 1, Open Angle, A (supp.)
C565095	Megaloblastic Anemia due to Dihydrofolate Reductase Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105967 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 5 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.00	Kd	99	nM	CHEMBL339587
6.19	Kd	650	nM	CHEMBL1432046

PubChem BioAssay actives

3 with measured affinity, of 24 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
1-(4-hydroxyphenyl)-3-(3-methoxyphenyl)thiourea	1488869: Binding affinity myocilin-OLF domain (unknown origin) by Sypro Orange dye-based DSF assay	kd	<0.0001	uM
(E)-3-(3,4-dihydroxyphenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one	1488869: Binding affinity myocilin-OLF domain (unknown origin) by Sypro Orange dye-based DSF assay	kd	0.0990	uM
1-(4-nitrophenyl)-3-[4-[4-[(4-nitrophenyl)carbamoylamino]phenoxy]phenyl]urea	1488869: Binding affinity myocilin-OLF domain (unknown origin) by Sypro Orange dye-based DSF assay	kd	0.6500	uM

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
arsenite	decreases methylation	1
Ginkgo biloba extract	decreases reaction, increases expression	1
CGP 52608	affects binding, increases reaction	1
Benzo(a)pyrene	affects methylation	1
Dexamethasone	decreases reaction, increases expression	1
Nickel	decreases expression	1
Zinc	decreases expression	1
Aflatoxin B1	increases methylation	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4058245	Binding	Binding affinity myocilin-OLF domain (unknown origin) by SRP assay	Pocket detection and interaction-weighted ligand-similarity search yields novel high-affinity binders for Myocilin-OLF, a protein implicated in glaucoma. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07396441	PHASE4	RECRUITING	Supplementary Kelulut Honey Therapy in Juvenile Open-Angle Glaucoma: Effects on IL-6, RNFL and Dry Eye
NCT00047606	PHASE4	TERMINATED	Phase 4 Study Comparing IOP Lowering in OAG or OH in Caucasian or Japanese Subjects C-02-32
NCT00273429	PHASE4	COMPLETED	Cosopt Versus Xalatan
NCT00273442	PHASE4	COMPLETED	Assessing Cosopt Switch Patients
NCT00273455	PHASE4	COMPLETED	Lumigan Versus Cosopt
NCT00273481	PHASE4	COMPLETED	Cosopt Versus Xalacom
NCT00300079	PHASE4	COMPLETED	Study of the Intraocular Pressure (IOP)-Lowering Efficacy of Azopt 1.0% Compared to Timolol 0.5% in Patients With Glaucoma or Ocular Hypertension
NCT00304785	PHASE4	COMPLETED	Latanoprost Versus Fotil
NCT00308945	PHASE4	COMPLETED	Influence of Prostaglandins on Ocular Blood Flow in Glaucoma Patients
NCT00326014	PHASE4	COMPLETED	A Study of the Trabecular Micro-Bypass Stent in Combination With Cataract Surgery in Open Angle Glaucoma Subjects.
NCT00326040	PHASE4	COMPLETED	A Study of the Glaukos Trabecular Micro-Bypass Stent in Refractory Open Angle Glaucoma Subjects
NCT00326079	PHASE4	UNKNOWN	A Study of the Glaukos Trabecular Micro-bypass Stent in Open Angle Glaucoma Subjects 1 Stent Versus 2
NCT00330577	PHASE4	COMPLETED	24-Hour Intraocular Pressure (IOP) And Blood Pressure Control In Glaucoma And Ocular Hypertension Patients
NCT00372827	PHASE4	COMPLETED	Study of Brinzolamide and Timolol When Added to Travoprost in Primary Open-angle Glaucoma or Ocular Hypertension
NCT00397241	PHASE4	COMPLETED	24-hour Study of Dorzolamide/Timolol and Latanoprost/Timolol Fixed Combinations
NCT00457795	PHASE4	COMPLETED	24-hour IOP-lowering Effect of Brimonidine 0.1%
NCT00471068	PHASE4	TERMINATED	Study of Travatan and Cosopt in Primary Open-Angle Glaucoma or Ocular Hypertension
NCT00508469	PHASE4	COMPLETED	Adherence Assessment With Travalert Dosing Aid
NCT00527592	PHASE4	COMPLETED	A Single Dose Comfort Comparison of Travatan Z in One Eye Versus Xalatan in the Opposite Eye in Patients With Primary Open-Angle Glaucoma or Ocular Hypertension
NCT00538590	PHASE4	COMPLETED	Ologen Collagen Matrix Safety and Effective Comparison With Mitomycin-C(MMC) in Glaucoma Surgery
NCT00539526	PHASE4	COMPLETED	Evaluation of Hyperemia With the Use of Ocular Prostaglandin Analogues
NCT00545064	PHASE4	COMPLETED	Dry Eye Study With Cosopt® Over 8 Weeks in Patients With Open-Angle Glaucoma or Ocular Hypertension (0507A-152)(COMPLETED)
NCT00675207	PHASE4	COMPLETED	Comparison of Brimonidine Purite, Dorzolamide, and Brinzolamide as Adjunctive Therapy to Prostaglandin Analogs
NCT00698945	PHASE4	COMPLETED	Comparison of Istalol™ 0.5% QD (Timolol Maleate/Sorbitol Complex, ISTA Pharmaceutical) to Brimonidine Tartrate 0.1% BID as Adjunctive Therapy to Latanoprost 0.005% in Adults With Ocular Hypertension (OHT) or Open-Angle Glaucoma (OAG)
NCT00759239	PHASE4	COMPLETED	Phase IV Randomised Double-masked Clinical Trial: Assessing Morning Versus Evening Dosing of a Fixed Dose Combination of Travoprost 0.004% / Timolol Maleate 0.5% in Patients With Primary Open-angle Glaucoma or Ocular Hypertension
NCT00798759	PHASE4	COMPLETED	Examination of Ocular Surface Effects With Administration of Travatan Z and XALATAN
NCT00803803	PHASE4	COMPLETED	Dose, Effects and Characteristics of Pilocarpine
NCT00822055	PHASE4	COMPLETED	Comparison of the Fixed Combinations of Brimonidine/Timolol and Dorzolamide/Timolol in Subjects With Open-Angle Glaucoma or Ocular Hypertension
NCT00822081	PHASE4	COMPLETED	Comparison of the Fixed Combinations of Brimonidine/Timolol and Dorzolamide/Timolol in Subjects With Open-Angle Glaucoma or Ocular Hypertension
NCT00828906	PHASE4	COMPLETED	DuoTrav® Eye Drops As Replacement Therapy Program
NCT00887029	PHASE4	COMPLETED	A 12 Week Comparison of DuoTrav and Xalacom in Open-Angle Glaucoma
NCT00941525	PHASE4	COMPLETED	Central Corneal Thickness and 24-hour Fluctuation of Intraocular Pressure
NCT01055366	PHASE4	COMPLETED	ELAZOP Switching Study in Korea
NCT01162603	PHASE4	COMPLETED	Latanoprost Versus Tafluprost: 24-hour Intraocular Pressure (IOP)
NCT01327599	PHASE4	COMPLETED	Efficacy of Changing to DUOTRAV® From Prior Therapy
NCT01340014	PHASE4	COMPLETED	Patient Preference Comparison of AZARGA Versus COSOPT
NCT01369771	PHASE4	COMPLETED	The Effects of Preservative-free Prostaglandin Eye Drops in Sign and Symptoms on the Eyes of Patients With Glaucoma
NCT01415401	PHASE4	COMPLETED	Efficacy and Tolerability of AZARGA® as Replacement Therapy in Patients on COMBIGAN® Therapy in Canada
NCT01443988	PHASE4	COMPLETED	Subjects With Open-angle Glaucoma, Pseudoexfoliative Glaucoma, or Ocular Hypertension Naïve to Medical and Surgical Therapy, Treated With Two Trabecular Micro-bypass Stents (iStent)or Travoprost
NCT01444040	PHASE4	COMPLETED	Subjects With Open-angle Glaucoma, Pseudoexfoliative Glaucoma, or Ocular Hypertension Naïve to Medical and Surgical Therapy, Treated With Two Trabecular Micro-bypass Stents (iStent Inject) or Travoprost