CYGB

Summary

CYGB (cytoglobin, HGNC:16505) is a protein-coding gene on chromosome 17q25.1, encoding Cytoglobin (Q8WWM9). Probable multifunctional globin with a hexacoordinated heme iron required for the catalysis of various reactions depending on redox condition of the cell as well as oxygen availability.

This gene encodes a globin protein found in vertebrate cells. The encoded protein is described as a hexacoordinate hemoglobin which binds ligand differently from the pentacoordinate hemoglobins involved in oxygen transport, and may be involved in protection during oxidative stress. This gene is located on chromosome 17 in the same region as a retinal gene which is mutated in progressive rod-cone degeneration, but in the opposite orientation.

Source: NCBI Gene 114757 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 157 total — 5 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 1
• MANE Select transcript: NM_134268

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16505
Approved symbol	CYGB
Name	cytoglobin
Location	17q25.1
Locus type	gene with protein product
Status	Approved
Aliases	HGB, STAP
Ensembl gene	ENSG00000161544
Ensembl biotype	protein_coding
OMIM	608759
Entrez	114757

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000293230, ENST00000586160, ENST00000589145, ENST00000589342, ENST00000590175

RefSeq mRNA: 1 — MANE Select: NM_134268 NM_134268

CCDS: CCDS11746

Canonical transcript exons

ENST00000293230 — 4 exons

Exon	Start	End
ENSE00001118062	76530979	76531142
ENSE00001193939	76527356	76528611
ENSE00002806906	76537400	76537709
ENSE00003501143	76531460	76531691

Expression profiles

Bgee: expression breadth ubiquitous, 219 present calls, max score 98.50.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.9170 / max 606.6914, expressed in 1131 samples.

FANTOM5 promoters (18 alternative TSS)

Promoter ID	TPM avg	Samples expressed
168233	12.1845	979
168231	1.3162	541
168235	1.2172	472
168236	0.8987	444
168232	0.3990	243
168237	0.3893	228
168242	0.2684	139
168239	0.2258	73
168227	0.2048	107
168225	0.1936	92

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cardiac muscle of right atrium	UBERON:0003379	98.50	gold quality
left ventricle myocardium	UBERON:0006566	96.62	gold quality
right atrium auricular region	UBERON:0006631	96.57	gold quality
apex of heart	UBERON:0002098	96.55	gold quality
cardiac atrium	UBERON:0002081	96.37	gold quality
omental fat pad	UBERON:0010414	95.27	gold quality
peritoneum	UBERON:0002358	95.18	gold quality
subcutaneous adipose tissue	UBERON:0002190	95.13	gold quality
adipose tissue of abdominal region	UBERON:0007808	95.13	gold quality
right lobe of thyroid gland	UBERON:0001119	94.64	gold quality
adipose tissue	UBERON:0001013	93.70	gold quality
left lobe of thyroid gland	UBERON:0001120	92.90	gold quality
heart left ventricle	UBERON:0002084	92.72	gold quality
cardiac ventricle	UBERON:0002082	92.36	gold quality
mucosa of stomach	UBERON:0001199	92.26	gold quality
endocervix	UBERON:0000458	92.21	gold quality
heart	UBERON:0000948	92.18	gold quality
ileal mucosa	UBERON:0000331	91.88	gold quality
thyroid gland	UBERON:0002046	91.65	gold quality
tibial nerve	UBERON:0001323	91.55	gold quality
urinary bladder	UBERON:0001255	90.21	gold quality
right coronary artery	UBERON:0001625	89.83	gold quality
left coronary artery	UBERON:0001626	89.32	gold quality
coronary artery	UBERON:0001621	89.31	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	89.09	gold quality
right hemisphere of cerebellum	UBERON:0014890	89.02	gold quality
muscle layer of sigmoid colon	UBERON:0035805	88.71	gold quality
lower esophagus muscularis layer	UBERON:0035833	88.49	gold quality
lower esophagus	UBERON:0013473	88.44	gold quality
cerebellar hemisphere	UBERON:0002245	88.39	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	660.53
E-HCAD-11	yes	56.11
E-HCAD-4	yes	43.17
E-GEOD-135922	yes	18.88
E-ANND-3	yes	12.41

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, ETS1, HIF1A, SP1

miRNA regulators (miRDB)

53 targeting CYGB, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-8076	99.78	68.52	1170
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-9851-3P	99.63	69.68	1110
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-18A-3P	99.56	65.68	1092
HSA-MIR-190A-5P	99.54	71.45	933
HSA-MIR-190B-5P	99.54	71.40	925
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-593-5P	99.34	69.50	965
HSA-MIR-4777-5P	99.33	67.53	1148
HSA-MIR-1912-3P	99.32	67.40	936
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-1295B-5P	99.03	67.50	810
HSA-MIR-4270	99.02	66.26	1987

Literature-anchored findings (GeneRIF, showing 40)

• A ubiquitously expressed human hexacoordinate hemoglobin (PMID:11893755)
• vertebrate myoglobins are in fact a specialized intracellular globin that evolved in adaptation to the special needs of muscle cells (PMID:11919282)
• cloned, deduced amino acid sequence and expressed in diseased liver tissue where stellate cells were present (PMID:12359339)
• characterization of the heme environmental structure of this protein, a fourth globin in humans (PMID:12718557)
• results suggest a novel mechanism for the regulation of oxygen binding; contact with an appropriate electron donor would provoke the release of oxygen. Hence the oxygen affinity would be directly linked to the redox state of the cell. (PMID:14530264)
• differential expression of cytoglobin argues against a general respiratory function of this molecule, but rather indicates a connective tissue-specific function (PMID:14660570)
• hereditary neuralgic amyotrophy is not caused by point mutations of cytoglobin (PMID:15052627)
• Results describe the crystal structure of cytoglobin, which displays heme hexa-coordination. (PMID:15095869)
• reporting of X-ray crystallographic structure (PMID:15165856)
• oxygen binding in human neuroglobin and cytoglobin is allosterically regulated and temperature-dependent (PMID:15299006)
• molecular characterization of human and Drosophila cytoglobulins and neuroglobulins (PMID:15819897)
• analysis of the proximal and distal histidine environment of cytoglobin and neuroglobin (PMID:16201751)
• Cytoglobin is a novel candidate tumour suppressor gene highly methylated in upper aero-digestive tract squamous cancer (PMID:16449996)
• We now show that cytoglobin gene expression in oesophageal biopsies from tylotic patients is dramatically reduced by approximately 70% compared with normal oesophagus. Furthermore, both alleles are equally repressed (PMID:16510494)
• Results provide the first evidence to suggest the implication of CYGB in the pathogenesis of non-small cell lung cancer. (PMID:16698880)
• The structure of a new crystal form of cytoglobin reveals a new dimerization arrangement of cytoglobin. (PMID:16699195)
• Pomoter elements of human CYGB gene are located between -1113 to -10 relative to the translation start site. (PMID:16797742)
• hypoxia responsive elements (HREs) at positions -141, -144 and -448 were essential for activation of CYGB expression under hypoxic conditions. The binding of hypoxia inducible factor protein to the HREs was confirmed. (PMID:17936249)
• A role for cytoglobin in cytoprotection of neuronal cells from oxidative-related damage. (PMID:18353768)
• Data constitute the first direct functional evidence for CYGB, the newest member of the globin family, as a tumor suppressor gene. (PMID:18794132)
• Neuroglobin and cytoglobin are colocalized within human retinal neurons and retinal pigment epithelium but not within glial cells. (PMID:19001220)
• cytoglobin contributes to cell-mediated NO dioxygenation and represents an important NO sink in the vascular wall. (PMID:19147491)
• CYGB gene is regulated by both promoter methylation and tumour hypoxia in HNSCC and that increased expression of this gene correlates with clincopathological measures of a tumour’s biological aggression. (PMID:19568272)
• Cygb has a nitric-oxide dioxygenase function and ascorbate and cytochrome b(5) have roles as reductants (PMID:20511233)
• Cytoglobin displays biphasic kinetics after the photolysis of CO, as a result of competition with an internal protein ligand, the E7 distal histidine. (PMID:20553503)
• Binding of ferric cytoglobin to lipids and their subsequent transformation may be integral to the physiological function of cytoglobin, generating cell signalling lipid molecules under an oxidative environment. (PMID:21171964)
• knockdown of cytoglobin expression can sensitize human glioma cells to oxidative stress (PMID:21631290)
• Caenorhabditis elegans globin GLB-26 (expressed from gene T22C1.2) has been studied in comparison with human neuroglobin (Ngb) and cytoglobin (Cygb) for its electron transfer properties (PMID:21674044)
• Cytoglobin, a protein that can be induced in response to oxidative stress, is elevated in most atrophic foci in adenocarcinoma of the prostate, suggesting hypoxic, and/or oxidative damage. (PMID:22025306)
• RHBDF2 and CYGB may play distinctive roles in ovarian cancer and could be added to the growing roster of chromosome 17 genes implicated in this disease. (PMID:22344671)
• normal physiological concentrations of cytoglobin do not offer cytoprotection from reactive oxygen species (PMID:22359545)
• Coexistence of Cygb with efficient reductants in tissues allows Cygb to function as an oxygen-dependent regulator of nitric oxide (NO) decay. A related kinetic model predicts the NO consumption rate. (PMID:22577939)
• This suggests that Cytoglobin is likely not important for global neuronal protection following ischemia and the role of Cytoglobin in relation to endogenous neuroprotection remains unresolved. (PMID:22750003)
• Cygb-mediated nitrite reduction can play an important role in NO generation and soluble guanylyl cyclase activation under hypoxic conditions (PMID:22896706)
• Report cytoglobin expression in human brain. (PMID:23160832)
• A substantial change in both protein dynamics and inner cavities is observed upon transition from the CO-liganded to the pentacoordinated and bis-histidyl hexacoordinated species, which could be exploited as a signalling state. (PMID:23308092)
• Results show that CYGB revealed Tumor Suppressor Gene properties in normoxia but promoted tumourigenic potential of the cells exposed to stress, suggesting a bimodal function in lung tumourigenesis. (PMID:23591990)
• Reduction of Cygb by cellular reductants enables Cygb to efficiently regulate nitric oxide metabolism in the vascular wall in an oxygen-dependent manner. (PMID:23710929)
• Ngb and Cygb are expressed in the solitary tract nucleus and in the carotid body, and may have roles in the processing of cardiovascular and respiratory reflex inputs (PMID:23835959)
• Reduction of the internal disulfide bond between Cys 38 and 83 switches the ligand migration pathway in cytoglobin. (PMID:24008134)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	cygb2	ENSDARG00000070148
danio_rerio	cygb1	ENSDARG00000099371
mus_musculus	Cygb	ENSMUSG00000020810
rattus_norvegicus	Cygb	ENSRNOG00000011541
drosophila_melanogaster	glob1	FBGN0027657
caenorhabditis_elegans		WBGENE00008996
caenorhabditis_elegans		WBGENE00077763

Paralogs (11): HBQ1 (ENSG00000086506), HBZ (ENSG00000130656), HBA2 (ENSG00000188536), HBG2 (ENSG00000196565), MB (ENSG00000198125), HBA1 (ENSG00000206172), HBM (ENSG00000206177), HBE1 (ENSG00000213931), HBG1 (ENSG00000213934), HBD (ENSG00000223609), HBB (ENSG00000244734)

Protein

Protein identifiers

Cytoglobin — Q8WWM9 (reviewed: Q8WWM9)

Alternative names: Histoglobin, Nitric oxygen dioxygenase CYGB, Nitrite reductase CYGB, Pseudoperoxidase CYGB, Stellate cell activation-associated protein, Superoxide dismutase CYGB

All UniProt accessions (4): A0A1K0FUB6, Q8WWM9, K7EIM9, K7EMC7

UniProt curated annotations — full annotation on UniProt →

Function. Probable multifunctional globin with a hexacoordinated heme iron required for the catalysis of various reactions depending on redox condition of the cell as well as oxygen availability. Has a nitric oxide dioxygenase (NOD) activity and is most probably involved in cell-mediated and oxygen-dependent nitric oxide consumption. By scavenging this second messenger may regulate several biological processes including endothelium-mediated vasodilation and vascular tone. Under normoxic conditions functions as a nitric oxide dioxygenase (NOD) but under hypoxic conditions the globin may switch its function to that of a nitrite (NO2) reductase (NiR), generating nitric oxide. Could also have peroxidase and superoxide dismutase activities, detoxifying reactive oxygen species and protecting cells against oxidative stress. Also binds dioxygen with low affinity and could function as an oxygen sensor but has probably no function as a respiratory oxygen carrier.

Subunit / interactions. Monomeric. Homodimer; disulfide-linked in vitro. Also homooligomeric in vitro.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Widely expressed. Highest expression in heart, stomach, bladder and small intestine.

Post-translational modifications. The formation of an intramolecular disulfide bond between cysteines Cys-38 and Cys-83 specifically enhances the nitrite reductase activity.

Activity regulation. The nitric oxide dioxygenase activity is activated by a reducing system composed of cytochrome b5, its upstream reductase CYB5R3 and NADH.

Similarity. Belongs to the globin family.

RefSeq proteins (1): NP_599030* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000971	Globin	Domain
IPR009050	Globin-like_sf	Homologous_superfamily
IPR012292	Globin/Proto	Homologous_superfamily
IPR013314	Globin_lamprey/hagfish	Family

Pfam: PF00042

Catalyzed reactions (Rhea), 4 shown:

• 2 superoxide + 2 H(+) = H2O2 + O2 (RHEA:20696)
• H2O2 + AH2 = A + 2 H2O (RHEA:30275)
• Fe(III)-heme b-[protein] + nitric oxide + H2O = Fe(II)-heme b-[protein] + nitrite + 2 H(+) (RHEA:77711)
• Fe(II)-heme b-[protein] + nitric oxide + O2 = Fe(III)-heme b-[protein] + nitrate (RHEA:78091)

UniProt features (24 total): helix 10, mutagenesis site 4, disulfide bond 3, turn 2, binding site 2, chain 1, domain 1, sequence conflict 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
2DC3	X-RAY DIFFRACTION	1.68
1URV	X-RAY DIFFRACTION	2
1UT0	X-RAY DIFFRACTION	2.1
1URY	X-RAY DIFFRACTION	2.4
1UX9	X-RAY DIFFRACTION	2.4
1V5H	X-RAY DIFFRACTION	2.4
1UMO	X-RAY DIFFRACTION	2.59
3AG0	X-RAY DIFFRACTION	2.6
4B3W	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WWM9-F1	87.75	0.76

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 (2): 81 (distal binding residue); 113 (proximal binding residue)

Disulfide bonds (3): 38–83, 38, 83

Mutagenesis-validated functional residues (4):

Position	Phenotype
83	loss of interchain disulfide bond and loss of solubility but no effect on homodimerization; when associated with s-38.
38	decreased nitrite reductase activity; when associated with r-83.
38	loss of interchain disulfide bond and loss of solubility but no effect on homodimerization; when associated with s-83.
83	decreased nitrite reductase activity; when associated with r-38.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-203615	eNOS activation
R-HSA-8981607	Intracellular oxygen transport

MSigDB gene sets: 148 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_LIPID_MODIFICATION, AGGAAGC_MIR5163P, PEREZ_TP63_TARGETS, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_SUPEROXIDE_METABOLIC_PROCESS, GOBP_REGULATION_OF_FIBROBLAST_MIGRATION, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_AMEBOIDAL_TYPE_CELL_MIGRATION, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_CELLULAR_RESPONSE_TO_TOXIC_SUBSTANCE, GOBP_REACTIVE_NITROGEN_SPECIES_METABOLIC_PROCESS, AML_Q6, GOBP_RESPONSE_TO_OXYGEN_LEVELS

GO Biological Process (10): response to hypoxia (GO:0001666), response to oxidative stress (GO:0006979), negative regulation of fibroblast migration (GO:0010764), oxygen transport (GO:0015671), fatty acid oxidation (GO:0019395), removal of superoxide radicals (GO:0019430), negative regulation of collagen biosynthetic process (GO:0032966), nitric oxide metabolic process (GO:0046209), nitric oxide catabolic process (GO:0046210), negative regulation of hepatic stellate cell activation (GO:2000490)

GO Molecular Function (15): catalase activity (GO:0004096), peroxidase activity (GO:0004601), superoxide dismutase activity (GO:0004784), oxygen carrier activity (GO:0005344), iron ion binding (GO:0005506), oxidoreductase activity (GO:0016491), oxygen binding (GO:0019825), heme binding (GO:0020037), fatty acid peroxidase activity (GO:0047888), carbon monoxide binding (GO:0070025), nitrite reductase activity (GO:0098809), nitric oxide dioxygenase activity, heme protein as donor (GO:0141118), protein binding (GO:0005515), antioxidant activity (GO:0016209), metal ion binding (GO:0046872)

GO Cellular Component (6): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), nuclear speck (GO:0016607), neuron projection (GO:0043005), neuronal cell body (GO:0043025)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of nitric oxide: NOS3 activation and regulation	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to stress	2
cellular oxidant detoxification	2
peroxidase activity	2
antioxidant activity	2
small molecule binding	2
cellular anatomical structure	2
response to decreased oxygen levels	1
fibroblast migration	1
regulation of fibroblast migration	1
negative regulation of cell migration	1
gas transport	1
fatty acid metabolic process	1
lipid oxidation	1
superoxide metabolic process	1
cellular response to superoxide	1
negative regulation of biosynthetic process	1
negative regulation of collagen metabolic process	1
collagen biosynthetic process	1
regulation of collagen biosynthetic process	1
reactive nitrogen species metabolic process	1
catabolic process	1
nitric oxide metabolic process	1
hepatic stellate cell activation	1
negative regulation of cell activation	1
regulation of hepatic stellate cell activation	1
oxidoreductase activity, acting on peroxide as acceptor	1
oxidoreductase activity, acting on superoxide radicals as acceptor	1
removal of superoxide radicals	1
oxygen transport	1
oxygen binding	1
molecular carrier activity	1
transition metal ion binding	1
catalytic activity	1
tetrapyrrole binding	1
oxidoreductase activity, acting on other nitrogenous compounds as donors	1
oxidoreductase activity, acting on a heme group of donors	1
binding	1
molecular_function	1
cation binding	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1294 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CYGB	NGB	Q9NPG2	975
CYGB	RHBDF2	Q6PJF5	825
CYGB	ADGB	Q8N7X0	735
CYGB	EPO	P01588	722
CYGB	CRP	P02741	696
CYGB	GPT	P24298	696
CYGB	ALB	P02768	667
CYGB	GPX3	P22352	644
CYGB	GPX7	Q96SL4	642
CYGB	GPX2	P18283	635
CYGB	F2	P00734	625
CYGB	GPX5	O75715	623
CYGB	GPX6	P59796	622
CYGB	GPX8	Q8TED1	611
CYGB	F3	P13726	594

IntAct

28 interactions, top by confidence:

A	B	Type	Score
CYGB	DDI1	psi-mi:“MI:0915”(physical association)	0.720
DDI1	CYGB	psi-mi:“MI:0915”(physical association)	0.720
CYGB	AKR7A2	psi-mi:“MI:0914”(association)	0.570
CYGB	AKR7A2	psi-mi:“MI:0915”(physical association)	0.570
CYGB	ARHGAP8	psi-mi:“MI:0915”(physical association)	0.560
CYGB	MZT1	psi-mi:“MI:0915”(physical association)	0.560
CYGB	LRATD1	psi-mi:“MI:0915”(physical association)	0.560
MZT1	CYGB	psi-mi:“MI:0915”(physical association)	0.560
PRR5-ARHGAP8	CYGB	psi-mi:“MI:0915”(physical association)	0.560
ARHGAP8	CYGB	psi-mi:“MI:0915”(physical association)	0.560
CYGB	HNRNPA1L2	psi-mi:“MI:0915”(physical association)	0.400
GPR65	CYGB	psi-mi:“MI:0915”(physical association)	0.400
CYGB	ATP13A2	psi-mi:“MI:0915”(physical association)	0.370
ZNF747	TRIM28	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
CYGB	LRATD1	psi-mi:“MI:0915”(physical association)	0.000
CYGB	DDI1	psi-mi:“MI:0915”(physical association)	0.000
CYGB	PRR5-ARHGAP8	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (16): DDI1 (Two-hybrid), CYGB (Affinity Capture-MS), FAM84A (Two-hybrid), DDI1 (Two-hybrid), MZT1 (Two-hybrid), ARHGAP8 (Two-hybrid), PRR5-ARHGAP8 (Two-hybrid), HNRNPA1L2 (Affinity Capture-MS), CYGB (Affinity Capture-MS), CYGB (Affinity Capture-MS), CYGB (Cross-Linking-MS (XL-MS)), SKP2 (Affinity Capture-Western), CYGB (Affinity Capture-Western), CYGB (Proximity Label-MS), CYGB (Affinity Capture-Western)

ESM2 similar proteins: A0A0G2JTR4, A2AWP8, A4Q9F4, A5PJM7, A6QNS3, B1H3E1, D4ABL6, E9PTA2, E9PV86, O14508, O54804, O94759, P09851, P50904, P83900, P85298, Q12979, Q29RM4, Q4V8I4, Q5R5M3, Q5R6F2, Q5RA30, Q5SSL4, Q5XIS9, Q6DN14, Q6P5H6, Q6ZN54, Q7Z6J6, Q8BZ03, Q8CIW5, Q8NHH1, Q8QGV6, Q8TBP0, Q8WWM9, Q91X46, Q91YD4, Q96RR1, Q99J78, Q9BQS2, Q9BZL6

Diamond homologs: B3EWE1, P01923, P01924, P01928, P01929, P01930, P01934, P01935, P01937, P01938, P01951, P01956, P01957, P01958, P01959, P01960, P01961, P01971, P02007, P02008, P02009, P02137, P02207, P02208, P02209, P04442, P06347, P06635, P07402, P07405, P07421, P09904, P09908, P09967, P09968, P0C0U6, P0C227, P0CH25, P0CH26, P10059

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
SKP2	“down-regulates quantity by destabilization”	CYGB	binding
“Cullin 1-RBX1-Skp1”	“down-regulates quantity by destabilization”	CYGB	polyubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	4
Uncertain significance	85
Likely benign	46
Benign	6

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
1184568	NM_001077620.3(PRCD):c.143+1G>A	Pathogenic
1379691	NM_001077620.3(PRCD):c.70C>T (p.Gln24Ter)	Pathogenic
1427185	NM_001077620.3(PRCD):c.102_111del (p.Arg35fs)	Pathogenic
813201	NM_001077620.3(PRCD):c.73C>A (p.Pro25Thr)	Pathogenic
866216	NM_001077620.3(PRCD):c.61_64del (p.Asn21fs)	Pathogenic
1929516	NM_001077620.3(PRCD):c.102_111dup (p.Ser38Ter)	Likely pathogenic
1976161	NM_001077620.3(PRCD):c.75-2A>C	Likely pathogenic
3583072	NM_001077620.3(PRCD):c.9del (p.Thr4fs)	Likely pathogenic
3637386	NM_001077620.3(PRCD):c.74+2T>C	Likely pathogenic

SpliceAI

1277 predictions. Top by Δscore:

Variant	Effect	Δscore
17:76530972:T:TA	donor_gain	1.0000
17:76530977:A:AC	donor_gain	1.0000
17:76530978:C:CC	donor_gain	1.0000
17:76531015:T:TA	donor_gain	1.0000
17:76531016:C:A	donor_gain	1.0000
17:76531142:TC:T	acceptor_loss	1.0000
17:76531143:C:CA	acceptor_loss	1.0000
17:76531143:C:CC	acceptor_gain	1.0000
17:76531144:T:G	acceptor_loss	1.0000
17:76531687:AGAAC:A	acceptor_gain	1.0000
17:76531688:GAAC:G	acceptor_gain	1.0000
17:76531690:AC:A	acceptor_gain	1.0000
17:76531691:CC:C	acceptor_gain	1.0000
17:76531692:C:CA	acceptor_loss	1.0000
17:76531692:C:CC	acceptor_gain	1.0000
17:76531693:T:A	acceptor_loss	1.0000
17:76531696:C:CT	acceptor_gain	1.0000
17:76540216:G:GG	donor_gain	1.0000
17:76530974:CTCAC:C	donor_loss	0.9900
17:76530975:TCACG:T	donor_loss	0.9900
17:76530976:CACG:C	donor_loss	0.9900
17:76530977:A:G	donor_loss	0.9900
17:76530978:C:G	donor_loss	0.9900
17:76531012:ACTT:A	donor_gain	0.9900
17:76531013:CTTC:C	donor_gain	0.9900
17:76531138:AGGAT:A	acceptor_gain	0.9900
17:76531139:GGAT:G	acceptor_gain	0.9900
17:76531150:C:CT	acceptor_gain	0.9900
17:76531477:C:CT	donor_gain	0.9900
17:76531478:C:CT	donor_gain	0.9900

AlphaMissense

1243 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:76531655:G:C	F60L	0.999
17:76531655:G:T	F60L	0.999
17:76531657:A:G	F60L	0.999
17:76531494:G:T	A114D	0.997
17:76531498:G:C	H113D	0.996
17:76531496:G:C	H113Q	0.995
17:76531496:G:T	H113Q	0.995
17:76531506:C:T	G110E	0.995
17:76531590:G:T	A82D	0.995
17:76531647:A:G	F63S	0.995
17:76531676:G:C	F53L	0.995
17:76531676:G:T	F53L	0.995
17:76531678:A:G	F53L	0.995
17:76537419:C:A	G42W	0.995
17:76531463:G:C	F124L	0.994
17:76531463:G:T	F124L	0.994
17:76531464:A:G	F124S	0.994
17:76531465:A:G	F124L	0.994
17:76531498:G:T	H113N	0.994
17:76531507:C:A	G110W	0.994
17:76531656:A:G	F60S	0.994
17:76531664:C:A	K57N	0.994
17:76531664:C:G	K57N	0.994
17:76537452:A:G	W31R	0.994
17:76537452:A:T	W31R	0.994
17:76531495:C:G	A114P	0.993
17:76531560:A:T	V92D	0.993
17:76531646:G:C	F63L	0.993
17:76531646:G:T	F63L	0.993
17:76531648:A:G	F63L	0.993

dbSNP variants (sampled 300 via entrez): RS1000024337 (17:76528830 G>C,T), RS1000033374 (17:76530597 GGGA>G), RS1000106451 (17:76530842 A>G), RS1000308964 (17:76527670 G>A,C), RS1000313371 (17:76536586 G>C,T), RS1000344192 (17:76541620 G>T), RS1000483914 (17:76542941 G>A,T), RS1000577548 (17:76547315 G>C), RS1000685078 (17:76536252 A>C), RS1000688015 (17:76552030 T>G), RS1000711510 (17:76548661 T>C), RS1000779083 (17:76550153 A>C,G), RS1000905016 (17:76546982 G>A), RS1000985664 (17:76536277 C>A,G,T), RS1001193039 (17:76531778 G>A)

Disease associations

OMIM: gene MIM:608759 | disease phenotypes: MIM:610599, MIM:268000

GenCC curated gene-disease

Mondo (3): inherited retinal dystrophy (MONDO:0019118), retinitis pigmentosa 36 (MONDO:0012523), retinitis pigmentosa (MONDO:0019200)

Orphanet (2): OBSOLETE: Inherited retinal disorder (Orphanet:71862), Retinitis pigmentosa (Orphanet:791)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000556	Retinal dystrophy

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
C566431	Retinitis Pigmentosa 36 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation	7
Particulate Matter	decreases expression, increases abundance, increases expression, affects cotreatment	4
bisphenol A	increases expression, affects expression, decreases expression	3
Valproic Acid	affects cotreatment, increases expression, increases methylation	3
Aflatoxin B1	affects expression, increases expression	3
Acetaminophen	decreases expression, increases expression	2
Air Pollutants	increases expression, decreases expression, increases abundance	2
Smoke	increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
alpha-naphthoflavone	decreases reaction, increases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
sodium arsenite	increases expression	1
cerous chloride	affects expression, affects cotreatment, increases expression	1
lanthanum chloride	increases expression, affects expression, affects cotreatment	1
nickel sulfate	decreases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
puerarin	decreases expression	1
cadmium sulfide	increases expression	1
isobutyl alcohol	affects cotreatment, increases abundance, increases expression	1
epigallocatechin gallate	decreases expression	1
cyfluthrin	decreases expression	1
polyhexamethyleneguanidine	affects expression	1
4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole	decreases reaction, increases expression	1
chloropicrin	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole	increases expression, decreases reaction	1
pyrazolanthrone	decreases reaction, increases expression	1
EUK-134	increases expression, decreases reaction	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa
NCT05392179	PHASE2	COMPLETED	A Study in Subjects With Retinitis Pigmentosa
NCT06627179	PHASE2	RECRUITING	Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
NCT06628947	PHASE2	RECRUITING	A Phase II Study of Intravitreal KIO-301 in Patients With Late-stage Retinitis Pigmentosa
NCT06912633	PHASE2	RECRUITING	Safety of a Single, Intravitreal Injection of 6.0M jCell (Famzeretcel) in Retinitis Pigmentosa (RP)
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT06455826	PHASE1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)