OS9

Summary

OS9 (OS9 endoplasmic reticulum lectin, HGNC:16994) is a protein-coding gene on chromosome 12q13.3-q14.1, encoding Protein OS-9 (Q13438). Lectin component of the HRD1 complex, which functions in endoplasmic reticulum (ER) quality control and ER-associated degradation (ERAD).

This gene encodes a protein that is highly expressed in osteosarcomas. This protein binds to the hypoxia-inducible factor 1 (HIF-1), a key regulator of the hypoxic response and angiogenesis, and promotes the degradation of one of its subunits. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.

Source: NCBI Gene 10956 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 132 total
• MANE Select transcript: NM_006812

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16994
Approved symbol	OS9
Name	OS9 endoplasmic reticulum lectin
Location	12q13.3-q14.1
Locus type	gene with protein product
Status	Approved
Aliases	OS-9, ERLEC2
Ensembl gene	ENSG00000135506
Ensembl biotype	protein_coding
OMIM	609677
Entrez	10956

Gene structure

Transcript identifiers

Ensembl transcripts: 87 — 70 protein_coding, 8 retained_intron, 8 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000257966, ENST00000315970, ENST00000389142, ENST00000389146, ENST00000413095, ENST00000435406, ENST00000439210, ENST00000546916, ENST00000547079, ENST00000549307, ENST00000549897, ENST00000550202, ENST00000550372, ENST00000550438, ENST00000550699, ENST00000550793, ENST00000550848, ENST00000551035, ENST00000551285, ENST00000552285, ENST00000552423, ENST00000552787, ENST00000553208, ENST00000700656, ENST00000700657, ENST00000700658, ENST00000700659, ENST00000700660, ENST00000700661, ENST00000700662, ENST00000700663, ENST00000700664, ENST00000700665, ENST00000700666, ENST00000700667, ENST00000700668, ENST00000700670, ENST00000856487, ENST00000856488, ENST00000856489, ENST00000856490, ENST00000856491, ENST00000856492, ENST00000856493, ENST00000856494, ENST00000856495, ENST00000856496, ENST00000856497, ENST00000856498, ENST00000856499, ENST00000856500, ENST00000856501, ENST00000856502, ENST00000856503, ENST00000856504, ENST00000856505, ENST00000856506, ENST00000856507, ENST00000856508, ENST00000856509, ENST00000856510, ENST00000856511, ENST00000856512, ENST00000856513, ENST00000856514, ENST00000856515, ENST00000939700, ENST00000939701, ENST00000939702, ENST00000939703, ENST00000959823, ENST00000959824, ENST00000959825, ENST00000959826, ENST00000959827, ENST00000959828, ENST00000959829, ENST00000959830, ENST00000959831, ENST00000959832, ENST00000959833, ENST00000959834, ENST00000959835, ENST00000959836, ENST00000959837, ENST00000959838, ENST00000959839

RefSeq mRNA: 11 — MANE Select: NM_006812 NM_001017956, NM_001017957, NM_001017958, NM_001261420, NM_001261421, NM_001261422, NM_001261423, NM_001410978, NM_001410979, NM_001410980, NM_006812

CCDS: CCDS31843, CCDS31844, CCDS31845, CCDS31846, CCDS58246, CCDS58247, CCDS58248, CCDS58249, CCDS91712, CCDS91713, CCDS91714

Canonical transcript exons

ENST00000315970 — 15 exons

Exon	Start	End
ENSE00000920474	57720099	57720263
ENSE00000920480	57716092	57716193
ENSE00000920481	57715760	57715970
ENSE00003464638	57716693	57716744
ENSE00003504412	57696275	57696373
ENSE00003518354	57717870	57717958
ENSE00003533681	57718993	57719182
ENSE00003539159	57718146	57718421
ENSE00003586286	57695780	57695843
ENSE00003672074	57694750	57694926
ENSE00003675779	57695962	57696038
ENSE00003676831	57716412	57716512
ENSE00003980483	57694132	57694323
ENSE00003980492	57720406	57720518
ENSE00003980493	57720784	57721557

Expression profiles

Bgee: expression breadth ubiquitous, 306 present calls, max score 99.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 55.4067 / max 783.5622, expressed in 1824 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
126300	54.1143	1824
126299	0.8552	519
126309	0.4372	161

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	99.22	gold quality
tendon of biceps brachii	UBERON:0008188	99.17	gold quality
stromal cell of endometrium	CL:0002255	99.12	gold quality
granulocyte	CL:0000094	98.96	gold quality
monocyte	CL:0000576	98.96	gold quality
body of pancreas	UBERON:0001150	98.94	gold quality
islet of Langerhans	UBERON:0000006	98.93	gold quality
minor salivary gland	UBERON:0001830	98.90	gold quality
right lobe of thyroid gland	UBERON:0001119	98.88	gold quality
tendon	UBERON:0000043	98.87	gold quality
ileal mucosa	UBERON:0000331	98.84	gold quality
saliva-secreting gland	UBERON:0001044	98.78	gold quality
mononuclear cell	CL:0000842	98.77	gold quality
left lobe of thyroid gland	UBERON:0001120	98.76	gold quality
leukocyte	CL:0000738	98.75	gold quality
body of stomach	UBERON:0001161	98.74	gold quality
right ovary	UBERON:0002118	98.71	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.71	gold quality
mucosa of transverse colon	UBERON:0004991	98.71	gold quality
metanephros cortex	UBERON:0010533	98.70	gold quality
descending thoracic aorta	UBERON:0002345	98.69	gold quality
upper lobe of left lung	UBERON:0008952	98.69	gold quality
right lung	UBERON:0002167	98.68	gold quality
left ovary	UBERON:0002119	98.66	gold quality
right coronary artery	UBERON:0001625	98.65	gold quality
thyroid gland	UBERON:0002046	98.63	gold quality
transverse colon	UBERON:0001157	98.62	gold quality
stomach	UBERON:0000945	98.61	gold quality
thoracic aorta	UBERON:0001515	98.61	gold quality
ascending aorta	UBERON:0001496	98.60	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	1286.21
E-ANND-3	yes	18.75
E-CURD-112	yes	8.24
E-MTAB-7037	no	396.96
E-GEOD-124858	no	171.70

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ERN1

miRNA regulators (miRDB)

28 targeting OS9, 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-6851-5P	100.00	65.63	1294
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-6513-3P	99.59	69.77	1102
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-449B-3P	99.20	67.24	1047
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-6814-5P	99.03	66.68	1273
HSA-MIR-1228-3P	99.00	66.53	857
HSA-MIR-3135B	98.61	65.33	1470
HSA-MIR-653-3P	98.31	67.71	1542
HSA-MIR-6824-5P	97.41	68.43	583
HSA-MIR-4445-5P	97.21	66.16	832
HSA-MIR-939-5P	97.10	65.80	1579
HSA-MIR-6736-3P	96.98	65.22	1342
HSA-MIR-1343-5P	96.48	66.06	1506
HSA-MIR-541-3P	96.07	66.11	1271
HSA-MIR-654-5P	96.07	66.18	1280
HSA-MIR-6777-3P	95.35	64.30	699
HSA-MIR-3927-5P	94.90	68.11	399
HSA-MIR-4745-3P	83.50	60.58	126

Literature-anchored findings (GeneRIF, showing 20)

• Identification of a peptide, resulting from a point mutation in gene OS-9, recognized by cytolytic T lymphocytes on a human melanoma. (PMID:12747754)
• OS-9 regulates the secretory transport of TRPV4 and appears to protect TRPV4 subunits from the precocious ubiquitination and ER-associated degradation. (PMID:17932042)
• OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1-SEL1L ubiquitin ligase complex for ERAD (PMID:18264092)
• Xbp1-responsive OS-9 variants in the mammalian endoplasmic reticulum inhibit secretion of misfolded protein conformers and enhancing their disposal (PMID:18417469)
• OS9 is critically involved in the modulation of ER-to-Golgi transport of DC-STAMP in response to TLR triggering, suggesting a novel role for OS9 in myeloid differentiation and cell fusion. (PMID:18952287)
• OS-9 recognises terminally misfolded proteins via polypeptide-based rather than glycan-based signals, but is only required for transferring those bearing N-glycans to the ubiquitination machinery. (PMID:19084021)
• model for mannose trimming and the requirement for OS-9 lectin activity in glycoprotein ERAD in which N-glycans lacking the terminal mannose from the C branch are recognized by OS-9 and targeted for degradation (PMID:19346256)
• The sugar-binding ability of human OS-9 and its involvement in ER-associated degradation (PMID:19914915)
• The OS-9 specifically recognizes Manalpha1,6Manalpha1,6Man residues on the processed C-arm through the continuous double tryptophan (WW) motif. (PMID:21172656)
• It regulates endoplasmic reticulum-associated degradation. (review) (PMID:21404621)
• OS-9 plays no direct functional role in HIF degradation since physical interaction of OS-9 with oxygen sensing HIF prolyl hydroxylases cannot occur in vivo due to their different subcellular localization (PMID:21559462)
• Data indicate that the interaction of OS-9 and XTP3-B with CD147(CG) was inhibited by mutations to conserved residues in their lectin domains. (PMID:23097496)
• It delivers mutant neuroserpin to ERAD by recognition of glycan side chains and provide the first in vivo proof of involvement of ERAD in degradation of mutant neuroserpin. (PMID:24795221)
• Unique regions mediate the interaction between OS-9 and GRP94. (PMID:24899641)
• EDEM2 and OS-9 are required for ER-associated degradation of non-glycosylated sonic hedgehog (PMID:24910992)
• long non-coding RNA ENST00000480739 suppresses tumour cell invasion by regulating OS-9 and HIF-1alpha in pancreatic ductal adenocarcinoma. (PMID:25314054)
• OS-9 up-regulates occludin and claudin-1 by activating the MAP kinase (MAPK) pathway, and thus protects the epithelial barrier function of Caco-2 monolayer under hypoxia condition. (PMID:25999789)
• The endoplasmic reticulum-associated protein, OS-9, behaves as a lectin in targeting the immature calcium-sensing receptor. (PMID:28419469)
• The relative expression of OS9 and XTP3B and the distribution of glycan and non-glycan degrons within the same protein contribute to the fidelity. (PMID:29706535)
• Monochorionic twins with selective fetal growth restriction: insight from placental whole-transcriptome analysis. (PMID:32437666)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	os9	ENSDARG00000020301
mus_musculus	Os9	ENSMUSG00000040462
rattus_norvegicus	Os9	ENSRNOG00000025570
caenorhabditis_elegans		WBGENE00018611

Paralogs (1): ERLEC1 (ENSG00000068912)

Protein

Protein identifiers

Protein OS-9 — Q13438 (reviewed: Q13438)

Alternative names: Amplified in osteosarcoma 9

All UniProt accessions (20): A0A8V8TPZ4, A0A8V8TPZ9, A0A8V8TQ04, A0A8V8TQI0, A0A8V8TQI2, A0A8V8TQI4, A0A8V8TQI8, A0A8V8TQI9, A0A8V8TR31, A0A8V8TR34, A0A8V8TR37, A0A8V8TRD7, A0A8V8TRE0, B4E321, Q13438, F8VWQ2, F8VZI7, F8W0R2, F8W1N0, F8W1V2

UniProt curated annotations — full annotation on UniProt →

Function. Lectin component of the HRD1 complex, which functions in endoplasmic reticulum (ER) quality control and ER-associated degradation (ERAD). Specifically recognizes and binds improperly folded glycoproteins as well as hyperglycosylated proteins, retain them in the ER, and transfers them to the ubiquitination machinery and promote their degradation. Possible targets include TRPV4 as well as hyperglycosylated HSP90B1.

Subunit / interactions. Component of the HRD1 complex, which comprises at least SYNV1/HRD1, DERL1/2, FAM8A1, HERPUD1/HERP, OS9, SEL1L and UBE2J1. FAM8A1 is stabilized by interaction with SYNV1, which prevents its proteasomal degradation. OS9 and UBE2J1 recruitment to the complex may be mediated by SEL1L. Through this complex, may interact with ERLEC1 and HSPA5. Interacts (via C-terminus) with CPNE6 (via second C2 domain); this interaction occurs in a calcium-dependent manner in vitro. Interacts with CREB3.

Subcellular location. Endoplasmic reticulum lumen.

Tissue specificity. Ubiquitously expressed. Found as well in all tumor cell lines analyzed, amplified in sarcomas. Highly expressed in osteosarcoma SJSA-1 and rhabdomyosarcoma Rh30 cell lines. Isoform 2 is the major isoform detected in all cell types examined.

Post-translational modifications. Intramolecular disulfide bonds. Isoform 1 and isoform 2 are N-glycosylated.

Induction. Up-regulated in response to endoplasmic reticulum stress (at protein level).

Miscellaneous. Major isoform. Major isoform.

Similarity. Belongs to the OS-9 family.

Isoforms (8)

UniProt ID	Names	Canonical?
Q13438-1	1, OS-9-1	yes
Q13438-2	2, OS-9-2
Q13438-3	3, OS-9-3
Q13438-4	4
Q13438-5	5
Q13438-6	6
Q13438-7	7
Q13438-8	8

RefSeq proteins (11): NP_001017956, NP_001017957, NP_001017958, NP_001248349, NP_001248350, NP_001248351, NP_001248352, NP_001397907, NP_001397908, NP_001397909, NP_006803* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009011	Man6P_isomerase_rcpt-bd_dom_sf	Homologous_superfamily
IPR012913	OS9-like_dom	Domain
IPR044865	MRH_dom	Domain
IPR045149	OS-9-like	Family

Pfam: PF07915

UniProt features (53 total): strand 8, compositionally biased region 7, binding site 7, splice variant 6, sequence conflict 6, region of interest 5, disulfide bond 3, sequence variant 3, turn 2, signal peptide 1, chain 1, domain 1, glycosylation site 1, mutagenesis site 1, helix 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3AIH	X-RAY DIFFRACTION	2.1
9OG0	ELECTRON MICROSCOPY	3.64

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13438-F1	64.83	0.17

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 (7): 117; 118; 130; 182; 188; 212; 218

Disulfide bonds (3): 110–123, 181–216, 196–228

Glycosylation sites (1): 177

Mutagenesis-validated functional residues (1):

Position	Phenotype
188	loss of glycan-binding activity and partial inhibition of erad of the misfolded glycoprotein nhk (pubmed:19346256). redu

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-382556	ABC-family protein mediated transport
R-HSA-5358346	Hedgehog ligand biogenesis
R-HSA-5362768	Hh mutants are degraded by ERAD
R-HSA-5678895	Defective CFTR causes cystic fibrosis
R-HSA-901032	ER Quality Control Compartment (ERQC)
R-HSA-9931269	AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)

MSigDB gene sets: 192 (showing top): GOBP_ENDOPLASMIC_RETICULUM_TO_CYTOSOL_TRANSPORT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOBP_PROTEIN_TARGETING, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, HSIAO_HOUSEKEEPING_GENES, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_CELLULAR_RESPONSE_TO_TOPOLOGICALLY_INCORRECT_PROTEIN, GOBP_PROTEIN_LOCALIZATION_TO_ENDOPLASMIC_RETICULUM, MARTINEZ_RB1_TARGETS_UP, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT

GO Biological Process (10): ubiquitin-dependent protein catabolic process (GO:0006511), protein targeting (GO:0006605), protein retention in ER lumen (GO:0006621), protein ubiquitination (GO:0016567), endoplasmic reticulum unfolded protein response (GO:0030968), retrograde protein transport, ER to cytosol (GO:0030970), response to endoplasmic reticulum stress (GO:0034976), ERAD pathway (GO:0036503), negative regulation of retrograde protein transport, ER to cytosol (GO:1904153), intracellular protein localization (GO:0008104)

GO Molecular Function (4): protease binding (GO:0002020), carbohydrate binding (GO:0030246), glycosylation-dependent protein binding (GO:0140032), protein binding (GO:0005515)

GO Cellular Component (4): Hrd1p ubiquitin ligase complex (GO:0000836), endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), endoplasmic reticulum membrane (GO:0005789)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Transport of small molecules	1
Signaling by Hedgehog	1
Hh mutants abrogate ligand secretion	1
ABC transporter disorders	1
Calnexin/calreticulin cycle	1
Regulation of PD-L1(CD274) Post-translational modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to endoplasmic reticulum stress	2
binding	2
protein ubiquitination	1
modification-dependent protein catabolic process	1
establishment of protein localization	1
maintenance of protein localization in endoplasmic reticulum	1
protein modification by small protein conjugation	1
cellular response to unfolded protein	1
intracellular signal transduction	1
protein exit from endoplasmic reticulum	1
ERAD pathway	1
endoplasmic reticulum to cytosol transport	1
cellular response to stress	1
proteasomal protein catabolic process	1
response to chemical	1
retrograde protein transport, ER to cytosol	1
negative regulation of protein exit from endoplasmic reticulum	1
regulation of retrograde protein transport, ER to cytosol	1
macromolecule localization	1
enzyme binding	1
modification-dependent protein binding	1
ER ubiquitin ligase complex	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
endoplasmic reticulum	1
intracellular organelle lumen	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1

Protein interactions and networks

STRING

1691 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
OS9	SEL1L	Q9UBV2	989
OS9	HSP90B1	P14625	980
OS9	DERL2	Q9GZP9	973
OS9	SYVN1	Q86TM6	956
OS9	CANX	P27824	949
OS9	FAF2	Q96CS3	947
OS9	UBE2J1	Q9Y385	942
OS9	AUP1	Q9Y679	935
OS9	HSPA5	P11021	928
OS9	EGLN1	Q9GZT9	921
OS9	EDEM1	Q92611	917
OS9	VCP	P55072	896
OS9	MAN1B1	Q9UKM7	892
OS9	DNAJC10	Q8IXB1	883
OS9	DERL3	Q96Q80	865

IntAct

206 interactions, top by confidence:

A	B	Type	Score
HIF1A	VHL	psi-mi:“MI:0914”(association)	0.970
SEL1L	OS9	psi-mi:“MI:0914”(association)	0.860
SEL1L	OS9	psi-mi:“MI:0915”(physical association)	0.860
SYVN1	OS9	psi-mi:“MI:0914”(association)	0.690
OS9	SYVN1	psi-mi:“MI:0914”(association)	0.690
B3GNT3	PGRMC1	psi-mi:“MI:0914”(association)	0.670
HIF1A	OS9	psi-mi:“MI:0915”(physical association)	0.650
OS9	HIF1A	psi-mi:“MI:0407”(direct interaction)	0.650
OS9	HIF1A	psi-mi:“MI:0914”(association)	0.650
OS9	HIF1A	psi-mi:“MI:0915”(physical association)	0.650
HIF1A	OS9	psi-mi:“MI:0914”(association)	0.650
KLK5	DENND11	psi-mi:“MI:0914”(association)	0.640
OS9	HSP90B1	psi-mi:“MI:0914”(association)	0.640
GXYLT1	CANX	psi-mi:“MI:0914”(association)	0.640
SLC39A5	FAM171A2	psi-mi:“MI:0914”(association)	0.640
EGFR	OS9	psi-mi:“MI:0915”(physical association)	0.620
IGF1R	PIK3R2	psi-mi:“MI:2364”(proximity)	0.590

BioGRID (391): OS9 (Affinity Capture-MS), SYVN1 (Affinity Capture-Western), OS9 (Affinity Capture-MS), OS9 (Affinity Capture-MS), HSP90B1 (Affinity Capture-MS), MYH9 (Affinity Capture-MS), SEL1L (Affinity Capture-MS), LONP2 (Affinity Capture-MS), OS9 (Affinity Capture-MS), OS9 (Affinity Capture-MS), OS9 (Affinity Capture-MS), RPN1 (Affinity Capture-MS), SERPINH1 (Affinity Capture-MS), GGH (Affinity Capture-MS), SYVN1 (Affinity Capture-Western)

ESM2 similar proteins: A2BD09, A3KNS2, A5GFQ5, P15943, P24338, Q01580, Q06175, Q06186, Q06335, Q06481, Q08AE8, Q08DX0, Q09118, Q0P5N1, Q0VCT2, Q0VDN7, Q13438, Q2L6K8, Q3MHX6, Q3SWX1, Q58D79, Q58T08, Q5HZV5, Q5MJS3, Q5RKH6, Q68BL7, Q6GN40, Q701R2, Q86VZ4, Q8BHP7, Q8BQ47, Q8CB67, Q8CD91, Q8K2C7, Q8N129, Q8TEQ0, Q92563, Q96C34, Q96KC8, Q99075

Diamond homologs: Q13438, Q3MHX6, Q4IEA7, Q4WCG2, Q5BDB9, Q5R8S4, Q5RKH6, Q67WM9, Q6CNH1, Q8GWH3, Q8K2C7, Q8VEH8, Q96DZ1, Q872S3, Q6C3U1, Q08B78, Q28IT1, Q5ACR4, Q6BJ08

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
ERN1	“up-regulates quantity by expression”	OS9	“transcriptional regulation”
OS9	“up-regulates quantity by stabilization”	TRPV4	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 232 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha	8	9.8×	9e-04
Defective CFTR causes cystic fibrosis	7	9.6×	2e-03
Hh mutants are degraded by ERAD	6	9.1×	8e-03
AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	7	8.5×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
retrograde protein transport, ER to cytosol	6	30.4×	2e-05
ERAD pathway	15	13.9×	3e-10
endoplasmic reticulum unfolded protein response	7	10.6×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	110
Likely benign	7
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

2585 predictions. Top by Δscore:

Variant	Effect	Δscore
12:57694264:GAGC:G	donor_gain	1.0000
12:57694267:C:G	donor_gain	1.0000
12:57694271:G:GG	donor_gain	1.0000
12:57694845:G:GT	donor_gain	1.0000
12:57694846:G:T	donor_gain	1.0000
12:57696061:G:GT	donor_gain	1.0000
12:57696084:C:G	donor_gain	1.0000
12:57696105:G:T	donor_gain	1.0000
12:57696369:TTCGG:T	donor_loss	1.0000
12:57696371:CGGG:C	donor_loss	1.0000
12:57696372:GGGTG:G	donor_loss	1.0000
12:57696373:GGTG:G	donor_loss	1.0000
12:57696374:G:C	donor_loss	1.0000
12:57696375:T:A	donor_loss	1.0000
12:57696376:GA:G	donor_loss	1.0000
12:57715754:T:A	acceptor_gain	1.0000
12:57715757:CAG:C	acceptor_loss	1.0000
12:57715758:A:AG	acceptor_gain	1.0000
12:57715759:G:GA	acceptor_gain	1.0000
12:57715759:GT:G	acceptor_gain	1.0000
12:57715759:GTT:G	acceptor_gain	1.0000
12:57715759:GTTC:G	acceptor_gain	1.0000
12:57715759:GTTCC:G	acceptor_gain	1.0000
12:57715967:GCCG:G	donor_gain	1.0000
12:57715969:CGGTG:C	donor_loss	1.0000
12:57715970:GGT:G	donor_loss	1.0000
12:57715971:G:GG	donor_gain	1.0000
12:57715971:GTG:G	donor_loss	1.0000
12:57716402:T:A	acceptor_gain	1.0000
12:57716405:A:AG	acceptor_gain	1.0000

AlphaMissense

4353 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:57694804:T:A	C73S	1.000
12:57694804:T:C	C73R	1.000
12:57694805:G:C	C73S	1.000
12:57695791:G:C	W117C	1.000
12:57695791:G:T	W117C	1.000
12:57695792:T:A	W118R	1.000
12:57695792:T:C	W118R	1.000
12:57695794:G:C	W118C	1.000
12:57695794:G:T	W118C	1.000
12:57696020:G:C	W154C	1.000
12:57696020:G:T	W154C	1.000
12:57696335:T:A	C181S	1.000
12:57696335:T:C	C181R	1.000
12:57696336:G:C	C181S	1.000
12:57715827:G:A	C216Y	1.000
12:57715916:T:A	C246S	1.000
12:57715916:T:C	C246R	1.000
12:57715917:G:C	C246S	1.000
12:57694775:T:A	V63D	0.999
12:57694805:G:A	C73Y	0.999
12:57694806:T:G	C73W	0.999
12:57695789:T:A	W117R	0.999
12:57695789:T:C	W117R	0.999
12:57695823:T:A	I128N	0.999
12:57695834:C:G	H132D	0.999
12:57695994:G:C	G146R	0.999
12:57695995:G:A	G146D	0.999
12:57696326:G:T	G178W	0.999
12:57696327:G:A	G178E	0.999
12:57696336:G:A	C181Y	0.999

dbSNP variants (sampled 300 via entrez): RS1000093469 (12:57713546 C>T), RS1000138920 (12:57695768 T>G), RS1000192750 (12:57704240 A>G), RS1000308820 (12:57705424 C>A,T), RS1000417600 (12:57699355 A>T), RS1000470135 (12:57699655 G>A), RS1000528584 (12:57693091 T>C), RS1000651324 (12:57708480 T>C), RS1000729531 (12:57694023 A>G), RS1000963065 (12:57692814 C>G,T), RS1001000752 (12:57708192 A>T), RS1001264460 (12:57706599 C>T), RS1001295482 (12:57706211 G>T), RS1001530437 (12:57705934 A>C), RS1001692822 (12:57698576 G>C,T)

Disease associations

OMIM: gene MIM:609677 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST006048_15	Rheumatoid arthritis (ACPA-positive)	1.000000e-06
GCST007294_104	Body fat distribution (trunk fat ratio)	4.000000e-08
GCST007294_177	Body fat distribution (trunk fat ratio)	3.000000e-09
GCST007295_100	Body fat distribution (leg fat ratio)	1.000000e-07
GCST007295_116	Body fat distribution (leg fat ratio)	4.000000e-06
GCST009597_277	Multiple sclerosis	1.000000e-30
GCST010703_209	Brain morphology (MOSTest)	2.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004341	body fat distribution
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases methylation, affects cotreatment, decreases expression, increases expression	4
Valproic Acid	affects expression, decreases methylation, increases expression	3
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	2
Acrolein	affects cotreatment, increases oxidation, increases abundance	2
Ozone	affects cotreatment, increases oxidation, increases abundance	2
Tretinoin	increases expression, affects cotreatment, decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
lasiocarpine	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, increases oxidation	1
deoxynivalenol	decreases expression	1
glycidyl methacrylate	increases expression	1
beta-lapachone	decreases expression, increases expression	1
sodium arsenite	increases expression	1
nivalenol	decreases expression	1
2,3-dimethoxy-1,4-naphthoquinone	decreases expression	1
(+)-JQ1 compound	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Bortezomib	increases expression	1
Arsenic Trioxide	decreases expression	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Antimony	decreases expression	1
Antimony Potassium Tartrate	decreases expression	1
Ascorbic Acid	affects cotreatment, decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cadmium	decreases expression	1
Chromium	decreases expression	1
Curcumin	increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Gold	affects binding, decreases expression	1

Cellosaurus cell lines

15 cell lines: 15 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C5U8	LG2-MEL	Cancer cell line	Male
CVCL_C5UA	LG2-MEL-205	Cancer cell line	Male
CVCL_C5UB	LG2-MEL-206	Cancer cell line	Male
CVCL_C5UC	LG2-MEL-207	Cancer cell line	Male
CVCL_C5UK	LG2-MEL-5-21	Cancer cell line	Male
CVCL_C5UL	LG2-MEL-5-22	Cancer cell line	Male
CVCL_C5UM	LG2-MEL-5-23	Cancer cell line	Male
CVCL_C5UN	LG2-MEL-5-30	Cancer cell line	Male
CVCL_C5UP	LG2-MEL-5-31	Cancer cell line	Male
CVCL_C5UQ	LG2-MEL-5-32	Cancer cell line	Male

Clinical trials (associated diseases)

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