HTRA3

Summary

HTRA3 (HtrA serine peptidase 3, HGNC:30406) is a protein-coding gene on chromosome 4p16.1, encoding Serine protease HTRA3 (P83110). Serine protease that cleaves beta-casein/CSN2 as well as several extracellular matrix (ECM) proteoglycans such as decorin/DCN, biglycan/BGN and fibronectin/FN1.

Enables endopeptidase activity; identical protein binding activity; and serine-type peptidase activity. Involved in proteolysis. Predicted to be located in extracellular region.

Source: NCBI Gene 94031 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 90 total
• MANE Select transcript: NM_053044

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30406
Approved symbol	HTRA3
Name	HtrA serine peptidase 3
Location	4p16.1
Locus type	gene with protein product
Status	Approved
Aliases	Tasp, Prsp
Ensembl gene	ENSG00000170801
Ensembl biotype	protein_coding
OMIM	608785
Entrez	94031

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000307358, ENST00000382512, ENST00000853954, ENST00000853955, ENST00000968934, ENST00000968935, ENST00000968936

RefSeq mRNA: 2 — MANE Select: NM_053044 NM_001297559, NM_053044

CCDS: CCDS3400, CCDS75105

Canonical transcript exons

ENST00000307358 — 9 exons

Exon	Start	End
ENSE00001134412	8294087	8294201
ENSE00001134419	8269754	8270353
ENSE00001136244	8305971	8307098
ENSE00001136249	8304184	8304279
ENSE00001136255	8302463	8302511
ENSE00001136260	8292321	8292353
ENSE00001136267	8291370	8291564
ENSE00001136273	8286561	8286783
ENSE00001136279	8282437	8282536

Expression profiles

Bgee: expression breadth ubiquitous, 222 present calls, max score 98.37.

FANTOM5 (CAGE): breadth broad, TPM avg 6.9505 / max 323.5907, expressed in 877 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
46876	6.6722	855
46875	0.2783	157

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	98.37	gold quality
right atrium auricular region	UBERON:0006631	97.47	gold quality
cardiac atrium	UBERON:0002081	96.89	gold quality
left ovary	UBERON:0002119	95.38	gold quality
cardiac muscle of right atrium	UBERON:0003379	95.32	silver quality
right ovary	UBERON:0002118	95.01	gold quality
mucosa of stomach	UBERON:0001199	94.24	gold quality
heart left ventricle	UBERON:0002084	93.45	gold quality
heart	UBERON:0000948	93.07	gold quality
cardiac ventricle	UBERON:0002082	93.07	gold quality
left ventricle myocardium	UBERON:0006566	92.85	silver quality
subcutaneous adipose tissue	UBERON:0002190	91.67	gold quality
gall bladder	UBERON:0002110	91.32	gold quality
endocervix	UBERON:0000458	91.27	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	91.23	gold quality
omental fat pad	UBERON:0010414	91.15	gold quality
peritoneum	UBERON:0002358	91.09	gold quality
right coronary artery	UBERON:0001625	91.03	gold quality
lower esophagus muscularis layer	UBERON:0035833	91.02	gold quality
lower esophagus	UBERON:0013473	90.90	gold quality
adipose tissue of abdominal region	UBERON:0007808	90.61	gold quality
body of uterus	UBERON:0009853	90.51	gold quality
tendon of biceps brachii	UBERON:0008188	90.46	gold quality
ovary	UBERON:0000992	90.34	gold quality
right lung	UBERON:0002167	90.31	gold quality
myocardium	UBERON:0002349	89.70	silver quality
left coronary artery	UBERON:0001626	89.51	gold quality
coronary artery	UBERON:0001621	89.22	gold quality
tibialis anterior	UBERON:0001385	89.16	gold quality
left uterine tube	UBERON:0001303	88.62	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-9906	yes	675.15
E-HCAD-24	yes	504.12
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

46 targeting HTRA3, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-34B-5P	99.78	67.56	1175
HSA-MIR-449C-5P	99.78	67.63	1168
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-2682-5P	99.73	67.38	1055
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-4663	99.62	65.33	957
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-6832-5P	99.58	64.82	1132
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-1224-5P	99.48	65.59	803
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-8077	99.17	66.67	862
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-936	98.87	70.51	1124
HSA-MIR-4751	98.80	64.95	525
HSA-MIR-4763-5P	98.75	63.89	854
HSA-MIR-589-5P	98.72	66.96	927

Literature-anchored findings (GeneRIF, showing 40)

• We cloned the full-length sequences of two forms (long and short) of human HtrA3 mRNA, located the gene on chromosome 4p16.1, determined its genomic structure and revealed how the two mRNA variants are produced through alternative splicing (PMID:12513693)
• Upregulation of HTRA3 expression in association with placental development was revealed by a significant elevation of this protein in the maternal serum during the first trimester (PMID:16251496)
• RT-PCR analysis showed a significant reduction of HTRA1 and HTRA3 mRNA in endometrial cancer compared to normal endometrium. HTRA1 and HTRA3 protein showed a similar pattern of expression in EC tissue. (PMID:16650464)
• Structural and functional analysis of the PDZ domains of human HtrA1 and HtrA3 (PMID:17962403)
• In ovarian cancer there is a dramatic decrease of HtrA3 mRNA and protein levels in all ovarian tumor groups; HtrA3 may function as a tumor suppressor. (PMID:18241672)
• critical for normal placental development; different expression profile during abnormal pregnancy (PMID:19359045)
• HtrA3 was down-regulated in endometrial cancers. (PMID:19424634)
• these data indicate that 15dPGJ2 is able to stimulate the expression of HtrA3 through an indirect mechanism involving the MEK/ERK pathway but independent of PPARgamma. (PMID:19951697)
• cigarette smoke-induced methylation of HtrA3 could contribute to the etiology of chemoresistant disease in smoking-related lung cancer. (PMID:20068077)
• HtrA3 may be a previously uncharacterized mitochondrial cell death effector whose serine protease function may be crucial to modulating etoposide- and cisplatin-induced cytotoxicity in lung cancer cell lines. (PMID:20154083)
• role of HtrA3 (along with HtrA1 and HtrA2) in development/progression of cancer, neurodegenerative disorders and arthritic diseases [REVIEW] (PMID:20469960)
• inhibitor of trophoblast invasion during placental development (PMID:21035848)
• Abnormally high levels of serum HtrA3 at approximately 13-14 wk of gestation is associated with preeclampsia (PMID:21047919)
• decidual HtrA3 negatively regulates trophoblast invasion (PMID:21321049)
• HTRA3 is a target gene of the BACH1 transcription factor according to ChIP-seq analysis in HEK 293 cells. (PMID:21555518)
• results suggest that HtrA3 variants may play different roles in cancer development, and that the increased HtrA3-L levels in thyroid tissue could be correlated with the development of malignant lesions (PMID:22923201)
• HtrA3 may have a role as an early marker for preeclampsia (PMID:23049902)
• Data indicate that in breast cancers with no lymphatic metastasis, the expression of HtrA3 was lower in patients with estrogen receptor (ER)- and progesterone receptor (PR)-positive tumors. (PMID:23812730)
• HtrA1 and HtrA3 are crucial for trophoblast-decidual cell interaction in the control of trophoblast invasion. (PMID:25002585)
• Data indicate that the levels of high temperature requirement factor A3 (HtrA3)protein were lower in all subtypes of ovarian cancer and the lowest levels of HtrA3 were in epithelial ovarian cancer. (PMID:25274382)
• HtrA3 is likely to be associated with the acquisition of the invasive phenotype in oral squamous cell carcinoma cells and may be a potential prognostic marker for oral cance (PMID:25456008)
• New insights into the structure and function of DeltaN-HtrA3, which seems to have a unique combination of features among human HtrA proteases. (PMID:26110759)
• HTRA3 suppresses tumor cell invasiveness and may serve as a prognostic biomarker for postoperative recurrence or survival in NSCLC (PMID:27166271)
• Removal of the 6 additional LB loop residues caused a complete loss of the proper trimeric structure. Impairing their interactions with the PDZ domain decreased the amount of the trimers. The LB loop helps stabilize the DeltaN-HtrA3L oligomer structure suggesting involvement of the LB-PDZ interactions in the stabilization. A monomeric form of the DeltaN-HtrA3L is proteolytically inactive. (PMID:28642151)
• Study demonstrated that in women serum levels of HtrA3 during early pregnancy were significantly lower in IUGR pregnancies, establishing an association between lower HtrA3 levels and placental insufficiency. (PMID:28676687)
• HtrA3 expression in the peritumoral stroma of patients with stage II colorectal cancer is associated with high-grade tumor budding and may be a novel marker of poor outcome. (PMID:28716573)
• Our findings demonstrated a novel pro-apoptotic role of HTRA3 in pancreatic cancer cells via inducing Bax. (PMID:28860718)
• The HtrA1-PDZ and HtrA4-PDZ as well as HtrA2-PDZ and HtrA3-PDZ respond similarly to different halogen substitutions of peptide; -Br substitution at R2-position and -I substitution at R4-position are most effective in improving peptide selectivity for HtrA1-PDZ/HtrA4-PDZ and HtrA2-PDZ/HtrA3-PDZ, respectively; -F substitution would not address substantial effect on peptide selectivity for all the 4 domains (PMID:29266444)
• results indicate that actin, beta-tubulin, vimentin, and TCP1alpha are HtrA3 cellular partners and suggest that HtrA3 may influence cytoskeleton dynamics. (PMID:29477555)
• Hypoxia is responsible for the reduction of HtrA3 which in turn promotes endometrial cancer progression. (PMID:30139517)
• Low HTRA3 expression is associated with Metastasis in Non-Small Cell Lung Cancer. (PMID:30940659)
• Low expression of HtrA3 at 15 weeks is associated with, and may be useful for, the early detection of late-onset preeclampsia development and small for gestational age birth. (PMID:31013509)
• Knockdown of linc00467 altered the expression of downstream genes, including HtrA serine peptidase 3 (HTRA3), and RNA immunoprecipitation and chromatin immunoprecipitation assays indicated that linc00467 recruited EZH2 to the HTRA3 promoter to inhibit its expression. (PMID:31180543)
• HtrA3 isoforms stimulate drug-induced apoptotic death of lung cancer cells via XIAP cleavage. (PMID:31260151)
• This study reports allosteric modulation of Human HtrA3 (High temperature requirement protease A3) enzyme activity for the first time. A novel non-classical allosteric ligand binding pocket mediates allostery in HtrA3. (PMID:31280864)
• Our study also reports an intricate ligand-induced allosteric switch, which redefines the existing hypothesis of HtrA3 activation besides opening up avenues for modulating protease activity favorably through suitable effector molecules. (PMID:31899476)
• Expression of HTRA Genes and Its Association with Microsatellite Instability and Survival of Patients with Colorectal Cancer. (PMID:32486357)
• Hsa-miR-494-3p attenuates gene HtrA3 transcription to increase inflammatory response in hypoxia/reoxygenation HK2 Cells. (PMID:33462352)
• Study on the Correlation between the Levels of HtrA3 and TGF-beta2 in Late Pregnancy and Preeclampsia. (PMID:35035835)
• mmu-lncRNA 121686/hsa-lncRNA 520657 induced by METTL3 drive the progression of AKI by targeting miR-328-5p/HtrA3 signaling axis. (PMID:35869629)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	HTRA3	ENSDARG00000010925
danio_rerio	htra3a	ENSDARG00000052895
mus_musculus	Htra3	ENSMUSG00000029096
rattus_norvegicus	Htra3	ENSRNOG00000008182

Paralogs (3): HTRA2 (ENSG00000115317), HTRA1 (ENSG00000166033), HTRA4 (ENSG00000169495)

Protein

Protein identifiers

Serine protease HTRA3 — P83110 (reviewed: P83110)

Alternative names: High-temperature requirement factor A3, Pregnancy-related serine protease

All UniProt accessions (1): P83110

UniProt curated annotations — full annotation on UniProt →

Function. Serine protease that cleaves beta-casein/CSN2 as well as several extracellular matrix (ECM) proteoglycans such as decorin/DCN, biglycan/BGN and fibronectin/FN1. Inhibits signaling mediated by TGF-beta family proteins possibly indirectly by degradation of these ECM proteoglycans. May act as a tumor suppressor. Negatively regulates, in vitro, trophoblast invasion during placental development and may be involved in the development of the placenta in vivo. May also have a role in ovarian development, granulosa cell differentiation and luteinization.

Subunit / interactions. Homotrimer. Interacts with TGFB1; the interaction inhibits TGFB-mediated signaling. Interacts with BMP4; the interaction inhibits BMP4-mediated signaling. Interacts with TGFB2 and GDF5. Interacts with MYH9.

Subcellular location. Secreted.

Tissue specificity. Widely expressed, with highest levels in both adult and fetal heart, ovary, uterus placenta, and bladder. In the endometrium, expressed in epithelial glands and the stroma. Also present in leukocytes. Isoform 1 is predominant in heart and skeletal muscle, whereas isoform 2 is predominant in placenta and kidney.

Induction. Down-regulated in ovarian and endometrial cancers (EC). Decrease of 3.2-fold in endometrial cancer.

Similarity. Belongs to the peptidase S1C family.

Isoforms (2)

UniProt ID	Names	Canonical?
P83110-1	1, Long, pL	yes
P83110-2	2, Short, pS

RefSeq proteins (2): NP_001284488, NP_444272* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000867	IGFBP-like	Domain
IPR001478	PDZ	Domain
IPR001940	Peptidase_S1C	Family
IPR002350	Kazal_dom	Domain
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily
IPR036058	Kazal_dom_sf	Homologous_superfamily

Pfam: PF00219, PF07648, PF13180, PF13365

Enzyme classification (BRENDA):

• EC 3.4.21.108 — HtrA2 peptidase (BRENDA: 23 organisms, 127 substrates, 42 inhibitors, 35 Km, 23 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
BETA-CASEIN	0.001–0.0093	24
ALA(7-METHOXYCOUMARIN-4-ACETIC ACID)-IRRVSYSF-(5	0.0007–0.001	3
(7-METHOXYCOUMARIN-4-YL)AIRRVSYSF-(5-AMINO-2-NIT	0.0016	1
2-AMINOBENZOIC ACID-ILE-MET-THR-ABU-TYR-MET-HIS-	0.0391	1
2-AMINOBENZOIC ACID-ILE-MET-THR-ABU-TYR-MET-PHE-	0.0227	1
2-AMINOBENZOIC ACID-ILE-MET-THR-ABU-TYR-MET-TRP-	0.107	1
2-AMINOBENZOIC ACID-ILE-MET-THR-SER-TYR-MET-PHE-	0.354	1
2-AMINOBENZOIC ACID-ILE-MET-VAL-ABU-TYR-MET-PHE-	0.0315	1
2-AMINOBENZOIC ACID-ILE-MET-VAL-SER-TYR-MET-PHE-	0.177	1
OLIGOMERIC ALPHA-SYNUCLEIN	0.0026	1
SPMFKGV-PARA-NITROANILINE	—	0

UniProt features (52 total): strand 20, disulfide bond 8, helix 8, turn 4, domain 3, active site 3, splice variant 2, signal peptide 1, chain 1, mutagenesis site 1, region of interest 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2P3W	X-RAY DIFFRACTION	1.7
4RI0	X-RAY DIFFRACTION	3.27

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P83110-F1	84.47	0.46

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 (3): 191 (charge relay system); 227 (charge relay system); 305 (charge relay system)

Disulfide bonds (8): 29–50, 34–51, 39–54, 62–76, 70–81, 83–101, 90–126, 25–48

Mutagenesis-validated functional residues (1):

Position	Phenotype
305	abolishes protease activity. stabilizes the protein.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 114 (showing top): TAKEDA_TARGETS_OF_NUP98_HOXA9_FUSION_6HR_DN, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, BENPORATH_ES_WITH_H3K27ME3, LIEN_BREAST_CARCINOMA_METAPLASTIC, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY, ROZANOV_MMP14_TARGETS_UP, GOBP_RESPONSE_TO_TRANSFORMING_GROWTH_FACTOR_BETA, GOBP_NEGATIVE_REGULATION_OF_BMP_SIGNALING_PATHWAY, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_6, chr4p16, TSENG_IRS1_TARGETS_DN, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_TRANSFORMING_GROWTH_FACTOR_BETA_STIMULUS, GOBP_RESPONSE_TO_BMP, GOBP_RESPONSE_TO_GROWTH_FACTOR

GO Biological Process (3): proteolysis (GO:0006508), negative regulation of transforming growth factor beta receptor signaling pathway (GO:0030512), negative regulation of BMP signaling pathway (GO:0030514)

GO Molecular Function (7): endopeptidase activity (GO:0004175), serine-type endopeptidase activity (GO:0004252), serine-type peptidase activity (GO:0008236), identical protein binding (GO:0042802), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (1): extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	2
peptidase activity	2
protein metabolic process	1
transforming growth factor beta receptor signaling pathway	1
regulation of transforming growth factor beta receptor signaling pathway	1
BMP signaling pathway	1
regulation of BMP signaling pathway	1
negative regulation of cellular response to growth factor stimulus	1
endopeptidase activity	1
serine-type peptidase activity	1
serine hydrolase activity	1
protein binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1458 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HTRA3	A0A494C0M2	A0A494C0M2	474
HTRA3	WFDC1	Q9HC57	469
HTRA3	F6RGN5	F6RGN5	433
HTRA3	TCP1	P17987	412
HTRA3	INS	P01308	366
HTRA3	DDX5	P17844	353
HTRA3	CLIC1	O00299	353
HTRA3	NET1	Q7Z628	353
HTRA3	OLFM1	Q99784	353
HTRA3	TPRKB	Q9Y3C4	353
HTRA3	DNAJC10	Q8IXB1	351
HTRA3	CKS2	P33552	351
HTRA3	RTN4	Q9NQC3	351
HTRA3	AP3S1	Q92572	350
HTRA3	GAK	O14976	349

IntAct

440 interactions, top by confidence:

A	B	Type	Score
HTRA3	CSN2	psi-mi:“MI:0407”(direct interaction)	0.770
HTRA3	CSN2	psi-mi:“MI:0570”(protein cleavage)	0.770
CSN2	HTRA3	psi-mi:“MI:0570”(protein cleavage)	0.770
CSN2	HTRA3	psi-mi:“MI:0194”(cleavage reaction)	0.770
HTRA3	XIAP	psi-mi:“MI:0915”(physical association)	0.700
HTRA3	XIAP	psi-mi:“MI:0403”(colocalization)	0.700
HTRA3	XIAP	psi-mi:“MI:2364”(proximity)	0.700
XIAP	HTRA3	psi-mi:“MI:0194”(cleavage reaction)	0.700
HTRA3	HTRA3	psi-mi:“MI:0915”(physical association)	0.670
HTRA3	HTRA3	psi-mi:“MI:0407”(direct interaction)	0.670
TNFSF8	TOR1B	psi-mi:“MI:0914”(association)	0.640
E	HTRA3	psi-mi:“MI:0915”(physical association)	0.610
E	HTRA3	psi-mi:“MI:0407”(direct interaction)	0.610
HTRA4	HTRA3	psi-mi:“MI:0915”(physical association)	0.540
HTRA3	HTRA4	psi-mi:“MI:0915”(physical association)	0.540
HTRA4	HTRA3	psi-mi:“MI:0570”(protein cleavage)	0.540
HTRA3	TCP1	psi-mi:“MI:0914”(association)	0.540
HTRA3	ACTB	psi-mi:“MI:0915”(physical association)	0.540
TCP1	HTRA3	psi-mi:“MI:0915”(physical association)	0.540

BioGRID (28): HTRA3 (Affinity Capture-MS), HTRA3 (Affinity Capture-MS), HTRA3 (Affinity Capture-MS), HTRA3 (Synthetic Lethality), HTRA3 (Affinity Capture-MS), XIAP (Biochemical Activity), HTRA3 (Reconstituted Complex), XIAP (Affinity Capture-Western), HTRA3 (Affinity Capture-Western), XIAP (Biochemical Activity), XIAP (Reconstituted Complex), HTRA3 (Reconstituted Complex), HTRA3 (Co-localization), HTRA3 (Affinity Capture-MS), SH2D3A (Affinity Capture-MS)

ESM2 similar proteins: A0JNK3, A2RT60, A4IHA1, A6YFB5, A9JRB3, B3LVG7, B3P3J9, B4G316, B4HEM8, B4JTT7, B4K835, B4LY58, B4N937, B4PST0, B4QZU6, D3ZA76, D3ZKF5, E1BJW1, F1N152, F4J3G5, O22609, O23614, O43464, P14543, P38935, P73940, P83105, P83110, Q14689, Q14703, Q297U2, Q3U213, Q5SNQ7, Q5XIL0, Q6GMI0, Q852K0, Q8BMS2, Q8IUL8, Q8IZJ1, Q91XF4

Diamond homologs: A0JNK3, A2RNT9, A2RT60, A4IHA1, A4XSC0, A5W8F5, A6VUA4, A6YFB5, A9JRB3, B0KV30, B1J4D7, B3LVG7, B3P3J9, B4G316, B4HEM8, B4JTT7, B4K835, B4LY58, B4N937, B4PST0, B4QZU6, D0ZY51, D3ZA76, D3ZKF5, E1BJW1, E1V4H2, F1N152, F6AA62, O05942, O06291, O22609, O34358, O43464, O53896, O85291, P05676, P0A3Z5, P0AEE3, P0AEE4, P0C0V0

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 169 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
Tight junction interactions	10	30.4×	3e-10
EPHB-mediated forward signaling	6	13.2×	9e-04
Cell-cell junction organization	5	10.3×	5e-03
Neurexins and neuroligins	6	9.8×	2e-03
Cell death signalling via NRAGE, NRIF and NADE	5	9.1×	7e-03
RHOQ GTPase cycle	6	9.0×	2e-03
RHOB GTPase cycle	6	7.7×	5e-03
G alpha (12/13) signalling events	6	6.8×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
calcium-independent cell-cell adhesion	9	46.6×	1e-10
bicellular tight junction assembly	10	21.3×	2e-08
maintenance of blood-brain barrier	6	18.6×	2e-04
protein-containing complex assembly	10	7.3×	3e-04
regulation of actin cytoskeleton organization	7	7.1×	7e-03
cell-cell adhesion	10	6.5×	6e-04
chemical synaptic transmission	12	6.0×	2e-04
cell adhesion	19	4.6×	2e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	80
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

2935 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:8286761:C:A	A229D	1.000
4:8291484:A:C	S275R	1.000
4:8291486:C:A	S275R	1.000
4:8291486:C:G	S275R	1.000
4:8292333:G:T	G306W	1.000
4:8292334:G:A	G306E	1.000
4:8292343:T:C	L309P	1.000
4:8294138:T:C	F330L	1.000
4:8294140:T:A	F330L	1.000
4:8294140:T:G	F330L	1.000
4:8286605:G:A	G177D	0.999
4:8286642:T:A	N189K	0.999
4:8286642:T:G	N189K	0.999
4:8286755:A:T	D227V	0.999
4:8286760:G:C	A229P	0.999
4:8291418:G:T	G253W	0.999
4:8291419:G:A	G253E	0.999
4:8291433:G:C	A258P	0.999
4:8291434:C:A	A258D	0.999
4:8291439:G:C	G260R	0.999
4:8291440:G:A	G260D	0.999
4:8291464:C:T	T268I	0.999
4:8291475:G:C	G272R	0.999
4:8291476:G:A	G272D	0.999
4:8291482:T:A	V274D	0.999
4:8291546:G:C	Q295H	0.999
4:8291546:G:T	Q295H	0.999
4:8291550:G:C	D297H	0.999
4:8291550:G:T	D297Y	0.999
4:8291551:A:G	D297G	0.999

dbSNP variants (sampled 300 via entrez): RS10000359 (4:8288949 T>A,C), RS1000072166 (4:8274533 G>A), RS1000085674 (4:8283409 A>G), RS1000112930 (4:8274590 C>T), RS1000172930 (4:8293683 C>A,T), RS1000310355 (4:8279476 G>A), RS1000327859 (4:8302324 G>A,C,T), RS1000330228 (4:8287965 A>T), RS1000438557 (4:8274707 G>A,T), RS1000454805 (4:8275486 C>G,T), RS1000554842 (4:8280636 C>G), RS1000608318 (4:8293865 A>T), RS1000674736 (4:8303513 G>A), RS1000850748 (4:8307520 T>A), RS1000858079 (4:8270599 G>A)

Disease associations

OMIM: gene MIM:608785 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008361_3	Response to cognitive-behavioural therapy in major depressive disorder	2.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007820	cognitive behavioural therapy

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, decreases expression, increases abundance	5
Valproic Acid	decreases expression, increases methylation, affects cotreatment	4
Benzo(a)pyrene	affects expression, affects methylation, increases methylation	3
Air Pollutants	increases abundance, increases expression	2
Nickel	increases expression	2
Smoke	increases expression, decreases expression	2
Cadmium Chloride	increases expression	2
aristolochic acid I	increases expression	1
tungsten carbide	affects cotreatment, increases expression	1
bisphenol A	decreases expression	1
2-butenal	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	decreases methylation, increases methylation	1
cupric oxide	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
perfluorooctane sulfonic acid	increases expression	1
fipronil	increases expression, affects cotreatment	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
perfluorohexanesulfonic acid	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
bisphenol AF	increases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	increases expression	1
Arsenic	increases abundance, increases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Cobalt	affects cotreatment, increases expression	1
DEET	affects cotreatment, increases expression	1
Diethylhexyl Phthalate	decreases expression	1

Clinical trials (associated diseases)

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