HTRA2

Summary

HTRA2 (HtrA serine peptidase 2, HGNC:14348) is a protein-coding gene on chromosome 2p13.1, encoding Serine protease HTRA2, mitochondrial (O43464). Serine protease that shows proteolytic activity against a non-specific substrate beta-casein.

This gene encodes a serine protease. The protein has been localized in the endoplasmic reticulum and interacts with an alternatively spliced form of mitogen-activated protein kinase 14. The protein has also been localized to the mitochondria with release to the cytosol following apoptotic stimulus. The protein is thought to induce apoptosis by binding the apoptosis inhibitory protein baculoviral IAP repeat-containing 4. Nuclear localization of this protein has also been observed. Alternate splicing of this gene results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 27429 — RefSeq curated summary.

At a glance

• Gene–disease (curated): 3-methylglutaconic aciduria type 8 (Definitive, ClinGen)
• Clinical variants (ClinVar): 345 total — 10 pathogenic, 4 likely-pathogenic (top 9% of genes corpus-wide)
• GTEx eGene: eQTL in 9 tissues, sQTL in 5 (q < 0.05)
• Phenotypes (HPO): 70
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.78 (unconstrained)
• MANE Select transcript: NM_013247
• Interaction hub: 1,816 STRING partners (top 9% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14348
Approved symbol	HTRA2
Name	HtrA serine peptidase 2
Location	2p13.1
Locus type	gene with protein product
Status	Approved
Aliases	OMI, PARK13
Ensembl gene	ENSG00000115317
Ensembl biotype	protein_coding
OMIM	606441
Entrez	27429

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 12 protein_coding, 7 retained_intron, 5 protein_coding_CDS_not_defined, 4 nonsense_mediated_decay

MANE Select: ENST00000258080

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 4, TSL 2: 3, TSL 3: 1, TSL 5: 2

ENST00000258080, ENST00000352222, ENST00000437202, ENST00000462909, ENST00000465521, ENST00000467961, ENST00000482205, ENST00000482331, ENST00000484352, ENST00000484881, ENST00000696725, ENST00000696726, ENST00000696727, ENST00000696728, ENST00000696729, ENST00000696730, ENST00000696731, ENST00000854416, ENST00000854417, ENST00000994778, ENST00000994779, ENST00000994780, ENST00001014791, ENST00001014792, ENST00001114062, ENST00001122704, ENST00001122705, ENST00001142984

RefSeq mRNA: 4 — MANE Select: NM_013247 NM_001321727, NM_001321728, NM_013247, NM_145074

CCDS: CCDS1951, CCDS1952, CCDS92785, CCDS92786

Canonical transcript exons

ENST00000258080 — 8 exons

Exon	Start	End
ENSE00000920849	74532820	74533319
ENSE00001276828	74529933	74530512
ENSE00003557589	74531597	74531702
ENSE00003573102	74531856	74531925
ENSE00003578709	74530911	74531105
ENSE00003599050	74532619	74532714
ENSE00003637787	74531339	74531371
ENSE00003670137	74530617	74530821

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 92.01.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.1520 / max 325.9846, expressed in 1798 samples.

Highest expression (Bgee): cortical plate, coronary artery, trabecular bone tissue, ganglionic eminence, apex of heart.

Genetic regulation across tissues (GTEx eQTL / sQTL)

HTRA2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 9 tissues and its splicing (sQTL) in 5 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

14 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	eqtl	1.2e-08	-0.59	2:74629108:A:G
Skin Not Sun Exposed Suprapubic	eqtl	2.9e-04	-0.36	2:74469618:T:C
Nerve Tibial	sqtl	4.9e-04	-0.75	2:74509676:G:A
Cells EBV-transformed lymphocytes	eqtl	3.2e-03	-0.57	2:74507239:G:C
Cells Cultured fibroblasts	sqtl	8.7e-03	-0.68	2:74451552:C:T
Adipose Subcutaneous	eqtl	1.8e-02	-0.24	2:73892535:C:T
Lung	sqtl	2.5e-02	-0.31	2:75495419:A:T
Artery Tibial	sqtl	2.8e-02	-0.80	2:74732855:C:A
Testis	eqtl	3.0e-02	-0.16	2:73910224:G:GTA
Lung	eqtl	3.1e-02	+0.36	2:75413306:G:T
Skin Sun Exposed Lower leg	eqtl	3.7e-02	-0.25	2:74167339:G:A
Cells Cultured fibroblasts	eqtl	4.6e-02	-0.37	2:74681674:C:A
Prostate	eqtl	4.7e-02	-0.22	2:75150594:G:GT
Testis	sqtl	4.9e-02	-0.64	2:74551018:T:C

FANTOM5 promoters

showing 10 of 13 alternative TSS:

Promoter ID	TPM avg	Samples expressed
21053	10.3116	1758
21057	3.2809	1326
21054	1.3395	937
21055	0.7641	409
21056	0.4589	259
21060	0.3344	54
21052	0.1311	44
21049	0.1223	67
21059	0.1131	35
21051	0.1113	48

Top tissues by expression

showing 100 of 294 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	92.01	gold quality
right coronary artery	UBERON:0001625	91.90	gold quality
trabecular bone tissue	UBERON:0002483	91.79	gold quality
ganglionic eminence	UBERON:0004023	91.38	gold quality
apex of heart	UBERON:0002098	91.37	gold quality
mucosa of transverse colon	UBERON:0004991	91.35	gold quality
granulocyte	CL:0000094	91.16	gold quality
spleen	UBERON:0002106	90.99	gold quality
right ovary	UBERON:0002118	90.81	gold quality
ascending aorta	UBERON:0001496	90.77	gold quality
thoracic aorta	UBERON:0001515	90.75	gold quality
omental fat pad	UBERON:0010414	90.73	gold quality
left coronary artery	UBERON:0001626	90.72	gold quality
peritoneum	UBERON:0002358	90.71	gold quality
coronary artery	UBERON:0001621	90.70	gold quality
adipose tissue of abdominal region	UBERON:0007808	90.68	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	90.66	gold quality
prefrontal cortex	UBERON:0000451	90.55	gold quality
right frontal lobe	UBERON:0002810	90.53	gold quality
mucosa of stomach	UBERON:0001199	90.49	gold quality
lower esophagus muscularis layer	UBERON:0035833	90.46	gold quality
lower esophagus	UBERON:0013473	90.44	gold quality
left ovary	UBERON:0002119	90.42	gold quality
right adrenal gland	UBERON:0001233	90.25	gold quality
aorta	UBERON:0000947	90.22	gold quality
muscle layer of sigmoid colon	UBERON:0035805	90.18	gold quality
left adrenal gland	UBERON:0001234	90.13	gold quality
left adrenal gland cortex	UBERON:0035825	90.13	gold quality
body of uterus	UBERON:0009853	90.03	gold quality
descending thoracic aorta	UBERON:0002345	90.02	gold quality
lymph node	UBERON:0000029	89.96	gold quality
popliteal artery	UBERON:0002250	89.89	gold quality
tibial artery	UBERON:0007610	89.88	gold quality
right adrenal gland cortex	UBERON:0035827	89.88	gold quality
cingulate cortex	UBERON:0003027	89.76	gold quality
endocervix	UBERON:0000458	89.66	gold quality
anterior cingulate cortex	UBERON:0009835	89.64	gold quality
right lobe of thyroid gland	UBERON:0001119	89.63	gold quality
adrenal cortex	UBERON:0001235	89.47	gold quality
heart left ventricle	UBERON:0002084	89.47	gold quality
right atrium auricular region	UBERON:0006631	89.35	gold quality
left lobe of thyroid gland	UBERON:0001120	89.32	gold quality
adenohypophysis	UBERON:0002196	89.23	gold quality
right lung	UBERON:0002167	89.22	gold quality
ventricular zone	UBERON:0003053	89.15	gold quality
cardiac ventricle	UBERON:0002082	89.09	gold quality
left uterine tube	UBERON:0001303	89.03	gold quality
ovary	UBERON:0000992	89.01	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	88.99	gold quality
adipose tissue	UBERON:0001013	88.96	gold quality
bone marrow	UBERON:0002371	88.96	gold quality
gastrocnemius	UBERON:0001388	88.88	gold quality
right testis	UBERON:0004534	88.88	gold quality
tibial nerve	UBERON:0001323	88.87	gold quality
adrenal gland	UBERON:0002369	88.86	gold quality
connective tissue	UBERON:0002384	88.82	gold quality
left testis	UBERON:0004533	88.74	gold quality
amygdala	UBERON:0001876	88.69	gold quality
subcutaneous adipose tissue	UBERON:0002190	88.63	gold quality
neocortex	UBERON:0001950	88.62	gold quality
heart	UBERON:0000948	88.61	gold quality
thyroid gland	UBERON:0002046	88.61	gold quality
transverse colon	UBERON:0001157	88.58	gold quality
metanephros cortex	UBERON:0010533	88.57	gold quality
ectocervix	UBERON:0012249	88.57	gold quality
frontal cortex	UBERON:0001870	88.56	gold quality
pituitary gland	UBERON:0000007	88.54	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.54	gold quality
cardiac atrium	UBERON:0002081	88.53	gold quality
esophagus	UBERON:0001043	88.45	gold quality
muscle of leg	UBERON:0001383	88.42	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.39	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	88.33	gold quality
hindlimb stylopod muscle	UBERON:0004252	88.28	gold quality
embryo	UBERON:0000922	88.26	gold quality
upper lobe of left lung	UBERON:0008952	88.23	gold quality
superficial temporal artery	UBERON:0001614	88.21	gold quality
Brodmann (1909) area 9	UBERON:0013540	88.20	gold quality
islet of Langerhans	UBERON:0000006	88.19	gold quality
upper lobe of lung	UBERON:0008948	88.14	gold quality
spinal cord	UBERON:0002240	88.13	gold quality
lower esophagus mucosa	UBERON:0035834	88.05	gold quality
right lobe of liver	UBERON:0001114	88.00	gold quality
cerebellar hemisphere	UBERON:0002245	87.99	gold quality
blood	UBERON:0000178	87.91	gold quality
cerebellar cortex	UBERON:0002129	87.88	gold quality
body of stomach	UBERON:0001161	87.86	gold quality
testis	UBERON:0000473	87.82	gold quality
nucleus accumbens	UBERON:0001882	87.82	gold quality
stromal cell of endometrium	CL:0002255	87.74	gold quality
caudate nucleus	UBERON:0001873	87.72	gold quality
hypothalamus	UBERON:0001898	87.70	gold quality
vermiform appendix	UBERON:0001154	87.48	gold quality
putamen	UBERON:0001874	87.41	gold quality
cerebral cortex	UBERON:0000956	87.38	gold quality
minor salivary gland	UBERON:0001830	87.38	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.34	gold quality
forebrain	UBERON:0001890	87.23	gold quality
esophagus mucosa	UBERON:0002469	87.15	gold quality
telencephalon	UBERON:0001893	87.14	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	45.19
E-ANND-3	yes	6.15
E-CURD-11	no	59.46

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Frontal cortex	tissue	24.0
Caudate putamen	tissue	16.9
Ovary	tissue	15.3	not detected
Skeletal muscle	tissue	14.1	not detected
Thalamus	tissue	13.6
Pons	tissue	13.4
Locus coeruleus	tissue	13.4
Superior colliculi	tissue	13.0
Hippocampal formation	tissue	12.9
Midbrain	tissue	12.7
Cerebral cortex	tissue	12.6	medium
Somatosensory cortex	tissue	12.6
Bone marrow	tissue	12.3	medium
Parathyroid gland	tissue	12.1	medium
Adipose tissue	tissue	11.7	low
Medulla oblongata	tissue	11.7
Hippocampus	tissue	11.6	low
Tongue	tissue	11.2
Motor cortex	tissue	10.9
Postcentral gyrus	tissue	10.9
Nucleus accumbens	tissue	10.8
Choroid plexus	tissue	10.6
Occipital cortex	tissue	10.5
Substantia nigra	tissue	10.3
Heart muscle	tissue	10.2	not detected
Hypothalamus	tissue	10.1
Prefrontal cortex	tissue	10.0
Spinal cord	tissue	10.0
Retrosplenial and cingulate cortex	tissue	10.0
Adrenal gland	tissue	9.8	medium
Septum	tissue	9.8
Spleen	tissue	9.7	not detected
Retrosplenial cortex	tissue	9.7
Temporal cortex	tissue	9.7
Vagina	tissue	9.6	low
Entorhinal cortex	tissue	9.6
Thymus	tissue	9.5
Periaqueductal gray	tissue	9.4
Amygdala	tissue	9.2
Fallopian tube	tissue	9.0	medium
Salivary gland	tissue	8.9	low
Ventral forebrain	tissue	8.9
Lymph node	tissue	8.6	low
Corpus callosum	tissue	8.6
Insular cortex	tissue	8.6
Pituitary gland	tissue	8.4
Putamen	tissue	8.4
Small intestine	tissue	8.1	medium
Cerebellum	tissue	7.8	low
Olfactory bulb	tissue	7.8
Appendix	tissue	7.8	medium
Pancreas	tissue	7.7	medium
Basal ganglia	tissue	7.4	low
Duodenum	tissue	7.2	medium
Placenta	tissue	7.1	medium
Kidney	tissue	7.0	medium
Endometrium 1	tissue	6.9	medium
Urinary bladder	tissue	6.8	medium
Lung	tissue	6.8	low
Seminal vesicle	tissue	6.6	medium

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Posterior thalamic nucleus (17.2), Medial dorsal thalamic nucleus (15.8), Cerebellar nuclei (15.5), Habenula (15.3), Corpus callosum, splenium (white matter) (15.2).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, WT1

miRNA regulators (miRDB)

Targeting HTRA2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

20 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-4777-3P	99.15	68.92	626
HSA-MIR-625-5P	99.02	68.64	2031
HSA-MIR-4764-5P	98.88	65.53	894
HSA-MIR-6501-3P	98.71	67.45	1480
HSA-MIR-138-5P	98.43	70.49	1292
HSA-MIR-4456	97.50	64.88	1678
HSA-MIR-3137	97.26	66.78	761
HSA-MIR-4491	96.53	66.20	935
HSA-MIR-4657	96.53	66.57	895
HSA-MIR-4278	95.28	65.49	351

Functional genomics

gnomAD constraint: pLI 0.000205, LOEUF 0.778, missense Z 2.37 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000258080 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
2:74,530,007–74,530,449	222 / 205.1	1.08	no
2:74,530,450–74,531,660	115 / 245.4	0.47	no
2:74,531,661–74,532,982	129 / 163.1	0.79	no

Literature-anchored findings (GeneRIF, showing 40)

• 2.0 A crystal structure; structural insights into the pro-apoptotic function of mitochondrial serine protease HtrA2/Omi (PMID:11967569)
• these results indicate that unlike Smac/DIABLO, Omi/HtrA2’s catalytic cleavage of IAPs is a key mechanism for it to irreversibly inactivate IAPs and promote apoptosis. (PMID:12815069)
• identification of inhibitor of apoptosis proteins as substrate (PMID:12835328)
• protease activity of Omi/HtrA2 promotes caspase activation through multiple pathways (PMID:14605674)
• mitochondrial release of the serine protease Omi/HtrA2 into the cytosol of the cells treated with imatinib mesylate or zVAD-fmk plus imatinib mesylate (PMID:14645012)
• Amyloid-beta interacts with HtrA2/Omi, an essential human serine protease with proapoptotic activity. Additionally, we mapped the C-terminal region containing the PDZ domain of HtrA2/Omi as the binding determinant for Abeta. (PMID:15036614)
• autocatalytic processing of HtrA2/Omi is crucial for regulating HtrA2/Omi-mediated apoptotic cell death (PMID:15201285)
• effect of temperature on proteolytic activity of HtrA2 and related structural properties were investigated (PMID:15236609)
• C terminus of PS1 is an activation peptide ligand for the PDZ domain of Omi/HtrA2 and may regulate the protease activity of Omi/HtrA2 after its release from the mitochondria during apoptosis. (PMID:15294909)
• apoptosis following Omi/HtrA2 mitochondrial release is mediated by reduction in ped/pea-15 cellular levels (PMID:15328349)
• On the basis of functional genomics, our results provide a novel link between mitochondrial dysfunction and neurodegeneration in PD. (PMID:15961413)
• Beta-amyloid precursor protein is a direct cleavage target of HtrA2 serine protease. (PMID:16968707)
• Mediates processing of WARTS mitotic kinase in negative regulation of cell cycle progression at interphase, suggesting a novel function of Omi other than apoptosis. (PMID:17130845)
• HtrA2/Omi has a rather narrow cleavage site preference and cytoskeletal proteins are prime targets of this protease. (PMID:17266347)
• HtrA2 has a role as a regulator of APP metabolism through endoplasmic reticulum-associated degradation (PMID:17684015)
• This article summarizes recent studies regarding the HtrA family of proteins, their structure, regulation and function. It also presents practical applications of this knowledge and perspective of its use in the future. (PMID:17718385)
• expression of Smac/DIABLO, but not Omi/HtrA2, is inversely associated with outcome of renal cell carcinoma patients. (PMID:17922292)
• These data indicate that S100A8/A9-induced cell death involves Bak, selective release of Smac/DIABLO and Omi/HtrA2 from mitochondria, and modulation of the balance between pro- and anti-apoptotic proteins. (PMID:18060880)
• A significant downregulation of HtrA2 transcription is found in the group of borderline tumors of the ovary; HtrA2 may function as a tumor suppressor. (PMID:18241672)
• Data show that following apoptotic stimuli, HtrA2 accumulates in the nucleus and cleaves p73alpha in the C-terminal portion, enabling the protein to increase its transactivation activity on Bax but not on the cell-cycle regulator gene p21. (PMID:18259191)
• elimination of excess or spontaneously misfolded wild-type intermembrane space proteins is monitored by ubiquitination and as a second checkpoint by Omi cleavage when the proteasome function is deficient (PMID:18362145)
• Polymorphism of OMI/HTRA2 previously shown to be associated with Parkinson’s disease was present in the neurologically normal controls. (PMID:18364387)
• The study of HTRA2 to Parkinson disease risk in an extended series of 266 Belgian PD patients and 273 control individuals identified a novel p.Arg404Trp mutation within the PDZ domain predicted to freeze HTRA2 in an inactive form. (PMID:18401856)
• Omi/Htra2 serine protease activity participates in the cell death induced by CDDP but not of 5-FU in colon cancer cells. (PMID:18606591)
• These results collectively suggest that the homeostatic but not proapoptotic function of Omi/HtrA2 is linked to selective vulnerability of striatal neurons in HD pathology. (PMID:18662332)
• HtrA2/Omi sensitizes cytomegalovirus infected cells to death that can be blocked by vMIA or protease inhibitors (PMID:18769594)
• the results of this study do not support a role for Omi/HtrA2 variants in the pathogenesis of Parkinson’s disease. (PMID:18790661)
• HtrA2/Omi may be associated with the pathogenesis of alpha-synucleinopathies (PMID:18800009)
• These data suggest that a down-regulation of Smac/DIABLO and HtrA2 is implicated in the development and progression of TGCT, whereas overexpression of XAF1 in TGCT might contribute to their extraordinary sensitivity to chemotherapy. (PMID:18979398)
• Point mutations in another mitochondrial protein, HtrA2, are a susceptibility factor for Parkinson disease (PARK13 locus) (PMID:19076428)
• This study found that no associations were seen for HTRA2 in Australia patient with Parkinson’s disease (PMID:19224617)
• This review introduces HtrA2 from its molecular origins and discusses its modulation and potential as a novel drug target. (PMID:19355862)
• HtrA2 was down-regulated in endometrial cancers. (PMID:19424634)
• THAP5 and its regulation by Omi/HtrA2 provide a new link between cell cycle control and apoptosis in cardiomyocytes (PMID:19502560)
• Translocation of Omi/HtrA2 from mitochondria into cytoplasm may play an important role in its intracellular signal transduction mechanism in induction of apoptosis. (PMID:19570340)
• Studies show that GSK-3 and Omi/HtrA2 synergistically cause annexin A2 cleavage and then cell cycle inhibition or apoptosis. (PMID:19656851)
• results indicate a different function and mechanism of Hax1 in apoptosis and re-opens the question of whether mammalian PARL, in addition to apoptosis, regulates mitochondrial stress response through Omi/HtrA2 processing. (PMID:19680265)
• omi has a regulatory role in neurodegenerative disorders (PMID:19763263)
• PINK1, Omi/HtrA2 and parkin participate at different levels in mitochondrial quality control, converging through some overlapping and some distinct steps to maintain a common phenotype of healthy mitochondrial networks [REVIEW] (PMID:20012177)
• This largest association study performed revealed no overall strong association of Omi/HtrA2 variants with Parkinson dusease in populations worldwide. (PMID:20036034)

Cross-species orthologs

28 orthologs

Organism	Symbol	Gene ID
danio_rerio	htra2-9	ENSDARG00000069909
danio_rerio		ENSDARG00000070138
danio_rerio	htra2-12	ENSDARG00000076713
danio_rerio	si:dkey-271n12.1	ENSDARG00000088743
danio_rerio	htra2-3	ENSDARG00000092061
danio_rerio	htra2-2	ENSDARG00000092094
danio_rerio	si:dkey-84o3.3	ENSDARG00000092133
danio_rerio	htra2-6	ENSDARG00000092202
danio_rerio	htra2-11	ENSDARG00000092380
danio_rerio	si:dkey-10b15.8	ENSDARG00000092625
danio_rerio	htra2-8	ENSDARG00000093005
danio_rerio	htra2-5	ENSDARG00000094236
danio_rerio	htra2-7	ENSDARG00000094403
danio_rerio	htra2-10	ENSDARG00000094741
danio_rerio	si:dkey-84o3.2	ENSDARG00000094749
danio_rerio	si:dkey-84o3.6	ENSDARG00000094878
danio_rerio	si:dkey-84o3.4	ENSDARG00000094995
danio_rerio	si:dkey-112g5.14	ENSDARG00000095314
danio_rerio	si:dkey-33c12.12	ENSDARG00000095545
danio_rerio	si:dkey-84o3.7	ENSDARG00000095687
danio_rerio	htra2-4	ENSDARG00000111633
danio_rerio		ENSDARG00000114913
danio_rerio	si:dkey-19p15.3	ENSDARG00000115106
danio_rerio	htra2-1	ENSDARG00000115120
danio_rerio		ENSDARG00000116494
mus_musculus	Htra2	ENSMUSG00000068329
rattus_norvegicus	Htra2	ENSRNOG00000022448
drosophila_melanogaster	HtrA2	FBGN0038233

Paralogs (3): HTRA1 (ENSG00000166033), HTRA4 (ENSG00000169495), HTRA3 (ENSG00000170801)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1928676) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 68 distinct phenotype terms.

Mouse phenotype (MP)	Records
impaired balance	4
postnatal growth retardation	4
decreased locomotor activity	3
hunched posture	3
premature death	3
tremors	2
decreased body weight	2
impaired coordination	2
abnormal gait	2
akinesia	2
spleen atrophy	2
abnormal mitochondrial morphology	2
sparse hair	1
abnormal immune system morphology	1
small spleen	1
abnormal thymus morphology	1
small thymus	1
muscle spasm	1
muscle weakness	1
dystrophic muscle	1
paralysis	1
decreased brain size	1
motor neuron degeneration	1
abnormal spinal cord morphology	1
decreased body size	1

+43 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Brucella suis 1330	P0A3Z5	100.0%	Diamond
Escherichia coli K-12	P0AEE3	100.0%	Diamond
Escherichia coli O157:H7	P0AEE4	100.0%	Diamond
Brucella abortus bv. 1 str. 9-941	P0C114	100.0%	Diamond
Mycobacterium tuberculosis CDC1551	P9WHR8	100.0%	Diamond
Mycobacterium tuberculosis H37Rv	P9WHR9	100.0%	Diamond
Brucella abortus 2308	Q2YMX6	100.0%	Diamond
Brucella melitensis bv. 1 str. 16M	Q8YG32	99.8%	Diamond
Drosophila sechellia	B4HEM8	99.3%	Diamond
Drosophila simulans	B4QZU6	99.3%	Diamond
Drosophila persimilis	B4G316	98.8%	Diamond
Drosophila pseudoobscura pseudoobscura	Q297U2	98.8%	Diamond
Pseudomonas putida F1	A5W8F5	98.1%	Diamond
Pseudomonas putida GB-1	B0KV30	98.1%	Diamond
Drosophila yakuba	B4PST0	97.2%	Diamond
Drosophila erecta	B3P3J9	96.7%	Diamond
Pseudomonas putida W619	B1J4D7	95.4%	Diamond
Bos taurus	F1N152	94.4%	Diamond
Xenopus tropicalis	A4IHA1	93.9%	Diamond
Xenopus laevis	A6YFB5	93.9%	Diamond
Chlamydia trachomatis D/UW-3/CX	P18584	93.4%	Diamond
Chlamydia muridarum str. Nigg	Q9PL97	93.4%	Diamond
Salmonella enterica subsp. enterica serovar Typhimurium str. LT2	P26982	92.8%	Diamond
Drosophila ananassae	B3LVG7	92.6%	Diamond
Lactococcus cremoris subsp. cremoris MG1363	A2RNT9	92.2%	Diamond
Lactococcus lactis subsp. lactis Il1403	Q9LA06	92.2%	Diamond
Drosophila mojavensis	B4K835	92.0%	Diamond
Drosophila willistoni	B4N937	91.8%	Diamond
Salmonella enterica subsp. enterica serovar Typhimurium str. 14028S	D0ZY51	91.6%	Diamond
Drosophila virilis	B4LY58	91.2%	Diamond
Drosophila grimshawi	B4JTT7	90.3%	Diamond
Rickettsia prowazekii str. Madrid E	O05942	83.6%	Diamond
Rickettsia conorii str. Malish 7	Q92JA1	83.6%	Diamond
Pseudomonas savastanoi pv. phaseolicola 1448A	Q48EU9	81.9%	Diamond
Pseudomonas protegens Pf-5	Q4KGQ4	80.0%	Diamond
Ectopseudomonas mendocina ymp	A4XSC0	79.9%	Diamond
Pseudomonas fulva 12-X	F6AA62	79.9%	Diamond
Buchnera aphidicola str. Sg (Schizaphis graminum)	O85291	78.0%	Diamond
Buchnera aphidicola str. APS (Acyrthosiphon pisum)	P57322	78.0%	Diamond
Chlamydia pneumoniae	Q9Z6T0	74.6%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
SEMA4F	protein-coding	10505
M1AP	protein-coding	130951
DOK1	protein-coding	1796
AUP1	protein-coding	550
LOXL3	protein-coding	84695
DQX1	protein-coding	165545
LBX2-AS1	ncRNA	151534
TLX2	protein-coding	3196
PCGF1	protein-coding	84759
LBX2	protein-coding	85474

Protein

Protein identifiers

Serine protease HTRA2, mitochondrial — O43464 (reviewed: O43464)

Alternative names: High temperature requirement protein A2, Omi stress-regulated endoprotease, Serine protease 25, Serine proteinase OMI

All UniProt accessions (5): A0A0C4DG44, A0A384MDW9, A0A8Q3SIX7, A0A8Q3SJ36, O43464

UniProt curated annotations — full annotation on UniProt →

Function. Serine protease that shows proteolytic activity against a non-specific substrate beta-casein. Promotes apoptosis by either relieving the inhibition of BIRC proteins on caspases, leading to an increase in caspase activity; or by a BIRC inhibition-independent, caspase-independent and serine protease activity-dependent mechanism. Cleaves BIRC6 and relieves its inhibition on CASP3, CASP7 and CASP9, but it is also prone to inhibition by BIRC6. Cleaves THAP5 and promotes its degradation during apoptosis. Seems to be proteolytically inactive.

Subunit / interactions. Homotrimer. Interacts with MXI2. Interacts with THAP5 under apoptotic conditions. The mature protein, but not the precursor, binds to BIRC2/c-IAP1, BIRC3/c-IAP2 and XIAP/BIRC4. Interacts with AREL1 (via HECT domain); in the cytoplasm following induction of apoptosis.

Subcellular location. Mitochondrion intermembrane space. Mitochondrion membrane Endoplasmic reticulum.

Tissue specificity. Ubiquitously expressed.

Post-translational modifications. Ubiquitinated by BIRC6; this activity is inhibited by DIABLO/SMAC. Autoproteolytically activated.

Disease relevance. 3-methylglutaconic aciduria 8 (MGCA8) [MIM:617248] An autosomal recessive inborn error of metabolism resulting in early death. Clinical features include extreme hypertonia observed at birth, alternating with hypotonia, subsequent appearance of extrapyramidal symptoms, lack of psychomotor development, microcephaly, and intractable seizures. Patients show lactic acidemia, 3-methylglutaconic aciduria, intermittent neutropenia, and progressive brain atrophy. The disease is caused by variants affecting the gene represented in this entry. Parkinson disease 13 (PARK13) [MIM:610297] A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability, as well as by a clinically significant response to treatment with levodopa. The pathology involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Activity regulation. Inhibited by BIRC6.

Domain organisation. The mature N-terminus is involved in the interaction with XIAP. The PDZ domain mediates interaction with MXI2.

Similarity. Belongs to the peptidase S1C family.

Isoforms (4)

UniProt ID	Names	Canonical?
O43464-1	1, 13B	yes
O43464-2	2, D-Omi
O43464-3	3, p7
O43464-4	4, p4

RefSeq proteins (4): NP_001308656, NP_001308657, NP_037379, NP_659540 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001478	PDZ	Domain
IPR001940	Peptidase_S1C	Family
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily
IPR041489	PDZ_6	Domain

Pfam: PF13365, PF17820

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 (62 total): strand 22, helix 11, sequence variant 9, splice variant 4, turn 4, active site 3, mutagenesis site 2, transit peptide 1, propeptide 1, chain 1, transmembrane region 1, domain 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

13 structures by resolution:

PDB	Title	Method	Resolution (Å)
5M3N	HTRA2 wild-type structure	X-RAY DIFFRACTION	1.65
5TO1	HtrA2 exposed (L266R, F303A) mutant	X-RAY DIFFRACTION	1.69
5M3O	HTRA2 A141S mutant structure	X-RAY DIFFRACTION	1.7
5TNY	HTRA2 G399S mutant	X-RAY DIFFRACTION	1.7
5TNZ	HtrA2 S142D mutant	X-RAY DIFFRACTION	1.75
5TO0	HTRA2 S276C mutant	X-RAY DIFFRACTION	1.9
5FHT	HtrA2 protease mutant V226K	X-RAY DIFFRACTION	1.95
1LCY	Crystal Structure of the Mitochondrial Serine Protease HtrA2	X-RAY DIFFRACTION	2
5WYN	HtrA2 Pathogenic Mutant	X-RAY DIFFRACTION	2.05
2PZD	Crystal Structure of the HtrA2/Omi PDZ Domain Bound to a Phage-Derived Ligand (WTMFWV)	X-RAY DIFFRACTION	2.75
8E2K	Cryo-EM structure of BIRC6/HtrA2-S306A	ELECTRON MICROSCOPY	3.21
7VGE	Structure of the PDZ deleted variant of HtrA2 protease (S306A)	X-RAY DIFFRACTION	4
8AUK	Cryo-EM structure of human BIRC6 in complex with HTRA2.	ELECTRON MICROSCOPY	6.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43464-F1	74.83	0.51

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Peptidases, Serine-type peptidases, Predicted membrane proteins, Plasma proteins, Disease related genes, Potential drug targets, Human disease related genes, Congenital disorders of metabolism, Congenital disorders of amino acid metabolism

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): mitochondria

Antibody reliability (HPA): IH uncertain · IF supported

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)

Position	Role
198	charge relay system
228	charge relay system
306	charge relay system

Mutagenesis-validated functional residues (2)

Position	Phenotype
134	loss of interaction with xiap. loss of inhibition of xiap activity.
306	loss of protease activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 5; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

5 pathways:

ID	Pathway	Evidence
R-HSA-9837999	Mitochondrial protein degradation	curated
R-HSA-9841251	Mitochondrial unfolded protein response (UPRmt)	curated
R-HSA-8953897	Cellular responses to stimuli	—
R-HSA-2262752	Cellular responses to stress	—
R-HSA-392499	Metabolism of proteins	—

MSigDB gene sets: 447 (showing top): MODULE_52, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_BEHAVIOR, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GOBP_ADULT_BEHAVIOR, MODULE_45, GOBP_GROWTH, GOBP_PROTEIN_TARGETING, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY

GO Biological Process (27): proteolysis (GO:0006508), mitochondrion organization (GO:0007005), intrinsic apoptotic signaling pathway in response to DNA damage (GO:0008630), response to herbicide (GO:0009635), programmed cell death (GO:0012501), protein autoprocessing (GO:0016540), protein catabolic process (GO:0030163), cellular response to oxidative stress (GO:0034599), cellular response to heat (GO:0034605), cellular response to interferon-beta (GO:0035458), intracellular signal transduction (GO:0035556), mitochondrial protein catabolic process (GO:0035694), positive regulation of apoptotic process (GO:0043065), negative regulation of neuron apoptotic process (GO:0043524), negative regulation of cell cycle (GO:0045786), neuron apoptotic process (GO:0051402), cellular response to retinoic acid (GO:0071300), cellular response to growth factor stimulus (GO:0071363), execution phase of apoptosis (GO:0097194), positive regulation of execution phase of apoptosis (GO:1900119), negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway (GO:1902176), regulation of autophagy of mitochondrion (GO:1903146), negative regulation of type 2 mitophagy (GO:1905090), positive regulation of extrinsic apoptotic signaling pathway in absence of ligand (GO:2001241), apoptotic process (GO:0006915), intrinsic apoptotic signaling pathway (GO:0097193), positive regulation of protein localization to mitochondrion (GO:1903749)

GO Molecular Function (8): serine-type endopeptidase activity (GO:0004252), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), protein serine/threonine kinase inhibitor activity (GO:0030291), identical protein binding (GO:0042802), ubiquitin ligase inhibitor activity (GO:1990948), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (14): chromatin (GO:0000785), nucleus (GO:0005634), mitochondrion (GO:0005739), mitochondrial intermembrane space (GO:0005758), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), cytoskeleton (GO:0005856), cytoplasmic side of plasma membrane (GO:0009898), membrane (GO:0016020), mitochondrial membrane (GO:0031966), CD40 receptor complex (GO:0035631), serine-type endopeptidase complex (GO:1905370), protein-containing complex (GO:0032991)

Reactome top-level categories

3 top-level categories:

Category	Pathways
Metabolism of proteins	1
Cellular responses to stress	1
Cellular responses to stimuli	1

GO top-level categories

showing 60 of 68 GO namespaces:

Category	Terms
apoptotic process	3
cellular anatomical structure	3
intracellular membrane-bounded organelle	3
cytoplasm	3
protein metabolic process	2
signal transduction	2
mitochondrion	2
mitochondrial envelope	2
organelle membrane	2
organelle organization	1
DNA damage response	1
intrinsic apoptotic signaling pathway	1
response to stress	1
response to toxic substance	1
cell death	1
protein processing	1
macromolecule catabolic process	1
response to oxidative stress	1
cellular response to chemical stress	1
response to heat	1
cellular response to stress	1
response to interferon-beta	1
cellular response to cytokine stimulus	1
intracellular anatomical structure	1
mitochondrion organization	1
protein catabolic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
cell cycle	1
negative regulation of cellular process	1
regulation of cell cycle	1
response to retinoic acid	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
response to growth factor	1
cellular response to endogenous stimulus	1
cellular process	1
bleb assembly	1
positive regulation of apoptotic process	1
execution phase of apoptosis	1
regulation of execution phase of apoptosis	1
endopeptidase activity	1
serine-type peptidase activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
serine hydrolase activity	1
protein serine/threonine kinase activity	1
protein kinase inhibitor activity	1
protein binding	1
ubiquitin-protein transferase inhibitor activity	1
binding	1
catalytic activity	1
chromosome	1
organelle envelope lumen	1
endomembrane system	1
nuclear outer membrane-endoplasmic reticulum membrane network	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 27 of 51 annotations. The rest are phylogenetic / computational / electronic (IEA).

27 experimentally-supported GO terms:

GO term	NS	Evidence
cellular response to growth factor stimulus	BP	mutant phenotype
cellular response to heat	BP	direct assay
cellular response to interferon-beta	BP	direct assay
cellular response to oxidative stress	BP	mutant phenotype
cellular response to retinoic acid	BP	direct assay
intracellular signal transduction	BP	direct assay
intrinsic apoptotic signaling pathway in response to DNA damage	BP	mutant phenotype
mitochondrion organization	BP	mutant phenotype
positive regulation of apoptotic process	BP	direct assay
positive regulation of execution phase of apoptosis	BP	direct assay
positive regulation of extrinsic apoptotic signaling pathway in absence of ligand	BP	mutant phenotype
protein catabolic process	BP	direct assay
proteolysis	BP	mutant phenotype
chromatin	CC	direct assay
cytoskeleton	CC	direct assay
cytosol	CC	direct assay
membrane	CC	direct assay
mitochondrial intermembrane space	CC	direct assay
mitochondrion	CC	direct assay
nucleus	CC	direct assay
serine-type endopeptidase complex	CC	mutant phenotype
identical protein binding	MF	physical interaction
peptidase activity	MF	direct assay
protein serine/threonine kinase inhibitor activity	MF	direct assay
serine-type endopeptidase activity	MF	direct assay
serine-type peptidase activity	MF	direct assay
ubiquitin ligase inhibitor activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,816 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HTRA2	DIABLO	Q9NR28	917
HTRA2	PARL	Q9H300	891
HTRA2	A0A1W2PP11	A0A1W2PP11	885
HTRA2	GIGYF2	Q6Y7W6	793
HTRA2	HAX1	O00165	788
HTRA2	XIAP	P98170	775
HTRA2	CYCS	P00001	774
HTRA2	ENDOG	Q14249	767
HTRA2	FBXO7	Q9Y3I1	757
HTRA2	PLA2G6	O60733	749
HTRA2	PINK1	Q9BXM7	730
HTRA2	BAX	P55269	725
HTRA2	RBMX	P38159	719
HTRA2	BCL2	P10415	705
HTRA2	SNCA	P37840	705

IntAct

Human interaction partners of HTRA2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 475 partners by confidence:

Partner	Interaction type	MIscore	Records
XIAP	protein cleavage	0.960	22
CSN2	protein cleavage	0.800	7
NDUFA13	physical association	0.750	6
ARMC8	association	0.750	3
TRAF2	association	0.750	3
TTC19	physical association	0.660	3
BIRC2	physical association	0.650	3
BIRC7	physical association	0.640	4
GID8	association	0.610	1
PLEKHG7	direct interaction	0.590	1
POLR1D	direct interaction	0.590	1
RCN1	direct interaction	0.570	1
ANKRD13D	physical association	0.560	3
ARNT2	physical association	0.560	3
ASB3	physical association	0.560	3
ASB9	physical association	0.560	3
ASIC4	physical association	0.560	3
CENPV	physical association	0.560	3
CRYAA	physical association	0.560	3
DCAF8	physical association	0.560	3
EIF3F	physical association	0.560	3
ENKUR	physical association	0.560	3
ERCC8	physical association	0.560	3
HAUS7	physical association	0.560	3
ID2	physical association	0.560	3
IFT20	physical association	0.560	3
KCTD17	physical association	0.560	3
KLC3	physical association	0.560	3
KLF3	physical association	0.560	3
KLHL20	physical association	0.560	3

BioGRID (381 interactions; top human partners by supporting records): XIAP (Reconstituted Complex; 20 records), BIRC6 (Proximity Label-MS; 14 records), LATS1 (Biochemical Activity; 8 records), BIRC2 (Affinity Capture-MS; 7 records), ARMC8 (Affinity Capture-MS; 6 records), BIRC7 (Affinity Capture-MS; 4 records), ITGA7 (Two-hybrid; 4 records), RMND5A (Affinity Capture-MS; 4 records), TRAF2 (Proximity Label-MS; 4 records), AREL1 (Affinity Capture-Western; 3 records), BIRC3 (Reconstituted Complex; 3 records), BIRC8 (Affinity Capture-MS; 3 records), DIABLO (Proximity Label-MS; 3 records), HAX1 (Proximity Label-MS; 3 records), IMMT (Proximity Label-MS; 3 records)

SIGNOR signaling

12 signaling interactions:

A	Effect	B	Mechanism
HTRA2	down-regulates	XIAP	binding
BAK1	up-regulates	HTRA2	relocalization
HTRA2	down-regulates	PEA15	binding
AKT	down-regulates	HTRA2	phosphorylation
AKT2	down-regulates	HTRA2	phosphorylation
PINK1	up-regulates	HTRA2	phosphorylation
BAK1	up-regulates	HTRA2
CDK5	up-regulates	HTRA2	phosphorylation
AKT1	down-regulates	HTRA2	phosphorylation
AREL1	“down-regulates quantity by destabilization”	HTRA2	ubiquitination
BAX	up-regulates	HTRA2	relocalization
BCL2	down-regulates	HTRA2

Protein complexes (CORUM) (3)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

3 complexes by size:

Complex	Subunits	Members
★ TNFR1 signaling complex, TNF-induced	24	TNIP1, TRAF2, BIRC2, BIRC3, IKBKB, MAP3K7, SHARPIN, TAB2, TBK1, TNIP2, RNF31, TNFAIP3, CYLD, HTRA2, IKBKE, RBCK1, RIPK1, TANK, TNFRSF1A, TRADD, CHUK, IKBKG, SPATA2, TNF
CTLH complex, submodule of the IFT/lebercilin complex	12	HTRA2, MAEA, RANBP9, RMND5A, ARMC8, MKLN1, PGAM5, RANBP10, WDR26, YPEL5, GID4, GID8
LATS1-HTRA2-BIRC4 complex	3	HTRA2, LATS1, XIAP

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 475 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
Unblocking of NMDA receptors, glutamate binding and activation	7	11.5×	7e-04
Tight junction interactions	10	11.1×	1e-05
Regulation of pyruvate metabolism	6	10.3×	2e-03
Long-term potentiation	7	10.0×	8e-04
MECP2 regulates neuronal receptors and channels	5	9.1×	9e-03
TNFR1-induced proapoptotic signaling	6	7.9×	7e-03
TNFR1-induced NF-kappa-B signaling pathway	7	7.1×	4e-03
Neurexins and neuroligins	10	5.9×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
glutamate receptor signaling pathway	9	19.0×	3e-07
calcium-independent cell-cell adhesion	10	18.1×	1e-07
positive regulation of synaptic transmission, glutamatergic	10	14.1×	7e-07
sodium-independent organic anion transport	5	12.7×	3e-03
regulation of cardiac conduction	6	11.4×	1e-03
regulation of monoatomic ion transmembrane transport	6	9.9×	2e-03
inner ear receptor cell stereocilium organization	5	9.5×	9e-03
regulation of canonical Wnt signaling pathway	7	8.6×	2e-03

Disease & clinical

Genetic variants

Variant evidence for HTRA2: 345 ClinVar records (14 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	4
Uncertain significance	145
Likely benign	145
Benign	9

Top pathogenic / likely-pathogenic (14)

Showing all 14 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
1424738	NM_013247.5(HTRA2):c.244C>T (p.Gln82Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1455851	NM_013247.5(HTRA2):c.1138C>T (p.Arg380Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1452577	NM_013247.5(HTRA2):c.949del (p.Glu316_Val317insTer)	Pathogenic	criteria provided, single submitter	1
2799046	NM_013247.5(HTRA2):c.403_419dup (p.Ala141fs)	Pathogenic	criteria provided, single submitter	1
2875923	NM_013247.5(HTRA2):c.139dup (p.Arg47fs)	Pathogenic	criteria provided, single submitter	1
4697380	NM_013247.5(HTRA2):c.336_342dup (p.Gly115fs)	Pathogenic	criteria provided, single submitter	1
4772221	NM_013247.5(HTRA2):c.587dup (p.Asn196fs)	Pathogenic	criteria provided, single submitter	1
3384181	NM_013247.5(HTRA2):c.1216G>T (p.Gly406Cys)	Likely pathogenic	criteria provided, single submitter	1
3586941	NM_013247.5(HTRA2):c.420del (p.Ala141fs)	Likely pathogenic	criteria provided, single submitter	1
4715258	NM_013247.5(HTRA2):c.506+1G>C	Likely pathogenic	criteria provided, single submitter	1
372210	NM_013247.5(HTRA2):c.1316_1320del (p.Val439fs)	Pathogenic	no assertion criteria provided	1
372211	NM_013247.5(HTRA2):c.906+1G>C	Pathogenic	no assertion criteria provided	1
372212	NM_013247.5(HTRA2):c.728_730delinsCAT (p.Leu243_Pro244delinsProSer)	Pathogenic	no assertion criteria provided	1
1252041	NM_013247.5(HTRA2):c.1013_1015del (p.Leu338del)	Likely pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore HTRA2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 33 predictions of 495):

Position(s)	Effect	Δscore	Sites
2:74530615–74530616	acceptor_loss	1.0000	5
2:74530804	donor_gain	1.0000
2:74530817	donor_gain	1.0000
2:74530822–74530823	donor_loss	1.0000	5
2:74531098	donor_gain	1.0000
2:74531121	donor_gain	1.0000
2:74531854–74531855	acceptor_loss	1.0000	6
2:74532617–74532618	acceptor_loss	1.0000	6
2:74532715–74532716	donor_loss	1.0000	5
2:74532817–74532819	acceptor_gain	1.0000	2

AlphaMissense

981 missense substitutions predicted likely pathogenic (of 2,869 scored), across 231 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D228	8	0.999	1.000
D298	8	0.998	0.999
H198	8	0.996	0.999
F331	8	0.996	1.000
S276	8	0.992	1.000
D411	8	0.991	0.997
N305	8	0.978	1.000
F185	8	0.973	0.999
D224	8	0.966	0.997
F256	8	0.963	0.999
F264	8	0.961	0.990
F149	8	0.960	0.998
N321	8	0.935	0.999
F384	8	0.934	0.989
N312	8	0.929	1.000
D314	8	0.929	0.981
Q296	7	0.991	1.000
N196	7	0.989	0.999
E255	7	0.973	0.998
F341	7	0.967	0.995

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

4 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	3.18e-08
Liver Hepatocellular Carcinoma (validation)	unfavorable	3.97e-07
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	1.17e-05
Glioblastoma Multiforme (validation)	favorable	0.000392

Disease associations

OMIM: gene MIM:606441 | disease phenotypes: MIM:617248, MIM:610297

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
3-methylglutaconic aciduria type 8	Definitive	Autosomal recessive	4

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
3-methylglutaconic aciduria type 8	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (15 panels, 15 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

15 panels:

Panel	Rating
Bilateral congenital or childhood onset cataracts	green
COVID-19 research	green
Dystonia, chorea or related movement disorder, childhood onset	green
Early onset dystonia	green
Early onset or syndromic epilepsy	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Likely inborn error of metabolism	green
Mitochondrial disorders	green
Paediatric disorders	green
Possible mitochondrial disorder, nuclear genes	green
Primary immunodeficiency or monogenic inflammatory bowel disease	green
Undiagnosed metabolic disorders	green
Unexplained death in infancy and sudden unexplained death in childhood	green

Mondo (2): 3-methylglutaconic aciduria type 8 (MONDO:0044723), Parkinson disease 13, autosomal dominant, susceptibility to (MONDO:0012466)

Orphanet (2): 3-methylglutaconic aciduria type 8 (Orphanet:505208), Young-onset Parkinson disease (Orphanet:2828)

HPO phenotypes

showing 60 of 70 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0000518	Cataract
HP:0000551	Color vision defect
HP:0000651	Diplopia
HP:0000713	Agitation
HP:0000716	Depression
HP:0000726	Dementia
HP:0000727	Frontal lobe dementia
HP:0000736	Short attention span
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000741	Apathy
HP:0000952	Jaundice
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001276	Hypertonia
HP:0001290	Generalized hypotonia
HP:0001332	Dystonia
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001522	Death in infancy
HP:0001643	Patent ductus arteriosus
HP:0001662	Bradycardia
HP:0001875	Decreased total neutrophil count
HP:0001998	Neonatal hypoglycemia
HP:0002014	Diarrhea
HP:0002015	Dysphagia
HP:0002018	Nausea
HP:0002019	Constipation
HP:0002033	Poor suck
HP:0002059	Cerebral atrophy
HP:0002063	Rigidity
HP:0002067	Bradykinesia
HP:0002079	Hypoplasia of the corpus callosum
HP:0002104	Apnea
HP:0002119	Ventriculomegaly
HP:0002141	Gait imbalance
HP:0002151	Increased circulating lactate concentration
HP:0002169	Clonus
HP:0002172	Postural instability
HP:0002490	Increased CSF lactate
HP:0002548	Parkinsonism with favorable response to dopaminergic medication
HP:0002578	Gastroparesis
HP:0002878	Respiratory failure
HP:0003344	3-Methylglutaric aciduria
HP:0003394	Muscle spasm
HP:0003535	3-Methylglutaconic aciduria
HP:0003623	Neonatal onset
HP:0003811	Neonatal death
HP:0004409	Hyposmia
HP:0005484	Secondary microcephaly
HP:0005943	Respiratory arrest
HP:0011968	Feeding difficulties
HP:0012332	Abnormal autonomic nervous system physiology
HP:0012452	Restless legs

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
C565204	Parkinson Disease 13 *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523137 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

19 measured of 29 human assays (29 total across all organisms); most potent 19 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(2S)-N-[(2S,5S,8S,11R,12S,15S,18S,21R)-5-benzyl-21-hydroxy-4-methyl-2-(2-methylpropyl)-3,6,9,13,16,22-hexaoxo-8,11,15-tri(propan-2-yl)-10-oxa-1,4,7,14,17-pentazabicyclo[16.3.1]docosan-12-yl]-2-(3-phenylpropanoylamino)propanamide	KI	7 nM	US-11149067: Tailored cyclodepsipeptides as potent non-covalent serine protease inhibitors
benzyl N-[1-[[(2S)-1-[[(2S,5S,8S,11R,12S,15S,18S,21R)-5-benzyl-21-hydroxy-4,11,15-trimethyl-2-(2-methylpropyl)-3,6,9,13,16,22-hexaoxo-8-propan-2-yl-10-oxa-1,4,7,14,17-pentazabicyclo[16.3.1]docosan-12-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]carbamate	KI	26 nM	US-11149067: Tailored cyclodepsipeptides as potent non-covalent serine protease inhibitors
benzyl N-[1-[[(2S)-1-[[(2S,5S,8S,11R,12S,15S,18S,21R)-5-benzyl-21-hydroxy-4,11-dimethyl-2-(2-methylpropyl)-3,6,9,13,16,22-hexaoxo-8-propan-2-yl-15-propyl-10-oxa-1,4,7,14,17-pentazabicyclo[16.3.1]docosan-12-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]carbamate	KI	130 nM	US-11149067: Tailored cyclodepsipeptides as potent non-covalent serine protease inhibitors
benzyl N-[1-[[(2S)-1-[[(2S,5S,8S,11R,12S,15S,18S,21R)-5-benzyl-21-hydroxy-4,11-dimethyl-2-(2-methylpropyl)-3,6,9,13,16,22-hexaoxo-8-propan-2-yl-15-prop-2-enyl-10-oxa-1,4,7,14,17-pentazabicyclo[16.3.1]docosan-12-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]carbamate	KI	160 nM	US-11149067: Tailored cyclodepsipeptides as potent non-covalent serine protease inhibitors
benzyl N-[1-[[(2S)-1-[[(2S,5S,8S,11R,12S,15S,18S,21R)-5,15-dibenzyl-21-hydroxy-4,11-dimethyl-2-(2-methylpropyl)-3,6,9,13,16,22-hexaoxo-8-propan-2-yl-10-oxa-1,4,7,14,17-pentazabicyclo[16.3.1]docosan-12-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]carbamate	KI	370 nM	US-11149067: Tailored cyclodepsipeptides as potent non-covalent serine protease inhibitors
benzyl N-[1-[[(2S)-1-[[(2S,5S,8S,11R,12S,15S,18S,21R)-5-benzyl-15-ethyl-21-hydroxy-4,11-dimethyl-2-(2-methylpropyl)-3,6,9,13,16,22-hexaoxo-8-propan-2-yl-10-oxa-1,4,7,14,17-pentazabicyclo[16.3.1]docosan-12-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]carbamate	KI	470 nM	US-11149067: Tailored cyclodepsipeptides as potent non-covalent serine protease inhibitors
benzyl N-[1-[[(2S)-1-[[(2S,5S,8S,11R,12S,15S,18S,21R)-5-benzyl-15-butan-2-yl-21-hydroxy-4,11-dimethyl-2-(2-methylpropyl)-3,6,9,13,16,22-hexaoxo-8-propan-2-yl-10-oxa-1,4,7,14,17-pentazabicyclo[16.3.1]docosan-12-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]carbamate	KI	500 nM	US-11149067: Tailored cyclodepsipeptides as potent non-covalent serine protease inhibitors
CHEMBL5277138	IC50	590 nM
benzyl N-[1-[[(2S)-1-[[(2S,5S,8S,11R,12S,15S,18S,21R)-5-benzyl-15-cyclopropyl-21-hydroxy-4,11-dimethyl-2-(2-methylpropyl)-3,6,9,13,16,22-hexaoxo-8-propan-2-yl-10-oxa-1,4,7,14,17-pentazabicyclo[16.3.1]docosan-12-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]carbamate	KI	1930 nM	US-11149067: Tailored cyclodepsipeptides as potent non-covalent serine protease inhibitors
CHEMBL5274566	IC50	2000 nM
benzyl N-[1-[[(2S)-1-[[(2S,5S,8S,11R,12S,15S,18S,21R)-5-benzyl-21-hydroxy-4,11-dimethyl-2,15-bis(2-methylpropyl)-3,6,9,13,16,22-hexaoxo-8-propan-2-yl-10-oxa-1,4,7,14,17-pentazabicyclo[16.3.1]docosan-12-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]carbamate	KI	2100 nM	US-11149067: Tailored cyclodepsipeptides as potent non-covalent serine protease inhibitors
benzyl N-[1-[[(2S)-1-[[(2S,5S,8S,11R,12S,15S,18S,21R)-5-benzyl-15-tert-butyl-21-hydroxy-4,11-dimethyl-2-(2-methylpropyl)-3,6,9,13,16,22-hexaoxo-8-propan-2-yl-10-oxa-1,4,7,14,17-pentazabicyclo[16.3.1]docosan-12-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]carbamate	KI	4320 nM	US-11149067: Tailored cyclodepsipeptides as potent non-covalent serine protease inhibitors
CHEMBL5284442	IC50	6000 nM
CHEMBL5278663	IC50	6300 nM
CHEMBL5280693	IC50	7300 nM
CHEMBL5275102	IC50	7700 nM
CHEMBL5283566	IC50	9900 nM
CHEMBL5286341	IC50	20000 nM
CHEMBL1256178	IC50	250000 nM

ChEMBL bioactivities

6 potent at pChembl≥5 of 11 total, top 6 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.28	IC50	5200	nM	CHEMBL5277138
5.27	IC50	5400	nM	CHEMBL5286341
5.11	IC50	7800	nM	CHEMBL5274566
5.09	IC50	8100	nM	CHEMBL5284442
5.08	IC50	8300	nM	CHEMBL5278663
5.02	IC50	9500	nM	CHEMBL4583184

PubChem BioAssay actives

5 with measured affinity, of 20 total; 5 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
4-[[6-[[(2S)-1-[[(2S)-1-[[(2S)-3-cyclopropyl-1-[[(1R)-1-diphenoxyphosphoryl-2-methylpropyl]amino]-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-6-oxohexyl]carbamoyl]-2-(3-hydroxy-6-oxoxanthen-9-yl)benzoic acid	1954718: Inhibition of recombinant human HTRA2 using H2-OPT as substrate assessed as increase in fluorescence and measured for 2 hrs by fluorescent plate reader analysis	ic50	5.2000	uM
4-[[6-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(1R)-1-diphenoxyphosphoryl-2-methylpropyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-naphthalen-2-yl-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-6-oxohexyl]carbamoyl]-2-(3-hydroxy-6-oxoxanthen-9-yl)benzoic acid	1954718: Inhibition of recombinant human HTRA2 using H2-OPT as substrate assessed as increase in fluorescence and measured for 2 hrs by fluorescent plate reader analysis	ic50	5.4000	uM
4-[[6-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(1R)-1-diphenoxyphosphoryl-2-methylpropyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-6-oxohexyl]carbamoyl]-2-(3-hydroxy-6-oxoxanthen-9-yl)benzoic acid	1954718: Inhibition of recombinant human HTRA2 using H2-OPT as substrate assessed as increase in fluorescence and measured for 2 hrs by fluorescent plate reader analysis	ic50	7.8000	uM
4-[[6-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(1R)-1-diphenoxyphosphoryl-2-methylpropyl]amino]-4,4-dimethyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-6-oxohexyl]carbamoyl]-2-(3-hydroxy-6-oxoxanthen-9-yl)benzoic acid	1954718: Inhibition of recombinant human HTRA2 using H2-OPT as substrate assessed as increase in fluorescence and measured for 2 hrs by fluorescent plate reader analysis	ic50	8.1000	uM
4-[[6-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-3-cyclopropyl-1-[[(1R)-1-diphenoxyphosphoryl-2-methylpropyl]amino]-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-6-oxohexyl]carbamoyl]-2-(3-hydroxy-6-oxoxanthen-9-yl)benzoic acid	1954718: Inhibition of recombinant human HTRA2 using H2-OPT as substrate assessed as increase in fluorescence and measured for 2 hrs by fluorescent plate reader analysis	ic50	8.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic Trioxide	affects localization, decreases localization, increases expression, increases reaction, affects cotreatment	5
Valproic Acid	affects expression, increases expression	4
Air Pollutants	affects cotreatment, increases abundance, increases expression, decreases expression	2
Cannabidiol	affects cotreatment, decreases expression	2
Paraquat	decreases reaction, increases transport, affects localization	2
Tobacco Smoke Pollution	affects expression, increases expression	2
GSK-J4	decreases expression	1
bisphenol F	increases expression	1
moringin	affects cotreatment, decreases expression	1
tempol	affects cotreatment, affects localization, decreases reaction	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
trichostatin A	affects cotreatment, affects localization	1
cinnamaldehyde	affects localization, decreases reaction	1
beta-lapachone	decreases expression	1
lonidamine	affects cotreatment, affects localization	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
dinophysistoxin 1	increases expression	1
acetovanillone	affects cotreatment, affects localization, decreases reaction	1
oren gedoku to	decreases reaction, affects localization	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	increases expression	1
alvocidib	affects localization	1
5,6-dichlorobenzimidazole	affects localization, increases reaction	1
bisphenol B	increases expression	1
UCF 101	affects cotreatment, affects localization, decreases reaction	1

ChEMBL screening assays

11 unique, capped per target: 11 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4482652	Binding	Inhibition of Omi/HtrA2 (unknown origin)-induced caspase-independent apoptosis in caspase 9 (-/-) fibroblasts transfected with Omi-GFP up to 10 uM incubated for 36 hrs by propidium iodide and 4’,6-diamidino-2-phenylindole staining based flu	Method and compounds for inhibition of cell death

Cellosaurus cell lines

7 cell lines: 4 cancer cell line, 1 transformed cell line, 1 stromal cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_D9GI	Ubigene HEK293 HTRA2 KO	Transformed cell line	Female
CVCL_E1ZM	HAP1 HTRA2 (-) 2	Cancer cell line	Male
CVCL_E1ZN	HAP1 HTRA2 (-) 3	Cancer cell line	Male
CVCL_E1ZP	HAP1 HTRA2 (-) 4	Cancer cell line	Male
CVCL_RG44	MS-5-Omi/HTRA2-mCherry	Stromal cell line	Male
CVCL_XP64	HAP1 HTRA2 (-) 1	Cancer cell line	Male
CVCL_YT00	CIBi007-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 300 trials:

NCT	Phase	Status	Title
NCT00211796	Phase 4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	Phase 4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	Phase 4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	Phase 4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	Phase 4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	Phase 4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	Phase 4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
NCT01333865	Phase 4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	Phase 4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	Phase 4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02069977	Phase 4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	Phase 4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	Phase 4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	Phase 4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	Phase 4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
NCT02940574	Phase 4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	Phase 4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	Phase 4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	Phase 4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	Phase 4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	Phase 4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	Phase 4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	Phase 4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	Phase 4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	Phase 4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	Phase 4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	Phase 4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	Phase 4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	Phase 4	RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT07770152	Phase 4	NOT_YET_RECRUITING	Semaglutide in Youth With Autism Spectrum Disorder
NCT03414970	Phase 3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT00036231	Phase 3	TERMINATED	Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction
NCT00036244	Phase 3	COMPLETED	Synthetic Human Secretin in Children With Autism
NCT00065884	Phase 3	UNKNOWN	Valproate Response in Aggressive Autistic Adolescents
NCT00065962	Phase 3	COMPLETED	Secretin for the Treatment of Autism
NCT00252603	Phase 3	COMPLETED	Galantamine Versus Placebo in Childhood Autism
NCT00346736	Phase 3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00352248	Phase 3	COMPLETED	Randomized Controlled Trial of Acupuncture Versus Sham Acupuncture in Autistic Spectrum Disorder
NCT00352352	Phase 3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00355329	Phase 3	COMPLETED	Randomized Control Trial of Using Tongue Acupuncture in Autistic Spectrum Disorder Using PET Scan for Clinical Correlation
NCT00498173	Phase 3	COMPLETED	Effectiveness of Atomoxetine in Treating ADHD Symptoms in Children and Adolescents With Autism
NCT00541346	Phase 3	COMPLETED	A Pilot Study of Daytrana TM in Children With Autism Co-Morbid for Attention Deficit Hyperactivity Disorder (ADHD) Symptoms
NCT00549562	Phase 3	COMPLETED	Study of Paliperidone ER in Adolescents and Young Adults With Autism
NCT00584480	Phase 3	COMPLETED	Pilot Study of the Effect of Hyperbaric Oxygen Treatment on Behavioral and Biomarker Measures in Children With Autism
NCT00655174	Phase 3	COMPLETED	Fluvoxamine and Sertraline in Childhood Autism - Does SSRI Therapy Improve Behaviour and/or Mood?
NCT00881452	Phase 3	COMPLETED	A Trial of CM-AT in Children With Autism
NCT00912691	Phase 3	COMPLETED	A Trial of CM-AT in Children With Autism- Open Label Extension Study
NCT01302964	Phase 3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	Phase 3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01740869	Phase 3	COMPLETED	Autologous Bone Marrow Stem Cells for Children With Autism Spectrum Disorders
NCT01825798	Phase 3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01911442	Phase 3	COMPLETED	Lurasidone Pediatric Autism Study
NCT01914393	Phase 3	COMPLETED	Pediatric Open-Label Extension Study
NCT01972074	Phase 3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02410902	Phase 3	COMPLETED	A Trial of CM-AT in Children With Autism With All Levels of FCT (The Blum Study)
NCT02649959	Phase 3	ACTIVE_NOT_RECRUITING	An Open Label Study of CM-AT for the Treatment of Children With Autism
NCT02654743	Phase 3	COMPLETED	Open Label of Clinical Trial of Sulforaphane in Children With Autism
NCT02985749	Phase 3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	Phase 3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	Phase 3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for HTRA2 across ~30M SureChEMBL compounds — explore on Sugi Predict.