HTRA1

Summary

HTRA1 (HtrA serine peptidase 1, HGNC:9476) is a protein-coding gene on chromosome 10q26.13, encoding Serine protease HTRA1 (Q92743). Serine protease with a variety of targets, including extracellular matrix proteins such as fibronectin.

This gene encodes a member of the trypsin family of serine proteases. This protein is a secreted enzyme that is proposed to regulate the availability of insulin-like growth factors (IGFs) by cleaving IGF-binding proteins. It has also been suggested to be a regulator of cell growth. Variations in the promoter region of this gene are the cause of susceptibility to age-related macular degeneration type 7.

Source: NCBI Gene 5654 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 2 (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 41 (top 2% of genes corpus-wide)
• Clinical variants (ClinVar): 414 total — 14 pathogenic, 18 likely-pathogenic (top 8% of genes corpus-wide)
• GTEx eGene: eQTL in 27 tissues, sQTL in 6 (q < 0.05)
• Phenotypes (HPO): 71
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.87 (unconstrained)
• MANE Select transcript: NM_002775

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9476
Approved symbol	HTRA1
Name	HtrA serine peptidase 1
Location	10q26.13
Locus type	gene with protein product
Status	Approved
Aliases	HtrA, IGFBP5-protease, ARMD7
Ensembl gene	ENSG00000166033
Ensembl biotype	protein_coding
OMIM	602194
Entrez	5654

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 10 protein_coding

MANE Select: ENST00000368984

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

ENST00000368984, ENST00000420892, ENST00000648167, ENST00000869937, ENST00000869938, ENST00000962536, ENST00000962537, ENST00001121889, ENST00001121890, ENST00001142656

RefSeq mRNA: 1 — MANE Select: NM_002775 NM_002775

CCDS: CCDS7630

Canonical transcript exons

ENST00000368984 — 9 exons

Exon	Start	End
ENSE00001099153	122510096	122510153
ENSE00001099157	122511970	122512065
ENSE00001099158	122507370	122507402
ENSE00001099160	122508656	122508770
ENSE00001448520	122514191	122514907
ENSE00001448527	122461553	122462124
ENSE00001656483	122489422	122489626
ENSE00001691312	122506691	122506885
ENSE00001727698	122488902	122489001

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 99.72.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 73.4566 / max 1133.9481, expressed in 1450 samples.

Highest expression (Bgee): tendon of biceps brachii, renal glomerulus, metanephric glomerulus, descending thoracic aorta, stromal cell of endometrium.

Genetic regulation across tissues (GTEx eQTL / sQTL)

HTRA1 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 27 tissues and its splicing (sQTL) in 6 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 33 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Pituitary	eqtl	2.0e-15	+0.48	10:122456868:C:CTA
Pancreas	eqtl	6.4e-13	-0.42	10:122701914:G:A
Testis	eqtl	8.0e-10	+0.27	10:122454932:G:T
Cells Cultured fibroblasts	eqtl	1.5e-07	-0.17	10:122450644:G:C
Skin Sun Exposed Lower leg	eqtl	5.0e-06	-0.20	10:122327582:G:A
Colon Sigmoid	sqtl	7.2e-06	+0.70	10:122490577:G:C
Heart Atrial Appendage	eqtl	2.4e-05	-0.27	10:122377013:G:A
Thyroid	eqtl	1.8e-04	-0.17	10:122446563:GA:G
Heart Left Ventricle	eqtl	3.5e-04	-0.17	10:122483941:A:G
Brain Putamen basal ganglia	eqtl	1.1e-03	-0.13	10:122483941:A:G
Artery Tibial	sqtl	2.3e-03	-0.41	10:122490577:G:C
Brain Nucleus accumbens basal ganglia	eqtl	2.6e-03	-0.14	10:122482041:A:G
Colon Sigmoid	eqtl	3.2e-03	-0.17	10:122475472:G:A
Brain Anterior cingulate cortex BA24	eqtl	4.3e-03	+0.19	10:122443094:T:A
Esophagus Muscularis	sqtl	5.6e-03	+0.52	10:122487407:C:T
Adrenal Gland	eqtl	1.0e-02	+0.97	10:122003031:C:T
Esophagus Muscularis	eqtl	1.0e-02	+0.13	10:122523560:A:G
Spleen	sqtl	1.0e-02	-1.80	10:123101323:T:A
Esophagus Mucosa	eqtl	1.2e-02	-0.18	10:122409426:TTATAGTGGAAATATA:T
Brain Hypothalamus	eqtl	1.2e-02	-0.16	10:122478637:C:T

FANTOM5 promoters

5 alternative TSS:

Promoter ID	TPM avg	Samples expressed
107451	46.3408	1409
107450	17.8092	1318
107452	5.4317	897
107449	3.5626	768
107456	0.3122	170

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	99.72	gold quality
renal glomerulus	UBERON:0000074	99.57	gold quality
metanephric glomerulus	UBERON:0004736	99.54	gold quality
descending thoracic aorta	UBERON:0002345	99.49	gold quality
stromal cell of endometrium	CL:0002255	99.48	gold quality
ascending aorta	UBERON:0001496	99.43	gold quality
thoracic aorta	UBERON:0001515	99.43	gold quality
middle frontal gyrus	UBERON:0002702	99.42	gold quality
layer of synovial tissue	UBERON:0007616	99.42	gold quality
synovial joint	UBERON:0002217	99.38	gold quality
putamen	UBERON:0001874	99.35	gold quality
calcaneal tendon	UBERON:0003701	99.34	gold quality
periodontal ligament	UBERON:0008266	99.32	gold quality
caudate nucleus	UBERON:0001873	99.31	gold quality
gall bladder	UBERON:0002110	99.31	gold quality
amygdala	UBERON:0001876	99.29	gold quality
right coronary artery	UBERON:0001625	99.26	gold quality
left ovary	UBERON:0002119	99.24	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.24	gold quality
nucleus accumbens	UBERON:0001882	99.18	gold quality
aorta	UBERON:0000947	99.12	gold quality
spinal cord	UBERON:0002240	99.12	gold quality
right ovary	UBERON:0002118	99.10	gold quality
corpus callosum	UBERON:0002336	98.99	gold quality
hypothalamus	UBERON:0001898	98.98	gold quality
inferior vagus X ganglion	UBERON:0005363	98.98	gold quality
endocervix	UBERON:0000458	98.96	gold quality
Ammon’s horn	UBERON:0001954	98.96	gold quality
substantia nigra	UBERON:0002038	98.96	gold quality
popliteal artery	UBERON:0002250	98.94	gold quality
tibial artery	UBERON:0007610	98.93	gold quality
midbrain	UBERON:0001891	98.92	gold quality
left coronary artery	UBERON:0001626	98.89	gold quality
coronary artery	UBERON:0001621	98.86	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.81	gold quality
inferior olivary complex	UBERON:0002127	98.80	gold quality
right frontal lobe	UBERON:0002810	98.79	gold quality
tendon	UBERON:0000043	98.78	gold quality
medial globus pallidus	UBERON:0002477	98.78	gold quality
decidua	UBERON:0002450	98.77	gold quality
germinal epithelium of ovary	UBERON:0001304	98.73	gold quality
temporal lobe	UBERON:0001871	98.71	gold quality
globus pallidus	UBERON:0001875	98.68	gold quality
Brodmann (1909) area 10	UBERON:0013541	98.67	gold quality
body of uterus	UBERON:0009853	98.66	gold quality
postcentral gyrus	UBERON:0002581	98.63	gold quality
ventral tegmental area	UBERON:0002691	98.62	gold quality
pituitary gland	UBERON:0000007	98.61	gold quality
cingulate cortex	UBERON:0003027	98.60	gold quality
anterior cingulate cortex	UBERON:0009835	98.59	gold quality
omental fat pad	UBERON:0010414	98.55	gold quality
placenta	UBERON:0001987	98.54	gold quality
peritoneum	UBERON:0002358	98.54	gold quality
prefrontal cortex	UBERON:0000451	98.49	gold quality
skin of hip	UBERON:0001554	98.49	gold quality
adipose tissue of abdominal region	UBERON:0007808	98.49	gold quality
parietal lobe	UBERON:0001872	98.47	gold quality
tibial nerve	UBERON:0001323	98.38	gold quality
subthalamic nucleus	UBERON:0001906	98.38	gold quality
subcutaneous adipose tissue	UBERON:0002190	98.38	gold quality
adenohypophysis	UBERON:0002196	98.37	gold quality
forebrain	UBERON:0001890	98.36	gold quality
paraflocculus	UBERON:0005351	98.36	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	98.36	gold quality
adipose tissue	UBERON:0001013	98.33	gold quality
left uterine tube	UBERON:0001303	98.31	gold quality
telencephalon	UBERON:0001893	98.31	gold quality
ovary	UBERON:0000992	98.26	gold quality
parietal pleura	UBERON:0002400	98.25	gold quality
mucosa of stomach	UBERON:0001199	98.21	gold quality
frontal pole	UBERON:0002795	98.21	gold quality
frontal cortex	UBERON:0001870	98.20	gold quality
medulla oblongata	UBERON:0001896	98.17	gold quality
dorsal plus ventral thalamus	UBERON:0001897	98.15	gold quality
ectocervix	UBERON:0012249	98.14	gold quality
connective tissue	UBERON:0002384	98.10	gold quality
ventricular zone	UBERON:0003053	98.10	gold quality
superior frontal gyrus	UBERON:0002661	98.08	gold quality
superior vestibular nucleus	UBERON:0007227	98.04	gold quality
entorhinal cortex	UBERON:0002728	98.00	gold quality
tibia	UBERON:0000979	97.96	gold quality
central nervous system	UBERON:0001017	97.94	gold quality
dorsal root ganglion	UBERON:0000044	97.92	gold quality
brain	UBERON:0000955	97.91	gold quality
mammary duct	UBERON:0001765	97.90	gold quality
neocortex	UBERON:0001950	97.90	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.86	gold quality
lateral globus pallidus	UBERON:0002476	97.85	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	97.85	gold quality
cerebral cortex	UBERON:0000956	97.84	gold quality
pleura	UBERON:0000977	97.81	gold quality
thoracic mammary gland	UBERON:0005200	97.81	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.80	gold quality
CA1 field of hippocampus	UBERON:0003881	97.78	gold quality
mammary gland	UBERON:0001911	97.77	gold quality
smooth muscle tissue	UBERON:0001135	97.76	gold quality
skin of abdomen	UBERON:0001416	97.75	gold quality
occipital lobe	UBERON:0002021	97.73	gold quality
skin of leg	UBERON:0001511	97.64	gold quality
myometrium	UBERON:0001296	97.62	gold quality

Single-cell (SCXA)

Detected in 16 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-MTAB-8322	yes	7740.61
E-GEOD-114530	yes	1012.11
E-MTAB-8530	yes	842.63
E-HCAD-13	yes	784.87
E-MTAB-8410	yes	33.57
E-GEOD-84465	yes	26.91
E-MTAB-10287	yes	26.80
E-CURD-114	yes	23.61
E-MTAB-6678	yes	16.69
E-GEOD-83139	yes	7.71
E-GEOD-137537	yes	6.11
E-MTAB-5061	yes	5.80
E-MTAB-10290	no	2216.10
E-MTAB-7037	no	812.79
E-MTAB-8381	no	460.15

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Ovary	tissue	751.4	high
Locus coeruleus	tissue	286.5
Spinal cord	tissue	282.7
Gallbladder	tissue	282.0	medium
Placenta	tissue	264.8	not detected
Nucleus accumbens	tissue	242.5
Epididymis	tissue	233.4	low
Retina	tissue	225.9
Postcentral gyrus	tissue	223.6
Hippocampus	tissue	202.2	low
Medulla oblongata	tissue	190.1
Vagina	tissue	182.2	not detected
Pituitary gland	tissue	176.4
Endometrium 1	tissue	169.6	not detected
Periaqueductal gray	tissue	168.9
Cervix	tissue	168.3	low
Breast	tissue	167.5	not detected
Substantia nigra	tissue	161.2
Pons	tissue	161.1
Adipose tissue	tissue	156.8	not detected
Midbrain	tissue	154.1
Thalamus	tissue	151.1
Superior colliculi	tissue	150.1
Hypothalamus	tissue	147.9
Smooth muscle	tissue	142.2	not detected
Corpus callosum	tissue	140.5
Urinary bladder	tissue	128.4	low
Kidney	tissue	128.4	medium
Putamen	tissue	115.5
Cerebral cortex	tissue	114.4	low
Somatosensory cortex	tissue	114.4
Septum	tissue	109.8
Skin 1	tissue	109.7	not detected
Liver	tissue	108.7	not detected
Hippocampal formation	tissue	108.3
Seminal vesicle	tissue	107.8	not detected
Heart muscle	tissue	107.3	medium
Motor cortex	tissue	106.9
Parathyroid gland	tissue	105.0	medium
Ventral forebrain	tissue	102.7
Occipital cortex	tissue	101.7
Amygdala	tissue	100.7
Temporal cortex	tissue	97.7
Insular cortex	tissue	93.8
Entorhinal cortex	tissue	93.2
Prefrontal cortex	tissue	92.9
Choroid plexus	tissue	92.3
Olfactory bulb	tissue	91.8
Retrosplenial cortex	tissue	86.5
Retrosplenial and cingulate cortex	tissue	85.7
Basal ganglia	tissue	84.1	not detected
Adrenal gland	tissue	76.7	not detected
Tongue	tissue	75.5
Salivary gland	tissue	69.0	low
Fallopian tube	tissue	66.4	medium
Prostate	tissue	64.1	not detected
Esophagus	tissue	54.3	low
Lung	tissue	53.3	not detected
Pancreas	tissue	52.7	not detected
Rectum	tissue	48.7	medium

Brain sub-regions (HPA Brain Atlas): detected in 190; highest nTPM — Blood vessel (591.0), Cerebellar white matter (390.1), Red nucleus (366.2), Globus pallidus, externus (342.7), Spinal trigeminal nucleus, interpolar (329.3).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1, IRF6, NFKB, PITX2, RELA, STAT1, TCF3

miRNA regulators (miRDB)

Targeting HTRA1 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 47 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-323A-3P	99.79	70.30	1739
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-548AU-3P	99.70	68.22	1373
HSA-MIR-5689	99.50	71.26	1154
HSA-MIR-217-5P	99.49	69.93	1419
HSA-MIR-19A-5P	99.36	66.93	1675
HSA-MIR-19B-1-5P	99.36	67.07	1669
HSA-MIR-19B-2-5P	99.36	67.07	1669
HSA-MIR-145-3P	99.33	67.66	764
HSA-MIR-1264	99.25	66.81	1317
HSA-MIR-6807-3P	99.15	69.23	1275
HSA-MIR-181A-2-3P	98.91	67.60	1168

Functional genomics

gnomAD constraint: pLI 0.000308, LOEUF 0.873, missense Z 0.692 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000368984 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
10:122,461,653–122,461,842	111 / 83.7	1.33	no
10:122,461,843–122,508,707	271 / 410.0	0.66	no
10:122,508,708–122,514,356	179 / 173.4	1.03	no

Literature-anchored findings (GeneRIF, showing 40)

• HTRA1 is a candidate tumor suppressor in ovarian cancer. (PMID:14716297)
• An HtrA1 inhibitor causes accumulation of Abeta in astrocyte cell culture supernatants and colocalizes with beta-amyloid deposits in human brain samples. (PMID:15855271)
• no association either with age-at-onset in AD cases or with disease risk in the case-control cohort but haplotype analysis revealed a modest association of one haplotype with AD risk (p = 0.04). (PMID:15917099)
• Contributes to the destruction of extracellular matrix through both direct and indirect mechanisms; its overexpression may contribute to arthritis. (PMID:16377621)
• 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)
• Data suggest that serine protease HtrA1 mediates paclitaxel- and cisplatin-induced cytotoxicity and suggest that loss of HtrA1 in ovarian and gastric cancers may contribute to in vivo chemoresistance. (PMID:16767218)
• it is reported that a single-nucleotide polymorphism in the promoter region of HTRA1 is a major genetic risk factor for wet age-related macular degeneration (PMID:17053108)
• findings show a single-nucleotide polymorphism, rs11200638, in the promoter region of HTRA1 is the most likely causal variant for age-related macular degeneration at 10q26 (PMID:17053109)
• The distinct distribution of HtrA1 at the maternal-trophoblast interface suggests that HtrA1 may play a role in placental development. (PMID:17072861)
• Low expression of HtrA1 is associated with lymph node metastasis of lung cancer (PMID:17094466)
• highly upregulated during mucosal mast cell differentiation (PMID:17292962)
• the role of HTRA1 in Age-related macular degeneration (PMID:17426452)
• HTRA1 promoter polymorphism, rs11200638, is a strong candidate with a functional consequence that predisposes Japanese to develop neovascular age-related macular degeneration . (PMID:17438519)
• May increase susceptibility to age-related macular degeneration (AMD) development and can participate in a potential new molecular pathway for AMD pathogenesis. (PMID:17568988)
• Both the HTRA1 -625A allele and the complement factor H 402H allele are independently associated with exudative age-related macular degeneration in a Central European population. (PMID:17679948)
• The LOC387715/HTRA1 variants are associated with polypoidal choroidal vasculopathy (PCV) and wet age-related macular degeneration (AMD) in the Japanese population. (PMID:17692272)
• 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)
• HTRA1 mRNA expression exhibits no significant change between control and age-related macular degeneration retinas. (PMID:17884985)
• the association of HTRA1 with wet age-related macular degeneration (choroidal neovascularization) (PMID:17904186)
• Structural and functional analysis of the PDZ domains of human HtrA1 and HtrA3 (PMID:17962403)
• Although a role for PLEKHA1 could not be totally excluded, there was a four times higher age-related macular degeneration risk was associated with haplotype “A-T-A” involving “PLEKHA1-LOC387715-HTRA1” risk alleles. (PMID:18079691)
• HtrA1 may regulate matrix calcification via the inhibition of BMP-2 signaling, modulating osteoblast gene expression, and/or via the degradation of specific matrix proteins (PMID:18156628)
• Polymorphisms in the complement factor H gene, LOC387715, and the HTRA1 promoter are strongly associated with age-related macular degeneration. (PMID:18162041)
• Independent of CFH genotype or smoking history, an individual’s risk of AMD (age-related macular degeneration) could be increased or decreased, depending on their genotype or haplotype in the 10q26 region. (PMID:18164066)
• There is a significant decrease in HtrA1 mRNA in malignant ovarian tumors compared to benign; HtrA1 may function as a tumor suppressor. (PMID:18241672)
• The study demonstrated that both single-nucleotide polymorphisms were significantly associated with dry and wet (age-related macular degeneration) AMD. (PMID:18301036)
• A high impact of the additive effect of CFH and HTRA1 in the development of exudative AMD was shown. The HTRA1-smoking additive effect found in this study further suggests the importance of this environmental risk factor in AMD. (PMID:18316707)
• Possible association between occult or minimally classic choroidal neovascularization(CNV) and CFH polymorphism and between classic and predominantly classic CNV and HTRA1 polymorphism. (PMID:18362109)
• Up-regulation of HtrA1 is detected in the macular lesions of age-related macular degeneration suggest that rs11200638 in HtrA1 promoter is associated with disease development. (PMID:18427598)
• The present data provided an independent validation of the association of LOC387715 and HTRA1 SNPs, along with their risk estimates among Indian patients with AMD. (PMID:18436811)
• expression of HPV E6/E7 proteins is associated with a post-transcriptional up-regulation of HtrA1 (PMID:18452160)
• The SNPs rs3753394 and rs800292 of CFH and rs11200638 of HTRA1 are significantly associated with the risk of PCV (polypoidal choroidal vasculopathy) in Chinese patients. (PMID:18515590)
• A low HtrA1 score is strongly associated with a shorter overall survival in mesothelioma patients, independently from epidermal growth factor receptor expression levels. (PMID:18681782)
• Both the HTRA1 and LOC387715/ARMS2 single nucleotide polymorphysms appear to contribute equally to disease risk (both geographic atrophy and choroidal neovascularization) with no evidence of interaction with CFH. (PMID:18682806)
• The purpose of this study was to investigate the association of reported common single-nucleotide polymorphisms (SNPs) in CFH, LOC387715, and HTRA1 with exudative age-related macular degeneration in a northern Chinese population. (PMID:18682812)
• Findings from multiple samples support an AMD genetic variant harbored within HtrA1. The risk of advanced AMD increased when the presence of risk alleles from HtrA1 was combined with either CFH risk alleles or history of smoking. (PMID:18718667)
• Patients with a homozygous HTRA1 rs11200638 risk allele had larger choroidal neovascular lesions. (PMID:18939352)
• The approximately 30 kDa HtrA1 form can be correlated to maternal preeclampsia while the significant down-regulation of total HtrA1 can be correlated to placental preeclampsia. (PMID:19056122)
• The rs10490924 Single nucleotide polymorphisms (SNP) in LOC387715/ARMS2 and the rs11200638 SNP in HTRA1 are strongly associated with neovascular age-related macular degeneration in this Israeli population. (PMID:19065273)
• In a Han Chinese population, HTRA1 polymorphisms appear to be independently and possibly additively hereditary contributors to exudative age-related macular degeneration. (PMID:19187590)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	htra1b	ENSDARG00000014907
danio_rerio	htra1a	ENSDARG00000032831
mus_musculus	Htra1	ENSMUSG00000006205
rattus_norvegicus	Htra1	ENSRNOG00000020533

Paralogs (3): HTRA2 (ENSG00000115317), HTRA4 (ENSG00000169495), HTRA3 (ENSG00000170801)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1929076) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 2 distinct phenotype terms.

Mouse phenotype (MP)	Records
increased trabecular bone thickness	1
increased bone volume	1

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
Brucella abortus 2308	Q2YMX6	100.0%	Diamond
Staphylococcus epidermidis RP62A	Q5HQE2	100.0%	Diamond
Staphylococcus epidermidis ATCC 12228	Q8CT52	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
Drosophila melanogaster	Q9VFJ3	98.6%	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
Ictidomys tridecemlineatus	Q6Q484	79.8%	Diamond
Buchnera aphidicola str. Sg (Schizaphis graminum)	O85291	78.0%	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
HTRA1-AS1	ncRNA	105378525
BTBD16	protein-coding	118663
ARMS2	protein-coding	387715
PLEKHA1	protein-coding	59338
MIR3941	ncRNA	100500866
DMBT1	protein-coding	1755
C10orf120	protein-coding	399814
SPADH	protein-coding	112577516

Protein

Protein identifiers

Serine protease HTRA1 — Q92743 (reviewed: Q92743)

Alternative names: High-temperature requirement A serine peptidase 1, L56, Serine protease 11

All UniProt accessions (3): Q92743, A0A3B3IU24, H0Y7G9

UniProt curated annotations — full annotation on UniProt →

Function. Serine protease with a variety of targets, including extracellular matrix proteins such as fibronectin. HTRA1-generated fibronectin fragments further induce synovial cells to up-regulate MMP1 and MMP3 production. May also degrade proteoglycans, such as aggrecan, decorin and fibromodulin. Through cleavage of proteoglycans, may release soluble FGF-glycosaminoglycan complexes that promote the range and intensity of FGF signals in the extracellular space. Regulates the availability of insulin-like growth factors (IGFs) by cleaving IGF-binding proteins. Inhibits signaling mediated by TGF-beta family members. This activity requires the integrity of the catalytic site, although it is unclear whether TGF-beta proteins are themselves degraded. By acting on TGF-beta signaling, may regulate many physiological processes, including retinal angiogenesis and neuronal survival and maturation during development. Intracellularly, degrades TSC2, leading to the activation of TSC2 downstream targets.

Subunit / interactions. Forms homotrimers. In the presence of substrate, may form higher-order multimers in a PDZ-independent manner. Interacts with TGF-beta family members, including BMP4, TGFB1, TGFB2, activin A and GDF5.

Subcellular location. Cell membrane. Secreted. Cytoplasm. Cytosol.

Tissue specificity. Widely expressed, with strongest expression in placenta (at protein level). Secreted by synovial fibroblasts. Up-regulated in osteoarthritis and rheumatoid arthritis synovial fluids and cartilage as compared with non-arthritic (at protein level).

Disease relevance. A variant in the HTRA1 promoter may be associated with increased risk for developing age-related macular degeneration (ARMD), a multifactorial eye disease and common cause of vision loss. Cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 2 (CARASIL2) [MIM:600142] A cerebrovascular disease characterized by non-hypertensive arteriopathy of cerebral small vessels with subcortical infarcts, alopecia, and spondylosis. Small cerebral arteries show arteriosclerotic changes, fibrous intimal proliferation, and hyaline degeneration with splitting of the intima and/or the internal elastic membrane. Neurologic features include progressive dementia, gait disturbances, extrapyramidal and pyramidal signs, and demyelination of the cerebral white matter with sparing of U fibers. The disease is caused by variants affecting the gene represented in this entry. Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, 2 (CADASIL2) [MIM:616779] A cerebrovascular disease characterized by multiple subcortical infarcts, pseudobulbar palsy, dementia, and the presence of granular deposits in small cerebral arteries producing ischemic stroke. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The IGFBP N-terminal domain mediates interaction with TSC2 substrate.

Similarity. Belongs to the peptidase S1C family.

RefSeq proteins (1): NP_002766* (*=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
IPR041489	PDZ_6	Domain

Pfam: PF00219, PF07648, PF13365, PF17820

Enzyme classification (BRENDA)

• EC 3.4.21.107 — peptidase Do (BRENDA: 41 organisms, 234 substrates, 57 inhibitors, 4 Km, 2 kcat entries)
• EC 3.4.21.108 — HtrA2 peptidase (BRENDA: 23 organisms, 127 substrates, 42 inhibitors, 35 Km, 23 kcat entries)

Substrate kinetics (BRENDA)

15 substrates with measured Km, best-characterized 15. 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
BETA-CASEIN	0.0013	1
CSP-1 FRET PEPTIDE	—	1
L-ALA(MCA)IRRVSYSF-ANB-NH2	0.0002	1
SUCCINYL-LEU-LEU-VAL-TYR-4-METHYLCOUMARIN 7-AMID	0.0346	1
(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 (84 total): strand 30, sequence variant 14, helix 13, disulfide bond 8, turn 5, site 3, domain 3, active site 3, signal peptide 1, chain 1, mutagenesis site 1, sequence conflict 1, region of interest 1

Structure

Experimental structures (PDB)

18 structures by resolution:

PDB	Title	Method	Resolution (Å)
3TJQ	N-domain of HtrA1	X-RAY DIFFRACTION	2
7SJP	anti-HtrA1 Fab15H6.v4 bound to HtrA1-LoopA peptide	X-RAY DIFFRACTION	2.1
6Z0Y	HtrA1 inactive protease domain S328A with CARASIL mutations D174R R274Q	X-RAY DIFFRACTION	2.2
3TJO	HtrA1 catalytic domain, mutationally inactivated	X-RAY DIFFRACTION	2.3
6Z0E	HtrA1 inactive protease domain S328A with CARASIL mutation R274Q	X-RAY DIFFRACTION	2.6
3NUM	Substrate induced remodeling of the active site regulates HtrA1 activity	X-RAY DIFFRACTION	2.75
3NZI	Substrate induced remodeling of the active site regulates HtrA1 activity	X-RAY DIFFRACTION	2.75
8SDP	HTRA-1 PDSA bound to CKP 3A7	X-RAY DIFFRACTION	2.87
8SE7	HTRA-1 PDSA bound to CKP 1A8	X-RAY DIFFRACTION	2.96
3TJN	HtrA1 catalytic domain, apo form	X-RAY DIFFRACTION	3
8SDM	HTRA-1 PDSA bound to CKP 3B3	X-RAY DIFFRACTION	3.05
6Z0X	HtrA1 inactive protease domain S328A with CARASIL mutations D174R R274Q	X-RAY DIFFRACTION	3.1
8SE8	HTRA-1 PD/SA bound to CKP 1G10	X-RAY DIFFRACTION	3.18
3NWU	Substrate induced remodeling of the active site regulates HtrA1 activity	X-RAY DIFFRACTION	3.2
7SJO	HtrA1S328A:Fab15H6.v4 complex	ELECTRON MICROSCOPY	3.3
7SJN	HtrA1:Fab15H6.v4 complex	ELECTRON MICROSCOPY	3.4
2JOA	HtrA1 bound to an optimized peptide: NMR assignment of PDZ domain and ligand resonances	SOLUTION NMR
2YTW	Solution structure of the PDZ-domain of human protease HTRA 1 precursor	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92743-F1	83.30	0.50

Antibody-complex structures (SAbDab)

3 antibodies co-crystallized with this protein: 7SJN, 7SJO, 7SJP

Human Protein Atlas

Protein class: Enzymes, Peptidases, Serine-type peptidases, Predicted secreted proteins, Predicted intracellular proteins, Plasma proteins, Disease related genes, Potential drug targets, Human disease related genes, Congenital malformations, Congenital malformations of the nervous system, Eye disease

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): plasma membrane

Antibody reliability (HPA): IH approved · 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 (6)

Position	Role
171	involved in trimer stabilization
278	involved in trimer stabilization
220	charge relay system
250	charge relay system
328	charge relay system
169	involved in trimer stabilization

Disulfide bonds (8)

Type	Positions
Disulfide bond	37–62, 41–64, 46–65, 53–68, 76–89, 83–110, 112–130, 119–155

Mutagenesis-validated functional residues (1)

Position	Phenotype
328	loss of activity.

Function

Pathways and Gene Ontology

Reactome pathways

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

2 pathways:

ID	Pathway	Evidence
R-HSA-1474228	Degradation of the extracellular matrix	curated
R-HSA-1474244	Extracellular matrix organization	—

MSigDB gene sets: 394 (showing top): WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, LEE_NEURAL_CREST_STEM_CELL_DN, MULLIGHAN_NPM1_SIGNATURE_3_UP, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, HSIAO_HOUSEKEEPING_GENES, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, COLIN_PILOCYTIC_ASTROCYTOMA_VS_GLIOBLASTOMA_UP, MODULE_66, CAIRO_HEPATOBLASTOMA_CLASSES_DN, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, ONKEN_UVEAL_MELANOMA_UP, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, CASTELLANO_NRAS_TARGETS_DN, GOBP_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY

GO Biological Process (3): proteolysis (GO:0006508), programmed cell death (GO:0012501), positive regulation of apoptotic process (GO:0043065)

GO Molecular Function (8): serine-type endopeptidase activity (GO:0004252), serine-type peptidase activity (GO:0008236), growth factor binding (GO:0019838), identical protein binding (GO:0042802), molecular function activator activity (GO:0140677), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (5): extracellular region (GO:0005576), cytosol (GO:0005829), plasma membrane (GO:0005886), extracellular matrix (GO:0031012), extracellular exosome (GO:0070062)

Reactome top-level categories

1 top-level categories:

Category	Pathways
Extracellular matrix organization	1

GO top-level categories

22 GO namespaces:

Category	Terms
protein binding	2
cellular anatomical structure	2
protein metabolic process	1
signal transduction	1
cell death	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
endopeptidase activity	1
serine-type peptidase activity	1
peptidase activity	1
serine hydrolase activity	1
molecular function regulator activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
cytoplasm	1
membrane	1
cell periphery	1
external encapsulating structure	1
extracellular vesicle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 5 of 17 annotations. The rest are phylogenetic / computational / electronic (IEA).

5 experimentally-supported GO terms:

GO term	NS	Evidence
extracellular exosome	CC	high-throughput assay
extracellular matrix	CC	high-throughput assay
plasma membrane	CC	direct assay
identical protein binding	MF	physical interaction
molecular function activator activity	MF	experiment

Protein interactions and networks

STRING

showing 15 of 1,308 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HTRA1	ARMS2	P0C7Q2	765
HTRA1	CFH	P08603	763
HTRA1	PLEKHA1	Q9HB21	696
HTRA1	CDH1	P12830	658
HTRA1	PRSS3	P15951	656
HTRA1	CSN2	P05814	654
HTRA1	CLPP	Q16740	642
HTRA1	CTRC	Q99895	642
HTRA1	PRSS2	P07478	618
HTRA1	HSPD1	P10809	588
HTRA1	CTRB2	Q6GPI1	586
HTRA1	GRPEL1	Q9HAV7	567
HTRA1	SPINK1	P00995	566
HTRA1	CTRB1	P17538	559
HTRA1	CLPB	Q9H078	552

IntAct

Human interaction partners of HTRA1 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 372 partners by confidence:

Partner	Interaction type	MIscore	Records
MAPT	protein cleavage	0.750	6
E	physical association	0.710	12
RPS6KA1	direct interaction	0.610	6
PTEN	direct interaction	0.610	4
JAG1	physical association	0.610	2
CTNND2	physical association	0.590	2
HTRA4	physical association	0.540	5
MIF	physical association	0.530	3
E6	direct interaction	0.440	5
THBS1	cleavage reaction	0.440	3
NRXN3	direct interaction	0.440	2
PDLIM4	direct interaction	0.440	2
ABCA1	direct interaction	0.440	1
ABCA2	direct interaction	0.440	1
ABCA7	direct interaction	0.440	1
ABCC4	direct interaction	0.440	1
ABCC6	direct interaction	0.440	1
ACE2	direct interaction	0.440	1
ACOT6	direct interaction	0.440	1
ACTN2	direct interaction	0.440	1
ACVR2A	direct interaction	0.440	1
ADAM22	direct interaction	0.440	1
ADGRA1	direct interaction	0.440	1
ADGRA2	direct interaction	0.440	1
ADGRA3	direct interaction	0.440	1
ADGRE5	direct interaction	0.440	1
ADGRG1	direct interaction	0.440	1
ADRA1D	direct interaction	0.440	1
ADRB1	direct interaction	0.440	1
AGMAT	direct interaction	0.440	1

BioGRID (59 interactions; top human partners by supporting records): TMEM25 (Affinity Capture-MS; 3 records), AVP (Affinity Capture-MS; 2 records), C12orf49 (Affinity Capture-MS; 2 records), DEFA5 (Affinity Capture-MS; 2 records), DEFB127 (Affinity Capture-MS; 2 records), FUT1 (Affinity Capture-MS; 2 records), LTBP1 (Biochemical Activity; 2 records), MGAT4C (Affinity Capture-MS; 2 records), REG4 (Affinity Capture-MS; 2 records), SPINK4 (Affinity Capture-MS; 2 records), XIAP (Affinity Capture-Western; 2 records), APOE (Two-hybrid), BRD4 (Affinity Capture-MS), CEACAM8 (Affinity Capture-MS), CSNK2B (Two-hybrid)

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 372 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	13.9×	7e-07
Ephrin signaling	6	12.9×	5e-04
Long-term potentiation	7	12.6×	1e-04
Unblocking of NMDA receptors, glutamate binding and activation	6	12.3×	6e-04
MECP2 regulates neuronal receptors and channels	5	11.3×	3e-03
SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)	6	11.2×	9e-04
Trafficking of AMPA receptors	5	10.3×	4e-03
EPHB-mediated forward signaling	10	10.0×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
calcium-independent cell-cell adhesion	9	20.7×	4e-07
glutamate receptor signaling pathway	7	18.8×	2e-05
prepulse inhibition	5	16.1×	1e-03
positive regulation of synaptic transmission, glutamatergic	8	14.3×	2e-05
maintenance of blood-brain barrier	9	12.4×	2e-05
non-canonical Wnt signaling pathway	7	11.7×	3e-04
bicellular tight junction assembly	10	9.5×	2e-05
transmission of nerve impulse	5	9.3×	8e-03

Disease & clinical

Genetic variants

Variant evidence for HTRA1: 414 ClinVar records (32 pathogenic / likely pathogenic); 1 PharmGKB clinical annotation; 41 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	18
Uncertain significance	195
Likely benign	101
Benign	23

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 32 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
221228	NM_002775.5(HTRA1):c.497G>T (p.Arg166Leu)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
523577	NM_002775.5(HTRA1):c.865C>T (p.Gln289Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
523574	NM_002775.5(HTRA1):c.543del (p.Ala182fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
7489	NM_002775.5(HTRA1):c.889G>A (p.Val297Met)	Pathogenic	criteria provided, single submitter	4
7490	NM_002775.5(HTRA1):c.754G>A (p.Ala252Thr)	Pathogenic	criteria provided, single submitter	4
560164	NM_002775.5(HTRA1):c.614C>G (p.Ser205Cys)	Pathogenic	criteria provided, single submitter	1
2570778	NM_002775.5(HTRA1):c.272dup (p.Pro92fs)	Pathogenic	criteria provided, single submitter	1
4072349	NM_002775.5(HTRA1):c.89C>A (p.Ser30Ter)	Pathogenic	criteria provided, single submitter	1
424966	NM_002775.5(HTRA1):c.451C>T (p.Gln151Ter)	Likely pathogenic	criteria provided, single submitter	1
523572	NM_002775.5(HTRA1):c.359G>A (p.Gly120Asp)	Likely pathogenic	criteria provided, single submitter	1
523573	NM_002775.5(HTRA1):c.536T>A (p.Ile179Asn)	Likely pathogenic	criteria provided, single submitter	1
523576	NM_002775.5(HTRA1):c.827G>C (p.Gly276Ala)	Likely pathogenic	criteria provided, single submitter	1
523578	NM_002775.5(HTRA1):c.971A>C (p.Asn324Thr)	Likely pathogenic	criteria provided, single submitter	1
1341619	NM_002775.5(HTRA1):c.278_280delinsCC (p.Phe93fs)	Likely pathogenic	criteria provided, single submitter	1
1687432	NM_002775.5(HTRA1):c.972+1G>C	Likely pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore HTRA1’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; 35 predictions of 1,175):

Position(s)	Effect	Δscore	Sites
10:122489627–122489628	donor_loss	1.0000	5
10:122506886–122506887	donor_loss	1.0000	2
10:122508654–122508655	acceptor_loss	1.0000	5
10:122508771	donor_loss	1.0000	2
10:122510085	acceptor_gain	1.0000
10:122510154–122510155	donor_loss	1.0000	5
10:122511962–122511963	acceptor_gain	1.0000	2
10:122511968	acceptor_loss	1.0000
10:122514189–122514190	acceptor_loss	1.0000	6
10:122489420–122489421	acceptor_loss	0.9900	6

AlphaMissense

1,440 missense substitutions predicted likely pathogenic (of 3,099 scored), across 324 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
M387	9	0.898	0.995
H220	8	1.000	1.000
D250	8	1.000	1.000
D320	8	1.000	1.000
F353	8	0.999	1.000
S298	8	0.998	1.000
N327	8	0.998	1.000
D432	8	0.996	0.999
F286	8	0.994	1.000
F278	8	0.993	1.000
F171	8	0.990	1.000
D246	8	0.988	0.998
N324	8	0.987	1.000
N343	8	0.987	1.000
F207	8	0.986	1.000
S284	8	0.983	1.000
F363	8	0.979	1.000
D336	8	0.977	0.996
N218	8	0.976	1.000
H185	8	0.972	0.997

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

1 prognostic cancer types:

Cancer	Prognostic	p-value
Stomach Adenocarcinoma (TCGA)	unfavorable	0.000515

Disease associations

OMIM: gene MIM:602194 | disease phenotypes: MIM:616779, MIM:600142, MIM:610149

GenCC curated gene-disease

4 curated gene-disease records:

Disease	Classification	Inheritance	Records
cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 2	Definitive	Autosomal recessive	5
cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2	Strong	Autosomal dominant	3
genetic cerebral small vessel disease	Strong	Autosomal dominant
HTRA1-related autosomal dominant cerebral small vessel disease	Moderate	Autosomal dominant	2

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (4 panels, 4 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

4 panels:

Panel	Rating
Adult-onset neurological disorders	green
Familial cerebral small vessel disease	green
Leukodystrophy, adult onset	green
Neurodegenerative disorders, adult onset	green

Mondo (7): cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2 (MONDO:0014768), vascular dementia (MONDO:0004648), cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 2 (MONDO:0010829), cerebral arterial disease (MONDO:0006693), age related macular degeneration 7 (MONDO:0012419), HTRA1-related autosomal dominant cerebral small vessel disease (MONDO:0018832), (MONDO:0018787)

Orphanet (3): HTRA1-related cerebral small vessel disease (Orphanet:482072), Cerebral autosomal recessive arteriopathy-subcortical infarcts-leukoencephalopathy (Orphanet:199354), HTRA1-related autosomal dominant cerebral small vessel disease (Orphanet:482077)

HPO phenotypes

showing 60 of 71 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000020	Urinary incontinence
HP:0000639	Nystagmus
HP:0000708	Atypical behavior
HP:0000712	Emotional lability
HP:0000718	Aggressive behavior
HP:0000726	Dementia
HP:0000737	Irritability
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000741	Apathy
HP:0000746	Delusion
HP:0000822	Hypertension
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001268	Mental deterioration
HP:0001269	Hemiparesis
HP:0001288	Gait disturbance
HP:0001297	Stroke
HP:0001310	Dysmetria
HP:0001347	Hyperreflexia
HP:0001596	Alopecia
HP:0002063	Rigidity
HP:0002069	Bilateral tonic-clonic seizure
HP:0002071	Abnormality of extrapyramidal motor function
HP:0002200	Pseudobulbar signs
HP:0002293	Alopecia of scalp
HP:0002315	Headache
HP:0002326	Transient ischemic attack
HP:0002352	Leukoencephalopathy
HP:0002381	Aphasia
HP:0002401	Stroke-like episode
HP:0002448	Progressive encephalopathy
HP:0002497	Spastic ataxia
HP:0002506	Diffuse cerebral atrophy
HP:0002607	Bowel incontinence
HP:0002634	Arteriosclerosis
HP:0002751	Kyphoscoliosis
HP:0003418	Back pain
HP:0003419	Low back pain
HP:0003474	Somatic sensory dysfunction
HP:0003487	Babinski sign
HP:0003584	Late onset
HP:0003596	Middle age onset
HP:0003621	Juvenile onset
HP:0003657	Vascular granular osmiophilic material deposition
HP:0004931	Arteriosclerosis of small cerebral arteries
HP:0007024	Pseudobulbar paralysis
HP:0007162	Diffuse demyelination of the cerebral white matter
HP:0007204	Diffuse white matter abnormalities
HP:0007236	Recurrent subcortical infarcts
HP:0007256	Abnormal pyramidal sign
HP:0008480	Cervical spondylosis
HP:0010521	Gait apraxia
HP:0012444	Brain atrophy
HP:0012514	Lower limb pain
HP:0012520	Dilation of Virchow-Robin spaces

GWAS associations

showing 30 of 41 associations:

Study	Trait	p-value
GCST001884_11	Age-related macular degeneration	0.000000e+00
GCST003219_31	Advanced age-related macular degeneration	0.000000e+00
GCST010284_4	Age-related macular degeneration (MTAG)	0.000000e+00
GCST001100_7	Age-related macular degeneration	4e-322
GCST001579_6	Age-related macular degeneration (choroidal neovascularisation)	2e-138
GCST000653_9	Age-related macular degeneration	5e-119
GCST010723_8	Early age-related macular degeneration	1e-116
GCST002766_5	Exudative age-related macular degeneration	1e-103
GCST001571_1	Age-related macular degeneration	3e-72
GCST000806_2	Age-related macular degeneration	1e-60
GCST000652_7	Age-related macular degeneration	4e-60
GCST001578_6	Age-related macular degeneration (geographic atrophy)	7e-47
GCST005359_1	Disease progression in age-related macular degeneration	8e-43
GCST001987_1	Age-related macular degeneration (extreme sampling)	3e-29
GCST001986_3	Age-related macular degeneration	8e-27
GCST001814_29	Age-related macular degeneration	1e-25
GCST005358_4	Disease progression to choroidal neovascularization form in age-related macular degeneration	1e-25
GCST005360_2	Disease progression to geographic atrophy form in age-related macular degeneration	1e-25
GCST001814_1	Age-related macular degeneration	4e-24
GCST010002_179	Refractive error	6e-23
GCST011317_2	Age-related macular degeneration	2e-20
GCST004737_4	Neovascular age-related macular degeneration	5e-17
GCST001899_2	Age-related macular degeneration	1e-16
GCST001577_1	Age-related macular degeneration (choroidal neovascularisation vs. geographic atrophy)	7e-14
GCST010866_144	Coronary artery disease	2e-12
GCST006628_23	Systolic blood pressure	3e-12
GCST000006_1	Age-related macular degeneration (wet)	8e-12
GCST005195_136	Coronary artery disease	8e-11
GCST007431_106	Lung function (FEV1/FVC)	2e-10
GCST005194_37	Coronary artery disease	5e-10

EFO canonical traits (from GWAS)

7 canonical traits:

EFO ID	Trait name
EFO:1001492	atrophic macular degeneration
EFO:0008372	laterality measurement
EFO:0008336	disease progression measurement
EFO:0009959	diverticular disease
EFO:0004713	FEV/FVC ratio
EFO:0006335	systolic blood pressure
EFO:0005665	white matter hyperintensity measurement

MeSH disease descriptors

4 disease descriptors:

Descriptor	Name	Tree numbers
D002539	Cerebral Arterial Diseases	C10.228.140.300.510.200; C14.907.253.560.200
D015140	Dementia, Vascular	C10.228.140.300.400; C10.228.140.300.510.800.500; C10.228.140.380.230; C10.228.140.695.500; C14.907.137.126.372.500; C14.907.253.560.350.500; F03.615.400.350
C563990	Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy *(supp.)*
C565718	Macular Degeneration, Age-Related, 7 *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523419 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

1 annotations by evidence level (1 strongest → 4):

Variant	Association	Level	Drugs	Phenotypes
rs11200638	Efficacy	4	bevacizumab;ranibizumab	Macular Degeneration

PharmGKB variants

1 variants:

Variant	Genes	Level	Score	#Clin annots	Drugs
rs11200638	HTRA1	4	-2.75	1	bevacizumab;ranibizumab

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

1 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs11200638	bevacizumab	Efficacy	Genotype AA is associated with decreased response to bevacizumab in people with Macular Degeneration as compared to genotype GG.	PMID:22594510

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — S1: Chymotrypsin

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
galegenimab	Inhibition	9.23	pKd

Binding affinities (BindingDB)

882 measured of 892 human assays (892 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(2S,4R)-1-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-methoxypropanoyl]-N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide	IC50	0.262 nM	US-11001555: Difluoroketamide derivatives as HTRA1 inhibitors
(4S)-4-[[(2S)-2-[[(2R)-2- (3-chloro-5- cyanophenoxy)-3-(3- chlorophenyl)propanoyl] amino]-2- phenylacetyl]amino]-2,2- difluoro-5-methyl-3-oxo- N-(2,2,2- trifluoroethyl)hexanamide	IC50	0.293 nM	US-10865182: Difluoroketamide derivatives as HtrA1 inhibitors
5-chloro-N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]thiophene-2-carboxamide	IC50	0.3 nM	US-11059858: Difluoroketamide derivatives as HtrA1 inhibitors
3-chloro-N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-(3-fluorophenyl)-1-oxopropan-2-yl]benzamide	IC50	0.3 nM	US-11059858: Difluoroketamide derivatives as HtrA1 inhibitors
3-chloro-N-[(2S)-3-(4-chloro-3-cyanophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide	IC50	0.3 nM	US-11059858: Difluoroketamide derivatives as HtrA1 inhibitors
(2S,4R)-1-[(2S)-2-[(3-chlorobenzoyl)amino]-3-methoxypropanoyl]-N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide	IC50	0.351 nM	US-11001555: Difluoroketamide derivatives as HTRA1 inhibitors
N-[[4-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenyl]methyl]pyridine-2-carboxamide	IC50	0.4 nM	US-11014963: Trifluoromethylpropanamide derivatives as HTRA1 inhibitors
N-[3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide	IC50	0.4 nM	US-11059858: Difluoroketamide derivatives as HtrA1 inhibitors
2,5-dichloro-N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-(3-fluorophenyl)-1-oxopropan-2-yl]benzamide	IC50	0.4 nM	US-11059858: Difluoroketamide derivatives as HtrA1 inhibitors
(4S)-4-[[(2S)-2-[[(2S)-3-(3-chlorophenyl)-2-[[2-(3-chlorophenyl)acetyl]amino]propanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide	IC50	0.4 nM	US-11059858: Difluoroketamide derivatives as HtrA1 inhibitors
N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]-3-fluorobenzamide	IC50	0.4 nM	US-11059858: Difluoroketamide derivatives as HtrA1 inhibitors
3-cyano-N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-(3-fluorophenyl)-1-oxopropan-2-yl]benzamide	IC50	0.4 nM	US-11059858: Difluoroketamide derivatives as HtrA1 inhibitors
(4S)-4-[[(2S)-2-[[(2R)-2- (3-chlorophenoxy)-3-(3- fluorophenyl)propanoyl] amino]-2-(4- methoxyphenyl)acetyl] amino]-2,2-difluoro-5- methyl-3-oxo-N-(2,2,2- trifluoroethyl)hexanamide	IC50	0.461 nM	US-10865182: Difluoroketamide derivatives as HtrA1 inhibitors
(2S,4R)-1-[(2S)-2-[[2,2-difluoro-2-(3-fluorophenyl)acetyl]amino]propanoyl]-N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide	IC50	0.471 nM	US-11001555: Difluoroketamide derivatives as HTRA1 inhibitors
tert-butyl 2-[4-[(2S)-2-[[2-(2-chlorophenyl)-2,2-difluoroacetyl]amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenoxy]acetate	IC50	0.49 nM	US-11014963: Trifluoromethylpropanamide derivatives as HTRA1 inhibitors
tert-butyl N-[[4-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenyl]methyl]carbamate	IC50	0.5 nM	US-11014963: Trifluoromethylpropanamide derivatives as HTRA1 inhibitors
N-[3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-2-oxo-1-phenylethyl]amino]-1-oxopropan-2-yl]benzamide	IC50	0.5 nM	US-11059858: Difluoroketamide derivatives as HtrA1 inhibitors
N-[(2S)-3-(3-cyanophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide	IC50	0.5 nM	US-11059858: Difluoroketamide derivatives as HtrA1 inhibitors
N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide	IC50	0.5 nM	US-11059858: Difluoroketamide derivatives as HtrA1 inhibitors
3-chloro-N-[(2S)-3-(3-cyanophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide	IC50	0.5 nM	US-11059858: Difluoroketamide derivatives as HtrA1 inhibitors
5-chloro-N-[(2S)-3-(3-cyanophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]thiophene-2-carboxamide	IC50	0.5 nM	US-11059858: Difluoroketamide derivatives as HtrA1 inhibitors
N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]-3-cyanobenzamide	IC50	0.5 nM	US-11059858: Difluoroketamide derivatives as HtrA1 inhibitors
2,5-dichloro-N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide	IC50	0.5 nM	US-11059858: Difluoroketamide derivatives as HtrA1 inhibitors
N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-(3-fluorophenyl)-1-oxopropan-2-yl]pyridine-2-carboxamide	IC50	0.5 nM	US-11059858: Difluoroketamide derivatives as HtrA1 inhibitors
3-cyano-N-[(2S)-3-(3-cyanophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide	IC50	0.5 nM	US-11059858: Difluoroketamide derivatives as HtrA1 inhibitors
(2S,4R)-1-[(2S)-2-[(3-chlorobenzoyl)amino]-3-(3-fluorophenyl)propanoyl]-N-[(3S)-5,5-difluoro-2-methyl-6-(2-morpholin-4-ylethylamino)-4,6-dioxohexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide	IC50	0.538 nM	US-11001555: Difluoroketamide derivatives as HTRA1 inhibitors
tert-butyl N-[[4-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-[(2S,4R)-4-[(4-methoxyphenyl)methylsulfonyl]-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]carbamoyl]pyrrolidin-1-yl]-3-oxopropyl]phenyl]methyl]carbamate	IC50	0.55 nM	US-10870623: Trifluoromethylpropanamide derivatives as HTRA1 inhibitors
N-[(2S)-3-(3,4-Dichlorophenyl)-1-[(2S,4R)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]carbamoyl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]pyridine-2-carboxamide	IC50	0.574 nM	US-11001555: Difluoroketamide derivatives as HTRA1 inhibitors
(2S,4R)-1-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-[(2-methylpropan-2-yl)oxy]propanoyl]-N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide	IC50	0.579 nM	US-11001555: Difluoroketamide derivatives as HTRA1 inhibitors
tert-butyl N-[[4-[(2S)-2-[[(2S)-2-(4-chlorophenyl)-3-methylbutanoyl]amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenyl]methyl]carbamate	IC50	0.6 nM	US-11014963: Trifluoromethylpropanamide derivatives as HTRA1 inhibitors
N-[(2S)-3-(3-chloro-4-cyanophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]pyridine-2-carboxamide	IC50	0.6 nM	US-11059858: Difluoroketamide derivatives as HtrA1 inhibitors
3-chloro-N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide	IC50	0.6 nM	US-11059858: Difluoroketamide derivatives as HtrA1 inhibitors
(4S)-4-[[(2S)-2-[[(2S)-3-(3-chlorophenyl)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]propanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide	IC50	0.6 nM	US-11059858: Difluoroketamide derivatives as HtrA1 inhibitors
3,5-dichloro-N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide	IC50	0.6 nM	US-11059858: Difluoroketamide derivatives as HtrA1 inhibitors
1-(3-chlorophenyl)-N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]cyclopropane-1-carboxamide	IC50	0.6 nM	US-11059858: Difluoroketamide derivatives as HtrA1 inhibitors
(4S)-4-[[(2S)-2-[[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-(3-cyanophenyl)propanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide	IC50	0.6 nM	US-11059858: Difluoroketamide derivatives as HtrA1 inhibitors
tert-butyl N-[(5S)-5-[(3-chlorobenzoyl)amino]-6-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-6-oxohexyl]carbamate	IC50	0.602 nM	US-11014963: Trifluoromethylpropanamide derivatives as HTRA1 inhibitors
(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-(3-fluorophenyl)-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide	IC50	0.62 nM	US-11014963: Trifluoromethylpropanamide derivatives as HTRA1 inhibitors
(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-(3-cyanophenyl)-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide	IC50	0.62 nM	US-11014963: Trifluoromethylpropanamide derivatives as HTRA1 inhibitors
N-[(2S)-1-[(2S,4R)-4-benzylsulfonyl-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]carbamoyl]pyrrolidin-1-yl]-3-(3-chlorophenyl)-1-oxopropan-2-yl]pyridine-2-carboxamide	IC50	0.667 nM	US-11001555: Difluoroketamide derivatives as HTRA1 inhibitors
(4S)-4-[[(2S)-2-[[(2R)-2- (3-cyanophenoxy)-3-(3- fluorophenyl)propanoyl] amino]-2-(4- methoxyphenyl)acetyl] amino]-2,2-difluoro-5- methyl-3-oxo-N-(2,2,2- trifluoroethyl)hexanamide	IC50	0.686 nM	US-10865182: Difluoroketamide derivatives as HtrA1 inhibitors
(2S,4R)-1-[(2R)-3-(3-chlorophenyl)-2-(3,5-dichlorophenoxy)propanoyl]-N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide	IC50	0.694 nM	US-11001555: Difluoroketamide derivatives as HTRA1 inhibitors
(2S)-3-(3-Chlorophenyl)-2-[[2-(3-chlorophenyl)acetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide	IC50	0.695 nM	US-11014963: Trifluoromethylpropanamide derivatives as HTRA1 inhibitors
(2S)-2-[[2-(2,5-Dichlorophenyl)-2,2-difluoroacetyl]amino]-3-hydroxy-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide	IC50	0.7 nM	US-11014963: Trifluoromethylpropanamide derivatives as HTRA1 inhibitors
N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(1S)-1-cyclobutyl-3,3-difluoro-2,4-dioxo-4-(2,2,2-trifluoroethylamino)butyl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]pyridine-2-carboxamide	IC50	0.7 nM	US-11059858: Difluoroketamide derivatives as HtrA1 inhibitors
tert-butyl 2-[3-[[(2S)-3-(3-cyanophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetate	IC50	0.71 nM	US-11014963: Trifluoromethylpropanamide derivatives as HTRA1 inhibitors
(4S)-4-[[(2S)-2-[[(2R)-2- (3-chloro-5- cyanophenoxy)-3-(3- chlorophenyl)propanoyl] amino]-2-(4- methoxyphenyl)acetyl] amino]-2,2-difluoro-5- methyl-3-oxo-N-(2,2,2- trifluoroethyl)hexanamide	IC50	0.711 nM	US-10865182: Difluoroketamide derivatives as HtrA1 inhibitors
tert-butyl (4R)-4-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-5-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-5-oxopentanoate	IC50	0.76 nM	US-11014963: Trifluoromethylpropanamide derivatives as HTRA1 inhibitors
N-[(2S)-1-[(2S,4R)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]carbamoyl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidin-1-yl]-3-(3-methylphenyl)-1-oxopropan-2-yl]pyridine-2-carboxamide	IC50	0.781 nM	US-11001555: Difluoroketamide derivatives as HTRA1 inhibitors
tert-butyl N-[[4-[(2S)-2-[(3-chlorobenzoyl)amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenyl]methyl]carbamate	IC50	0.8 nM	US-11014963: Trifluoromethylpropanamide derivatives as HTRA1 inhibitors

ChEMBL bioactivities

1268 potent at pChembl≥5 of 1271 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.58	IC50	0.262	nM	CHEMBL4589967
9.53	IC50	0.293	nM	CHEMBL4554156
9.52	IC50	0.3	nM	CHEMBL4542635
9.52	IC50	0.3	nM	CHEMBL4471645
9.52	IC50	0.3	nM	CHEMBL4533165
9.46	IC50	0.351	nM	CHEMBL4471714
9.40	IC50	0.4	nM	CHEMBL4540590
9.40	IC50	0.4	nM	CHEMBL4461666
9.40	IC50	0.4	nM	CHEMBL4585025
9.40	IC50	0.4	nM	CHEMBL4588306
9.40	IC50	0.4	nM	CHEMBL4551033
9.40	IC50	0.4	nM	CHEMBL5085441
9.34	IC50	0.461	nM	CHEMBL4472162
9.33	IC50	0.471	nM	CHEMBL4472070
9.31	IC50	0.49	nM	CHEMBL5074107
9.30	IC50	0.5	nM	CHEMBL4446982
9.30	IC50	0.5	nM	CHEMBL4453892
9.30	IC50	0.5	nM	CHEMBL4462378
9.30	IC50	0.5	nM	CHEMBL4557186
9.30	IC50	0.5	nM	CHEMBL4441695
9.30	IC50	0.5	nM	CHEMBL4542403
9.30	IC50	0.5	nM	CHEMBL4520550
9.30	IC50	0.5	nM	CHEMBL4576875
9.30	IC50	0.5	nM	CHEMBL4447637
9.30	IC50	0.5	nM	CHEMBL5085715
9.30	IC50	0.5	nM	CHEMBL6004725
9.27	IC50	0.538	nM	CHEMBL4517216
9.26	IC50	0.55	nM	CHEMBL4451038
9.24	IC50	0.574	nM	CHEMBL4462973
9.24	IC50	0.579	nM	CHEMBL4447513
9.22	IC50	0.6	nM	CHEMBL4530656
9.22	IC50	0.6	nM	CHEMBL4459683
9.22	IC50	0.6	nM	CHEMBL4468950
9.22	IC50	0.6	nM	CHEMBL4533961
9.22	IC50	0.6	nM	CHEMBL4524175
9.22	IC50	0.6	nM	CHEMBL4581447
9.22	IC50	0.602	nM	CHEMBL5083134
9.22	IC50	0.6	nM	CHEMBL5080837
9.21	IC50	0.62	nM	CHEMBL5075130
9.21	IC50	0.62	nM	CHEMBL5089492
9.18	IC50	0.667	nM	CHEMBL4587944
9.16	IC50	0.694	nM	CHEMBL4449164
9.16	IC50	0.686	nM	CHEMBL4450427
9.16	IC50	0.695	nM	CHEMBL5074725
9.15	IC50	0.7	nM	CHEMBL4444635
9.15	IC50	0.711	nM	CHEMBL4436099
9.15	IC50	0.71	nM	CHEMBL5076217
9.15	IC50	0.7	nM	CHEMBL5087160
9.12	IC50	0.76	nM	CHEMBL5075529
9.12	IC50	0.76	nM	CHEMBL5778730

PubChem BioAssay actives

23 with measured affinity, of 58 total; 23 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
[(1R)-1-[[(2S)-2-[[(2S)-3-(3-chlorophenyl)-2-(phenylmethoxycarbonylamino)propanoyl]amino]-4-methylpentanoyl]amino]-2-methylpropyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	0.0100	uM
[(1R)-1-[[(2S)-2-[[(2S)-3-(3-chlorophenyl)-2-[(2,2-dimethyl-3-phenylpropanoyl)amino]propanoyl]amino]-4-methylpentanoyl]amino]-2-methylpropyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	0.0110	uM
[(R)-[[(2S)-2-[[(2S)-3-(3-chlorophenyl)-2-[(2,2-dimethyl-3-phenylpropanoyl)amino]propanoyl]amino]-4-methylpentanoyl]amino]-cyclobutylmethyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	0.0130	uM
[(1R)-1-[[(2S)-2-[[(2S)-3-(3-bromophenyl)-2-(phenylmethoxycarbonylamino)propanoyl]amino]-4-methylpentanoyl]amino]-2-methylpropyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	0.0170	uM
[(1R)-2-methyl-1-[[(2S)-4-methyl-2-[[(2S)-3-(3-methylphenyl)-2-(phenylmethoxycarbonylamino)propanoyl]amino]pentanoyl]amino]propyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	0.0450	uM
[(1R)-1-[[(2S)-2-[[(2S)-3-(4-chlorophenyl)-2-(phenylmethoxycarbonylamino)propanoyl]amino]-4-methylpentanoyl]amino]-2-methylpropyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	0.0730	uM
[(1R)-1-[[(2S)-2-[[(2S)-3-(3-fluorophenyl)-2-(phenylmethoxycarbonylamino)propanoyl]amino]-4-methylpentanoyl]amino]-2-methylpropyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	0.0880	uM
[(1R)-1-[[(2S)-2-[[(2S)-3-(3-chlorophenyl)-2-(3-phenylpropanoylamino)propanoyl]amino]-4-methylpentanoyl]amino]-2-methylpropyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	0.1040	uM
[(1R)-2-methyl-1-[[(2S)-4-methyl-2-[[(2S)-3-phenyl-2-(phenylmethoxycarbonylamino)propanoyl]amino]pentanoyl]amino]propyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	0.4110	uM
[(1R)-1-[[(2S)-2-[[(2S)-3-cyclohexyl-2-(phenylmethoxycarbonylamino)propanoyl]amino]-4-methylpentanoyl]amino]-2-methylpropyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	0.4660	uM
[(1R)-1-[[(2S)-2-[[(2S)-2-(benzylcarbamoylamino)-3-(3-chlorophenyl)propanoyl]amino]-4-methylpentanoyl]amino]-2-methylpropyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	0.4950	uM
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	1954717: Inhibition of recombinant human HTRA1 using H2-OPT as substrate assessed as increase in fluorescence and measured for 2 hrs by fluorescent plate reader analysis	ic50	0.5900	uM
[(1R)-2-methyl-1-[[(2S)-4-methyl-2-[[(2S)-3-(1-oxidopyridin-1-ium-3-yl)-2-(phenylmethoxycarbonylamino)propanoyl]amino]pentanoyl]amino]propyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	0.6540	uM
[(1R)-2-methyl-1-[[(2S)-4-methyl-2-[[(2S)-3-(1-oxidopyridin-1-ium-4-yl)-2-(phenylmethoxycarbonylamino)propanoyl]amino]pentanoyl]amino]propyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	1.5400	uM
[(1R)-2-methyl-1-[[(2S)-4-methyl-2-[[(2S)-2-(phenylmethoxycarbonylamino)heptanoyl]amino]pentanoyl]amino]propyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	1.9200	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	1954717: Inhibition of recombinant human HTRA1 using H2-OPT as substrate assessed as increase in fluorescence and measured for 2 hrs by fluorescent plate reader analysis	ic50	2.0000	uM
(3S)-3-amino-4-[(2S)-2-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(1R)-1-borono-2-methylpropyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-5-methylsulfanyl-1-oxopentan-2-yl]carbamoyl]pyrrolidin-1-yl]-4-oxobutanoic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	2.6000	uM
[(1R)-1-[[(2S)-2-[[(2S)-3-(3-chlorophenyl)-2-(3-phenylpropylamino)propanoyl]amino]-4-methylpentanoyl]amino]-2-methylpropyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	4.9000	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	1954717: Inhibition of recombinant human HTRA1 using H2-OPT as substrate assessed as increase in fluorescence and measured for 2 hrs by fluorescent plate reader analysis	ic50	6.0000	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	1954717: Inhibition of recombinant human HTRA1 using H2-OPT as substrate assessed as increase in fluorescence and measured for 2 hrs by fluorescent plate reader analysis	ic50	6.3000	uM
4-[[6-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(1R)-1-diphenoxyphosphoryl-2-methylpropyl]amino]-1-oxobutan-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	1954717: Inhibition of recombinant human HTRA1 using H2-OPT as substrate assessed as increase in fluorescence and measured for 2 hrs by fluorescent plate reader analysis	ic50	7.3000	uM
4-[[6-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(1R)-1-diphenoxyphosphoryl-2-methylpropyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-naphthalen-2-yl-1-oxopropan-2-yl]amino]-6-oxohexyl]carbamoyl]-2-(3-hydroxy-6-oxoxanthen-9-yl)benzoic acid	1954717: Inhibition of recombinant human HTRA1 using H2-OPT as substrate assessed as increase in fluorescence and measured for 2 hrs by fluorescent plate reader analysis	ic50	7.7000	uM
4-[[6-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(1R)-1-diphenoxyphosphoryl-2-methylpropyl]amino]-4-methyl-1-oxopentan-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	1954717: Inhibition of recombinant human HTRA1 using H2-OPT as substrate assessed as increase in fluorescence and measured for 2 hrs by fluorescent plate reader analysis	ic50	9.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression	4
sodium arsenite	decreases expression, increases expression	3
graphene oxide	increases expression	2
bisphenol A	decreases expression, increases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
chloropicrin	decreases expression, affects expression	2
(+)-JQ1 compound	affects cotreatment, increases expression, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
WT161	affects cotreatment, increases expression	1
sotorasib	affects cotreatment, increases expression	1
tirbanibulin	decreases reaction, increases expression	1
terbufos	increases methylation	1
trichostatin A	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
zinc chromate	increases abundance, increases expression	1
potassium chromate(VI)	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases expression	1
octa-2,4,6-trienoic acid	increases expression	1
chromium hexavalent ion	increases abundance, increases expression	1
seocalcitol	increases expression	1
corosolic acid	increases expression	1
monomethylarsonous acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dimethylarsinous acid	decreases expression	1
nutlin 3	affects cotreatment, increases expression	1

ChEMBL screening assays

28 unique, capped per target: 28 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4418419	Binding	Inhibition of N-terminal 6xHis-SUMO tagged human HTRA1 catalytic-PDZ domain (D161 to P480 residues) expressed in Escherichia coli BL21 (DE3) cells using Mca-Ile-Arg-Arg-Val-Ser-Tyr-Ser-Phe-Lys(Dnp)-Lys as substrate preincubated for 30 mins	New difluoroketamide derivatives as htra1 inhibitors

Cellosaurus cell lines

5 cell lines: 3 cancer cell line, 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_1870	MEC-1	Cancer cell line	Male
CVCL_C0JG	KEIOi003-A	Induced pluripotent stem cell	Female
CVCL_C1LH	HAP1 HTRA1 (-) 1	Cancer cell line	Male
CVCL_C1LI	HAP1 HTRA1 (-) 2	Cancer cell line	Male
CVCL_C9ME	BJTTHi003-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

showing 60 of 301 trials:

NCT	Phase	Status	Title
NCT00312351	Phase 4	TERMINATED	A Clinical Trial to Explore the Safety and Efficacy of Three Different Doses of Pegaptanib Sodium in Patients With Wet Age-Related Macular Degeneration (AMD)
NCT00324116	Phase 4	COMPLETED	Evaluation Of Safety And Efficacy Of 0.3 Mg/Eye Macugen In Patients With Small Age-Related Macular Degeneration Lesions
NCT00327470	Phase 4	TERMINATED	An Open Label Trial to Investigate Macugen for the Preservation of Visual Function in Subjects With Neovascular AMD
NCT00533520	Phase 4	COMPLETED	Evaluation of Dosing Interval of Higher Doses of Ranibizumab
NCT00813891	Phase 4	UNKNOWN	Efficacy of Ranibizumab in Combination With Photodynamic Therapy for Wet Age-Related Macular Degeneration
NCT01006538	Phase 4	COMPLETED	Macular EpiRetinal Brachytherapy Versus Lucentis® Only Treatment (MERLOT)
NCT01213667	Phase 4	UNKNOWN	Genetics in Non-response to Anti-VEGF Treatment in Exudative AMD
NCT01831947	Phase 4	COMPLETED	Efficacy Study of Ranibizumab on Patients With Age-related Macular Degeneration.
NCT02581891	Phase 4	COMPLETED	Managing Neovascular (Known as Wet) Age-related Macular Degeneration Over 2 Years Using Different Treatment Schedules of 2 mg Intravitreal Aflibercept Injected in the Eye
NCT02689518	Phase 4	COMPLETED	EAGLE: Evaluating Genotypes Using Intravitreal Aflibercept Injection
NCT03804099	Phase 4	COMPLETED	Effect Aflibercept on Ocular Perfusion
NCT07367282	Phase 4	RECRUITING	Evaluate the Efficacy of Faricimab in Patients With Neovascular Age-related Macular Degeneration
NCT07779356	Phase 4	COMPLETED	Patient Comfort Following Intravitreal Injections Using Iheezo Versus Standard Anesthesia
NCT00165763	Phase 4	COMPLETED	Efficacy and Safety of Donepezil Hydrochloride (Aricept) in Vascular Dementia
NCT00847860	Phase 4	COMPLETED	Cilostazol Verse Asprin for Vascular Dementia in Poststroke Patients With White Matter Lesions
NCT00947531	Phase 4	COMPLETED	A Clinical Trial to Evaluate the Safety and Efficacy of 20 ml Cerebrolysin in Patients With Vascular Dementia
NCT00950430	Phase 4	ENROLLING_BY_INVITATION	Imaging of Brain Amyloid Plaques in the Aging Population
NCT00000145	Phase 3	COMPLETED	Age-Related Eye Disease Study (AREDS)
NCT00000150	Phase 3	COMPLETED	Submacular Surgery Trials (SST)
NCT00000152	Phase 3	UNKNOWN	Randomized Trial of Beta-Carotene and Macular Degeneration
NCT00000158	Phase 3	UNKNOWN	Macular Photocoagulation Study (MPS)
NCT00000161	Phase 3	UNKNOWN	Randomized Trials of Vitamin Supplements and Eye Disease
NCT00000162	Phase 3	COMPLETED	Branch Vein Occlusion Study
NCT00000167	Phase 3	COMPLETED	Complications of Age-Related Macular Degeneration Prevention Trial
NCT00041483	Phase 3	COMPLETED	Phase 3 Study to Evaluate Anecortave Acetate vs. Visudyne for the Treatment of the Wet Form of AMD
NCT00042211	Phase 3	COMPLETED	Preventing Depression in Patients With Macular Degeneration
NCT00050479	Phase 3	COMPLETED	Laser and Medical Treatment of Diabetic Macular Edema
NCT00051129	Phase 3	COMPLETED	Anecortave Acetate in Subfoveal Choroidal Neovascularization (CNV) Due to Wet Age-Related Macular Degeneration (AMD)
NCT00056836	Phase 3	COMPLETED	A Study to Evaluate rhuFab V2 in Subjects With Minimally Classic or Occult Subfoveal Neovascular Macular Degeneration
NCT00058994	Phase 3	COMPLETED	An Evaluation of Safety and Efficacy of Anecortave Acetate Versus Placebo in Patients With Subfoveal CNV Due to Exudative AMD
NCT00061594	Phase 3	COMPLETED	A Study to Compare rhuFab V2 With Verteporfin Photodynamic in Treating Subfoveal Neovascular Macular Degeneration
NCT00065728	Phase 3	TERMINATED	Open-Label Posterior Juxtascleral Injections of Anecortave Acetate 15mg Dose for Long Term Use in Patients With AMD
NCT00078221	Phase 3	UNKNOWN	Rheopheresis Blood Filtration Study for the Treatment of Dry Age-Related Macular Degeneration (AMD)
NCT00090623	Phase 3	COMPLETED	A Study of rhuFab V2 (Ranibizumab) in Subjects With Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration (AMD)
NCT00095433	Phase 3	COMPLETED	Extension Study of rhuFab V2 in Subjects With Neovascular Age-Related Macular Degeneration (AMD)
NCT00100009	Phase 3	COMPLETED	Triamcinolone Acetonide Plus Laser Therapy to Treat Age-Related Macular Degeneration
NCT00121407	Phase 3	COMPLETED	Visudyne® in Occult (VIO)
NCT00150202	Phase 3	COMPLETED	Clinical Study Of EYE001 For Wet-Type AMD (Age-Related Macular Degeneration)
NCT00157976	Phase 3	UNKNOWN	Double-Masked Study of Photrex (Rostaporfin) Photodynamic Therapy in the Treatment of Age-Related Macular Degeneration
NCT00242580	Phase 3	COMPLETED	A Safety and Efficacy Study Comparing the Combination Treatments of Verteporfin Therapy Plus One of Two Different Doses of Intravitreal Triamcinolone Acetonide and the Verteporfin Therapy Plus Intravitreal Pegaptanib
NCT00299507	Phase 3	COMPLETED	Anecortave Acetate in Patients With Exudative Age-related Macular Degeneration (AMD)
NCT00436553	Phase 3	COMPLETED	Efficacy/Safety of Verteporfin Photodynamic Therapy and Ranibizumab Compared With Ranibizumab in Patients With Subfoveal Choroidal Neovascularization
NCT00454389	Phase 3	UNKNOWN	A Study of Strontium90 Beta Radiation With Lucentis to Treat Age-Related Macular Degeneration
NCT00469352	Phase 3	COMPLETED	A Study of Genetic and Environmental Factors and Their Effect on Response to Treatment With Lucentis (Ranibizumab) for Wet AMD
NCT00499590	Phase 3	TERMINATED	Safety & Efficacy Study Evaluating the Combination of Bevasiranib & Lucentis Therapy in Wet AMD
NCT00509795	Phase 3	COMPLETED	Vascular Endothelial Growth Factor VEGF Trap-Eye:Investigation of Efficacy and Safety in Wet Age-Related Macular Degeneration(AMD)
NCT00523406	Phase 3	COMPLETED	Comparison of Reduced Fluence Versus Standard Photodynamic Therapy (in Combination With Intravitreal Triamcinolone Acetate)
NCT00619229	Phase 3	TERMINATED	Alprostadil in Maculopathy Study (AIMS)
NCT00637377	Phase 3	COMPLETED	Vascular Endothelial Growth Factor (VEGF) Trap-Eye: Investigation of Efficacy and Safety in Wet Age-Related Macular Degeneration (AMD)
NCT00784225	Phase 3	COMPLETED	S0000B: Vitamin E and/or Selenium in Preventing Cataract and Age-Related Macular Degeneration in Men on SELECT SWOG-S0000
NCT01482910	Phase 3	COMPLETED	VEGF Trap-Eye: Investigation of Efficacy and Safety in Chinese Subjects With Wet AMD (Age-Related Macular Degeneration)
NCT01748292	Phase 3	COMPLETED	Treat & Extend Treatment With 0.5mg Ranibizumab vs Monthly Treatment With 0.5mg Ranibizumab
NCT02032173	Phase 3	TERMINATED	Efficacy and Safety of Lucentis® Use in Patients With Diabetic Macular Edema Evaluating a Spaced Out Follow-up After Intensive Treatment Phase
NCT02157077	Phase 3	COMPLETED	Aflibercept After Ranibizumab in Exudative Age-related Macular Degeneration
NCT02462486	Phase 3	COMPLETED	Safety and Efficacy of Abicipar Pegol in Participants With Neovascular Age-related Macular Degeneration
NCT02462928	Phase 3	COMPLETED	A Safety and Efficacy Study of Abicipar Pegol in Participants With Neovascular Age-related Macular Degeneration
NCT02540954	Phase 3	COMPLETED	Efficacy and Safety of Two Different Aflibercept Regimens in Subjects With Neovascular Age-related Macular Degeneration (nAMD)
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Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for HTRA1 across ~30M SureChEMBL compounds — explore on Sugi Predict.