HTRA2

HtrA serine peptidase 2, the group of Serine proteases|PDZ domain containing

Basic information

Region (hg38): 2:74529596-74533350

Previous symbols: [ "PRSS25" ]

Links

ENSG00000115317 ∙ NCBI:27429 ∙ OMIM:606441 ∙ HGNC:14348 ∙ Uniprot:O43464 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• 3-methylglutaconic aciduria type 8 (Strong), mode of inheritance: AR
• 3-methylglutaconic aciduria type 8 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
3-methylglutaconic aciduria type VIII	AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Biochemical; Neurologic	27208207; 27696117

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HTRA2 gene.

• not provided (6 variants)
• 3-methylglutaconic aciduria type 8 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HTRA2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	59		61
missense	1		92	4	1	98
nonsense	2		3			5
start loss						0
frameshift	3	2				5
inframe indel			3			3
splice donor/acceptor (+/-2bp)						0
splice region			1	12		13
non coding			7	32	6	45
Total	6	2	107	95	7

Highest pathogenic variant AF is 0.0000263

Variants in HTRA2

This is a list of pathogenic ClinVar variants found in the HTRA2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-74529605-G-A		Parkinson disease 13, autosomal dominant, susceptibility to • not specified	Uncertain significance (May 09, 2023)
2-74529610-G-A		not specified	Uncertain significance (Apr 09, 2024)
2-74529620-G-C		not specified	Uncertain significance (May 03, 2023)
2-74529644-G-A		Parkinson disease 13, autosomal dominant, susceptibility to	Likely benign (Jan 12, 2018)
2-74529646-G-A		Parkinson disease 13, autosomal dominant, susceptibility to	Uncertain significance (Apr 27, 2017)
2-74529648-G-A		Parkinson disease 13, autosomal dominant, susceptibility to	Uncertain significance (Jan 12, 2018)
2-74529683-G-A		Parkinson disease 13, autosomal dominant, susceptibility to	Likely benign (Jan 13, 2018)
2-74529693-G-A		Parkinson disease 13, autosomal dominant, susceptibility to	Uncertain significance (Jan 12, 2018)
2-74529771-G-C		Parkinson disease 13, autosomal dominant, susceptibility to	Uncertain significance (Jan 13, 2018)
2-74529791-G-A		Parkinson disease 13, autosomal dominant, susceptibility to	Uncertain significance (Jan 13, 2018)
2-74529861-G-A		Parkinson disease 13, autosomal dominant, susceptibility to	Benign (Jan 13, 2018)
2-74529871-C-G		Parkinson disease 13, autosomal dominant, susceptibility to	Uncertain significance (Jan 13, 2018)
2-74529871-C-T		Parkinson disease 13, autosomal dominant, susceptibility to	Uncertain significance (Jan 19, 2018)
2-74529921-G-C		Parkinson disease 13, autosomal dominant, susceptibility to	Uncertain significance (Jan 13, 2018)
2-74530015-G-A			Likely benign (Feb 09, 2022)
2-74530016-C-T			Uncertain significance (Sep 19, 2021)
2-74530024-G-A			Likely benign (Oct 08, 2023)
2-74530031-G-C		Inborn genetic diseases	Uncertain significance (Jan 16, 2024)
2-74530032-G-T			Uncertain significance (Apr 28, 2022)
2-74530050-G-C			Uncertain significance (Feb 01, 2022)
2-74530068-G-C			Uncertain significance (Jun 21, 2022)
2-74530070-G-A		HTRA2-related disorder	Uncertain significance (Jun 09, 2023)
2-74530083-G-A		Parkinson disease 13, autosomal dominant, susceptibility to • 3-methylglutaconic aciduria type 8;Parkinson disease 13, autosomal dominant, susceptibility to	Uncertain significance (Dec 30, 2023)
2-74530084-G-A			Likely benign (Feb 20, 2023)
2-74530093-C-T			Likely benign (Jun 30, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HTRA2	protein_coding	protein_coding	ENST00000258080	8	3969

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00358	0.988	125718	0	30	125748	0.000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.70	186	264	0.705	0.0000147	2838
Missense in Polyphen		71	132.31	0.53662		1495
Synonymous	0.0507	108	109	0.994	0.00000547	1094
Loss of Function	2.31	7	17.4	0.403	9.96e-7	186

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000395	0.000395
Ashkenazi Jewish	0.000298	0.000298
East Asian	0.0000544	0.0000544
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000143	0.000141
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Serine protease that shows proteolytic activity against a non-specific substrate beta-casein. Promotes or induces cell death either by direct binding to and inhibition of BIRC proteins (also called inhibitor of apoptosis proteins, IAPs), leading to an increase in caspase activity, or by a BIRC inhibition-independent, caspase-independent and serine protease activity-dependent mechanism. Cleaves THAP5 and promotes its degradation during apoptosis. Isoform 2 seems to be proteolytically inactive. {ECO:0000269|PubMed:15200957, ECO:0000269|PubMed:19502560}.
• Disease: DISEASE: 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. {ECO:0000269|PubMed:27208207, ECO:0000269|PubMed:27696117}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:15961413, ECO:0000269|PubMed:18401856}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.
• Pathway: Apoptosis - multiple species - Homo sapiens (human);Parkinson,s disease - Homo sapiens (human);Apoptosis - Homo sapiens (human);Apoptosis Modulation and Signaling;Parkinsons Disease Pathway;Nanomaterial induced apoptosis (Consensus)

Recessive Scores

• pRec: 0.379

Intolerance Scores

• loftool: 0.416
• rvis_EVS: 0.28
• rvis_percentile_EVS: 71.27

Haploinsufficiency Scores

• pHI: 0.803
• hipred: Y
• hipred_score: 0.737
• ghis: 0.439

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.801

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Htra2
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); immune system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; muscle phenotype; cellular phenotype; homeostasis/metabolism phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype

Gene ontology

• Biological process: proteolysis;ceramide metabolic process;mitochondrion organization;aging;adult walking behavior;intrinsic apoptotic signaling pathway in response to DNA damage;response to herbicide;positive regulation of mitochondrion organization;positive regulation of cell death;protein autoprocessing;pentacyclic triterpenoid metabolic process;forebrain development;cellular response to oxidative stress;cellular response to heat;cellular response to interferon-beta;regulation of multicellular organism growth;positive regulation of apoptotic process;positive regulation of cysteine-type endopeptidase activity involved in apoptotic process;cellular protein catabolic process;negative regulation of cell cycle;neuron development;protein homotrimerization;cellular response to retinoic acid;cellular response to growth factor stimulus;execution phase of apoptosis;negative regulation of neuron death;negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway;regulation of autophagy of mitochondrion;positive regulation of protein targeting to mitochondrion;negative regulation of mitophagy in response to mitochondrial depolarization;positive regulation of extrinsic apoptotic signaling pathway in absence of ligand;positive regulation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway
• Cellular component: chromatin;nucleus;mitochondrion;mitochondrial intermembrane space;endoplasmic reticulum;endoplasmic reticulum membrane;cytosol;cytoskeleton;cytoplasmic side of plasma membrane;membrane;mitochondrial membrane;CD40 receptor complex;serine-type endopeptidase complex
• Molecular function: serine-type endopeptidase activity;protein binding;peptidase activity;serine-type peptidase activity;identical protein binding;unfolded protein binding