HTRA2

Chr 2AR

HtrA serine peptidase 2

Also known as: MGCA8, OMI, PARK13, PRSS25

NCBI Gene: 27429ENSG00000115317UniProt: O43464

This gene encodes a serine protease. The protein has been localized in the endoplasmic reticulum and interacts with an alternatively spliced form of mitogen-activated protein kinase 14. The protein has also been localized to the mitochondria with release to the cytosol following apoptotic stimulus. The protein is thought to induce apoptosis by binding the apoptosis inhibitory protein baculoviral IAP repeat-containing 4. Nuclear localization of this protein has also been observed. Alternate splicing of this gene results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]

Primary Disease Associations & Inheritance

{Parkinson disease 13}MIM #610297
3-methylglutaconic aciduria, type VIIIMIM #617248
AR
377
ClinVar variants
31
Pathogenic / LP
0.00
pLI score
2
Active trials
Clinical Summary— HTRA2
🧬
Gene-Disease Validity (ClinGen)
3-methylglutaconic aciduria type 8 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
31 Pathogenic / Likely Pathogenic· 164 VUS of 377 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.76LOEUF
pLI 0.004
Z-score 2.31
OE 0.40 (0.23–0.76)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.70Z-score
OE missense 0.70 (0.63–0.80)
186 obs / 263.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.40 (0.23–0.76)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.70 (0.63–0.80)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.99
0≤1.21.6
LoF obs/exp: 7 / 17.4Missense obs/exp: 186 / 263.9Syn Z: 0.05

ClinVar Variant Classifications

377 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22
Likely Pathogenic9
VUS164
Likely Benign160
Benign14
Conflicting8
22
Pathogenic
9
Likely Pathogenic
164
VUS
160
Likely Benign
14
Benign
8
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
2
14
0
22
Likely Pathogenic
4
1
4
0
9
VUS
0
136
26
2
164
Likely Benign
0
5
64
91
160
Benign
0
1
12
1
14
Conflicting
—8
Total1014512094377

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

HTRA2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

HTRA2-related early-onset mitochondrial syndrome associated with 3-methylglutaconic aciduria

limited
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Parkinson disease 13}

MIM #610297

Molecular basis of disorder known

3-methylglutaconic aciduria, type VIII

MIM #617248

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — HTRA2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Identification of sixteen novel candidate genes for late onset Parkinson's disease.
Gialluisi A et al.·Mol Neurodegener
2021
CLPB disaggregase dysfunction impacts the functional integrity of the proteolytic SPY complex.
Baker MJ et al.·J Cell Biol
2024Functional
Pathogenic Role of Serine Protease HtrA2/Omi in Neurodegenerative Diseases.
Goo HG et al.·Curr Protein Pept Sci
2017Review
Mitochondrial Protein Homeostasis and Cardiomyopathy.
Wachoski-Dark E et al.·Int J Mol Sci
2022Review
The genetic landscape of Parkinson's disease.
Lunati A et al.·Rev Neurol (Paris)
2018Review
Monogenic Parkinson's disease and parkinsonism: clinical phenotypes and frequencies of known mutations.
Puschmann A·Parkinsonism Relat Disord
2013Review
HtrA protease family as therapeutic targets.
Skorko-Glonek J et al.·Curr Pharm Des
2013Review
Mitochondrial quality control: insights on how Parkinson's disease related genes PINK1, parkin, and Omi/HtrA2 interact to maintain mitochondrial homeostasis.
Dagda RK et al.·J Bioenerg Biomembr
2009Review
[Progress in genetic research on essential tremor].
Zhao Y et al.·Zhonghua Yi Xue Yi Chuan Xue Za Zhi
2017Review
Novel variant Pro143Ala in HTRA2 contributes to Parkinson's disease by inducing hyperphosphorylation of HTRA2 protein in mitochondria.
Lin CH et al.·Hum Genet
2011
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Chronic co-exposure to BPA and alcohol synergizes hepatotoxicity via dysregulation of glycerolipid metabolism and ceramide/HtrA2-driven apoptosis in HepG2 cells.
Tan YQ et al.·J Hazard Mater
2026
HtrA2/Omi: potential therapeutic targets for neurodegenerative diseases.
Xu L et al.·Front Pharmacol
2026🔓 Open Access
BASP1/HTRA2 axis, targeted by miR-7a-5p, exerted a pro-apoptosis role in myocardial ischemia/reperfusion injury.
Zi C et al.·Toxicol Appl Pharmacol
2025
Reduced Expression of UPRmt Proteins HSP10, HSP60, HTRA2, OMA1, SPG7, and YME1L Is Associated with Accelerated Heart Failure in Humans.
Bakovic P et al.·Biomedicines
2025🔓 Open Access
Unraveling the genetic underpinnings of mitochondrial traits and associated circulating inflammatory proteins in Alzheimer's disease: Mitochondrial HtrA2-T cell CD5 negative axis.
Wang Y et al.·J Alzheimers Dis
2025
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Bruxism

mRNA Expression and Genetic Polymorphisms Affecting DRD3 (rs6280) and HTR2A (rs6313) in Bruxism

NOT YET RECRUITING
NCT06457646University of MonastirStarted 2024-06-02
Genetic polymorphism
Estrogen Receptor-positive Breast CancerMusculoskeletal ComplicationsProgesterone Receptor-positive Breast Cancer

A Study to Evaluate Genetic Predictors of Aromatase Inhibitor Musculoskeletal Symptoms (AIMSS)

ACTIVE NOT RECRUITING
NCT01824836Phase NAECOG-ACRIN Cancer Research GroupStarted 2013-06-11
anastrozole

External Resources

Links to major genomics databases and tools