HTRA2

Chr 2AR

HtrA serine peptidase 2

Also known as: MGCA8, OMI, PARK13, PRSS25

NCBI Gene: 27429 ENSG00000115317 UniProt: O43464 OMIM: 606441

The protein is a mitochondrial serine protease that promotes apoptosis by cleaving inhibitor proteins and relieving their suppression of caspases. Mutations cause autosomal recessive Parkinson disease 13 and 3-methylglutaconic aciduria type VIII. The gene shows low constraint against loss-of-function variants (pLI 0.004, LOEUF 0.756), which is consistent with recessive inheritance where heterozygous carriers are typically unaffected.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.762 OMIM phenotypes

Clinical Summary— HTRA2

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Gene-Disease Validity (ClinGen)

3-methylglutaconic aciduria type 8 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

18 unique Pathogenic / Likely Pathogenic· 161 VUS of 381 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — HTRA2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.76LOEUF

pLI 0.004

Z-score 2.31

OE 0.40 (0.23–0.76)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.70Z-score

OE missense 0.70 (0.63–0.80)

186 obs / 263.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.40 (0.23–0.76)

0≤0.351.4

Missense OE?0.70 (0.63–0.80)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 7 / 17.4Missense obs/exp: 186 / 263.9Syn Z: 0.05

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongHTRA2-related early-onset mitochondrial syndrome associated with 3-methylglutaconic aciduriaLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6743th %ile

GOF

0.6639th %ile

LOF

0.4627th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

381 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12

Likely Pathogenic6

VUS161

Likely Benign160

Benign13

Conflicting8

Pathogenic

Likely Pathogenic

161

VUS

160

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	9	2	1	0	12
Likely Pathogenic	4	2	0	0	6
VUS	3	139	17	2	161
Likely Benign	0	5	64	91	160
Benign	0	1	11	1	13
Conflicting	—				8
Total	16	149	93	94	360

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap HTRA2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →