HTRA2

Chr 2AR

HtrA serine peptidase 2

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.

OMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismARLOEUF 0.762 OMIM phenotypes
Clinical SummaryHTRA2
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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.
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Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint
0.76LOEUF
pLI 0.004
Z-score 2.31
OE 0.40 (0.230.76)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
1.70Z-score
OE missense 0.70 (0.630.80)
186 obs / 263.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.40 (0.230.76)
00.351.4
Missense OE0.70 (0.630.80)
00.61.4
Synonymous OE0.99
01.21.6
LoF obs/exp: 7 / 17.4Missense obs/exp: 186 / 263.9Syn Z: 0.05
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
limitedHTRA2-related early-onset mitochondrial syndrome associated with 3-methylglutaconic aciduriaLOFAR

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

DN
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.

ClinVar Variant Classifications

0 submitted variants 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.

3D Protein StructureAlphaFold
Clinical Literature
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