HTRA1

Chr 10ADAR

HtrA serine peptidase 1

Also known as: ARMD7, CADASIL2, CARASIL, CARASIL2, HtrA, L56, ORF480, PRSS11

NCBI Gene: 5654ENSG00000166033UniProt: Q92743

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. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy 2MIM #616779
AD
Cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 2MIM #600142
AR
421
ClinVar variants
90
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— HTRA1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
90 Pathogenic / Likely Pathogenic· 188 VUS of 421 total submissions
💊
Clinical Trials
1 active or recruiting trial — 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.
0.75LOEUF
pLI 0.000
Z-score 2.41
OE 0.43 (0.26–0.75)
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.
1.05Z-score
OE missense 0.81 (0.72–0.91)
195 obs / 241.1 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.0.43 (0.26–0.75)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.81 (0.72–0.91)
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.1.06
0≤1.21.6
LoF obs/exp: 9 / 20.9Missense obs/exp: 195 / 241.1Syn Z: -0.51

ClinVar Variant Classifications

421 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic62
Likely Pathogenic28
VUS188
Likely Benign97
Benign25
Conflicting21
62
Pathogenic
28
Likely Pathogenic
188
VUS
97
Likely Benign
25
Benign
21
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
6
50
0
62
Likely Pathogenic
7
13
8
0
28
VUS
4
155
26
3
188
Likely Benign
0
5
20
72
97
Benign
0
1
22
2
25
Conflicting
—21
Total1718012677421

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

View in ClinVar →

Protein Context — Lollipop Plot

HTRA1 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy 2

MIM #616779

Molecular basis of disorder known

Autosomal dominant

Cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 2

MIM #600142

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — HTRA1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Antigens in membranous nephropathy: discovery and clinical implications.
Sethi S et al.·Nat Rev Nephrol
2025Review
Heterogeneous blood-brain barrier dysfunction in cerebral small vessel diseases.
Ying Y et al.·Alzheimers Dement
2024
Monogenic cerebral small-vessel diseases: diagnosis and therapy. Consensus recommendations of the European Academy of Neurology.
Mancuso M et al.·Eur J Neurol
2020
The genetic and phenotypic spectra of adult genetic leukoencephalopathies in a cohort of 309 patients.
Wu C et al.·Brain
2023Cohort
CADASIL and CARASIL.
Tikka S et al.·Brain Pathol
2014Review
Fibrocyte enrichment and myofibroblastic adaptation causes nucleus pulposus fibrosis and associates with disc degeneration severity.
Sun Y et al.·Bone Res
2025
Systematic Review of Cerebral Phenotypes Associated With Monogenic Cerebral Small-Vessel Disease.
Whittaker E et al.·J Am Heart Assoc
2022Review
Monogenic causes of cerebral small vessel disease and stroke.
Guey S et al.·Handb Clin Neurol
2024Review
Prevalence of Mutations in Mendelian Stroke Genes in Early Onset Stroke Patients.
Park HK et al.·Ann Neurol
2023Cohort
[Carasil].
Fukutake T·Brain Nerve
2011Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
[A 57-year-old male case of high temperature requirement A serine peptidase 1 (HTRA1)-related cerebral small vessel disease with "Chocolate Chip Sign" on ‍susceptibility-weighted imaging].
Takasone K et al.·Rinsho Shinkeigaku
2026
HTRA1/lncRNA HTRA1-AS1 dominates in age-related macular degeneration reticular pseudodrusen genetic risk with no complement involvement.
Farashi S et al.·Nat Commun
2025🔓 Open Access
Human papillomavirus E7 inhibits immune responses in keratinocytes by activating HTRA1‑mediated mitophagy.
Zhang B et al.·Int J Mol Med
2026🔓 Open Access
Rare Variants in HTRA1, SGTB, and RBM12 Confer Risk of Atherosclerotic Cardiovascular Disease Independent of Traditional Cardiovascular Risk Factors.
Lockhart SM et al.·Circ Genom Precis Med
2025🔓 Open Access
Heterozygous HTRA1-related Cerebral Small Vessel Disease with Short Stature and Limbs.
Serizawa Y et al.·Intern Med
2025
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Cerebral Small Vessel DiseasesCadasilHTRA1-Related Autosomal Dominant Cerebral Angiopathy

Taiwan Associated Genetic and Nongenetic Small Vessel Disease

RECRUITING
NCT05473637National Taiwan University HospitalStarted 2019-01-01
MRI

External Resources

Links to major genomics databases and tools