HTRA1-related autosomal dominant cerebral small vessel disease

Summary

HTRA1-related autosomal dominant cerebral small vessel disease (MONDO:0018832) is a disease with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 2
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		21	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	HTRA1-related autosomal dominant cerebral small vessel disease
Mondo ID	MONDO:0018832
Orphanet	482077
UMLS	C5568568
MedGen	1799991
GARD	0017877
Is cancer (heuristic)	no

Also known as: HTRA1-related autosomal dominant cerebral angiopathy

Data availability: 2 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › cerebrovascular disorder › HTRA1-related autosomal dominant cerebral small vessel disease

Related subtypes (23): cerebral arteritis, intracranial thrombosis, occlusion precerebral artery, vascular dementia, stroke disorder, internal carotid artery stenosis, carotid artery disorder, brain ischemia, brain infarction, cerebral amyloid angiopathy, vascular brain injury, basal ganglia cerebrovascular disorder, intracranial arterial disease, intracranial vasospasm, subclavian steal syndrome, pseudotumor cerebri, cerebral sinovenous thrombosis, familial porencephaly, microangiopathy and leukoencephalopathy, pontine, autosomal dominant, cathepsin a-related arteriopathy-strokes-leukoencephalopathy, precerebral artery stenosis, cerebral artery stenosis, APP-related brain and vascular amyloidosis

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

2 retrieved; paginated sample, class counts are floors:

2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1959435	NM_002775.5(HTRA1):c.184_185del (p.Cys62fs)	HTRA1	Pathogenic	criteria provided, multiple submitters, no conflicts
4072349	NM_002775.5(HTRA1):c.89C>A (p.Ser30Ter)	HTRA1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
HTRA1	Strong	Autosomal dominant	cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HTRA1	Orphanet:199354	Cerebral autosomal recessive arteriopathy-subcortical infarcts-leukoencephalopathy
HTRA1	Orphanet:252128	Malignant peripheral nerve sheath tumor with perineurial differentiation
HTRA1	Orphanet:252212	Malignant triton tumor
HTRA1	Orphanet:482077	HTRA1-related autosomal dominant cerebral small vessel disease

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HTRA1	HGNC:9476	ENSG00000166033	Q92743	Serine protease HTRA1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HTRA1	Serine protease HTRA1	Serine protease with a variety of targets, including extracellular matrix proteins such as fibronectin.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HTRA1	Protease	yes	3.4.21.107	IGFBP-like, PDZ, Peptidase_S1C

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
metanephric glomerulus	1
renal glomerulus	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HTRA1	287	ubiquitous	marker	tendon of biceps brachii, renal glomerulus, metanephric glomerulus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HTRA1	2,843

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HTRA1	Q92743	18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Degradation of the extracellular matrix	1	117.7×	0.008	HTRA1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
chorionic trophoblast cell differentiation	1	2808.7×	0.002	HTRA1
programmed cell death	1	1296.3×	0.003	HTRA1
placenta development	1	443.5×	0.005	HTRA1
negative regulation of BMP signaling pathway	1	290.6×	0.006	HTRA1
negative regulation of transforming growth factor beta receptor signaling pathway	1	173.7×	0.008	HTRA1
positive regulation of apoptotic process	1	56.7×	0.021	HTRA1
proteolysis	1	34.2×	0.029	HTRA1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HTRA1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
HTRA1	28	Binding:28

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HTRA1	3.4.21.107, 3.4.21.108	peptidase Do, HtrA2 peptidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	HTRA1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
HTRA1	28	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05473637	Not specified	RECRUITING	Taiwan Associated Genetic and Nongenetic Small Vessel Disease