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

Summary

Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2 (MONDO:0014768) is a disease caused by HTRA1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: HTRA1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 41

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2
Mondo ID	MONDO:0014768
OMIM	616779
DOID	DOID:0111036
UMLS	C4225211
MedGen	895965
GARD	0025015
Is cancer (heuristic)	no

Also known as: CADASIL caused by mutation in HTRA1 · CADASIL type 2 · CADASIL2 · cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2 · HTRA1 CADASIL

Data availability: 41 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › syndromic disease › cerebral arteriopathy with subcortical infarcts and leukoencephalopathy › cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2

Related subtypes (2): cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1

Subtypes (1): CARASIL syndrome

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

41 retrieved; paginated sample, class counts are floors:

15 uncertain significance, 8 likely pathogenic, 8 pathogenic, 4 pathogenic/likely pathogenic, 3 conflicting classifications of pathogenicity, 2 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1801372	NM_002775.5(HTRA1):c.175_178del (p.Arg59fs)	ARMS2	Pathogenic	criteria provided, single submitter
1184940	NM_002775.5(HTRA1):c.847G>A (p.Gly283Arg)	HTRA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1325819	NM_002775.5(HTRA1):c.496C>T (p.Arg166Cys)	HTRA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1332825	NM_002775.5(HTRA1):c.905G>A (p.Arg302Gln)	HTRA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
221228	NM_002775.5(HTRA1):c.497G>T (p.Arg166Leu)	HTRA1	Pathogenic	criteria provided, multiple submitters, no conflicts
221229	NM_002775.5(HTRA1):c.517G>C (p.Ala173Pro)	HTRA1	Pathogenic	no assertion criteria provided
221230	NM_002775.5(HTRA1):c.852C>A (p.Ser284Arg)	HTRA1	Pathogenic	no assertion criteria provided
221231	NM_002775.5(HTRA1):c.973-1G>A	HTRA1	Pathogenic	no assertion criteria provided
523574	NM_002775.5(HTRA1):c.543del (p.Ala182fs)	HTRA1	Pathogenic	criteria provided, multiple submitters, no conflicts
523577	NM_002775.5(HTRA1):c.865C>T (p.Gln289Ter)	HTRA1	Pathogenic	criteria provided, multiple submitters, no conflicts
7488	NM_002775.5(HTRA1):c.904C>T (p.Arg302Ter)	HTRA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7490	NM_002775.5(HTRA1):c.754G>A (p.Ala252Thr)	HTRA1	Pathogenic	criteria provided, single submitter
1184139	NM_002775.5(HTRA1):c.820C>G (p.Arg274Gly)	HTRA1	Likely pathogenic	no assertion criteria provided
1687432	NM_002775.5(HTRA1):c.972+1G>C	HTRA1	Likely pathogenic	criteria provided, single submitter
1709968	NM_002775.5(HTRA1):c.671del (p.Asn224fs)	HTRA1	Likely pathogenic	criteria provided, single submitter
1910224	NM_002775.5(HTRA1):c.497G>A (p.Arg166His)	HTRA1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
523572	NM_002775.5(HTRA1):c.359G>A (p.Gly120Asp)	HTRA1	Likely pathogenic	criteria provided, single submitter
523573	NM_002775.5(HTRA1):c.536T>A (p.Ile179Asn)	HTRA1	Likely pathogenic	criteria provided, single submitter
523576	NM_002775.5(HTRA1):c.827G>C (p.Gly276Ala)	HTRA1	Likely pathogenic	criteria provided, single submitter
523578	NM_002775.5(HTRA1):c.971A>C (p.Asn324Thr)	HTRA1	Likely pathogenic	criteria provided, single submitter
156100	NM_002775.5(HTRA1):c.854C>T (p.Pro285Leu)	HTRA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
523575	NM_002775.5(HTRA1):c.767T>C (p.Ile256Thr)	HTRA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
870484	NM_002775.5(HTRA1):c.660C>G (p.His220Gln)	HTRA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1296998	NM_002775.5(HTRA1):c.983C>T (p.Ser328Leu)	HTRA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1333590	NM_002775.5(HTRA1):c.590G>A (p.Arg197Gln)	HTRA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1501480	NM_002775.5(HTRA1):c.820C>T (p.Arg274Trp)	HTRA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1679747	NM_002775.5(HTRA1):c.283G>T (p.Val95Leu)	HTRA1	Uncertain significance	criteria provided, single submitter
1709222	NM_002775.5(HTRA1):c.857T>C (p.Phe286Ser)	HTRA1	Uncertain significance	criteria provided, single submitter
2664005	NM_002775.5(HTRA1):c.1127C>T (p.Ala376Val)	HTRA1	Uncertain significance	no assertion criteria provided
2692368	NM_002775.5(HTRA1):c.910G>C (p.Gly304Arg)	HTRA1	Uncertain significance	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

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HTRA1	HGNC:9476	ENSG00000166033	Q92743	Serine protease HTRA1	gencc,clinvar
ARMS2	HGNC:32685	ENSG00000254636	P0C7Q2	Age-related maculopathy susceptibility protein 2	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: 1 · Druggable fraction: 0.5

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	18.3×	0.108
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HTRA1	Protease	yes	3.4.21.107	IGFBP-like, PDZ, Peptidase_S1C
ARMS2	Other/Unknown	no

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
metanephric glomerulus	1
renal glomerulus	1
tendon of biceps brachii	1
left ovary	1
placenta	1
primordial germ cell in gonad	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
ARMS2	99	tissue_specific	yes	primordial germ cell in gonad, placenta, left ovary

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HTRA1	2,843
ARMS2	461

Intra-cohort edges

A	B	Sources
ARMS2	HTRA1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HTRA1	Q92743	18

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARMS2	P0C7Q2	58.14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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 2 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	1404.3×	0.005	HTRA1
programmed cell death	1	648.1×	0.005	HTRA1
retina homeostasis	1	561.7×	0.005	ARMS2
placenta development	1	221.7×	0.009	HTRA1
negative regulation of BMP signaling pathway	1	145.3×	0.011	HTRA1
negative regulation of transforming growth factor beta receptor signaling pathway	1	86.9×	0.015	HTRA1
positive regulation of apoptotic process	1	28.4×	0.040	HTRA1
proteolysis	1	17.1×	0.058	HTRA1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
ARMS2	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: 2; 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	1	ARMS2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HTRA1	28	—
ARMS2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.