ACys amyloidosis

Summary

ACys amyloidosis (MONDO:0007098) is a disease caused by CST3 (GenCC Strong), with 1 cohort gene and 31 clinical trials. Top therapeutic interventions include minocycline and ponezumab.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CST3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 7
• Phenotypes (HPO): 5
• Clinical trials: 31

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		9	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

5 HPO clinical features (Orphanet curated; top 5 by frequency):

HPO ID	Term	Frequency
HP:0001297	Stroke	Very frequent (80-99%)
HP:0001342	Cerebral hemorrhage	Very frequent (80-99%)
HP:0011970	Cerebral amyloid angiopathy	Very frequent (80-99%)
HP:0011034	Amyloidosis	Frequent (30-79%)
HP:0100613	Death in early adulthood	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	ACys amyloidosis
Mondo ID	MONDO:0007098
OMIM	105150
Orphanet	100008
DOID	DOID:0070027
ICD-11	1349991114
SNOMED CT	703220002
UMLS	C1527338
MedGen	279656
GARD	0016930
Is cancer (heuristic)	no

Also known as: amyloidosis, Cerebroarterial, Icelandic type · cerebral amyloid angiopathy · cerebral hemorrhage, hereditary, with amyloidosis · CST3-related amyloidosis · cystatin amyloidosis · HCHWA, Icelandic type · hereditary cerebral haemorrhage with amyloidosis · hereditary cerebral haemorrhage with amyloidosis, Icelandic type · hereditary cerebral hemorrhage with amyloidosis · hereditary cerebral hemorrhage with amyloidosis, Icelandic type · hereditary cystatin C amyloid angiopathy

Data availability: 7 ClinVar variants · 2 GenCC gene-disease records · 8 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › cerebrovascular disorder › cerebral amyloid angiopathy › ACys amyloidosis

Related subtypes (3): ADan amyloidosis, ABri amyloidosis, cerebral amyloid angiopathy, APP-related

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

7 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
5634	NM_000099.4(CST3):c.281T>A (p.Leu94Gln)	CST3	Pathogenic	no assertion criteria provided
2672877	NM_000099.4(CST3):c.376C>T (p.Gln126Ter)	CST3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
809236	NM_000099.4(CST3):c.340C>T (p.Gln114Ter)	CST3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2440591	NM_000099.4(CST3):c.212G>A (p.Arg71His)	CST3	Uncertain significance	criteria provided, multiple submitters, no conflicts
3067942	NM_000099.4(CST3):c.196_198del (p.Asp66del)	CST3	Uncertain significance	criteria provided, single submitter
4078426	NM_000099.4(CST3):c.239A>G (p.Lys80Arg)	CST3	Uncertain significance	criteria provided, single submitter
5635	NM_000099.4(CST3):c.73G>A (p.Ala25Thr)	CST3	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 1 · 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
CST3	Strong	Autosomal dominant	ACys amyloidosis	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CST3	Orphanet:100008	ACys amyloidosis

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
CST3	HGNC:2475	ENSG00000101439	P01034	Cystatin-C	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CST3	Cystatin-C	As an inhibitor of cysteine proteinases, this protein is thought to serve an important physiological role as a local regulator of this enzyme activity.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CST3	Other/Unknown	no		Cystatin_dom, Prot_inh_cystat_CS, Cystatin_sf

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
amygdala	1
nucleus accumbens	1
right frontal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CST3	281	ubiquitous	marker	right frontal lobe, amygdala, nucleus accumbens

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CST3	2,165

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CST3	P01034	11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Amyloid fiber formation	1	102.9×	0.015	CST3
Post-translational protein phosphorylation	1	100.2×	0.015	CST3
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.015	CST3
Neutrophil degranulation	1	23.1×	0.043	CST3

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
negative regulation of collagen catabolic process	1	16852.0×	3e-04	CST3
negative regulation of elastin catabolic process	1	16852.0×	3e-04	CST3
negative regulation of blood vessel remodeling	1	8426.0×	4e-04	CST3
negative regulation of extracellular matrix disassembly	1	2808.7×	8e-04	CST3
regulation of tissue remodeling	1	2106.5×	9e-04	CST3
supramolecular fiber organization	1	1053.2×	0.001	CST3
negative regulation of proteolysis	1	674.1×	0.002	CST3
defense response	1	216.1×	0.005	CST3
immune response	1	47.1×	0.021	CST3

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
CST3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CST3	1	Binding:1

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CST3

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)
CST3	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 31.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	21
PHASE2	5
PHASE3	4
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07250035	PHASE3	NOT_YET_RECRUITING	Jiedu Huayu Oral Prescription in the Treatment of Intracranial Hemorrhage Associated With Cerebral Amyloid Angiopathy
NCT03542656	PHASE3	COMPLETED	Application of Amyloid PET in Cerebral Amyloid Angiopathy
NCT03969732	PHASE3	UNKNOWN	Multimodal Biomarkers for Diagnosis and Prognosis in CAA
NCT04604587	PHASE3	UNKNOWN	MRI-visible Enlarged Perivascular Spaces and the Alteration of Lymphatic Drainage System in CAA
NCT05709314	PHASE2	RECRUITING	A Study of AMDX-2011P in Participants With CAA
NCT06393712	PHASE2	RECRUITING	A Phase 2 Trial of ALN-APP in Patients With Cerebral Amyloid Angiopathy
NCT06421532	PHASE2	ENROLLING_BY_INVITATION	Stimulating Amyloid Clearance in Cerebral Amyloid Angiopathy
NCT07026994	PHASE2	RECRUITING	Colchicine for the Prevention of Recurrence in Cerebral Amyloid Angiopathy RElated IntraCerebral Hemorrhage
NCT01821118	PHASE2	COMPLETED	Study Evaluating the Safety,Tolerability and Efficacy of PF-04360365 in Adults With Probable Cerebral Amyloid Angiopathy
NCT05680389	PHASE1/PHASE2	UNKNOWN	Antibiotics Against Amyloid Angiopathy
NCT04204642	Not specified	RECRUITING	SEarchiNg biomarkErs Cerebral Amyloid Angiopathy (SENECA)
NCT05734378	Not specified	RECRUITING	Prognosis of Cerebral Small Vessel Disease
NCT06128824	Not specified	ACTIVE_NOT_RECRUITING	High Frequency Imaging in Cerebral Amyloid Angiopathy
NCT06714097	Not specified	RECRUITING	Application of Digital Twins’ Technology in Patients Who Had a Stroke, With Moyamoya Disease and With Cerebral Amyloid Angiopathy (CAA) During the Secondary Prevention Phase: A Proof of Concept Using a Randomized Control Trial (Clinical Study 6, STRATIF-AI Project)
NCT06933212	Not specified	RECRUITING	Effect of the Mediterranean Diet in Patients Affected by CADASIL and Cerebral Amyloid Angiopathy.
NCT01382849	Not specified	WITHDRAWN	F-18-AV-45 Uptake, Spot Sign Presence and Cerebral Amyloid Angiopathy (CAA) in Primary Intracranial Hemorrhage (ICH)
NCT01856699	Not specified	UNKNOWN	Superficial Siderosis in Patients With Suspected Cerebral Amyloid Angiopathy
NCT02361411	Not specified	UNKNOWN	Methods of Etiological Diagnosis of Cerebral Amyloid Angiopathy
NCT03464344	Not specified	COMPLETED	Cortical Superficial Siderosis and Risk of Recurrent Intracerebral Hemorrhage in Cerebral Amyloid Angiopathy.
NCT03824197	Not specified	COMPLETED	Auburn University Research on Olive Oil for Alzheimer’s Disease (AU-ROOAD)
NCT04654026	Not specified	UNKNOWN	the Safety and Efficacy of Antiplatelet Therapy in Patients of CAA
NCT04757597	Not specified	UNKNOWN	Remote Ischemic Conditioning for Cerebral Amyloid Angiopathy-related Intracerebral Hemorrhage
NCT04825808	Not specified	COMPLETED	Detailed Clinical and MRI Characteristics in Primary Non-traumatic Convexity Subarachnoid Haemorrhage Elderly Patients.
NCT05082194	Not specified	COMPLETED	Balance Eyesight and Muscle Tension in the Cervical Spine in Cerebral Amyloid Angiopathy
NCT05207475	Not specified	UNKNOWN	Safety and Efficacy of Remote Ischemic Conditioning on Cerebral Amyloid Angiopathy. (RIC-CAA)
NCT05394636	Not specified	COMPLETED	Cerebellar Superficial Siderosis in Cerebral Amyloid Angiopathy
NCT05486897	Not specified	COMPLETED	Periventricular White Matter Hyperintensities in Cerebral Amyloid Angiopathy and Hypertensive Arteriopathy
NCT05499169	Not specified	TERMINATED	Coach Pilot Study: Assessing Cognitive Function and Related Small Vessel Disease Markers After Intracerebral Hemorrhage
NCT05565144	Not specified	COMPLETED	Brain Hemorrhage and Functional Outcome in Stroke Patients With CAA Features on Pre-thrombolysis MRI Treated With Intravenous Thrombolysis (Thrombolysis in CAA) ( Thromb in CAA )
NCT06888882	Not specified	COMPLETED	Dilated Perivascular Spaces in the Dentate Nucleus on MRI in Patients With Hypertensive Angiopathy or Cerebral Amyloid Angiopathy
NCT06960538	Not specified	COMPLETED	Enpowering Progression Risk of Cerebral Amyloid Angiopathy

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
MINOCYCLINE	4	1
PONEZUMAB	2	1