Brain small vessel disease 1 with or without ocular anomalies

Summary

Brain small vessel disease 1 with or without ocular anomalies (MONDO:0008289) is a disease caused by COL4A1 (GenCC Strong), with 3 cohort genes and 2 clinical trials.

At a glance

• Causal gene: COL4A1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 588
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	brain small vessel disease 1 with or without ocular anomalies
Mondo ID	MONDO:0008289
MeSH	C531642, C564372
OMIM	175780, 607595
Orphanet	36383
DOID	DOID:0090125
UMLS	C4755307
MedGen	1663316
GARD	0015107
Is cancer (heuristic)	no

Also known as: ADT1P · brain small vessel disease with axenfeld-rieger anomaly · brain small vessel disease with haemorrhage · brain small vessel disease with hemorrhage · brain small vessel disease with or without ocular anomalies · BSVD · BSVD1 · COL4A1 porencephaly · COL4A1-related brain small vessel disease with haemorrhage · hemiplegia, infantile, with porencephaly · leukoencephalopathy with axenfeld-rieger anomaly · POREN1 · porencephaly 1 · porencephaly caused by mutation in COL4A1 · porencephaly type 1 · porencephaly, type 1, autosomal dominant · retinal arteriolar tortuosity, infantile hemiparesis, and leukoencephalopathy, autosomal dominant · T1P

Data availability: 588 ClinVar variants · 3 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 › familial porencephaly › brain small vessel disease 1 with or without ocular anomalies

Related subtypes (6): brain small vessel disease 2A, autosomal dominant, brain small vessel disease 3, brain small vessel disease 4, brain small vessel disease 5 with osteoporosis, brain small vessel disease 6 with leukoencephalopathy, brain small vessel disease 2B, autosomal recessive

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

588 retrieved; paginated sample, class counts are floors:

212 uncertain significance, 99 conflicting classifications of pathogenicity, 80 likely pathogenic, 51 benign/likely benign, 48 likely benign, 41 pathogenic, 41 benign, 15 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1027961	NM_001845.6(COL4A1):c.2458+1G>A	COL4A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1027966	NM_001845.6(COL4A1):c.4887C>G (p.Tyr1629Ter)	COL4A1	Pathogenic	criteria provided, single submitter
1064614	NM_001845.6(COL4A1):c.3742+1G>A	COL4A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1077129	NM_001845.6(COL4A1):c.388-1G>C	COL4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1297056	NM_001845.6(COL4A1):c.144+1G>A	COL4A1	Pathogenic	criteria provided, single submitter
1299527	NM_001845.6(COL4A1):c.3761G>A (p.Gly1254Glu)	COL4A1	Pathogenic	criteria provided, single submitter
1301893	NM_001845.6(COL4A1):c.4250-1G>A	COL4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
132791	NM_001845.6(COL4A1):c.3976G>A (p.Gly1326Arg)	COL4A1	Pathogenic	criteria provided, single submitter
1328516	NM_001845.6(COL4A1):c.4546C>T (p.Arg1516Ter)	COL4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1333877	NM_001845.6(COL4A1):c.2788G>A (p.Gly930Ser)	COL4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
135653	NM_001845.6(COL4A1):c.2086G>A (p.Gly696Ser)	COL4A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1417465	NM_001845.6(COL4A1):c.3187C>T (p.Arg1063Ter)	COL4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451906	NM_001845.6(COL4A1):c.2458+2T>C	COL4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1527881	NM_001845.6(COL4A1):c.2458+1G>C	COL4A1	Pathogenic	criteria provided, single submitter
161440	NM_001845.6(COL4A1):c.2085del (p.Gly696fs)	COL4A1	Pathogenic	no assertion criteria provided
161441	NM_001845.6(COL4A1):c.2194-1G>A	COL4A1	Pathogenic	no assertion criteria provided
161974	NM_001845.6(COL4A1):c.2263G>A (p.Gly755Arg)	COL4A1	Pathogenic	criteria provided, multiple submitters, no conflicts
161975	NM_001845.6(COL4A1):c.2317G>C (p.Gly773Arg)	COL4A1	Pathogenic	no assertion criteria provided
161976	NM_001845.6(COL4A1):c.4881C>G (p.Asn1627Lys)	COL4A1	Pathogenic	no assertion criteria provided
161977	NM_001845.6(COL4A1):c.2122G>A (p.Gly708Arg)	COL4A1	Pathogenic	no assertion criteria provided
1679252	NM_001845.6(COL4A1):c.3407-2del	COL4A1	Pathogenic	criteria provided, single submitter
1707545	NM_001845.6(COL4A1):c.2153_2154dup (p.Asn719fs)	COL4A1	Pathogenic	criteria provided, single submitter
1708132	NM_001845.6(COL4A1):c.665T>G (p.Leu222Ter)	COL4A1	Pathogenic	criteria provided, multiple submitters, no conflicts
17413	NM_001845.6(COL4A1):c.2245G>A (p.Gly749Ser)	COL4A1	Pathogenic	criteria provided, single submitter
17414	NM_001845.6(COL4A1):c.1685G>A (p.Gly562Glu)	COL4A1	Pathogenic	no assertion criteria provided
17415	NM_001845.6(COL4A1):c.1A>T (p.Met1Leu)	COL4A1	Pathogenic	no assertion criteria provided
17416	NM_001845.6(COL4A1):c.3389G>A (p.Gly1130Asp)	COL4A1	Pathogenic	no assertion criteria provided
17417	NM_001845.6(COL4A1):c.4267G>C (p.Gly1423Arg)	COL4A1	Pathogenic	no assertion criteria provided
17421	NM_001845.6(COL4A1):c.2159G>A (p.Gly720Asp)	COL4A1	Pathogenic	criteria provided, single submitter
17422	NM_001845.6(COL4A1):c.4738G>C (p.Gly1580Arg)	COL4A1	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 11 · 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
COL4A1	Strong	Autosomal dominant	brain small vessel disease 1 with or without ocular anomalies	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COL4A1	Orphanet:36383	COL4A1/2-related familial vascular leukoencephalopathy
COL4A1	Orphanet:477749	Pontine autosomal dominant microangiopathy with leukoencephalopathy
COL4A1	Orphanet:481986	Familial schizencephaly
COL4A1	Orphanet:73229	HANAC syndrome
COL4A1	Orphanet:75326	Familial isolated retinal arteriolar tortuosity
COL4A1	Orphanet:899	Walker-Warburg syndrome
COL4A1	Orphanet:99810	Familial porencephaly
KAT6B	Orphanet:3047	Blepharophimosis-intellectual disability syndrome, SBBYS type
KAT6B	Orphanet:85201	Genitopatellar syndrome
COL4A2	Orphanet:36383	COL4A1/2-related familial vascular leukoencephalopathy
COL4A2	Orphanet:99810	Familial porencephaly

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
COL4A1	HGNC:2202	ENSG00000187498	P02462	Collagen alpha-1(IV) chain	gencc,clinvar
KAT6B	HGNC:17582	ENSG00000156650	Q8WYB5	Histone acetyltransferase KAT6B	clinvar
COL4A2	HGNC:2203	ENSG00000134871	P08572	Collagen alpha-2(IV) chain	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL4A1	Collagen alpha-1(IV) chain	Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a ‘chicken-wire’ meshwork together with laminins, proteoglycans and entactin/nidogen.
KAT6B	Histone acetyltransferase KAT6B	Histone acetyltransferase which may be involved in both positive and negative regulation of transcription.
COL4A2	Collagen alpha-2(IV) chain	Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a ‘chicken-wire’ meshwork together with laminins, proteoglycans and entactin/nidogen.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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
Transcription factor	1	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL4A1	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold
KAT6B	Transcription factor	no	2.3.1.48	Znf_PHD, HAT_MYST-type, Histone_H1/H5_H15
COL4A2	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
placenta	2
right coronary artery	1
visceral pleura	1
cortical plate	1
sural nerve	1
ventricular zone	1
decidua	1
saphenous vein	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL4A1	283	ubiquitous	marker	visceral pleura, placenta, right coronary artery
KAT6B	140	ubiquitous	yes	cortical plate, ventricular zone, sural nerve
COL4A2	284	ubiquitous	marker	saphenous vein, decidua, placenta

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL4A1	2,909
COL4A2	2,746
KAT6B	2,214

Intra-cohort edges

A	B	Sources
COL4A1	COL4A2	intact, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL4A1	P02462	4
COL4A2	P08572	4
KAT6B	Q8WYB5	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Anchoring fibril formation	2	507.6×	4e-05	COL4A1, COL4A2
Scavenging by Class A Receptors	2	400.7×	4e-05	COL4A1, COL4A2
Fibronectin matrix formation	2	380.7×	4e-05	COL4A1, COL4A2
Crosslinking of collagen fibrils	2	380.7×	4e-05	COL4A1, COL4A2
Attachment of bacteria to epithelial cells	2	331.0×	4e-05	COL4A1, COL4A2
Laminin interactions	2	253.8×	6e-05	COL4A1, COL4A2
Collagen chain trimerization	2	173.0×	9e-05	COL4A1, COL4A2
Signaling by PDGF	2	169.2×	9e-05	COL4A1, COL4A2
NCAM1 interactions	2	165.5×	9e-05	COL4A1, COL4A2
Assembly of collagen fibrils and other multimeric structures	2	133.6×	1e-04	COL4A1, COL4A2
Collagen degradation	2	117.1×	2e-04	COL4A1, COL4A2
Collagen biosynthesis and modifying enzymes	2	113.6×	2e-04	COL4A1, COL4A2
Non-integrin membrane-ECM interactions	2	102.9×	2e-04	COL4A1, COL4A2
ECM proteoglycans	2	100.2×	2e-04	COL4A1, COL4A2
Integrin cell surface interactions	2	89.6×	2e-04	COL4A1, COL4A2
Chromatin organization	1	27.2×	0.040	KAT6B
HATs acetylate histones	1	26.4×	0.040	KAT6B
Chromatin modifying enzymes	1	24.1×	0.041	KAT6B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
collagen-activated tyrosine kinase receptor signaling pathway	2	864.2×	4e-05	COL4A1, COL4A2
collagen fibril organization	2	149.8×	8e-04	COL4A1, COL4A2
renal tubule morphogenesis	1	1404.3×	0.006	COL4A1
regulation of developmental process	1	802.5×	0.006	KAT6B
retinal blood vessel morphogenesis	1	802.5×	0.006	COL4A1
regulation of hemopoiesis	1	510.7×	0.008	KAT6B
blood vessel morphogenesis	1	267.5×	0.014	COL4A1
branching involved in blood vessel morphogenesis	1	175.5×	0.014	COL4A1
neuromuscular junction development	1	175.5×	0.014	COL4A1
basement membrane organization	1	170.2×	0.014	COL4A1
endodermal cell differentiation	1	165.2×	0.014	COL4A2
response to activity	1	108.0×	0.020	COL4A2
cellular response to amino acid stimulus	1	102.1×	0.020	COL4A1
cellular response to transforming growth factor beta stimulus	1	92.1×	0.020	COL4A2
DNA-templated transcription	1	74.9×	0.023	COL4A2
epithelial cell differentiation	1	58.5×	0.027	COL4A1
negative regulation of angiogenesis	1	56.2×	0.027	COL4A2
nucleosome assembly	1	46.8×	0.031	KAT6B
extracellular matrix organization	1	40.7×	0.033	COL4A2
brain development	1	26.5×	0.048	COL4A1
angiogenesis	1	20.8×	0.059	COL4A2
regulation of DNA-templated transcription	1	10.5×	0.104	KAT6B
negative regulation of DNA-templated transcription	1	10.5×	0.104	KAT6B
positive regulation of DNA-templated transcription	1	9.3×	0.112	KAT6B
positive regulation of transcription by RNA polymerase II	1	5.0×	0.196	KAT6B
regulation of transcription by RNA polymerase II	1	3.9×	0.236	KAT6B

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 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
COL4A1	0	0
KAT6B	0	0
COL4A2	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
KAT6B	22	Binding:20, Functional:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KAT6B	2.3.1.48	histone acetyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	COL4A1, KAT6B, COL4A2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
COL4A1	0	—
KAT6B	22	—
COL4A2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05473637	Not specified	RECRUITING	Taiwan Associated Genetic and Nongenetic Small Vessel Disease
NCT07374913	Not specified	RECRUITING	COL4A1COL4A2: Study of Pathological Conditions Involving Multiple Organs Caused by Mutations in the COL4A1 and COL4A2 Genes