Retinal arterial tortuosity

Summary

Retinal arterial tortuosity (MONDO:0008373) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 303

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	retinal arterial tortuosity
Mondo ID	MONDO:0008373
OMIM	180000
Orphanet	75326
DOID	DOID:0111547
UMLS	C0423401
MedGen	140840
GARD	0016693
Is cancer (heuristic)	no

Also known as: RATOR · retinal arterial tortuosity · retinal arterial tortuosity (disease) · retinal arteries, tortuosity OF · retinal arteriolar tortuosity · retinal haemorrhage with vascular tortuosity · retinal hemorrhage with vascular tortuosity · tortuosity of retinal arteries

Data availability: 303 ClinVar variants · 1 GenCC gene-disease record · 1 HPO phenotype.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › vascular disorder › arterial disorder › retinal arterial tortuosity

Related subtypes (29): vertebral artery insufficiency, splenic artery aneurysm, basilar artery insufficiency, arteriosclerosis disorder, subclavian artery aneurysm, pulmonary artery choriocarcinoma, pulmonary artery leiomyosarcoma, coronary artery disorder, hypertensive disorder, carotid artery disorder, pulmonary embolism, peripheral arterial disease, hypotensive disorder, large artery stroke, aortic disorder, cervical artery dissection, anterior spinal artery syndrome, fibromuscular dysplasia, Sneddon syndrome, celiac trunk compression syndrome, pediatric arterial ischemic stroke, absence of the pulmonary artery, arterial occlusion, aberrant subclavian artery, anterior spinal artery stroke, arteritis, pulmonary artery disease, fibromuscular dysplasia, multifocal, carotid web

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

303 retrieved; paginated sample, class counts are floors:

145 uncertain significance, 54 conflicting classifications of pathogenicity, 40 likely benign, 28 likely pathogenic, 24 benign/likely benign, 7 pathogenic/likely pathogenic, 4 pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1301893	NM_001845.6(COL4A1):c.4250-1G>A	COL4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1328516	NM_001845.6(COL4A1):c.4546C>T (p.Arg1516Ter)	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
18463	NM_001845.6(COL4A1):c.1528G>A (p.Gly510Arg)	COL4A1	Pathogenic	no assertion criteria provided
3575707	NM_001845.6(COL4A1):c.2987G>A (p.Gly996Asp)	COL4A1	Pathogenic	criteria provided, single submitter
3575715	NM_001845.6(COL4A1):c.2269_2276del (p.Lys757fs)	COL4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3575732	NM_001845.6(COL4A1):c.1504_1505dup (p.Leu502fs)	COL4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
379845	NM_001845.6(COL4A1):c.2317G>A (p.Gly773Arg)	COL4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1301894	NM_012330.4(KAT6B):c.5040C>G (p.Tyr1680Ter)	KAT6B	Pathogenic	criteria provided, single submitter
1027965	NM_001845.6(COL4A1):c.3770G>A (p.Gly1257Glu)	COL4A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1922707	NM_001845.6(COL4A1):c.1022G>C (p.Gly341Ala)	COL4A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2150881	NM_001845.6(COL4A1):c.1730G>T (p.Gly577Val)	COL4A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2690573	NM_001845.6(COL4A1):c.536G>C (p.Gly179Ala)	COL4A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2724594	NM_001845.6(COL4A1):c.1466-1G>C	COL4A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3061862	NM_001845.6(COL4A1):c.1996C>T (p.Arg666Ter)	COL4A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3575664	NM_001845.6(COL4A1):c.4886dup (p.Tyr1629Ter)	COL4A1	Likely pathogenic	criteria provided, single submitter
3575680	NM_001845.6(COL4A1):c.4286G>T (p.Gly1429Val)	COL4A1	Likely pathogenic	criteria provided, single submitter
3575683	NM_001845.6(COL4A1):c.4187G>A (p.Gly1396Asp)	COL4A1	Likely pathogenic	criteria provided, single submitter
3575684	NM_001845.6(COL4A1):c.4163T>A (p.Leu1388Ter)	COL4A1	Likely pathogenic	criteria provided, single submitter
3575688	NM_001845.6(COL4A1):c.4098_4104del (p.Pro1367fs)	COL4A1	Likely pathogenic	criteria provided, single submitter
3575689	NM_001845.6(COL4A1):c.4049del (p.Gly1350fs)	COL4A1	Likely pathogenic	criteria provided, single submitter
3575691	NM_001845.6(COL4A1):c.3991C>T (p.Gln1331Ter)	COL4A1	Likely pathogenic	criteria provided, single submitter
3575694	NM_001845.6(COL4A1):c.3778G>A (p.Gly1260Arg)	COL4A1	Likely pathogenic	criteria provided, single submitter
3575695	NM_001845.6(COL4A1):c.3771del (p.Leu1258fs)	COL4A1	Likely pathogenic	criteria provided, single submitter
3575711	NM_001845.6(COL4A1):c.2593C>T (p.Gln865Ter)	COL4A1	Likely pathogenic	criteria provided, single submitter
3575717	NM_001845.6(COL4A1):c.2182C>T (p.Gln728Ter)	COL4A1	Likely pathogenic	criteria provided, single submitter
3575719	NM_001845.6(COL4A1):c.2132G>C (p.Gly711Ala)	COL4A1	Likely pathogenic	criteria provided, single submitter
3575720	NM_001845.6(COL4A1):c.2100dup (p.Asp701Ter)	COL4A1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 9 · 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	autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome	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

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
COL4A1	HGNC:2202	ENSG00000187498	P02462	Collagen alpha-1(IV) chain	gencc,clinvar
KAT6B	HGNC:17582	ENSG00000156650	Q8WYB5	Histone acetyltransferase KAT6B	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.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

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

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
placenta	1
right coronary artery	1
visceral pleura	1
cortical plate	1
sural nerve	1
ventricular zone	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL4A1	2,909
KAT6B	2,214

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL4A1	P02462	4
KAT6B	Q8WYB5	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 2 evidence-associated genes (2 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 2 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	1	380.7×	0.014	COL4A1
Scavenging by Class A Receptors	1	300.5×	0.014	COL4A1
Fibronectin matrix formation	1	285.5×	0.014	COL4A1
Crosslinking of collagen fibrils	1	285.5×	0.014	COL4A1
Attachment of bacteria to epithelial cells	1	248.3×	0.014	COL4A1
Laminin interactions	1	190.3×	0.016	COL4A1
Collagen chain trimerization	1	129.8×	0.016	COL4A1
Signaling by PDGF	1	126.9×	0.016	COL4A1
NCAM1 interactions	1	124.1×	0.016	COL4A1
Assembly of collagen fibrils and other multimeric structures	1	100.2×	0.017	COL4A1
Collagen degradation	1	87.8×	0.017	COL4A1
Collagen biosynthesis and modifying enzymes	1	85.2×	0.017	COL4A1
Non-integrin membrane-ECM interactions	1	77.2×	0.017	COL4A1
ECM proteoglycans	1	75.1×	0.017	COL4A1
Integrin cell surface interactions	1	67.2×	0.018	COL4A1
Chromatin organization	1	40.8×	0.027	KAT6B
HATs acetylate histones	1	39.6×	0.027	KAT6B
Chromatin modifying enzymes	1	36.1×	0.027	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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
renal tubule morphogenesis	1	2106.5×	0.005	COL4A1
regulation of developmental process	1	1203.7×	0.005	KAT6B
retinal blood vessel morphogenesis	1	1203.7×	0.005	COL4A1
regulation of hemopoiesis	1	766.0×	0.006	KAT6B
collagen-activated tyrosine kinase receptor signaling pathway	1	648.1×	0.006	COL4A1
blood vessel morphogenesis	1	401.2×	0.008	COL4A1
branching involved in blood vessel morphogenesis	1	263.3×	0.008	COL4A1
neuromuscular junction development	1	263.3×	0.008	COL4A1
basement membrane organization	1	255.3×	0.008	COL4A1
cellular response to amino acid stimulus	1	153.2×	0.012	COL4A1
collagen fibril organization	1	112.3×	0.015	COL4A1
epithelial cell differentiation	1	87.8×	0.018	COL4A1
nucleosome assembly	1	70.2×	0.021	KAT6B
brain development	1	39.8×	0.034	COL4A1
regulation of DNA-templated transcription	1	15.8×	0.074	KAT6B
negative regulation of DNA-templated transcription	1	15.8×	0.074	KAT6B
positive regulation of DNA-templated transcription	1	14.0×	0.079	KAT6B
positive regulation of transcription by RNA polymerase II	1	7.4×	0.137	KAT6B
regulation of transcription by RNA polymerase II	1	5.8×	0.164	KAT6B

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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

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: 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	COL4A1, KAT6B

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)
COL4A1	0	—
KAT6B	22	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.