CAPN5-related vitreoretinopathy

Summary

CAPN5-related vitreoretinopathy (MONDO:0100450) is a disease caused by CAPN5 (GenCC Definitive), with 1 cohort gene and 28 clinical trials. Top therapeutic interventions include netarsudil, bupivacaine, and colchicine.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CAPN5 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 5
• Clinical trials: 28

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		99	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	CAPN5-related vitreoretinopathy
Mondo ID	MONDO:0100450
OMIM	193235
Orphanet	329211
DOID	DOID:9719
SNOMED CT	770791000
UMLS	C4721549
MedGen	1648542
GARD	0017497
MedDRA	10057896
Is cancer (heuristic)	no

Also known as: ADNIV · autosomal dominant neovascular inflammatory vitreoretinopathy · CAPN5 vitreoretinopathy · proliferative vitreoretinopathy · retinitis proliferans · vitreoretinopathy, neovascular inflammatory · vitreoretinopathy, neovascular inflammatory, autosomal dominant · VRNI

Data availability: 5 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › vitreous body disorder › vitreous disorder › vitreous syneresis › vitreoretinal degeneration › CAPN5-related vitreoretinopathy

Related subtypes (8): Wagner disease, snowflake vitreoretinal degeneration, X-linked retinoschisis, Stickler syndrome, exudative vitreoretinopathy, enhanced S-cone syndrome, BEST1-related vitreoretinochoroidopathy, Knobloch 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

5 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
39806	NM_004055.5(CAPN5):c.728G>T (p.Arg243Leu)	CAPN5	Pathogenic	criteria provided, multiple submitters, no conflicts
1045063	NM_004055.5(CAPN5):c.1238C>T (p.Thr413Met)	CAPN5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1062329	NM_004055.5(CAPN5):c.1063G>A (p.Glu355Lys)	CAPN5	Uncertain significance	criteria provided, multiple submitters, no conflicts
837208	NM_004055.5(CAPN5):c.346G>A (p.Ala116Thr)	CAPN5	Uncertain significance	criteria provided, multiple submitters, no conflicts
953460	NM_004055.5(CAPN5):c.650G>A (p.Arg217His)	CAPN5	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
CAPN5	Definitive	Autosomal dominant	CAPN5-related vitreoretinopathy	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CAPN5	Orphanet:329211	Autosomal dominant neovascular inflammatory vitreoretinopathy

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
CAPN5	HGNC:1482	ENSG00000149260	O15484	Calpain-5	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CAPN5	Calpain-5	Calcium-regulated non-lysosomal thiol-protease.

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)
CAPN5	Protease	yes	3.4.22.B25	C2_dom, Pept_cys_AS, Peptidase_C2_calpain_cat

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
gall bladder	1
mucosa of transverse colon	1
rectum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CAPN5	224	ubiquitous	marker	mucosa of transverse colon, rectum, gall bladder

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CAPN5	972

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CAPN5	O15484	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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×	0.016	CAPN5
Extracellular matrix organization	1	63.1×	0.016	CAPN5

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
proteolysis	1	34.2×	0.058	CAPN5
signal transduction	1	16.1×	0.062	CAPN5

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CAPN5	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CAPN5	3.4.22.B25

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	CAPN5
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)
CAPN5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 28.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	8
PHASE3	5
PHASE2	5
PHASE4	3
PHASE2/PHASE3	2
PHASE1/PHASE2	2
PHASE1	2
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01445028	PHASE4	COMPLETED	Isotretinoin for Proliferative Vitreoretinopathy
NCT01995045	PHASE4	COMPLETED	Postoperative Pain Control Following Vitreoretinal Surgery
NCT07162818	PHASE4	COMPLETED	Effects of 0.1% Nepafenac on Vitreous Inflammatory Biomarkers in Rhegmatogenous Retinal Detachment and Proliferative Vitreoretinopathy
NCT05660447	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	A Multi-Center Study on the Use of Rho-Kinase Inhibitor to Reduce or Prevent PVR in RRD Eyes at High Risk for PVR
NCT00000140	PHASE3	COMPLETED	The Silicone Study
NCT00370760	PHASE3	UNKNOWN	Oral Colchicine Combined With Intravitreal Infusion of Dexamethasone, LMW Heparin and 5-FU for Management of Proliferative Vitreoretinopathy (PVR)
NCT00371020	PHASE3	UNKNOWN	The Effect of 5-FU and LMW Heparin on the Rate of Retinal Redetachment After Silicone Oil Removal in Cases of PVR
NCT00373282	PHASE3	COMPLETED	Triamcinolone Acetonide in Silicone-Filled Eyes as Adjunctive Treatment for Proliferative Vitreoretinopathy
NCT04136366	PHASE3	COMPLETED	The GUARD Trial - Part 1: A Phase 3 Clinical Trial for Prevention of Proliferative Vitreoretinopathy
NCT04482543	PHASE2/PHASE3	UNKNOWN	Repeated Methotrexate for Proliferative Vitreoretinopathy Grade C
NCT06033703	PHASE1/PHASE2	RECRUITING	Topical Netarsudil for the Prevention of Proliferative Vitreoretinopathy in Patients With Retinal Detachment
NCT06541574	PHASE2	RECRUITING	Prevention of ProliFerative Vitreoretinopathy with Intravitreal MethotreXate in Primary Retinal DEtachment Repair (FIXER) Trial
NCT06818721	PHASE2	NOT_YET_RECRUITING	Intravitreal Topotecan for Prevention or Treatment of Proliferative Vitreoretinopathy in Retinal Detachment
NCT02192970	PHASE2	COMPLETED	Bevacizumab Against Recurrent Retinal Detachment
NCT04580147	PHASE2	UNKNOWN	Intravitreal Aflibercept for the Prevention of Proliferative Vitreoretinopathy Following Retinal Detachment Repair
NCT04891991	PHASE2	COMPLETED	Intravitreal Infliximab for Proliferative Vitreoretinopathy
NCT06289205	PHASE1/PHASE2	UNKNOWN	Comparing Methotrexate Usage Techniques to Prevent Proliferative Vitreoretinopaty After Retinal Detachment Vitrectomy
NCT06425419	PHASE1	NOT_YET_RECRUITING	The Safety and Efficacy of Intravitreal Topotecan for the Treatment of Proliferative Vitreoretinopathy
NCT04830878	PHASE1	WITHDRAWN	Methotrexate For The Prevention and Treatment of Proliferative Vitreoretinopathy in Pediatric Patients
NCT03727776	EARLY_PHASE1	COMPLETED	Adrenocorticotropic Hormone (ACTH) for Post-op Inflammation in Proliferative Vitreoretinopathy (PVR)
NCT05538156	Not specified	NOT_YET_RECRUITING	Internal Limiting Membrane Peeling in Retinal Detachment Surgery
NCT07386678	Not specified	NOT_YET_RECRUITING	Study of Imaging and Molecular Biomarkers in Uncomplicated Rhegmatogenous Retinal Detachment
NCT01255293	Not specified	COMPLETED	Comparative Study of 1000 Centistoke Versus 5000 Centistoke Silicone Oil for Repair of Complex Retinal Detachments
NCT02748421	Not specified	UNKNOWN	Optical Coherence Tomography - Rescan During Dissection of Macular Membranes
NCT04490876	Not specified	COMPLETED	Outcomes of Extensive Brilliant Blue G-Assisted Internal Limiting Membrane Peeling in Proliferative Vitreoretinopathy
NCT04682054	Not specified	UNKNOWN	Molecular Taxonomy of Surgically-harvested Ocular Tissues Defined by Single-cell Transcriptomics
NCT05561569	Not specified	UNKNOWN	Air Versus Gas Tamponade in Primary Retinal Detachment
NCT06166914	Not specified	COMPLETED	Efficacy of 5-fluorouracil and Low Molecular Weight Heparin in High-risk Pediatric Retinal Detachment

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
NETARSUDIL	4	2
BUPIVACAINE	4	1
COLCHICINE	4	1
CORTICOTROPIN	4	1
GLYCERIN	4	1
ISOTRETINOIN	4	1
NEPAFENAC	4	1
PERFLUTREN	4	1
SULFUR HEXAFLUORIDE	4	1
TRIAMCINOLONE	4	1
TRIAMCINOLONE ACETONIDE	4	1