Vitelliform macular dystrophy 3

Summary

Vitelliform macular dystrophy 3 (MONDO:0024561) is a disease caused by PRPH2 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: PRPH2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 32

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	vitelliform macular dystrophy 3
Mondo ID	MONDO:0024561
OMIM	608161
GARD	0025431
Is cancer (heuristic)	no

Also known as: PRPH2 vitelliform macular dystrophy · vitelliform macular dystrophy caused by mutation in PRPH2 · VMD3

Data availability: 32 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › retinal disorder › retinal degeneration › macular degeneration › vitelliform macular dystrophy › adult-onset foveomacular vitelliform dystrophy › vitelliform macular dystrophy 3

Related subtypes (3): vitelliform macular dystrophy 1, vitelliform macular dystrophy 4, vitelliform macular dystrophy 5

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

32 retrieved; paginated sample, class counts are floors:

7 pathogenic, 6 pathogenic/likely pathogenic, 5 benign, 5 conflicting classifications of pathogenicity, 4 uncertain significance, 4 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1175216	NM_000322.5(PRPH2):c.513dup (p.Arg172fs)	PRPH2	Pathogenic	criteria provided, multiple submitters, no conflicts
1175230	NM_000322.5(PRPH2):c.824_828+3delinsCATTTGGGCTCCTCATTTGG	PRPH2	Pathogenic	criteria provided, single submitter
1175277	NM_000322.5(PRPH2):c.914del (p.Gly305fs)	PRPH2	Pathogenic	criteria provided, multiple submitters, no conflicts
13167	NM_000322.5(PRPH2):c.515G>A (p.Arg172Gln)	PRPH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13168	NM_000322.5(PRPH2):c.774C>A (p.Tyr258Ter)	PRPH2	Pathogenic	no assertion criteria provided
13173	NM_000322.5(PRPH2):c.629C>G (p.Pro210Arg)	PRPH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13175	NM_000322.5(PRPH2):c.2T>C (p.Met1Thr)	PRPH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13176	NM_000322.5(PRPH2):c.947G>A (p.Trp316Ter)	PRPH2	Pathogenic	no assertion criteria provided
13177	NM_000322.5(PRPH2):c.113del (p.Gly38fs)	PRPH2	Pathogenic	criteria provided, multiple submitters, no conflicts
624247	NM_000322.5(PRPH2):c.331del (p.Ile111fs)	PRPH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
865787	NM_000322.5(PRPH2):c.934del (p.Val312fs)	PRPH2	Pathogenic	criteria provided, multiple submitters, no conflicts
98666	NM_000322.5(PRPH2):c.422A>G (p.Tyr141Cys)	PRPH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
98717	NM_000322.5(PRPH2):c.904G>T (p.Glu302Ter)	PRPH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2498213	NM_016247.4(IMPG2):c.478G>T (p.Glu160Ter)	IMPG2	Likely pathogenic	criteria provided, single submitter
2628022	NM_000322.5(PRPH2):c.530T>G (p.Ile177Ser)	PRPH2	Likely pathogenic	criteria provided, single submitter
3899360	NM_000322.5(PRPH2):c.920_921insCTTGAGGAATCTGAGAGCGAGAGCCAGGGCTGGCT (p.Glu309fs)	PRPH2	Likely pathogenic	criteria provided, single submitter
98706	NM_000322.5(PRPH2):c.736T>C (p.Trp246Arg)	PRPH2	Likely pathogenic	criteria provided, single submitter
3635280	NM_000322.5(PRPH2):c.476T>C (p.Leu159Pro)	PRPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
812383	NM_000322.5(PRPH2):c.927G>T (p.Glu309Asp)	PRPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
98698	NM_000322.5(PRPH2):c.658C>T (p.Arg220Trp)	PRPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
98715	NM_000322.5(PRPH2):c.866C>T (p.Ser289Leu)	PRPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
98722	NM_000322.5(PRPH2):c.94A>G (p.Ile32Val)	PRPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1492157	NM_000322.5(PRPH2):c.4G>A (p.Ala2Thr)	PRPH2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3061946	NM_000322.5(PRPH2):c.799G>A (p.Val267Ile)	PRPH2	Uncertain significance	criteria provided, single submitter
3593604	NM_000322.5(PRPH2):c.642C>T (p.Cys214=)	PRPH2	Uncertain significance	criteria provided, single submitter
3892197	NM_000322.5(PRPH2):c.205G>C (p.Val69Leu)	PRPH2	Uncertain significance	criteria provided, single submitter
138904	NM_000322.5(PRPH2):c.910C>G (p.Gln304Glu)	PRPH2	Benign	criteria provided, multiple submitters, no conflicts
138905	NM_000322.5(PRPH2):c.929G>A (p.Arg310Lys)	PRPH2	Benign	criteria provided, multiple submitters, no conflicts
138906	NM_000322.5(PRPH2):c.1013A>G (p.Asp338Gly)	PRPH2	Benign	criteria provided, multiple submitters, no conflicts
167542	NM_000322.5(PRPH2):c.*13C>T	PRPH2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · 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
PRPH2	Definitive	Autosomal dominant	hereditary macular dystrophy	21

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRPH2	Orphanet:1872	Cone rod dystrophy
PRPH2	Orphanet:227796	Fundus albipunctatus
PRPH2	Orphanet:52427	Retinitis punctata albescens
PRPH2	Orphanet:75377	Central areolar choroidal dystrophy
PRPH2	Orphanet:791	Retinitis pigmentosa
PRPH2	Orphanet:827	Stargardt disease
PRPH2	Orphanet:99000	Adult-onset foveomacular vitelliform dystrophy
PRPH2	Orphanet:99001	Butterfly-shaped pigment dystrophy
PRPH2	Orphanet:99003	Multifocal pattern dystrophy simulating fundus flavimaculatus
IMPG2	Orphanet:791	Retinitis pigmentosa
IMPG2	Orphanet:99000	Adult-onset foveomacular vitelliform dystrophy

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
PRPH2	HGNC:9942	ENSG00000112619	P23942	Peripherin-2	gencc,clinvar
IMPG2	HGNC:18362	ENSG00000081148	Q9BZV3	Interphotoreceptor matrix proteoglycan 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PRPH2	Peripherin-2	Essential for retina photoreceptor outer segment disk morphogenesis, may also play a role with ROM1 in the maintenance of outer segment disk structure.
IMPG2	Interphotoreceptor matrix proteoglycan 2	Chondroitin sulfate- and hyaluronan-binding proteoglycan involved in the organization of interphotoreceptor matrix; may participate in the maturation and maintenance of the light-sensitive photoreceptor outer segment.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRPH2	Other/Unknown	no		Peripherin/rom-1, Tetraspanin_EC2_sf, Peripherin/rom-1_CS
IMPG2	Other/Unknown	no		SEA_dom, EGF, SEA_dom_sf

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
hindlimb stylopod muscle	1
quadriceps femoris	1
vastus lateralis	1
male germ line stem cell (sensu Vertebrata) in testis	1
pineal body	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRPH2	176	tissue_specific	marker	quadriceps femoris, vastus lateralis, hindlimb stylopod muscle
IMPG2	81	tissue_specific	marker	right uterine tube, male germ line stem cell (sensu Vertebrata) in testis, pineal body

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRPH2	1,234
IMPG2	516

Intra-cohort edges

A	B	Sources
IMPG2	PRPH2	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PRPH2	P23942	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
IMPG2	Q9BZV3	54.28

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 evidence-associated genes (0 with Reactome annotation).

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
response to low light intensity stimulus	1	8426.0×	0.001	PRPH2
visual perception	2	79.5×	0.001	PRPH2, IMPG2
retina morphogenesis in camera-type eye	1	936.2×	0.005	IMPG2
photoreceptor cell outer segment organization	1	526.6×	0.005	PRPH2
protein heterooligomerization	1	526.6×	0.005	PRPH2
detection of light stimulus involved in visual perception	1	324.1×	0.007	PRPH2
retina development in camera-type eye	1	127.7×	0.015	PRPH2
protein maturation	1	81.8×	0.020	PRPH2
extracellular matrix organization	1	61.1×	0.021	IMPG2
protein homooligomerization	1	61.1×	0.021	PRPH2
protein localization to plasma membrane	1	54.4×	0.021	PRPH2
intracellular protein localization	1	52.3×	0.021	IMPG2
cell adhesion	1	18.7×	0.053	PRPH2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 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
PRPH2	0	0
IMPG2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	PRPH2, IMPG2

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)
PRPH2	0	—
IMPG2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.