Central areolar choroidal dystrophy

Summary

Central areolar choroidal dystrophy (MONDO:0008982) is a disease (an umbrella term covering 5 Mondo subtypes) with 5 cohort genes and 1 clinical trial.

At a glance

• Prevalence: 1-9 / 100 000 (Europe)
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 5
• ClinVar variants: 3
• Phenotypes (HPO): 17
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000		Europe	Not yet validated
Point prevalence	1-9 / 100 000	3.33	France	Not yet validated

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0030631	Hyperautofluorescent macular lesion	Very frequent (80-99%)
HP:0031152	Full-thickness macular hole	Very frequent (80-99%)
HP:0000505	Visual impairment	Frequent (30-79%)
HP:0000572	Visual loss	Frequent (30-79%)
HP:0007401	Macular atrophy	Frequent (30-79%)
HP:0007663	Reduced visual acuity	Frequent (30-79%)
HP:0007894	Hypopigmentation of the fundus	Frequent (30-79%)
HP:0007924	Slow decrease in visual acuity	Frequent (30-79%)
HP:0030615	Foveal photoreceptor outer segment loss on macular OCT	Frequent (30-79%)
HP:0000533	Chorioretinal atrophy	Occasional (5-29%)
HP:0007814	Retinal pigment epithelial mottling	Occasional (5-29%)
HP:0007980	Absent retinal pigment epithelium	Occasional (5-29%)
HP:0011510	Drusen	Occasional (5-29%)
HP:0030491	Choriocapillaris atrophy	Occasional (5-29%)
HP:0030629	Perifoveal ring of hyperautofluorescence	Occasional (5-29%)
HP:0000662	Nyctalopia	Very rare (<1-4%)
HP:0007641	Dyschromatopsia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	central areolar choroidal dystrophy
Mondo ID	MONDO:0008982
OMIM	215500
Orphanet	75377
ICD-10-CM	H31.22
ICD-11	2018537024
SNOMED CT	231996009, 312918002
UMLS	C1536451
MedGen	283932
GARD	0010049
Is cancer (heuristic)	no

Also known as: areolar atrophy of the macula · CACD · CACD1 · central areolar choroidal sclerosis · choroidal dystrophy · choroidal dystrophy central areolar · choroidal dystrophy, central areolar, 1

Data availability: 3 ClinVar variants · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › uveal disorder › optic choroid disorder › central areolar choroidal dystrophy

Related subtypes (6): choroiditis, retinal dystrophies primarily involving Bruch’s membrane, choroidal sclerosis, ornithine aminotransferase deficiency, choroideremia, choroid neoplasm

Subtypes (5): total central choroidal atrophy, partial central choroid dystrophy, choroidal dystrophy, central areolar 2, choroidal dystrophy, central areolar, 3, choroidal dystrophy, central areolar, 1

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

3 retrieved; paginated sample, class counts are floors:

2 pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
813077	NM_000322.5(PRPH2):c.273T>A (p.Tyr91Ter)	PRPH2	Pathogenic	criteria provided, single submitter
813098	NM_015072.5(TTLL5):c.1560dup (p.Asp521Ter)	TTLL5	Pathogenic	criteria provided, multiple submitters, no conflicts
813181	NM_001142800.2(EYS):c.7228G>T (p.Ala2410Ser)	EYS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 41 · Orphanet: 17 · 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
GUCA1A	Definitive	Autosomal dominant	cone-rod dystrophy 14	8
GUCY2D	Definitive	Autosomal dominant	cone-rod dystrophy	12
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
GUCA1A	Orphanet:1871	Progressive cone dystrophy
GUCA1A	Orphanet:1872	Cone rod dystrophy
GUCA1A	Orphanet:75377	Central areolar choroidal dystrophy
GUCY2D	Orphanet:1872	Cone rod dystrophy
GUCY2D	Orphanet:65	Leber congenital amaurosis
GUCY2D	Orphanet:75377	Central areolar choroidal dystrophy
TTLL5	Orphanet:1872	Cone rod dystrophy
EYS	Orphanet:791	Retinitis pigmentosa

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PRPH2	HGNC:9942	ENSG00000112619	P23942	Peripherin-2	gencc,clinvar
GUCA1A	HGNC:4678	ENSG00000048545	P43080	Guanylyl cyclase-activating protein 1	gencc
GUCY2D	HGNC:4689	ENSG00000132518	Q02846	Retinal guanylyl cyclase 1	gencc
TTLL5	HGNC:19963	ENSG00000119685	Q6EMB2	Tubulin polyglutamylase TTLL5	clinvar
EYS	HGNC:21555	ENSG00000188107	Q5T1H1	Protein eyes shut homolog	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.
GUCA1A	Guanylyl cyclase-activating protein 1	Stimulates retinal guanylyl cyclase when free calcium ions concentration is low and inhibits guanylyl cyclase when free calcium ions concentration is elevated.
GUCY2D	Retinal guanylyl cyclase 1	Catalyzes the synthesis of cyclic GMP (cGMP) in rods and cones of photoreceptors.
TTLL5	Tubulin polyglutamylase TTLL5	Polyglutamylase which modifies tubulin, generating polyglutamate side chains on the gamma-carboxyl group of specific glutamate residues within the C-terminal tail of tubulin.
EYS	Protein eyes shut homolog	Required to maintain the integrity of photoreceptor cells.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.2

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
Kinase	1	5.5×	0.269
Other/Unknown	4	1.4×	0.269

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRPH2	Other/Unknown	no		Peripherin/rom-1, Tetraspanin_EC2_sf, Peripherin/rom-1_CS
GUCA1A	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
GUCY2D	Kinase	yes	4.6.1.2	Prot_kinase_dom, A/G_cyclase, Ser-Thr/Tyr_kinase_cat_dom
TTLL5	Other/Unknown	no		TTL/TTLL_fam
EYS	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Laminin_G

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
hindlimb stylopod muscle	1
quadriceps femoris	1
vastus lateralis	1
hypothalamus	1
nucleus accumbens	1
putamen	1
buccal mucosa cell	1
esophagus mucosa	1
lower esophagus mucosa	1
left testis	1
right testis	1
testis	1
islet of Langerhans	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	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
GUCA1A	52	broad	marker	nucleus accumbens, putamen, hypothalamus
GUCY2D	121	tissue_specific	marker	buccal mucosa cell, esophagus mucosa, lower esophagus mucosa
TTLL5	288	ubiquitous	marker	left testis, right testis, testis
EYS	153	tissue_specific	marker	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EYS	1,877
GUCA1A	1,434
PRPH2	1,234
GUCY2D	1,083
TTLL5	872

Intra-cohort edges

A	B	Sources
EYS	PRPH2	string_interaction
GUCA1A	GUCY2D	string_interaction
GUCY2D	PRPH2	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PRPH2	P23942	1
TTLL5	Q6EMB2	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GUCY2D	Q02846	82.37
GUCA1A	P43080	71.28
EYS	Q5T1H1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 5 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
Inactivation, recovery and regulation of the phototransduction cascade	2	211.5×	6e-05	GUCA1A, GUCY2D
Carboxyterminal post-translational modifications of tubulin	1	79.3×	0.013	TTLL5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
detection of light stimulus involved in visual perception	2	259.3×	3e-04	PRPH2, EYS
visual perception	3	47.7×	3e-04	PRPH2, GUCA1A, GUCY2D
retina development in camera-type eye	2	102.1×	0.001	PRPH2, TTLL5
response to low light intensity stimulus	1	3370.4×	0.001	PRPH2
positive regulation of guanylate cyclase activity	1	3370.4×	0.001	GUCA1A
obsolete positive regulation of cGMP-mediated signaling	1	481.5×	0.008	GUCA1A
regulation of opsin-mediated signaling pathway	1	337.0×	0.009	GUCY2D
cGMP biosynthetic process	1	280.9×	0.009	GUCY2D
receptor guanylyl cyclase signaling pathway	1	259.3×	0.009	GUCY2D
photoreceptor cell outer segment organization	1	210.7×	0.009	PRPH2
protein heterooligomerization	1	210.7×	0.009	PRPH2
skeletal muscle tissue regeneration	1	177.4×	0.010	EYS
obsolete cGMP-mediated signaling	1	160.5×	0.011	GUCY2D
phototransduction	1	99.1×	0.016	GUCA1A
sperm axoneme assembly	1	93.6×	0.016	TTLL5
regulation of signal transduction	1	53.5×	0.026	GUCA1A
cellular response to calcium ion	1	40.1×	0.032	GUCA1A
protein maturation	1	32.7×	0.037	PRPH2
protein homooligomerization	1	24.4×	0.047	PRPH2
protein localization to plasma membrane	1	21.7×	0.050	PRPH2
cell adhesion	1	7.5×	0.133	PRPH2
signal transduction	1	3.2×	0.275	GUCA1A

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 0 of 5 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
GUCA1A	0	0
GUCY2D	0	0
TTLL5	0	0
EYS	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GUCY2D	4.6.1.2	guanylate cyclase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	1	GUCY2D
E	Difficult family or no structure, no drug	4	PRPH2, GUCA1A, TTLL5, EYS

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PRPH2	0	—
GUCA1A	0	—
GUCY2D	0	—
TTLL5	0	—
EYS	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02435940	Not specified	RECRUITING	Inherited Retinal Degenerative Disease Registry