Benign concentric annular macular dystrophy

Summary

Benign concentric annular macular dystrophy (MONDO:0007934) is a disease with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 18

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		27	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	benign concentric annular macular dystrophy
Mondo ID	MONDO:0007934
MeSH	C537833
OMIM	153870
Orphanet	251287
DOID	DOID:0061106
ICD-11	1839503243
SNOMED CT	719520001
UMLS	C5561925
MedGen	1794135
GARD	0009887
Is cancer (heuristic)	no

Also known as: macular dystrophy, benign concentric annular · macular dystrophy, concentric annular · maculopathy, bull’s eye · Mcdca · retinitis pigmentosa 91

Data availability: 18 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › retinal disorder › retinal degeneration › inherited retinal dystrophy › hereditary macular dystrophy › benign concentric annular macular dystrophy

Related subtypes (16): vitelliform macular dystrophy, cone dystrophy, coloboma of macula, coloboma of macula-brachydactyly type B syndrome, macular dystrophy, fenestrated sheen type, macular coloboma-cleft palate-hallux valgus syndrome, macular corneal dystrophy, EEM syndrome, renal hypomagnesemia 5 with ocular involvement, macular dystrophy, X-linked, AICA-ribosiduria, occult macular dystrophy, familial flecked retinopathy, patterned dystrophy of the retinal pigment epithelium, macular dystrophy, retinal, macular dystrophy with or without cone dysfunction

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

18 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 4 conflicting classifications of pathogenicity, 4 pathogenic/likely pathogenic, 3 pathogenic, 1 benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
92870	NM_000350.3(ABCA4):c.5461-10T>C	ABCA4	Pathogenic	reviewed by expert panel
99114	NM_000350.3(ABCA4):c.2041C>T (p.Arg681Ter)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
218921	NM_000554.6(CRX):c.449C>G (p.Ser150Ter)	CRX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
218922	NM_000554.6(CRX):c.660del (p.Tyr221fs)	CRX	Pathogenic	criteria provided, multiple submitters, no conflicts
218923	NM_000554.6(CRX):c.661del (p.Tyr221fs)	CRX	Pathogenic	criteria provided, multiple submitters, no conflicts
1240018	NM_001563.4(IMPG1):c.1824+1G>A	IMPG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2955296	NM_001563.4(IMPG1):c.1428del (p.Pro477fs)	IMPG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
424754	NM_015506.2(MMACHC):c.[271dupA];[482G>A]		Likely pathogenic	criteria provided, single submitter
1008228	NM_001563.4(IMPG1):c.1736T>C (p.Leu579Pro)	IMPG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1032753	NM_001563.4(IMPG1):c.1836T>G (p.Tyr612Ter)	IMPG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1063374	NM_001563.4(IMPG1):c.1876C>T (p.Leu626Phe)	IMPG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
846627	NM_001563.4(IMPG1):c.773A>G (p.Tyr258Cys)	IMPG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3779768	NC_000008.11:g.75728605_75728647del		Uncertain significance	criteria provided, single submitter
3779769	NC_000008.11:g.75819624_75819627dup		Uncertain significance	criteria provided, single submitter
1043806	NM_001563.4(IMPG1):c.1838T>C (p.Leu613Pro)	IMPG1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1709818	NM_001563.4(IMPG1):c.1079G>A (p.Ser360Asn)	IMPG1	Uncertain significance	criteria provided, single submitter
957728	NM_001563.4(IMPG1):c.1228C>A (p.Pro410Thr)	IMPG1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1165049	NM_001563.4(IMPG1):c.1552C>G (p.His518Asp)	IMPG1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CRX	Orphanet:1872	Cone rod dystrophy
CRX	Orphanet:65	Leber congenital amaurosis
CRX	Orphanet:791	Retinitis pigmentosa
ABCA4	Orphanet:1872	Cone rod dystrophy
ABCA4	Orphanet:791	Retinitis pigmentosa
ABCA4	Orphanet:827	Stargardt disease
IMPG1	Orphanet:251287	Benign concentric annular macular dystrophy
IMPG1	Orphanet:791	Retinitis pigmentosa
IMPG1	Orphanet:99000	Adult-onset foveomacular vitelliform dystrophy

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
CRX	HGNC:2383	ENSG00000105392	O43186	Cone-rod homeobox protein	clinvar
ABCA4	HGNC:34	ENSG00000198691	P78363	Retinal-specific phospholipid-transporting ATPase ABCA4	clinvar
IMPG1	HGNC:6055	ENSG00000112706	Q17R60	Interphotoreceptor matrix proteoglycan 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CRX	Cone-rod homeobox protein	Transcription factor that binds and transactivates the sequence 5’-TAATC[CA]-3’ which is found upstream of several photoreceptor-specific genes, including the opsin genes.
ABCA4	Retinal-specific phospholipid-transporting ATPase ABCA4	Flippase that catalyzes in an ATP-dependent manner the transport of retinal-phosphatidylethanolamine conjugates like 11-cis and all-trans isomers of N-retinylidene-phosphatidylethanolamine (N-Ret-PE) from the lumen to the cytoplasmic leafl…
IMPG1	Interphotoreceptor matrix proteoglycan 1	Chondroitin sulfate-, heparin- and hyaluronan-binding protein.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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
Transporter	1	25.9×	0.114
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CRX	Transcription factor	no		HD, Homeodomain-like_sf, Otx_TF_C
ABCA4	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABCA4/ABCR
IMPG1	Other/Unknown	no		SEA_dom, EGF, SEA_dom_sf

Expression context

Cohort genes with no expression data: 0.

3 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
pigmented layer of retina	2
primordial germ cell in gonad	2
male germ line stem cell (sensu Vertebrata) in testis	2
retina	1
nucleus accumbens	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CRX	54	tissue_specific	marker	pigmented layer of retina, retina, primordial germ cell in gonad
ABCA4	164	tissue_specific	marker	pigmented layer of retina, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
IMPG1	155	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, nucleus accumbens, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CRX	2,076
ABCA4	1,532
IMPG1	690

Intra-cohort edges

A	B	Sources
ABCA4	IMPG1	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCA4	P78363	8
CRX	O43186	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
IMPG1	Q17R60	59.26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 3 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
Defective visual phototransduction due to ABCA4 loss of function	1	11420.0×	9e-04	ABCA4
Retinoid cycle disease events	1	2855.0×	9e-04	ABCA4
Diseases associated with visual transduction	1	2855.0×	9e-04	ABCA4
Diseases of the neuronal system	1	2855.0×	9e-04	ABCA4
The canonical retinoid cycle in rods (twilight vision)	1	519.1×	0.004	ABCA4
Visual phototransduction	1	259.6×	0.006	ABCA4
ABC-family protein mediated transport	1	121.5×	0.012	ABCA4
Sensory Perception	1	95.2×	0.013	ABCA4
Transport of small molecules	1	25.1×	0.044	ABCA4
Disease	1	13.1×	0.076	ABCA4

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
visual perception	3	79.5×	3e-05	CRX, ABCA4, IMPG1
phospholipid transfer to membrane	1	1872.4×	0.005	ABCA4
phototransduction, visible light	1	432.1×	0.013	ABCA4
retinal metabolic process	1	312.1×	0.014	ABCA4
phospholipid translocation	1	208.1×	0.016	ABCA4
retinoid metabolic process	1	165.2×	0.017	ABCA4
photoreceptor cell maintenance	1	119.5×	0.020	ABCA4
lipid transport	1	87.8×	0.022	ABCA4
retina development in camera-type eye	1	85.1×	0.022	CRX
animal organ morphogenesis	1	63.8×	0.026	CRX
transmembrane transport	1	56.2×	0.027	ABCA4
extracellular matrix organization	1	40.7×	0.035	IMPG1
nervous system development	1	15.3×	0.084	CRX
regulation of DNA-templated transcription	1	10.5×	0.112	CRX
cell differentiation	1	9.7×	0.113	CRX
positive regulation of transcription by RNA polymerase II	1	5.0×	0.200	CRX
regulation of transcription by RNA polymerase II	1	3.9×	0.236	CRX

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
CRX	0	0
ABCA4	0	0
IMPG1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	1	ABCA4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	CRX, IMPG1

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)
CRX	0	—
ABCA4	0	—
IMPG1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.