Cone-rod dystrophy 3

Summary

Cone-rod dystrophy 3 (MONDO:0011395) is a disease caused by ABCA4 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: ABCA4 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 266

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cone-rod dystrophy 3
Mondo ID	MONDO:0011395
MeSH	C565827
OMIM	604116
DOID	DOID:0111013
UMLS	C1858806
MedGen	349030
GARD	0010653
Is cancer (heuristic)	no

Also known as: ABCA4 cone-rod dystrophy · cone-rod dystrophy 3 · cone-rod dystrophy caused by mutation in ABCA4 · cone-rod dystrophy type 3 · CORD3

Data availability: 266 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › retinal disorder › retinal degeneration › inherited retinal dystrophy › cone-rod dystrophy › cone-rod dystrophy 3

Related subtypes (27): cone-rod dystrophy 2, macular degeneration, X-linked atrophic, cone-rod dystrophy 1, cone-rod dystrophy 5, cone-rod dystrophy 6, cone dystrophy 3, cone-rod dystrophy 7, Leber congenital amaurosis 4, cone-rod dystrophy 8, Newfoundland cone-rod dystrophy, cone-rod dystrophy 13, cone-rod dystrophy 10, cone-rod dystrophy 11, retinal cone dystrophy 4, cone-rod dystrophy 12, cone-rod dystrophy 9, cone-rod dystrophy 15, cone-rod dystrophy 16, cone-rod dystrophy 17, cone-rod dystrophy 18, cone-rod dystrophy 19, cone-rod dystrophy 20, cone-rod dystrophy 21, X-linked cone-rod dystrophy, cone-rod dystrophy 22, cone-rod dystrophy 14, cone-rod dystrophy 24

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

266 retrieved; paginated sample, class counts are floors:

85 pathogenic/likely pathogenic, 70 pathogenic, 47 conflicting classifications of pathogenicity, 21 likely pathogenic, 18 uncertain significance, 16 benign, 7 benign/likely benign, 1 likely benign, 1 pathogenic/likely pathogenic; other

ClinVar	Variant (HGVS)	Gene	Classification	Review
7901	NM_000350.2(ABCA4):c.[1622T>C;3113C>T]		Pathogenic	reviewed by expert panel
1001082	NM_000350.3(ABCA4):c.1019A>C (p.Tyr340Ser)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1062657	NM_000350.3(ABCA4):c.2294GTG[1] (p.Gly766del)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067357	NM_000350.3(ABCA4):c.3522+1G>A	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073468	NM_000350.3(ABCA4):c.1761-2A>G	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1275763	NM_000350.3(ABCA4):c.5578C>T (p.Arg1860Trp)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
143076	NM_000350.3(ABCA4):c.6119G>A (p.Arg2040Gln)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1435338	NM_000350.3(ABCA4):c.6181_6184del (p.Thr2061fs)	ABCA4	Pathogenic	criteria provided, multiple submitters, no conflicts
1447532	NM_000350.3(ABCA4):c.4981del (p.Pro1660_Leu1661insTer)	ABCA4	Pathogenic	criteria provided, multiple submitters, no conflicts
1452669	NM_000350.3(ABCA4):c.2972G>T (p.Gly991Val)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456034	NM_000350.3(ABCA4):c.3304G>T (p.Asp1102Tyr)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456725	NM_000350.3(ABCA4):c.5714+1G>A	ABCA4	Pathogenic	criteria provided, multiple submitters, no conflicts
1476832	NM_000350.3(ABCA4):c.4327C>T (p.Arg1443Cys)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
198720	NM_000350.3(ABCA4):c.880C>T (p.Gln294Ter)	ABCA4	Pathogenic	criteria provided, multiple submitters, no conflicts
212727	NM_000350.3(ABCA4):c.1964T>G (p.Phe655Cys)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2202801	NM_000350.3(ABCA4):c.1906C>A (p.Gln636Lys)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
236078	NM_000350.3(ABCA4):c.1086T>A (p.Tyr362Ter)	ABCA4	Pathogenic	criteria provided, multiple submitters, no conflicts
236087	NM_000350.3(ABCA4):c.1822T>A (p.Phe608Ile)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
236095	NM_000350.3(ABCA4):c.2875A>G (p.Thr959Ala)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
236096	NM_000350.3(ABCA4):c.2894A>G (p.Asn965Ser)	ABCA4	Pathogenic	criteria provided, multiple submitters, no conflicts
236099	NM_000350.3(ABCA4):c.3093del (p.Gly1032fs)	ABCA4	Pathogenic	criteria provided, multiple submitters, no conflicts
236100	NM_000350.3(ABCA4):c.3292C>T (p.Arg1098Cys)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
236102	NM_000350.3(ABCA4):c.3482G>A (p.Arg1161His)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
236110	NM_000350.3(ABCA4):c.4253+5G>A	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
236115	NM_000350.3(ABCA4):c.4519G>A (p.Gly1507Arg)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
236122	NM_000350.3(ABCA4):c.4773+3A>G	ABCA4	Pathogenic	reviewed by expert panel
236129	NM_000350.3(ABCA4):c.5318C>T (p.Ala1773Val)	ABCA4	Pathogenic	reviewed by expert panel
236144	NM_000350.3(ABCA4):c.6077T>C (p.Leu2026Pro)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
236149	NM_000350.3(ABCA4):c.6647C>T (p.Ala2216Val)	ABCA4	Pathogenic	criteria provided, multiple submitters, no conflicts
2429001	NM_000350.3(ABCA4):c.5461-10T>G	ABCA4	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 5 · 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
ABCA4	Definitive	Autosomal recessive	severe early-childhood-onset retinal dystrophy	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ABCA4	Orphanet:1872	Cone rod dystrophy
ABCA4	Orphanet:791	Retinitis pigmentosa
ABCA4	Orphanet:827	Stargardt disease
USH2A	Orphanet:231178	Usher syndrome type 2
USH2A	Orphanet:791	Retinitis pigmentosa

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
ABCA4	HGNC:34	ENSG00000198691	P78363	Retinal-specific phospholipid-transporting ATPase ABCA4	gencc,clinvar
USH2A	HGNC:12601	ENSG00000042781	O75445	Usherin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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…
USH2A	Usherin	Involved in hearing and vision as member of the USH2 complex.

Protein-family classification

Druggable: 2 · 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
Transporter	1	38.9×	0.051
Antibody/Immunoglobulin	1	14.6×	0.067

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ABCA4	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABCA4/ABCR
USH2A	Antibody/Immunoglobulin	yes		Laminin_G, LE_dom, FN3_dom

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
male germ line stem cell (sensu Vertebrata) in testis	2
pigmented layer of retina	1
primordial germ cell in gonad	1
buccal mucosa cell	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ABCA4	164	tissue_specific	marker	pigmented layer of retina, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
USH2A	30	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, right lobe of liver, buccal mucosa cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
USH2A	2,332
ABCA4	1,532

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCA4	P78363	8

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
USH2A	O75445

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
photoreceptor cell maintenance	2	358.6×	1e-04	ABCA4, USH2A
visual perception	2	79.5×	0.001	ABCA4, USH2A
phospholipid transfer to membrane	1	2808.7×	0.002	ABCA4
maintenance of animal organ identity	1	1685.2×	0.002	USH2A
inner ear receptor cell differentiation	1	1685.2×	0.002	USH2A
hair cell differentiation	1	1053.2×	0.003	USH2A
sensory perception of light stimulus	1	936.2×	0.003	USH2A
phototransduction, visible light	1	648.1×	0.003	ABCA4
inner ear auditory receptor cell differentiation	1	601.9×	0.003	USH2A
retinal metabolic process	1	468.1×	0.004	ABCA4
phospholipid translocation	1	312.1×	0.005	ABCA4
retinoid metabolic process	1	247.8×	0.006	ABCA4
establishment of protein localization	1	216.1×	0.006	USH2A
lipid transport	1	131.7×	0.009	ABCA4
transmembrane transport	1	84.3×	0.013	ABCA4
establishment of localization in cell	1	80.2×	0.013	USH2A
sensory perception of sound	1	50.5×	0.020	USH2A

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
ABCA4	0	0
USH2A	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	1	ABCA4
D	Druggable family + AlphaFold only, no drug	1	USH2A
E	Difficult family or no structure, no drug	0

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)
ABCA4	0	—
USH2A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.