Cone-rod dystrophy 2

Summary

Cone-rod dystrophy 2 (MONDO:0007362) is a disease caused by CRX (GenCC Definitive), with 5 cohort genes.

At a glance

• Causal gene: CRX (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 475

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cone-rod dystrophy 2
Mondo ID	MONDO:0007362
OMIM	120970
DOID	DOID:0111005
NCIT	C162399
SNOMED CT	80328002
UMLS	C3489532
MedGen	483485
GARD	0006145
Is cancer (heuristic)	no

Also known as: cone-rod dystrophy 2 · cone-rod dystrophy caused by mutation in CRX · cone-rod dystrophy type 2 · cone-rod retinal dystrophy-2 · CORD2 · CRD2 · CRX cone-rod dystrophy · RCRD2

Data availability: 475 ClinVar variants · 1 GenCC gene-disease record · 1 cell line.

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 2

Related subtypes (27): macular degeneration, X-linked atrophic, cone-rod dystrophy 1, cone-rod dystrophy 5, cone-rod dystrophy 6, cone dystrophy 3, cone-rod dystrophy 7, cone-rod dystrophy 3, 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

475 retrieved; paginated sample, class counts are floors:

193 uncertain significance, 81 likely benign, 72 pathogenic, 38 conflicting classifications of pathogenicity, 33 benign, 24 benign/likely benign, 21 pathogenic/likely pathogenic, 13 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
638356	NM_014336.5(AIPL1):c.294del (p.Ile99fs)	AIPL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1004054	NM_000554.6(CRX):c.728dup (p.Pro244fs)	CRX	Pathogenic	criteria provided, single submitter
1013687	NM_000554.6(CRX):c.660dup (p.Tyr221fs)	CRX	Pathogenic	criteria provided, single submitter
1020865	NM_000554.6(CRX):c.263A>G (p.Lys88Arg)	CRX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1035273	NM_000554.6(CRX):c.323del (p.Pro108fs)	CRX	Pathogenic	criteria provided, single submitter
1037927	NM_000554.6(CRX):c.426C>A (p.Tyr142Ter)	CRX	Pathogenic	criteria provided, single submitter
1043624	NM_000554.6(CRX):c.592del (p.Ala198fs)	CRX	Pathogenic	criteria provided, single submitter
1046426	NC_000019.9:g.(?48337701)(48343224_?)del	CRX	Pathogenic	criteria provided, single submitter
1056395	NM_000554.6(CRX):c.76_80del (p.Met26fs)	CRX	Pathogenic	criteria provided, single submitter
1071706	NC_000019.9:g.(?48339500)(48343224_?)del	CRX	Pathogenic	criteria provided, single submitter
1185565	NM_000554.6(CRX):c.570dup (p.Tyr191fs)	CRX	Pathogenic	criteria provided, single submitter
1359713	NM_000554.6(CRX):c.509del (p.Pro170fs)	CRX	Pathogenic	criteria provided, single submitter
1370793	NM_000554.6(CRX):c.324del (p.Gly110fs)	CRX	Pathogenic	criteria provided, single submitter
1385024	NM_000554.6(CRX):c.381del (p.Ser128fs)	CRX	Pathogenic	criteria provided, single submitter
1387234	NM_000554.6(CRX):c.125_128dup (p.Thr44fs)	CRX	Pathogenic	criteria provided, single submitter
1393381	NM_000554.6(CRX):c.365del (p.Gly122fs)	CRX	Pathogenic	criteria provided, single submitter
1399832	NM_000554.6(CRX):c.590del (p.Pro197fs)	CRX	Pathogenic	criteria provided, multiple submitters, no conflicts
1418367	NM_000554.6(CRX):c.750del (p.Thr251fs)	CRX	Pathogenic	criteria provided, single submitter
1425620	NM_000554.6(CRX):c.176_177del (p.Ala59fs)	CRX	Pathogenic	criteria provided, single submitter
1466734	NM_000554.6(CRX):c.501del (p.Glu168fs)	CRX	Pathogenic	criteria provided, single submitter
1468996	NM_000554.6(CRX):c.108del (p.Arg37fs)	CRX	Pathogenic	criteria provided, single submitter
1478978	NM_000554.6(CRX):c.494del (p.Pro165fs)	CRX	Pathogenic	criteria provided, single submitter
1496447	NM_000554.6(CRX):c.624T>G (p.Tyr208Ter)	CRX	Pathogenic	criteria provided, single submitter
1499937	NM_000554.6(CRX):c.597del (p.Ala200fs)	CRX	Pathogenic	criteria provided, single submitter
1685674	NM_000554.6(CRX):c.545C>G (p.Ser182Ter)	CRX	Pathogenic	criteria provided, multiple submitters, no conflicts
1685675	NM_000554.6(CRX):c.586_587del (p.Ala196fs)	CRX	Pathogenic	criteria provided, single submitter
2007366	NM_000554.6(CRX):c.541_542del (p.Ala181fs)	CRX	Pathogenic	criteria provided, single submitter
2014678	NM_000554.6(CRX):c.116_127del (p.Gln39_Glu42del)	CRX	Pathogenic	criteria provided, single submitter
2017828	NM_000554.6(CRX):c.591_594dup (p.Ser199fs)	CRX	Pathogenic	criteria provided, single submitter
2033764	NM_000554.6(CRX):c.714del (p.Gly239fs)	CRX	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 9 · 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
CRX	Definitive	Autosomal dominant	cone-rod dystrophy 2	10

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
AIPL1	Orphanet:1872	Cone rod dystrophy
AIPL1	Orphanet:65	Leber congenital amaurosis
PROM1	Orphanet:1872	Cone rod dystrophy
PROM1	Orphanet:319640	Retinal macular dystrophy type 2
PROM1	Orphanet:791	Retinitis pigmentosa
PROM1	Orphanet:827	Stargardt disease

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
CRX	HGNC:2383	ENSG00000105392	O43186	Cone-rod homeobox protein	gencc,clinvar
TPRX1	HGNC:32174	ENSG00000178928	Q8N7U7	Tetra-peptide repeat homeobox protein 1	clinvar
TPRX2	HGNC:32175	ENSG00000259009	P0DV77	Tetrapeptide repeat homeobox protein 2	clinvar
AIPL1	HGNC:359	ENSG00000129221	Q9NZN9	Aryl-hydrocarbon-interacting protein-like 1	clinvar
PROM1	HGNC:9454	ENSG00000007062	O43490	Prominin-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.
TPRX1	Tetra-peptide repeat homeobox protein 1	Transcription factor expressed after fertilization required for zygotic genome activation (ZGA), a critical event in early embryonic development during which the developmental control passes from maternally provided mRNAs to the expression…
TPRX2	Tetrapeptide repeat homeobox protein 2	Transcription factor expressed after fertilization required for zygotic genome activation (ZGA), a critical event in early embryonic development during which the developmental control passes from maternally provided mRNAs to the expression…
AIPL1	Aryl-hydrocarbon-interacting protein-like 1	May be important in protein trafficking and/or protein folding and stabilization.
PROM1	Prominin-1	May play a role in cell differentiation, proliferation and apoptosis.

Protein-family classification

Druggable: 0 · Difficult: 3 · 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
Transcription factor	3	5.0×	0.029
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CRX	Transcription factor	no		HD, Homeodomain-like_sf, Otx_TF_C
TPRX1	Transcription factor	no		HD, Homeodomain-like_sf
TPRX2	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
AIPL1	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, AIP/AIPL1/TTC9
PROM1	Other/Unknown	no		Prominin

Expression context

Cohort genes with no expression data: 0.

4 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	1
moderate (6-20)	1
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
primordial germ cell in gonad	2
pigmented layer of retina	1
retina	1
left testis	1
right testis	1
bone marrow cell	1
colonic epithelium	1
ventricular zone	1
buccal mucosa cell	1
pancreatic ductal cell	1
tendon of biceps brachii	1
bronchial epithelial cell	1
bronchus	1
epithelium of bronchus	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
TPRX1	8		marker	primordial germ cell in gonad, left testis, right testis
TPRX2	0		yes	bone marrow cell, colonic epithelium, ventricular zone
AIPL1	62	tissue_specific	marker	buccal mucosa cell, pancreatic ductal cell, tendon of biceps brachii
PROM1	252	broad	marker	bronchial epithelial cell, epithelium of bronchus, bronchus

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PROM1	3,302
CRX	2,076
AIPL1	891
TPRX1	430
TPRX2	0

Intra-cohort edges

A	B	Sources
AIPL1	CRX	string_interaction
CRX	TPRX1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AIPL1	Q9NZN9	6
CRX	O43186	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PROM1	O43490	85.68
TPRX2	P0DV77	64.66
TPRX1	Q8N7U7	47.45

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
Zygotic genome activation (ZGA)	2	447.8×	1e-05	TPRX1, TPRX2
Developmental Lineage of Pancreatic Ductal Cells	1	76.1×	0.013	PROM1

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
maternal-to-zygotic transition of gene expression	2	2246.9×	5e-06	TPRX1, TPRX2
glomerular parietal epithelial cell differentiation	1	1685.2×	0.005	PROM1
protein farnesylation	1	1123.5×	0.005	AIPL1
positive regulation of nephron tubule epithelial cell differentiation	1	1123.5×	0.005	PROM1
camera-type eye photoreceptor cell differentiation	1	674.1×	0.006	PROM1
visual perception	2	31.8×	0.006	CRX, AIPL1
retina morphogenesis in camera-type eye	1	374.5×	0.008	PROM1
regulation of opsin-mediated signaling pathway	1	337.0×	0.008	AIPL1
podocyte differentiation	1	280.9×	0.008	PROM1
phototransduction, visible light	1	259.3×	0.008	AIPL1
retina homeostasis	1	224.7×	0.009	AIPL1
retina layer formation	1	129.6×	0.014	PROM1
photoreceptor cell maintenance	1	71.7×	0.023	PROM1
retina development in camera-type eye	1	51.1×	0.031	CRX
animal organ morphogenesis	1	38.3×	0.038	CRX
regulation of transcription by RNA polymerase II	2	4.7×	0.085	CRX, TPRX2
nervous system development	1	9.2×	0.135	CRX
negative regulation of apoptotic process	1	7.0×	0.166	AIPL1
regulation of DNA-templated transcription	1	6.3×	0.170	CRX
cell differentiation	1	5.8×	0.170	CRX
apoptotic process	1	5.7×	0.170	AIPL1
positive regulation of transcription by RNA polymerase II	1	3.0×	0.294	CRX

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 5 evidence-associated genes (20%) 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
TPRX1	0	0
TPRX2	0	0
AIPL1	0	0
PROM1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
AIPL1	1	Binding:1

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	0
E	Difficult family or no structure, no drug	5	CRX, TPRX1, TPRX2, AIPL1, PROM1

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)
CRX	0	—
TPRX1	0	—
TPRX2	0	—
AIPL1	1	—
PROM1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.