Cone dystrophy 4

Summary

Cone dystrophy 4 (MONDO:0013129) is a disease caused by PDE6C (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: PDE6C (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 114

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cone dystrophy 4
Mondo ID	MONDO:0013129
MeSH	C567758
OMIM	613093
NCIT	C164226
UMLS	C2751308
MedGen	416518
GARD	0016449
Is cancer (heuristic)	no

Also known as: COD4 · cone dystrophy 4 · cone dystrophy caused by mutation in PDE6C · cone dystrophy type 4 · PDE6C cone dystrophy

Data availability: 114 ClinVar variants · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › retinal disorder › retinal degeneration › inherited retinal dystrophy › hereditary macular dystrophy › cone dystrophy › cone dystrophy 4

Related subtypes (5): retinal cone dystrophy type 1, cone dystrophy, X-linked, with tapetal-like sheen, cone dystrophy 3, cone dystrophy with supernormal rod response, retinal cone dystrophy 4

Subtypes (1): achromatopsia 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

114 retrieved; paginated sample, class counts are floors:

39 uncertain significance, 33 conflicting classifications of pathogenicity, 12 pathogenic/likely pathogenic, 9 benign, 7 pathogenic, 6 benign/likely benign, 5 likely pathogenic, 3 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069941	NM_006204.4(PDE6C):c.1669C>T (p.Arg557Ter)	PDE6C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1687312	NM_006204.4(PDE6C):c.2283+1G>T	PDE6C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1723179	NM_006204.4(PDE6C):c.480+1del	PDE6C	Pathogenic	no assertion criteria provided
191009	NM_006204.4(PDE6C):c.712C>T (p.Arg238Ter)	PDE6C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
191010	NM_006204.4(PDE6C):c.939+5G>A	PDE6C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2133879	NM_006204.4(PDE6C):c.801_804del (p.Val268fs)	PDE6C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2136920	NM_006204.4(PDE6C):c.1004+1G>A	PDE6C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2412714	NM_006204.4(PDE6C):c.2053del (p.Gln685fs)	PDE6C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2572553	NM_006204.4(PDE6C):c.1336G>T (p.Glu446Ter)	PDE6C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3336624	NM_006204.4(PDE6C):c.1483-1G>A	PDE6C	Pathogenic	criteria provided, single submitter
4277336	NM_006204.4(PDE6C):c.1693C>T (p.Arg565Trp)	PDE6C	Pathogenic	criteria provided, single submitter
487691	NM_006204.4(PDE6C):c.775C>T (p.Arg259Ter)	PDE6C	Pathogenic	criteria provided, multiple submitters, no conflicts
487692	NM_006204.4(PDE6C):c.1579C>T (p.Arg527Ter)	PDE6C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
802622	NM_006204.4(PDE6C):c.2192G>A (p.Trp731Ter)	PDE6C	Pathogenic	criteria provided, multiple submitters, no conflicts
829820	NM_006204.4(PDE6C):c.2036+2T>G	PDE6C	Pathogenic	no assertion criteria provided
829826	NM_006204.4(PDE6C):c.435G>A (p.Trp145Ter)	PDE6C	Pathogenic	no assertion criteria provided
8763	NM_006204.4(PDE6C):c.85C>T (p.Arg29Trp)	PDE6C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8766	NM_006204.4(PDE6C):c.2367+1_2367+5del	PDE6C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
938789	NM_006204.4(PDE6C):c.2126_2129del (p.Thr709fs)	PDE6C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
216982	NM_006204.4(PDE6C):c.1958T>C (p.Leu653Pro)	PDE6C	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2920635	NM_006204.4(PDE6C):c.1188_1191del (p.Glu397fs)	PDE6C	Likely pathogenic	no assertion criteria provided
3775670	NM_006204.4(PDE6C):c.81del (p.Lys27fs)	PDE6C	Likely pathogenic	criteria provided, single submitter
438113	NM_006204.4(PDE6C):c.864+1G>A	PDE6C	Likely pathogenic	criteria provided, single submitter
599170	NM_006204.4(PDE6C):c.1589T>C (p.Phe530Ser)	PDE6C	Likely pathogenic	no assertion criteria provided
194755	NM_006204.4(PDE6C):c.2037-7T>C	PDE6C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
197268	NM_006204.4(PDE6C):c.742A>G (p.Asn248Asp)	PDE6C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
259945	NM_006204.4(PDE6C):c.2501A>G (p.Glu834Gly)	PDE6C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
259946	NM_006204.4(PDE6C):c.2503G>A (p.Gly835Arg)	PDE6C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
301617	NM_006204.4(PDE6C):c.252G>T (p.Leu84=)	PDE6C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
301620	NM_006204.4(PDE6C):c.446C>T (p.Thr149Met)	PDE6C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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
PDE6C	Definitive	Autosomal recessive	cone dystrophy 4	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PDE6C	Orphanet:1871	Progressive cone dystrophy
PDE6C	Orphanet:49382	Achromatopsia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PDE6C	HGNC:8787	ENSG00000095464	P51160	Cone cGMP-specific 3’,5’-cyclic phosphodiesterase subunit alpha'	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PDE6C	Cone cGMP-specific 3’,5’-cyclic phosphodiesterase subunit alpha'	As cone-specific cGMP phosphodiesterase, it plays an essential role in light detection and cone phototransduction by rapidly decreasing intracellular levels of cGMP.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PDE6C	Transcription factor	no		PDEase_catalytic_dom, GAF, HD/PDEase_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	1
male germ line stem cell (sensu Vertebrata) in testis	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PDE6C	159	tissue_specific	marker	secondary oocyte, male germ line stem cell (sensu Vertebrata) in testis, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PDE6C	903

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PDE6C	P51160	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
retinal cone cell development	1	1404.3×	0.002	PDE6C
phototransduction, visible light	1	1296.3×	0.002	PDE6C
negative regulation of cAMP/PKA signal transduction	1	601.9×	0.002	PDE6C
visual perception	1	79.5×	0.013	PDE6C

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PDE6C	VARDENAFIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PDE6C	6	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VARDENAFIL	4	PDE6C
SILDENAFIL	4	PDE6C
TADALAFIL	4	PDE6C
DIPYRIDAMOLE	4	PDE6C
ZAPRINAST	2	PDE6C
TBA-7371	2	PDE6C

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PDE6C	103	Binding:97, ADMET:6

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PDE6C	103

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

6 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.

Compound	Max phase	Cohort target (bioactivity)
VARDENAFIL	4	PDE6C
SILDENAFIL	4	PDE6C
TADALAFIL	4	PDE6C
DIPYRIDAMOLE	4	PDE6C
ZAPRINAST	2	PDE6C
TBA-7371	2	PDE6C

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PDE6C
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.