Retinal cone dystrophy 4

Summary

Retinal cone dystrophy 4 (MONDO:0012507) is a disease caused by CACNA2D4 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: CACNA2D4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 184

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	retinal cone dystrophy 4
Mondo ID	MONDO:0012507
MeSH	C566470
OMIM	610478
DOID	DOID:0081023
UMLS	C1864849
MedGen	355308
GARD	0010650
Is cancer (heuristic)	no

Also known as: CACNA2D4 cone dystrophy · cone dystrophy caused by mutation in CACNA2D4 · RCD4 · retinal cone dystrophy 4 · retinal cone dystrophy type 4

Data availability: 184 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 › hereditary macular dystrophy › cone dystrophy › retinal 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, cone dystrophy 4

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

184 retrieved; paginated sample, class counts are floors:

66 uncertain significance, 59 benign, 39 conflicting classifications of pathogenicity, 11 likely benign, 7 benign/likely benign, 1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
375308	NM_172364.4(CACNA2D4):c.1720-74_2551+1189delinsTG	CACNA2D4	Pathogenic	no assertion criteria provided
3767350	NM_172364.5(CACNA2D4):c.1644+1G>A	CACNA2D4	Likely pathogenic	criteria provided, single submitter
1027104	NM_172364.5(CACNA2D4):c.2958C>G (p.Tyr986Ter)	CACNA2D4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1324006	NM_172364.5(CACNA2D4):c.846C>G (p.Tyr282Ter)	CACNA2D4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
208566	NM_172364.5(CACNA2D4):c.1882C>T (p.Arg628Ter)	CACNA2D4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2504	NM_172364.5(CACNA2D4):c.2406C>A (p.Tyr802Ter)	CACNA2D4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
288899	NM_172364.5(CACNA2D4):c.1239G>A (p.Pro413=)	CACNA2D4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
290737	NM_172364.5(CACNA2D4):c.2054+4A>T	CACNA2D4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
290740	NM_172364.5(CACNA2D4):c.1968C>T (p.His656=)	CACNA2D4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
307829	NM_172364.5(CACNA2D4):c.3357G>A (p.Pro1119=)	CACNA2D4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
307830	NM_172364.5(CACNA2D4):c.3356C>T (p.Pro1119Leu)	CACNA2D4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
307831	NM_172364.5(CACNA2D4):c.3354G>A (p.Ser1118=)	CACNA2D4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
307832	NM_172364.5(CACNA2D4):c.3348A>T (p.Ser1116=)	CACNA2D4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
307837	NM_172364.5(CACNA2D4):c.2922-9G>A	CACNA2D4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
307843	NM_172364.5(CACNA2D4):c.2688C>T (p.Asn896=)	CACNA2D4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
307847	NM_172364.5(CACNA2D4):c.2523C>T (p.Thr841=)	CACNA2D4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
307850	NM_172364.5(CACNA2D4):c.2246+11G>A	CACNA2D4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
307855	NM_172364.5(CACNA2D4):c.2046C>T (p.Ala682=)	CACNA2D4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
307856	NM_172364.5(CACNA2D4):c.1926C>T (p.Ser642=)	CACNA2D4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
307861	NM_172364.5(CACNA2D4):c.1497G>A (p.Ser499=)	CACNA2D4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
307863	NM_172364.5(CACNA2D4):c.1272+14G>A	CACNA2D4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
307870	NM_172364.5(CACNA2D4):c.318G>A (p.Lys106=)	CACNA2D4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
307871	NM_172364.5(CACNA2D4):c.255C>T (p.Gly85=)	CACNA2D4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
421701	NM_172364.5(CACNA2D4):c.2109G>C (p.Glu703Asp)	CACNA2D4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
522360	NM_172364.5(CACNA2D4):c.2891C>T (p.Ala964Val)	CACNA2D4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
522361	NM_172364.5(CACNA2D4):c.2516C>T (p.Ala839Val)	CACNA2D4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
724357	NM_172364.5(CACNA2D4):c.2634G>A (p.Pro878=)	CACNA2D4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
749233	NM_172364.5(CACNA2D4):c.1218C>T (p.Gly406=)	CACNA2D4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
750250	NM_172364.5(CACNA2D4):c.2190G>A (p.Ala730=)	CACNA2D4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
881280	NM_172364.5(CACNA2D4):c.1368C>T (p.Ile456=)	CACNA2D4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
CACNA2D4	Strong	Autosomal recessive	retinal cone dystrophy 4	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CACNA2D4	Orphanet:1872	Cone rod dystrophy
CACNA2D4	Orphanet:714070	Incomplete congenital stationary night blindness, Schubert-Bornschein type

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
CACNA2D4	HGNC:20202	ENSG00000151062	Q7Z3S7	Voltage-dependent calcium channel subunit alpha-2/delta-4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CACNA2D4	Voltage-dependent calcium channel subunit alpha-2/delta-4	The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CACNA2D4	Other/Unknown	no		VWF_A, VWA_N, VDCC_a2/dsu

Expression context

Cohort genes with no expression data: 0.

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
granulocyte	1
leukocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CACNA2D4	136	broad	yes	monocyte, leukocyte, granulocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CACNA2D4	934

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CACNA2D4	Q7Z3S7	81.69

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
detection of light stimulus involved in visual perception	1	648.1×	0.003	CACNA2D4
calcium ion transmembrane transport	1	210.7×	0.005	CACNA2D4

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
CACNA2D4	NIMODIPINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA2D4	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIMODIPINE	4	CACNA2D4
TACRINE	4	CACNA2D4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CACNA2D4	13	Binding:13

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

2 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)
NIMODIPINE	4	CACNA2D4
TACRINE	4	CACNA2D4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CACNA2D4
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.