Cone dystrophy 3

Summary

Cone dystrophy 3 (MONDO:0011193) is a disease caused by GUCA1A (GenCC Definitive), with 6 cohort genes.

At a glance

• Causal gene: GUCA1A (GenCC Definitive)
• Cohort genes: 6
• ClinVar variants: 74

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cone dystrophy 3
Mondo ID	MONDO:0011193
OMIM	602093
DOID	DOID:0080314
UMLS	C1865869
MedGen	356104
GARD	0015342
Is cancer (heuristic)	no

Also known as: COD3 · cone dystrophy 3 · cone dystrophy caused by mutation in GUCA1A · cone dystrophy type 3 · cone dystrophy-3 · GUCA1A cone dystrophy

Data availability: 74 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 › cone dystrophy 3

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

74 retrieved; paginated sample, class counts are floors:

30 uncertain significance, 10 conflicting classifications of pathogenicity, 7 likely pathogenic, 7 pathogenic/likely pathogenic, 7 benign, 6 likely benign, 5 pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070956	NM_001384910.1(GUCA1A):c.312C>G (p.Asn104Lys)	GUCA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
225232	NM_001384910.1(GUCA1A):c.250C>T (p.Leu84Phe)	GUCA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4293408	NM_001384910.1(GUCA1A):c.300T>G (p.Asp100Glu)	GUCA1A	Pathogenic	criteria provided, single submitter
453246	NM_001384910.1(GUCA1A):c.359_360delinsTT (p.Arg120Leu)	GUCA1A	Pathogenic	criteria provided, single submitter
802212	NM_001384910.1(GUCA1A):c.359G>T (p.Arg120Leu)	GUCA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
867021	NM_001384910.1(GUCA1A):c.299A>G (p.Asp100Gly)	GUCA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9150	NM_001384910.1(GUCA1A):c.296A>G (p.Tyr99Cys)	GUCA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
974933	NM_001384910.1(GUCA1A):c.300T>A (p.Asp100Glu)	GUCA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
974935	NM_001384910.1(GUCA1A):c.464A>G (p.Glu155Gly)	GUCA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
962836	NM_001384910.1(GUCA1A):c.332A>T (p.Glu111Val)	GUCA1ANB-GUCA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
974938	NM_001384910.1(GUCA1A):c.312C>A (p.Asn104Lys)	GUCA1ANB-GUCA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
974939	NM_001384910.1(GUCA1A):c.256G>C (p.Gly86Arg)	GUCA1ANB-GUCA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048128	NM_001384910.1(GUCA1A):c.333G>C (p.Glu111Asp)	GUCA1A	Likely pathogenic	criteria provided, single submitter
1213842	NM_001384910.1(GUCA1A):c.431A>T (p.Asp144Val)	GUCA1A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2027963	NM_001384910.1(GUCA1A):c.256G>A (p.Gly86Arg)	GUCA1A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3776046	NM_001384910.1(GUCA1A):c.332A>G (p.Glu111Gly)	GUCA1A	Likely pathogenic	criteria provided, single submitter
974931	NM_001384910.1(GUCA1A):c.296A>C (p.Tyr99Ser)	GUCA1A	Likely pathogenic	criteria provided, single submitter
974930	NM_001384910.1(GUCA1A):c.295T>A (p.Tyr99Asn)	GUCA1ANB-GUCA1A	Likely pathogenic	criteria provided, single submitter
974934	NM_001384910.1(GUCA1A):c.431A>G (p.Asp144Gly)	GUCA1ANB-GUCA1A	Likely pathogenic	criteria provided, single submitter
1464056	NM_001384910.1(GUCA1A):c.465G>C (p.Glu155Asp)	GUCA1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
198078	NM_001384910.1(GUCA1A):c.526C>T (p.Leu176Phe)	GUCA1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
225233	NM_001384910.1(GUCA1A):c.320T>C (p.Ile107Thr)	GUCA1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
356692	NM_001384910.1(GUCA1A):c.10G>A (p.Val4Met)	GUCA1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
910954	NM_001384910.1(GUCA1A):c.551A>G (p.Gln184Arg)	GUCA1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
167160	NM_001384910.1(GUCA1A):c.142C>T (p.Leu48=)	GUCA1ANB-GUCA1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
910953	NM_001384910.1(GUCA1A):c.201+11G>T	GUCA1ANB-GUCA1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
9151	NM_001384910.1(GUCA1A):c.149C>T (p.Pro50Leu)	GUCA1ANB-GUCA1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
143162	NM_133497.4(KCNV2):c.80G>A (p.Arg27His)	KCNV2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
624227	NM_000539.3(RHO):c.755G>C (p.Arg252Pro)	RHO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
356687	NM_000409.5(GUCA1ANB-GUCA1A):c.-388C>A	CIMIP3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
GUCA1A	Definitive	Autosomal dominant	cone-rod dystrophy 14	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GUCA1A	Orphanet:1871	Progressive cone dystrophy
GUCA1A	Orphanet:1872	Cone rod dystrophy
GUCA1A	Orphanet:75377	Central areolar choroidal dystrophy
RHO	Orphanet:215	Congenital stationary night blindness
RHO	Orphanet:52427	Retinitis punctata albescens
RHO	Orphanet:791	Retinitis pigmentosa
KCNV2	Orphanet:209932	Cone dystrophy with supernormal rod response
CACNA2D4	Orphanet:1872	Cone rod dystrophy
CACNA2D4	Orphanet:714070	Incomplete congenital stationary night blindness, Schubert-Bornschein type

Cohort genes → proteins

6 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GUCA1A	HGNC:4678	ENSG00000048545	P43080	Guanylyl cyclase-activating protein 1	gencc,clinvar
RHO	HGNC:10012	ENSG00000163914	P08100	Rhodopsin	clinvar
KCNV2	HGNC:19698	ENSG00000168263	Q8TDN2	Potassium voltage-gated channel subfamily V member 2	clinvar
CACNA2D4	HGNC:20202	ENSG00000151062	Q7Z3S7	Voltage-dependent calcium channel subunit alpha-2/delta-4	clinvar
CIMIP3	HGNC:55126	ENSG00000287363	X6R8D5	Ciliary microtubule inner protein 3	clinvar
GUCA1ANB-GUCA1A	HGNC:56129	ENSG00000290147		GUCA1ANB-GUCA1A readthrough	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GUCA1A	Guanylyl cyclase-activating protein 1	Stimulates retinal guanylyl cyclase when free calcium ions concentration is low and inhibits guanylyl cyclase when free calcium ions concentration is elevated.
RHO	Rhodopsin	Photoreceptor required for image-forming vision at low light intensity.
KCNV2	Potassium voltage-gated channel subfamily V member 2	Potassium channel subunit.
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: 2 · Difficult: 0 · Unknown: 4 · 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
Ion channel	1	18.6×	0.158
GPCR	1	4.0×	0.339
Other/Unknown	4	1.2×	0.458

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GUCA1A	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
RHO	GPCR	yes		GPCR_Rhodpsn, Rhodopsin, Opsin
KCNV2	Ion channel	yes		T1-type_BTB, K_chnl_volt-dep_Kv, K_chnl_volt-dep_Kv5/Kv9
CACNA2D4	Other/Unknown	no		VWF_A, VWA_N, VDCC_a2/dsu
CIMIP3	Other/Unknown	no		CIMIP3-like
GUCA1ANB-GUCA1A	Other/Unknown	no

Expression context

Cohort genes with no expression data: 1.

4 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)	1
broad (>20)	4
unknown	1

Top tissues across cohort

Tissue	Cohort genes
hypothalamus	1
nucleus accumbens	1
putamen	1
diaphragm	1
neuron projection bundle connecting eye with brain	1
optic choroid	1
male germ cell	1
primordial germ cell in gonad	1
sperm	1
granulocyte	1
leukocyte	1
monocyte	1
left testis	1
right testis	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GUCA1A	52	broad	marker	nucleus accumbens, putamen, hypothalamus
RHO	38	tissue_specific	marker	optic choroid, neuron projection bundle connecting eye with brain, diaphragm
KCNV2	61	tissue_specific	marker	sperm, male germ cell, primordial germ cell in gonad
CACNA2D4	136	broad	yes	monocyte, leukocyte, granulocyte
CIMIP3	20	tissue_specific	marker	left testis, right testis, testis
GUCA1ANB-GUCA1A

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RHO	3,578
KCNV2	1,908
GUCA1A	1,434
CACNA2D4	934
CIMIP3	18
GUCA1ANB-GUCA1A	0

Intra-cohort edges

A	B	Sources
CACNA2D4	KCNV2	string_interaction
GUCA1A	RHO	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 4 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RHO	P08100	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CACNA2D4	Q7Z3S7	81.69
KCNV2	Q8TDN2	75.55
GUCA1A	P43080	71.28
CIMIP3	X6R8D5	58.15

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 6 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
Inactivation, recovery and regulation of the phototransduction cascade	2	211.5×	3e-04	GUCA1A, RHO
Opsins	1	423.0×	0.009	RHO
Activation of the phototransduction cascade	1	317.2×	0.009	RHO
The canonical retinoid cycle in rods (twilight vision)	1	173.0×	0.010	RHO
VxPx cargo-targeting to cilium	1	173.0×	0.010	RHO
Voltage gated Potassium channels	1	81.0×	0.018	KCNV2
Potassium Channels	1	44.8×	0.028	KCNV2
Neuronal System	1	14.8×	0.075	KCNV2
G alpha (i) signalling events	1	13.0×	0.075	RHO

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
phototransduction	2	247.8×	6e-04	GUCA1A, RHO
positive regulation of guanylate cyclase activity	1	4213.0×	0.003	GUCA1A
thermotaxis	1	2106.5×	0.003	RHO
rod bipolar cell differentiation	1	2106.5×	0.003	RHO
detection of temperature stimulus involved in thermoception	1	1404.3×	0.004	RHO
visual perception	2	39.8×	0.004	GUCA1A, RHO
G protein-coupled opsin signaling pathway	1	842.6×	0.004	RHO
absorption of visible light	1	702.2×	0.004	RHO
obsolete positive regulation of cGMP-mediated signaling	1	601.9×	0.004	GUCA1A
response to light intensity	1	526.6×	0.004	RHO
podosome assembly	1	526.6×	0.004	RHO
phototransduction, visible light	1	324.1×	0.006	RHO
cellular response to light stimulus	1	263.3×	0.007	RHO
detection of light stimulus involved in visual perception	1	162.0×	0.011	CACNA2D4
action potential	1	89.6×	0.017	KCNV2
photoreceptor cell maintenance	1	89.6×	0.017	RHO
regulation of signal transduction	1	66.9×	0.022	GUCA1A
calcium ion transmembrane transport	1	52.7×	0.026	CACNA2D4
cellular response to calcium ion	1	50.1×	0.026	GUCA1A
potassium ion transmembrane transport	1	34.0×	0.036	KCNV2
protein homooligomerization	1	30.5×	0.037	KCNV2
microtubule cytoskeleton organization	1	30.3×	0.037	RHO
gene expression	1	20.0×	0.053	RHO
G protein-coupled receptor signaling pathway	1	9.1×	0.110	RHO
signal transduction	1	4.0×	0.227	GUCA1A

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 6 evidence-associated genes (50%) 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
GUCA1A	0	0
RHO	0	0
KCNV2	0	0
CIMIP3	0	0
GUCA1ANB-GUCA1A	0	0

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
KCNV2	21	Binding:20, Toxicity:1
CACNA2D4	13	Binding:13
RHO	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

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	1	RHO
D	Druggable family + AlphaFold only, no drug	1	KCNV2
E	Difficult family or no structure, no drug	3	GUCA1A, CIMIP3, GUCA1ANB-GUCA1A

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)
GUCA1A	0	—
RHO	1	—
KCNV2	21	—
CIMIP3	0	—
GUCA1ANB-GUCA1A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.