Cone-rod dystrophy 6

Summary

Cone-rod dystrophy 6 (MONDO:0011143) is a disease caused by GUCY2D (GenCC Strong), with 6 cohort genes.

At a glance

• Causal gene: GUCY2D (GenCC Strong)
• Cohort genes: 6
• ClinVar variants: 1,388

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cone-rod dystrophy 6
Mondo ID	MONDO:0011143
MeSH	C538363
OMIM	601777
DOID	DOID:0111011
UMLS	C1866293
MedGen	400963
GARD	0010656
Is cancer (heuristic)	no

Also known as: cone-rod dystrophy 6 · cone-rod dystrophy caused by mutation in GUCY2D · cone-rod dystrophy type 6 · CORD6 · GUCY2D cone-rod dystrophy · RCD2 · retinal cone dystrophy 2

Data availability: 1,388 ClinVar variants · 1 GenCC gene-disease record.

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 6

Related subtypes (27): cone-rod dystrophy 2, macular degeneration, X-linked atrophic, cone-rod dystrophy 1, cone-rod dystrophy 5, 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

600 retrieved; paginated sample, class counts are floors:

296 uncertain significance, 246 likely benign, 22 pathogenic, 12 conflicting classifications of pathogenicity, 12 benign, 6 likely pathogenic, 4 pathogenic/likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1066142	NM_000180.4(GUCY2D):c.-2_3del (p.Met1fs)	GUCY2D	Pathogenic	criteria provided, single submitter
1069546	NM_000180.4(GUCY2D):c.1361_1367del (p.Asn454fs)	GUCY2D	Pathogenic	criteria provided, single submitter
1070768	NM_000180.4(GUCY2D):c.2383C>T (p.Arg795Trp)	GUCY2D	Pathogenic	criteria provided, multiple submitters, no conflicts
1070769	NM_000180.4(GUCY2D):c.2476C>T (p.Gln826Ter)	GUCY2D	Pathogenic	criteria provided, multiple submitters, no conflicts
1072504	NM_000180.4(GUCY2D):c.484dup (p.Ala162fs)	GUCY2D	Pathogenic	criteria provided, single submitter
1074833	NM_000180.4(GUCY2D):c.2646C>G (p.Tyr882Ter)	GUCY2D	Pathogenic	criteria provided, multiple submitters, no conflicts
1075556	NM_000180.4(GUCY2D):c.3105C>G (p.Tyr1035Ter)	GUCY2D	Pathogenic	criteria provided, single submitter
1076325	NM_000180.4(GUCY2D):c.564del (p.Ala189fs)	GUCY2D	Pathogenic	criteria provided, single submitter
1213843	NM_000180.4(GUCY2D):c.1567-1G>C	GUCY2D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1213844	NM_000180.4(GUCY2D):c.690_693del (p.Lys232fs)	GUCY2D	Pathogenic	criteria provided, multiple submitters, no conflicts
1366687	NM_000180.4(GUCY2D):c.2260G>T (p.Glu754Ter)	GUCY2D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1413732	NM_000180.4(GUCY2D):c.2871del (p.Ser958fs)	GUCY2D	Pathogenic	criteria provided, single submitter
1454622	NM_000180.4(GUCY2D):c.175del (p.Leu59fs)	GUCY2D	Pathogenic	criteria provided, single submitter
1456503	NM_000180.4(GUCY2D):c.2209C>T (p.Gln737Ter)	GUCY2D	Pathogenic	criteria provided, single submitter
1459421	NM_000180.4(GUCY2D):c.760G>T (p.Glu254Ter)	GUCY2D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685872	NM_000180.4(GUCY2D):c.1A>G (p.Met1Val)	GUCY2D	Pathogenic	criteria provided, multiple submitters, no conflicts
1915862	NM_000180.4(GUCY2D):c.2678_2679del (p.Ser893fs)	GUCY2D	Pathogenic	criteria provided, single submitter
198995	NM_000180.4(GUCY2D):c.1773del (p.Asn591fs)	GUCY2D	Pathogenic	criteria provided, multiple submitters, no conflicts
2021991	NM_000180.4(GUCY2D):c.860del (p.Pro287fs)	GUCY2D	Pathogenic	criteria provided, single submitter
2046697	NM_000180.4(GUCY2D):c.2323C>T (p.Gln775Ter)	GUCY2D	Pathogenic	criteria provided, single submitter
2060321	NM_000180.4(GUCY2D):c.781_782insT (p.Glu261fs)	GUCY2D	Pathogenic	criteria provided, single submitter
2069382	NM_000180.4(GUCY2D):c.3118_3125delinsAAGGTGAGGTAC (p.Arg1040fs)	GUCY2D	Pathogenic	criteria provided, single submitter
2086516	NM_000180.4(GUCY2D):c.1150del (p.Asp384fs)	GUCY2D	Pathogenic	criteria provided, single submitter
2108666	NM_000180.4(GUCY2D):c.1821_1824dup (p.Ala609fs)	GUCY2D	Pathogenic	criteria provided, single submitter
2137915	NM_000180.4(GUCY2D):c.1762C>T (p.Arg588Trp)	GUCY2D	Pathogenic	reviewed by expert panel
2142901	NM_000180.4(GUCY2D):c.2291del (p.Pro764fs)	GUCY2D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066403	NM_000180.4(GUCY2D):c.1749+1G>A	GUCY2D	Likely pathogenic	criteria provided, single submitter
1445009	NM_000180.4(GUCY2D):c.743C>G (p.Ser248Trp)	GUCY2D	Likely pathogenic	reviewed by expert panel
1491160	NM_000180.4(GUCY2D):c.2545A>G (p.Thr849Ala)	GUCY2D	Likely pathogenic	criteria provided, single submitter
1492836	NM_000180.4(GUCY2D):c.2412+2T>C	GUCY2D	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 16 · 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
GUCY2D	Definitive	Autosomal dominant	cone-rod dystrophy	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GUCY2D	Orphanet:1872	Cone rod dystrophy
GUCY2D	Orphanet:65	Leber congenital amaurosis
GUCY2D	Orphanet:75377	Central areolar choroidal dystrophy
BEST1	Orphanet:1243	Best vitelliform macular dystrophy
BEST1	Orphanet:139455	Autosomal recessive bestrophinopathy
BEST1	Orphanet:263347	MRCS syndrome
BEST1	Orphanet:3086	Autosomal dominant vitreoretinochoroidopathy
BEST1	Orphanet:35612	Nanophthalmos
BEST1	Orphanet:791	Retinitis pigmentosa
BEST1	Orphanet:99000	Adult-onset foveomacular vitelliform dystrophy
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
ALOX12B	Orphanet:281122	Self-improving collodion baby
ALOX12B	Orphanet:313	Lamellar ichthyosis
ALOX12B	Orphanet:79394	Congenital ichthyosiform erythroderma

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GUCY2D	HGNC:4689	ENSG00000132518	Q02846	Retinal guanylyl cyclase 1	gencc,clinvar
BEST1	HGNC:12703	ENSG00000167995	O76090	Bestrophin-1	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
CNTROB	HGNC:29616	ENSG00000170037	Q8N137	Centrobin	clinvar
ALOX12B	HGNC:430	ENSG00000179477	O75342	Arachidonate 12-lipoxygenase, 12R-type	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GUCY2D	Retinal guanylyl cyclase 1	Catalyzes the synthesis of cyclic GMP (cGMP) in rods and cones of photoreceptors.
BEST1	Bestrophin-1	Ligand-gated anion channel that allows the movement of anions across cell membranes when activated by calcium (Ca2+).
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.
CNTROB	Centrobin	Required for centriole duplication.
ALOX12B	Arachidonate 12-lipoxygenase, 12R-type	Catalyzes the regio and stereo-specific incorporation of a single molecule of dioxygen into free and esterified polyunsaturated fatty acids generating lipid hydroperoxides that can be further reduced to the corresponding hydroxy species.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.5

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×	0.210
Kinase	1	4.6×	0.396
Enzyme (other)	1	2.0×	0.543
Other/Unknown	3	0.9×	0.758

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GUCY2D	Kinase	yes	4.6.1.2	Prot_kinase_dom, A/G_cyclase, Ser-Thr/Tyr_kinase_cat_dom
BEST1	Other/Unknown	no		Bestrophin, Bestrophin-like
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
CNTROB	Other/Unknown	no		Centrobin
ALOX12B	Enzyme (other)	yes	1.13.11.31	LipOase, PLAT/LH2_dom, LipOase_mml

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)	0
moderate (6-20)	0
broad (>20)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
esophagus mucosa	1
lower esophagus mucosa	1
inferior olivary complex	1
lateral globus pallidus	1
pigmented layer of retina	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
ventricular zone	1
skin of abdomen	1
skin of leg	1
zone of skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GUCY2D	121	tissue_specific	marker	buccal mucosa cell, esophagus mucosa, lower esophagus mucosa
BEST1	209	ubiquitous	marker	pigmented layer of retina, lateral globus pallidus, inferior olivary complex
KCNV2	61	tissue_specific	marker	sperm, male germ cell, primordial germ cell in gonad
CACNA2D4	136	broad	yes	monocyte, leukocyte, granulocyte
CNTROB	239	ubiquitous	marker	left testis, right testis, ventricular zone
ALOX12B	168	broad	yes	skin of leg, skin of abdomen, zone of skin

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KCNV2	1,908
CNTROB	1,884
ALOX12B	1,126
GUCY2D	1,083
BEST1	959
CACNA2D4	934

Intra-cohort edges

A	B	Sources
CACNA2D4	KCNV2	string_interaction
GUCY2D	KCNV2	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 5 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BEST1	O76090	19

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ALOX12B	O75342	92.07
GUCY2D	Q02846	82.37
CACNA2D4	Q7Z3S7	81.69
KCNV2	Q8TDN2	75.55
CNTROB	Q8N137	67.31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 6 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Synthesis of 12-eicosatetraenoic acid derivatives	1	407.9×	0.029	ALOX12B
Arachidonate metabolism	1	142.8×	0.042	ALOX12B
Inactivation, recovery and regulation of the phototransduction cascade	1	79.3×	0.049	GUCY2D
Voltage gated Potassium channels	1	60.7×	0.049	KCNV2
Stimuli-sensing channels	1	34.0×	0.052	BEST1
Potassium Channels	1	33.6×	0.052	KCNV2
Fatty acid metabolism	1	32.8×	0.052	ALOX12B
Ion channel transport	1	24.0×	0.062	BEST1
Neuronal System	1	11.1×	0.116	KCNV2
Metabolism of lipids	1	7.9×	0.145	ALOX12B
Transport of small molecules	1	6.3×	0.163	BEST1
Metabolism	1	2.9×	0.302	ALOX12B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 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	2	216.1×	0.001	BEST1, CACNA2D4
gamma-aminobutyric acid secretion, neurotransmission	1	1404.3×	0.008	BEST1
mitotic cytokinetic process	1	1404.3×	0.008	CNTROB
centrosome separation	1	936.2×	0.009	CNTROB
protein lipidation	1	561.7×	0.010	ALOX12B
positive regulation of mucus secretion	1	561.7×	0.010	ALOX12B
lipid oxidation	1	351.1×	0.010	ALOX12B
hepoxilin biosynthetic process	1	351.1×	0.010	ALOX12B
transepithelial chloride transport	1	312.1×	0.010	BEST1
glutamate secretion	1	280.9×	0.010	BEST1
regulation of opsin-mediated signaling pathway	1	280.9×	0.010	GUCY2D
visual perception	2	26.5×	0.010	GUCY2D, BEST1
lipoxygenase pathway	1	255.3×	0.011	ALOX12B
cGMP biosynthetic process	1	234.1×	0.011	GUCY2D
receptor guanylyl cyclase signaling pathway	1	216.1×	0.011	GUCY2D
sphingolipid metabolic process	1	165.2×	0.013	ALOX12B
obsolete cGMP-mediated signaling	1	133.8×	0.014	GUCY2D
regulation of calcium ion transport	1	133.8×	0.014	BEST1
centriole replication	1	122.1×	0.015	CNTROB
linoleic acid metabolic process	1	117.0×	0.015	ALOX12B
protein complex oligomerization	1	112.3×	0.015	BEST1
regulation of cilium assembly	1	100.3×	0.016	CNTROB
arachidonate metabolic process	1	80.2×	0.018	ALOX12B
chloride transport	1	75.9×	0.018	BEST1
establishment of skin barrier	1	75.9×	0.018	ALOX12B
ceramide biosynthetic process	1	70.2×	0.019	ALOX12B
action potential	1	59.8×	0.022	KCNV2
regulation of synaptic plasticity	1	43.2×	0.029	BEST1
chloride transmembrane transport	1	39.6×	0.030	BEST1
calcium ion transmembrane transport	1	35.1×	0.032	CACNA2D4

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 6 evidence-associated genes (33%) 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
GUCY2D	0	0
BEST1	0	0
KCNV2	0	0
CNTROB	0	0
ALOX12B	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): 2.

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

Symbol	Assays	Type breakdown
KCNV2	21	Binding:20, Toxicity:1
CACNA2D4	13	Binding:13

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GUCY2D	4.6.1.2	guanylate cyclase
ALOX12B	1.13.11.31	arachidonate 12-lipoxygenase

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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	3	GUCY2D, KCNV2, ALOX12B
E	Difficult family or no structure, no drug	2	BEST1, CNTROB

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)
GUCY2D	0	—
BEST1	0	—
KCNV2	21	—
CNTROB	0	—
ALOX12B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.