Achromatopsia

Summary

Achromatopsia (MONDO:0018852) is a disease (an umbrella term covering 6 Mondo subtypes) caused by PDE6H (GenCC Strong), with 10 cohort genes and 12 clinical trials.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Causal gene: PDE6H (GenCC Strong)
• Umbrella term: 6 Mondo subtypes
• Cohort genes: 10
• ClinVar variants: 408
• Phenotypes (HPO): 20
• Clinical trials: 12

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	2.7	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0000539	Abnormality of refraction	Very frequent (80-99%)
HP:0000551	Color vision defect	Very frequent (80-99%)
HP:0000613	Photophobia	Very frequent (80-99%)
HP:0007803	Monochromacy	Very frequent (80-99%)
HP:0012043	Pendular nystagmus	Very frequent (80-99%)
HP:0030465	Undetectable light-adapted electroretinogram	Very frequent (80-99%)
HP:0030584	Color vision test abnormality	Very frequent (80-99%)
HP:0030620	Inner retinal layer loss on macular OCT	Very frequent (80-99%)
HP:0000540	Hypermetropia	Frequent (30-79%)
HP:0000545	Myopia	Frequent (30-79%)
HP:0000603	Central scotoma	Frequent (30-79%)
HP:0007663	Reduced visual acuity	Frequent (30-79%)
HP:0007750	Hypoplasia of the fovea	Frequent (30-79%)
HP:0030825	Absent foveal reflex	Frequent (30-79%)
HP:0001103	Abnormal macular morphology	Occasional (5-29%)
HP:0007695	Abnormal pupillary light reflex	Occasional (5-29%)
HP:0007814	Retinal pigment epithelial mottling	Occasional (5-29%)
HP:0007843	Attenuation of retinal blood vessels	Occasional (5-29%)
HP:0025549	Eccentric visual fixation	Occasional (5-29%)
HP:0007722	Retinal pigment epithelial atrophy	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	achromatopsia
Mondo ID	MONDO:0018852
Orphanet	49382
DOID	DOID:13911
ICD-10-CM	H53.51
NCIT	C84528
SNOMED CT	102450007
UMLS	C0152200
MedGen	57751
GARD	0015015
MedDRA	10000454
Is cancer (heuristic)	no

Also known as: ACHM · achromatopsia · complete or incomplete color blindness · complete or incomplete colour blindness · Pingelapese blindness · Rod monochromacy · Rod monochromatism · total color blindness · total colour blindness

Data availability: 408 ClinVar variants · 8 GenCC gene-disease records · 2 cell lines.

Disease family

An umbrella term covering 6 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › perceptual disorders › vision disorder › color vision disorder › achromatopsia

Related subtypes (4): colorblindness, partial, acquired color blindness, blue color blindness, red color blindness

Subtypes (6): achromatopsia 2, achromatopsia 3, blue cone monochromacy, achromatopsia 6, achromatopsia 4, achromatopsia 7

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

408 retrieved; paginated sample, class counts are floors:

139 uncertain significance, 76 conflicting classifications of pathogenicity, 58 pathogenic, 36 likely pathogenic, 32 pathogenic/likely pathogenic, 31 likely benign, 23 benign, 13 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
505015	NC_000001.11:g.161781912dup	ATF6	Pathogenic	criteria provided, single submitter
190959	NM_145200.5(CABP4):c.646C>T (p.Arg216Ter)	CABP4	Pathogenic	criteria provided, multiple submitters, no conflicts
1301856	NM_001298.3(CNGA3):c.1749del (p.Leu584fs)	CNGA3	Pathogenic	criteria provided, multiple submitters, no conflicts
337652	NM_001298.3(CNGA3):c.67C>T (p.Arg23Ter)	CNGA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
497256	NM_001298.3(CNGA3):c.1279C>T (p.Arg427Cys)	CNGA3	Pathogenic	criteria provided, multiple submitters, no conflicts
498768	NM_001298.3(CNGA3):c.667C>T (p.Arg223Trp)	CNGA3	Pathogenic	criteria provided, multiple submitters, no conflicts
503563	NM_001298.3(CNGA3):c.1320G>A (p.Trp440Ter)	CNGA3	Pathogenic	criteria provided, single submitter
635157	NM_001298.3(CNGA3):c.985G>T (p.Gly329Cys)	CNGA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
635158	NM_001298.3(CNGA3):c.934ATC[2] (p.Ile314del)	CNGA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
800983	NM_001298.3(CNGA3):c.830G>A (p.Arg277His)	CNGA3	Pathogenic	criteria provided, multiple submitters, no conflicts
812278	NM_001298.3(CNGA3):c.667C>G (p.Arg223Gly)	CNGA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
812281	NM_001298.3(CNGA3):c.1114C>T (p.Pro372Ser)	CNGA3	Pathogenic	criteria provided, multiple submitters, no conflicts
812282	NM_001298.3(CNGA3):c.1294del (p.Asp432fs)	CNGA3	Pathogenic	no assertion criteria provided
812283	NM_001298.3(CNGA3):c.1642G>A (p.Gly548Arg)	CNGA3	Pathogenic	criteria provided, multiple submitters, no conflicts
813038	NM_001298.3(CNGA3):c.1255T>C (p.Ser419Pro)	CNGA3	Pathogenic	criteria provided, single submitter
813039	NM_001298.3(CNGA3):c.499del (p.Leu167fs)	CNGA3	Pathogenic	criteria provided, multiple submitters, no conflicts
813041	NM_001298.3(CNGA3):c.704A>T (p.Asp235Val)	CNGA3	Pathogenic	criteria provided, single submitter
9473	NM_001298.3(CNGA3):c.488C>T (p.Pro163Leu)	CNGA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9475	NM_001298.3(CNGA3):c.848G>A (p.Arg283Gln)	CNGA3	Pathogenic	criteria provided, multiple submitters, no conflicts
9476	NM_001298.3(CNGA3):c.1669G>A (p.Gly557Arg)	CNGA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9478	NM_001298.3(CNGA3):c.1641C>A (p.Phe547Leu)	CNGA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9480	NM_001298.3(CNGA3):c.1585G>A (p.Val529Met)	CNGA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9481	NM_001298.3(CNGA3):c.829C>T (p.Arg277Cys)	CNGA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9482	NM_001298.3(CNGA3):c.1306C>T (p.Arg436Trp)	CNGA3	Pathogenic	criteria provided, multiple submitters, no conflicts
1048157	NM_019098.5(CNGB3):c.1167_1168insC (p.Glu390fs)	CNGB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066851	NM_019098.5(CNGB3):c.2181_2184del (p.Glu729fs)	CNGB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322099	NM_019098.5(CNGB3):c.442_446delinsGAAAAT (p.Lys148fs)	CNGB3	Pathogenic	criteria provided, multiple submitters, no conflicts
1408511	NM_019098.5(CNGB3):c.839dup (p.Gly281fs)	CNGB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188780	NM_019098.5(CNGB3):c.644-1G>C	CNGB3	Pathogenic	criteria provided, multiple submitters, no conflicts
188822	NM_019098.5(CNGB3):c.391C>T (p.Gln131Ter)	CNGB3	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 35 · Orphanet: 19 · 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
ATF6	Definitive	Autosomal recessive	achromatopsia 7	6
CNGA3	Definitive	Autosomal recessive	achromatopsia 2	5
CNGB3	Definitive	Autosomal recessive	achromatopsia 3	5
GNAT2	Definitive	Autosomal recessive	achromatopsia 4	6
PDE6H	Strong	Autosomal recessive	achromatopsia 6	6
PDE6C	Supportive	Autosomal recessive	achromatopsia	6
NDRG4	Limited	Autosomal recessive	achromatopsia

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CNGA3	Orphanet:1872	Cone rod dystrophy
CNGA3	Orphanet:49382	Achromatopsia
CNGB3	Orphanet:1871	Progressive cone dystrophy
CNGB3	Orphanet:49382	Achromatopsia
CNGB3	Orphanet:827	Stargardt disease
GNAT2	Orphanet:1871	Progressive cone dystrophy
GNAT2	Orphanet:49382	Achromatopsia
ATF6	Orphanet:1872	Cone rod dystrophy
ATF6	Orphanet:49382	Achromatopsia
PDE6C	Orphanet:1871	Progressive cone dystrophy
PDE6C	Orphanet:49382	Achromatopsia
PDE6H	Orphanet:49382	Achromatopsia
CABP4	Orphanet:714070	Incomplete congenital stationary night blindness, Schubert-Bornschein type
CABP4	Orphanet:98784	Sleep-related hypermotor epilepsy
OPN1MW	Orphanet:16	Blue cone monochromatism
OPN1MW	Orphanet:1872	Cone rod dystrophy
OPN1MW	Orphanet:90001	X-linked cone dysfunction syndrome with myopia
OPA3	Orphanet:67036	Autosomal dominant optic atrophy and cataract
OPA3	Orphanet:67047	3-methylglutaconic aciduria type 3

Cohort genes → proteins

10 cohort genes, 10 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CNGA3	HGNC:2150	ENSG00000144191	Q16281	Cyclic nucleotide-gated channel alpha-3	gencc,clinvar
CNGB3	HGNC:2153	ENSG00000170289	Q9NQW8	Cyclic nucleotide-gated channel beta-3	gencc,clinvar
GNAT2	HGNC:4394	ENSG00000134183	P19087	Guanine nucleotide-binding protein G(t) subunit alpha-2	gencc,clinvar
ATF6	HGNC:791	ENSG00000118217	P18850	Cyclic AMP-dependent transcription factor ATF-6 alpha	gencc,clinvar
PDE6C	HGNC:8787	ENSG00000095464	P51160	Cone cGMP-specific 3’,5’-cyclic phosphodiesterase subunit alpha'	gencc,clinvar
NDRG4	HGNC:14466	ENSG00000103034	Q9ULP0	Protein NDRG4	gencc
PDE6H	HGNC:8790	ENSG00000139053	Q13956	Retinal cone rhodopsin-sensitive cGMP 3’,5’-cyclic phosphodiesterase subunit gamma	gencc
CABP4	HGNC:1386	ENSG00000175544	P57796	Calcium-binding protein 4	clinvar
OPN1MW	HGNC:4206	ENSG00000268221	P04001	Medium-wave-sensitive opsin 1	clinvar
OPA3	HGNC:8142	ENSG00000125741	Q9H6K4	Optic atrophy 3 protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CNGA3	Cyclic nucleotide-gated channel alpha-3	Pore-forming subunit of the cone cyclic nucleotide-gated channel.
CNGB3	Cyclic nucleotide-gated channel beta-3	Pore-forming subunit of the cone cyclic nucleotide-gated channel.
GNAT2	Guanine nucleotide-binding protein G(t) subunit alpha-2	Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems.
ATF6	Cyclic AMP-dependent transcription factor ATF-6 alpha	Precursor of the transcription factor form (Processed cyclic AMP-dependent transcription factor ATF-6 alpha), which is embedded in the endoplasmic reticulum membrane.
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.
NDRG4	Protein NDRG4	Contributes to the maintenance of intracerebral BDNF levels within the normal range, which is necessary for the preservation of spatial learning and the resistance to neuronal cell death caused by ischemic stress.
PDE6H	Retinal cone rhodopsin-sensitive cGMP 3’,5’-cyclic phosphodiesterase subunit gamma	Participates in processes of transmission and amplification of the visual signal. cGMP-PDEs are the effector molecules in G-protein-mediated phototransduction in vertebrate rods and cones.
CABP4	Calcium-binding protein 4	Involved in normal synaptic function through regulation of Ca(2+) influx and neurotransmitter release in photoreceptor synaptic terminals and in auditory transmission.
OPN1MW	Medium-wave-sensitive opsin 1	Visual pigments are the light-absorbing molecules that mediate vision.
OPA3	Optic atrophy 3 protein	May play some role in mitochondrial processes.

Protein-family classification

Druggable: 3 · Difficult: 2 · Unknown: 5 · Druggable fraction: 0.3

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	2	22.3×	0.014
GPCR	1	2.4×	0.463
Transcription factor	2	1.6×	0.463
Other/Unknown	5	0.9×	0.756

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CNGA3	Ion channel	yes		cNMP-bd_dom, Ion_trans_dom, RmlC-like_jellyroll
CNGB3	Ion channel	yes		cNMP-bd_dom, Ion_trans_dom, RmlC-like_jellyroll
GNAT2	Other/Unknown	no		Gprotein_alpha_su, Gprotein_alpha_I, GproteinA_insert
ATF6	Transcription factor	no		bZIP, bZIP_sf, ATF_bZIP_TF
PDE6C	Transcription factor	no		PDEase_catalytic_dom, GAF, HD/PDEase_dom
NDRG4	Other/Unknown	no		NDRG, AB_hydrolase_fold
PDE6H	Other/Unknown	no		PDE6_gamma, PDE6_gamma_sf
CABP4	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
OPN1MW	GPCR	yes		GPCR_Rhodpsn, Opsin_red/grn, Opsin
OPA3	Other/Unknown	no		OPA3-like

Expression context

Cohort genes with no expression data: 0.

8 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)	9
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	5
secondary oocyte	2
cerebellar hemisphere	2
ganglionic eminence	1
ventricular zone	1
diaphragm	1
pigmented layer of retina	1
oocyte	1
primordial germ cell in gonad	1
corpus epididymis	1
skin of hip	1
upper leg skin	1
cerebellar cortex	1
right hemisphere of cerebellum	1
monocyte	1
mononuclear cell	1
cardia of stomach	1
vena cava	1
ventral tegmental area	1
colonic epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CNGA3	110	tissue_specific	marker	ventricular zone, male germ line stem cell (sensu Vertebrata) in testis, ganglionic eminence
CNGB3	161	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, pigmented layer of retina, diaphragm
GNAT2	153	tissue_specific	marker	oocyte, primordial germ cell in gonad, secondary oocyte
ATF6	283	ubiquitous	marker	corpus epididymis, skin of hip, upper leg skin
PDE6C	159	tissue_specific	marker	secondary oocyte, male germ line stem cell (sensu Vertebrata) in testis, cerebellar hemisphere
NDRG4	234	ubiquitous	marker	right hemisphere of cerebellum, cerebellar cortex, cerebellar hemisphere
PDE6H	83	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, monocyte, mononuclear cell
CABP4	226	broad	marker	vena cava, cardia of stomach, ventral tegmental area
OPN1MW	16		yes	male germ line stem cell (sensu Vertebrata) in testis, colonic epithelium, sural nerve
OPA3	213	ubiquitous	yes	tendon of biceps brachii, hindlimb stylopod muscle, apex of heart

Protein interactions among cohort

Intra-cohort edges: 10.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATF6	3,053
CABP4	1,897
GNAT2	1,675
NDRG4	1,622
CNGA3	1,166
CNGB3	919
PDE6C	903
PDE6H	875
OPA3	87
OPN1MW	0

Intra-cohort edges

A	B	Sources
CNGA3	CNGB3	biogrid_interaction, string_interaction
CNGA3	GNAT2	string_interaction
CNGA3	PDE6C	string_interaction
CNGA3	PDE6H	string_interaction
CNGB3	GNAT2	string_interaction
CNGB3	PDE6C	string_interaction
CNGB3	PDE6H	string_interaction
GNAT2	PDE6C	string_interaction
GNAT2	PDE6H	string_interaction
PDE6C	PDE6H	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CNGA3	Q16281	10
CNGB3	Q9NQW8	9
PDE6C	P51160	7
OPN1MW	P04001	3
GNAT2	P19087	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NDRG4	Q9ULP0	85.27
OPA3	Q9H6K4	83.13
PDE6H	Q13956	67.61
CABP4	P57796	65.01
ATF6	P18850	56.09

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 10 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
Defective visual phototransduction due to OPN1MW loss of function	1	3806.7×	0.004	OPN1MW
ATF6 (ATF6-alpha) activates chaperones	1	634.4×	0.007	ATF6
The retinoid cycle in cones (daylight vision)	1	543.8×	0.007	OPN1MW
Opsins	1	423.0×	0.007	OPN1MW
ATF6 (ATF6-alpha) activates chaperone genes	1	380.7×	0.007	ATF6
G alpha (i) signalling events	2	26.0×	0.007	GNAT2, OPN1MW
PERK regulates gene expression	1	271.9×	0.008	ATF6
Modulation of host responses by IFN-stimulated genes	1	200.3×	0.010	ATF6
ATF4 activates genes in response to endoplasmic reticulum stress	1	135.9×	0.013	ATF6
Unfolded Protein Response (UPR)	1	119.0×	0.013	ATF6
Ca2+ pathway	1	59.5×	0.024	GNAT2
Interferon Signaling	1	40.1×	0.033	ATF6
Cytokine Signaling in Immune system	1	13.6×	0.088	ATF6
Cellular responses to stress	1	12.3×	0.091	ATF6
Cellular responses to stimuli	1	10.5×	0.099	ATF6
Immune System	1	4.3×	0.214	ATF6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
visual perception	9	71.5×	5e-15	CNGA3, CNGB3, GNAT2, ATF6, PDE6C, CABP4, OPN1MW, OPA3 (+1 more)
retinal cone cell development	3	421.3×	1e-06	GNAT2, PDE6C, CABP4
phototransduction	3	148.7×	2e-05	GNAT2, CABP4, OPN1MW
monoatomic cation transport	2	153.2×	0.001	CNGA3, CNGB3
monoatomic cation transmembrane transport	2	124.8×	0.002	CNGA3, CNGB3
signal transduction	5	8.0×	0.002	CNGA3, CNGB3, ATF6, CABP4, NDRG4
positive regulation of ATF6-mediated unfolded protein response	1	1685.2×	0.006	ATF6
inorganic cation import across plasma membrane	1	842.6×	0.009	CNGA3
background adaptation	1	842.6×	0.009	GNAT2
homeostasis of number of retina cells	1	561.7×	0.011	GNAT2
cell migration involved in heart development	1	561.7×	0.011	NDRG4
neural tissue regeneration	1	421.3×	0.013	GNAT2
cone retinal bipolar cell differentiation	1	421.3×	0.013	GNAT2
visual behavior	1	280.9×	0.014	GNAT2
photoreceptor cell morphogenesis	1	280.9×	0.014	CABP4
absorption of visible light	1	280.9×	0.014	OPN1MW
L-glutamate import	1	280.9×	0.014	GNAT2
retinal bipolar neuron differentiation	1	280.9×	0.014	CABP4
clustering of voltage-gated sodium channels	1	240.7×	0.015	NDRG4
reactive gliosis	1	240.7×	0.015	GNAT2
ATF6-mediated unfolded protein response	1	210.7×	0.016	ATF6
negative regulation of platelet-derived growth factor receptor signaling pathway	1	187.2×	0.016	NDRG4
retinal rod cell differentiation	1	187.2×	0.016	GNAT2
regulation of endocytic recycling	1	168.5×	0.017	NDRG4
negative regulation of smooth muscle cell migration	1	153.2×	0.018	NDRG4
response to magnesium ion	1	140.4×	0.019	CNGA3
phototransduction, visible light	1	129.6×	0.019	PDE6C
tissue remodeling	1	129.6×	0.019	GNAT2
positive regulation of G protein-coupled receptor signaling pathway	1	105.3×	0.022	PDE6H
cellular response to light stimulus	1	105.3×	0.022	OPN1MW

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 8

Druggability breadth: 2 of 10 evidence-associated genes (20%) 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
PDE6H	VARDENAFIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PDE6C	6	4
PDE6H	6	4
CNGA3	0	0
CNGB3	0	0
GNAT2	0	0
ATF6	0	0
NDRG4	0	0
CABP4	0	0
OPN1MW	0	0
OPA3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VARDENAFIL	4	PDE6C, PDE6H
SILDENAFIL	4	PDE6C, PDE6H
TADALAFIL	4	PDE6C, PDE6H
DIPYRIDAMOLE	4	PDE6C, PDE6H
ZAPRINAST	2	PDE6C, PDE6H
TBA-7371	2	PDE6C, PDE6H

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
PDE6H	51	Binding:49, ADMET:2

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: 10; 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, PDE6H
SILDENAFIL	4	PDE6C, PDE6H
TADALAFIL	4	PDE6C, PDE6H
DIPYRIDAMOLE	4	PDE6C, PDE6H
ZAPRINAST	2	PDE6C, PDE6H
TBA-7371	2	PDE6C, PDE6H

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	PDE6C, PDE6H
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	3	CNGA3, CNGB3, OPN1MW
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	GNAT2, ATF6, NDRG4, CABP4, OPA3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CNGA3	0	PDE6C
CNGB3	0	PDE6C, PDE6H
GNAT2	0	PDE6C, PDE6H
ATF6	0	—
NDRG4	0	—
CABP4	0	—
OPN1MW	0	—
OPA3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 12.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	6
Not specified	5
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02599922	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Safety and Efficacy Trial of AAV Gene Therapy in Patients With CNGB3 Achromatopsia (A Clarity Clinical Trial)
NCT02610582	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Safety and Efficacy of rAAV.hCNGA3 Gene Therapy in Patients With CNGA3-linked Achromatopsia
NCT02935517	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Safety and Efficacy Trial of AAV Gene Therapy in Patients With CNGA3 Achromatopsia (A Clarity Clinical Trial)
NCT01648452	PHASE1/PHASE2	COMPLETED	CNTF Implants for CNGB3 Achromatopsia
NCT03001310	PHASE1/PHASE2	COMPLETED	Gene Therapy for Achromatopsia (CNGB3)
NCT03758404	PHASE1/PHASE2	COMPLETED	Gene Therapy for Achromatopsia (CNGA3)
NCT04041232	EARLY_PHASE1	SUSPENDED	PBA Use for Treatment of ATF6-/- Patients
NCT02435940	Not specified	RECRUITING	Inherited Retinal Degenerative Disease Registry
NCT07085533	Not specified	RECRUITING	Natural History Study of Inherited Retinal Diseases
NCT01846052	Not specified	COMPLETED	Clinical and Genetic Characterization of Individuals With Achromatopsia
NCT03278873	Not specified	TERMINATED	Long-Term Follow-Up Gene Therapy Study for Achromatopsia CNGB3 and CNGA3
NCT04124185	Not specified	COMPLETED	Natural History Study for Achromatopsia