CNGA3

Summary

CNGA3 (cyclic nucleotide gated channel subunit alpha 3, HGNC:2150) is a protein-coding gene on chromosome 2q11.2, encoding Cyclic nucleotide-gated channel alpha-3 (Q16281). Pore-forming subunit of the cone cyclic nucleotide-gated channel.

This gene encodes a member of the cyclic nucleotide-gated cation channel protein family which is required for normal vision and olfactory signal transduction. Mutations in this gene are associated with achromatopsia (rod monochromacy) and color blindness. Two alternatively spliced transcripts encoding different isoforms have been described.

Source: NCBI Gene 1261 — RefSeq curated summary.

At a glance

• Gene–disease (curated): CNGA3-related retinopathy (Definitive, ClinGen) — +3 more curated relationships
• Clinical variants (ClinVar): 809 total — 108 pathogenic, 88 likely-pathogenic
• Phenotypes (HPO): 39
• MANE Select transcript: NM_001298

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2150
Approved symbol	CNGA3
Name	cyclic nucleotide gated channel subunit alpha 3
Location	2q11.2
Locus type	gene with protein product
Status	Approved
Aliases	CCNC1, CCNCa, CNG3
Ensembl gene	ENSG00000144191
Ensembl biotype	protein_coding
OMIM	600053
Entrez	1261

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000272602, ENST00000393503, ENST00000409937, ENST00000436404, ENST00000853267, ENST00000853268, ENST00000853269

RefSeq mRNA: 2 — MANE Select: NM_001298 NM_001079878, NM_001298

CCDS: CCDS2034, CCDS42719

Canonical transcript exons

ENST00000272602 — 8 exons

Exon	Start	End
ENSE00000963915	98380175	98380354
ENSE00000963916	98383388	98383441
ENSE00000963918	98389658	98389774
ENSE00000963919	98391864	98391970
ENSE00001472196	98395844	98398601
ENSE00001515551	98346456	98346534
ENSE00002244308	98369939	98370076
ENSE00003460052	98377687	98377800

Expression profiles

Bgee: expression breadth ubiquitous, 110 present calls, max score 82.87.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1905 / max 46.3850, expressed in 49 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
21546	0.0990	35
21545	0.0914	28

Top tissues by expression

275 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	82.87	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.53	gold quality
ganglionic eminence	UBERON:0004023	78.55	gold quality
islet of Langerhans	UBERON:0000006	78.43	gold quality
pituitary gland	UBERON:0000007	78.36	gold quality
adenohypophysis	UBERON:0002196	75.06	gold quality
muscle layer of sigmoid colon	UBERON:0035805	71.43	gold quality
mucosa of stomach	UBERON:0001199	71.13	gold quality
lower esophagus muscularis layer	UBERON:0035833	69.71	gold quality
lower esophagus	UBERON:0013473	69.60	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	67.33	gold quality
embryo	UBERON:0000922	66.85	gold quality
sigmoid colon	UBERON:0001159	65.67	gold quality
right uterine tube	UBERON:0001302	64.39	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	63.15	gold quality
spinal cord	UBERON:0002240	62.98	gold quality
rectum	UBERON:0001052	62.34	gold quality
colon	UBERON:0001155	60.85	gold quality
cortical plate	UBERON:0005343	60.40	gold quality
large intestine	UBERON:0000059	60.22	gold quality
esophagus	UBERON:0001043	59.72	gold quality
colonic epithelium	UBERON:0000397	59.56	silver quality
hypothalamus	UBERON:0001898	59.47	gold quality
transverse colon	UBERON:0001157	59.11	gold quality
intestine	UBERON:0000160	59.06	gold quality
smooth muscle tissue	UBERON:0001135	58.37	gold quality
small intestine	UBERON:0002108	56.92	gold quality
small intestine Peyer’s patch	UBERON:0003454	56.29	gold quality
prefrontal cortex	UBERON:0000451	56.26	gold quality
pancreas	UBERON:0001264	55.95	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.42

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

55 targeting CNGA3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-2392	99.43	67.50	708
HSA-MIR-569	99.42	66.32	1009
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-888-5P	99.30	70.15	1855
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-3199	99.17	65.19	696
HSA-MIR-8052	99.17	65.01	719

Literature-anchored findings (GeneRIF, showing 40)

• mutations in cone photoreceptor disorders (PMID:11536077)
• The heteromeric cyclic nucleotide-gated channel adopts a 3A:1B stoichiometry (PMID:12432397)
• Novel causative CNGA3 missense mutations found in Achromatopsia patients in the United Kingdom. (PMID:14757870)
• the S4 structural motif of CNGA3 is important for cellular processing of cone photoreceptor cyclic GMP-gated ion channels (PMID:15024024)
• Functional markers for CNGA3 (A3) dimers confirms that A3 subunits gain membership into the pore-forming tetramers and that like subunits are positioned adjacent to each other in cone photoreceptors. (PMID:15134637)
• Out of 36 achromats, 12 (33%) had mutations in CNGA3 (13 different mutations including five novel mutations). (PMID:15712225)
• Plasma membrane localization and gating properties of cone CNGA3 channels are altered by progressive cone dystrophy-associated mutations, evidence of pathogenicity of these mutations. (PMID:15743887)
• Mutations in CNGA3 and CNGB3 account for achromatopsia in Hungarian patients including known mutations and a few new CNGB3 mutations. (PMID:16319819)
• The outcome suggests low frequency (7%, 1/14) of CNGA3 mutations (R436W, L633P) in Japanese patients. (PMID:16961972)
• Phospholipid metabolism and exogenously applied phosphatidylinositol 3,4,5-trisphosphate can modulate heterologously expressed cone CNG channels. (PMID:17018579)
• the T565M and E593K mutations of CNGA3 alter the apparent affinity for cGMP of the channels to cause cone dysfunction, resulting in rod monochromacy (PMID:17693388)
• identification of three new CNGA3 mutations in patients with achromatopsia (PMID:18445228)
• The identification of three novel CNGA3 missense mutations in achromatopsia patients. (PMID:18521937)
• Achromatopsia in these two United Arab Emirates families results from two different mutations in CNGA3. (PMID:18636117)
• The CNGB3 gene was by far the most important causal gene, and T383IfsX13 the most frequent mutation in complete and incomplete achromatopsia. (PMID:19592100)
• Our data indicate that these genes are involved in a broader spectrum of cone dysfunction, and it remains intriguing why initial cone function can be spared despite similar gene defects. (PMID:20079539)
• Genetic analysis of two Pakistani families with retinal disease enabled the establishment of the correct diagnosis of achromatopsia. Two novel mutations were identified in CNGA3 and CNGB3 that are both specifically expressed in cone photoreceptors. (PMID:20454696)
• Data identified three novel mutations in the pore-forming region of CNGA3 (L363P, G367V, and E376K) in achromatopsia patients, and reduced macroscopic currents for channels with the mutations G367V, and E376K. (PMID:20506298)
• haplotype analysis of c.1585G>A-bearing chromosomes from Middle Eastern and European origins showed a shared Muslim-Jewish haplotype, different from that detected in Europeans, indicating a recurrent mutation with a Jewish-Muslim founder effect (PMID:20549516)
• Missense mutations, nonsense mutations, splice mutations, and small deletions and insertions in the affected genes cause achromatopsia. (PMID:21267001)
• This is the second reported case of CNGA3 associated oligocone trichromacy (OT). (PMID:21268679)
• in a set of consanguineous patient families with Leber congenital amaurosis study identified five putative disease-causing mutations, including four novel alleles, in six families; These five mutations are located in four genes, ALMS1, IQCB1, CNGA3, and MYO7A (PMID:21901789)
• Two compound heterozygous mutations were identified in CNGA3 of this patient, c.829C>T p.R277C and c.1580T>G p.L527R; they were not observed in the normal population and cosegregated with the phenotype of achromatopsia in the patient’s family. (PMID:21911670)
• We describe a novel S4 motif mutation of CNGA3 in a Pakistani family. (PMID:21912902)
• observed a nuclear translocation of apoptosis-inducing factor (AIF) and endonuclease G in CNGA3(-/-)/Nrl(-/-) and CNGB3(-/-)/Nrl(-/-) retinas, implying a mitochondrial insult in the endoplasmic reticulum stress-activated cell death process (PMID:22493484)
• The majority (n = 12) of patients were either homozygotes or compound heterozygotes for known achromatopsia alleles, two in CNGB3 (p.T383fsX and p.T296YfsX9) and three in CNGA3 (p.R283Q, p.R427C and p.L527R). (PMID:23362848)
• These studies support a model in which intersubunit interactions control the sensitivity of cone CNG channels to regulation by phosphoinositides. (PMID:23552282)
• The biochemical feedback regulation of CNGA3 mutations in color blindness is reported. (PMID:23677796)
• CNGA3 alternative splicing may have evolved, in part, to tune the interactions between cone CNG channels and membrane-bound phosphoinositides. (PMID:24675082)
• Genetic testing revealed a common homozygous mutation in CNGB3 in 5 patients with complete achromatopsia and heterozygous mutations in CNGA3 in 2 patients with incomplete achromatopsia. (PMID:24676353)
• Our results suggest that CNGA3 mutations are a common cause of cone-rod dystrophies and achromatopsia in the Chinese population. (PMID:24903488)
• The c.955T>C change identified in large consanguineous Pakistani family represents the first variant of CNGA3 which was found to be responsible for the cone-rod dystrophy phenotype. (PMID:25052312)
• Among Israeli and Palestinian patients, CNGA3 mutations are the leading cause of achromatopsia. Retinal structural results support the candidacy of CNGA3 ACHM for clinical trials for therapy of cone photoreceptors. (PMID:25616768)
• CNGA3 mutation is the most frequent cause of achromatopsia in this cohort of patients. Ten novel mutations were identified in CNGA3. (PMID:25637600)
• The two novel mutations found in the CNGA3 gene, c.997_998delGA and p.M424V, can cause complete achromatopsia. The vision of the patient was stationary until the third decade of life although the FAF was altered at the age of 22 years. (PMID:27040408)
• Four mutations (c.1682G>A;p.G561E, c.139C>T;p.Q47*, c.784G>C;p.A282P, c.1116delC;p.V373*) represent novel mutations of CNGA3 reported herein for the first time in patients with Achromatopsia. (PMID:28159970)
• The c.1618G>A, p.Gly540Ser substitution in CNGA3 was identified as the causative mutation for a novel form of ACHM in Awassi sheep. Gene augmentation therapy restored vision in the affected sheep. This novel mutation provides a large-animal model that is valid for most human CNGA3 ACHM patients; the majority of them carry missense rather than premature-termination mutations. (PMID:28282490)
• Here, we report the identification of a novel isoform of human CNGA3 resulting from an in-frame alternative translation initiation site (TIS) 154 bp downstream of the first TIS. Results suggest that the short isoform is not able to compensate for the loss of the long isoform leaving the biological role of this variant unclear. (PMID:29499183)
• Also any toxic effects of AAV8-CNGA3 on visual function might be manifest by a worsening of visual acuity after the initial period of post-operative recovery. Potential toxic effects on retinal function are likely to be manifest as a significant drop in visual acuity (PMID:30187779)
• Three novel homozygous variants were detected in CNGA3, two novel variants were found in PDE6C. All patients had nonrecordable full-field electroretinography 30-Hz flicker responses, reduced single-flash cone responses but preserved rod responses. (PMID:30289319)

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
danio_rerio	cnga3b	ENSDARG00000012297
danio_rerio	cnga3a	ENSDARG00000070726
mus_musculus	Cnga3	ENSMUSG00000026114
rattus_norvegicus	Cnga3	ENSRNOG00000051950
drosophila_melanogaster	sei	FBGN0003353
drosophila_melanogaster	Elk	FBGN0011589
drosophila_melanogaster	CG6026	FBGN0038676
drosophila_melanogaster	CngA	FBGN0261612
drosophila_melanogaster	Cngl	FBGN0263257
drosophila_melanogaster	CngB	FBGN0266346
caenorhabditis_elegans		WBGENE00000487
caenorhabditis_elegans	tax-2	WBGENE00006525
caenorhabditis_elegans		WBGENE00006526
caenorhabditis_elegans		WBGENE00006830
caenorhabditis_elegans		WBGENE00022295

Paralogs (17): KCNH2 (ENSG00000055118), CNGB1 (ENSG00000070729), KCNH4 (ENSG00000089558), HCN2 (ENSG00000099822), CNGA4 (ENSG00000132259), KCNH3 (ENSG00000135519), HCN4 (ENSG00000138622), KCNH5 (ENSG00000140015), KCNH1 (ENSG00000143473), HCN3 (ENSG00000143630), HCN1 (ENSG00000164588), CNGB3 (ENSG00000170289), KCNH6 (ENSG00000173826), CNGA2 (ENSG00000183862), KCNH8 (ENSG00000183960), KCNH7 (ENSG00000184611), CNGA1 (ENSG00000198515)

Protein

Protein identifiers

Cyclic nucleotide-gated channel alpha-3 — Q16281 (reviewed: Q16281)

Alternative names: Cone photoreceptor cGMP-gated channel subunit alpha-3

All UniProt accessions (1): Q16281

UniProt curated annotations — full annotation on UniProt →

Function. Pore-forming subunit of the cone cyclic nucleotide-gated channel. Mediates cone photoresponses at bright light converting transient changes in intracellular cGMP levels into electrical signals. In the dark, cGMP levels are high and keep the channel open enabling a steady inward current carried by Na(+) and Ca(2+) ions that leads to membrane depolarization and neurotransmitter release from synaptic terminals. Upon photon absorption cGMP levels decline leading to channel closure and membrane hyperpolarization that ultimately slows neurotransmitter release and signals the presence of light, the end point of the phototransduction cascade. Pore-forming subunit of the gustatory cyclic nucleotide-gated channel. In the taste buds, may sense oral extracellular pH and conduct ion currents that modulate the excitability of taste cells. Conducts cGMP- and cAMP-gated ion currents, with permeability for monovalent and divalent cations.

Subunit / interactions. Forms heterotetrameric channels composed of CNGA3 and CNGB3 subunits with 3:1 stoichiometry.

Subcellular location. Cell membrane.

Tissue specificity. Prominently expressed in retina.

Disease relevance. Achromatopsia 2 (ACHM2) [MIM:216900] An autosomal recessive, ocular stationary disorder due to the absence of functioning cone photoreceptors in the retina. It is characterized by total colorblindness, low visual acuity, photophobia and nystagmus. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by L-cis-diltiazem.

Domain organisation. The C-terminal coiled-coil domain mediates homotrimerization of CNGA subunits. The cyclic nucleotide-binding domain (CNBD) comprises three helices and a beta-roll of eight beta-strands from CNGA3 and CNGB3 subunits. Upon cNMP binding transmits the conformational changes to the C-linker domain of the S6 helix to open the ion conduction pathway. The ion conduction pathway consists of S5, S6 and pore helices from CNGA3 and CNGB3 subunits. It contains a central hydrophobic gate that opens upon cNMP binding.

Similarity. Belongs to the cyclic nucleotide-gated cation channel (TC 1.A.1.5) family. CNGA3 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q16281-1	1	yes
Q16281-2	2
Q16281-3	3

RefSeq proteins (2): NP_001073347, NP_001289* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000595	cNMP-bd_dom	Domain
IPR005821	Ion_trans_dom	Domain
IPR014710	RmlC-like_jellyroll	Homologous_superfamily
IPR018488	cNMP-bd_CS	Conserved_site
IPR018490	cNMP-bd_dom_sf	Homologous_superfamily
IPR032406	CLZ_dom	Domain
IPR050866	CNG_cation_channel	Family

Pfam: PF00027, PF00520, PF16526

Catalyzed reactions (Rhea), 7 shown:

• NH4(+)(in) = NH4(+)(out) (RHEA:28747)
• K(+)(in) = K(+)(out) (RHEA:29463)
• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)
• Na(+)(in) = Na(+)(out) (RHEA:34963)
• Rb(+)(in) = Rb(+)(out) (RHEA:78547)
• Li(+)(in) = Li(+)(out) (RHEA:78551)
• Cs(+)(in) = Cs(+)(out) (RHEA:78555)

UniProt features (143 total): sequence variant 70, helix 22, strand 14, topological domain 7, transmembrane region 7, region of interest 7, binding site 6, compositionally biased region 2, site 2, splice variant 2, chain 1, turn 1, coiled-coil region 1, glycosylation site 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
3SWY	X-RAY DIFFRACTION	1.9
7RHS	ELECTRON MICROSCOPY	2.93
8EV8	ELECTRON MICROSCOPY	3.11
8EV9	ELECTRON MICROSCOPY	3.33
8EVA	ELECTRON MICROSCOPY	3.33
8EVC	ELECTRON MICROSCOPY	3.33
8ETP	ELECTRON MICROSCOPY	3.52
8EVB	ELECTRON MICROSCOPY	3.6
8EUC	ELECTRON MICROSCOPY	3.61
8EU3	ELECTRON MICROSCOPY	3.62

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16281-F1	75.33	0.44

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 392 (central gate); 396 (central gate)

Ligand- & substrate-binding residues (6): 548; 549; 551; 564; 565; 609

Glycosylation sites (1): 339

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 172 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, PID_CONE_PATHWAY, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_RESPONSE_TO_METAL_ION, GOBP_RESPONSE_TO_MAGNESIUM_ION, GOBP_RESPONSE_TO_CAMP, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, KEGG_OLFACTORY_TRANSDUCTION, GOBP_SENSORY_PERCEPTION, GOCC_NEURON_PROJECTION, GOBP_SENSORY_ORGAN_DEVELOPMENT, MODULE_287, GOBP_CALCIUM_ION_TRANSMEMBRANE_TRANSPORT

GO Biological Process (15): monoatomic cation transport (GO:0006812), signal transduction (GO:0007165), visual perception (GO:0007601), response to magnesium ion (GO:0032026), response to cAMP (GO:0051591), retina development in camera-type eye (GO:0060041), monoatomic cation transmembrane transport (GO:0098655), inorganic cation import across plasma membrane (GO:0098659), monoatomic ion transport (GO:0006811), sodium ion transport (GO:0006814), calcium ion transport (GO:0006816), monoatomic ion transmembrane transport (GO:0034220), sodium ion transmembrane transport (GO:0035725), transmembrane transport (GO:0055085), calcium ion transmembrane transport (GO:0070588)

GO Molecular Function (12): intracellularly cAMP-activated cation channel activity (GO:0005222), intracellularly cGMP-activated cation channel activity (GO:0005223), calcium channel activity (GO:0005262), sodium channel activity (GO:0005272), ligand-gated monoatomic ion channel activity (GO:0015276), myosin binding (GO:0017022), cGMP binding (GO:0030553), cadherin binding (GO:0045296), nucleotide binding (GO:0000166), monoatomic ion channel activity (GO:0005216), intracellularly cyclic nucleotide-activated monoatomic cation channel activity (GO:0005221), protein binding (GO:0005515)

GO Cellular Component (9): plasma membrane (GO:0005886), intracellular cyclic nucleotide activated cation channel complex (GO:0017071), dendrite (GO:0030425), axon initial segment (GO:0043194), perikaryon (GO:0043204), glial cell projection (GO:0097386), transmembrane transporter complex (GO:1902495), membrane (GO:0016020), neuronal cell body (GO:0043025)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
monoatomic ion transport	2
cellular process	2
transport	2
metal ion transport	2
monoatomic cation transmembrane transport	2
intracellularly cyclic nucleotide-activated monoatomic cation channel activity	2
monoatomic cation channel activity	2
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
sensory perception of light stimulus	1
response to metal ion	1
response to purine-containing compound	1
response to organophosphorus	1
response to oxygen-containing compound	1
camera-type eye development	1
anatomical structure development	1
monoatomic cation transport	1
monoatomic ion transmembrane transport	1
inorganic ion import across plasma membrane	1
transmembrane transport	1
sodium ion transport	1
calcium ion transport	1
calcium ion transmembrane transporter activity	1
sodium ion transmembrane transporter activity	1
monoatomic ion channel activity	1
ligand-gated channel activity	1
cytoskeletal protein binding	1
cyclic nucleotide binding	1
guanyl ribonucleotide binding	1
anion binding	1
cell adhesion molecule binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
monoatomic ion transmembrane transporter activity	1
channel activity	1
intracellularly ligand-gated monoatomic ion channel activity	1
cyclic nucleotide-activated monoatomic ion channel activity	1

Protein interactions and networks

STRING

1102 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CNGA3	GNAT2	P19087	982
CNGA3	PDE6C	P51160	975
CNGA3	CNGB3	Q9NQW8	972
CNGA3	OPN4	Q9UHM6	941
CNGA3	GNAT1	P11488	871
CNGA3	RPE65	Q16518	870
CNGA3	PDE6H	Q13956	826
CNGA3	GLYATL1	Q969I3	812
CNGA3	CNGA2	Q16280	784
CNGA3	LRAT	O95237	762
CNGA3	SEMA4C	Q9C0C4	745
CNGA3	GUCY2D	Q02846	736
CNGA3	RHO	P08100	714
CNGA3	RPGR	Q92834	688
CNGA3	PDE6A	P16499	680

IntAct

10 interactions, top by confidence:

A	B	Type	Score
CNGA3	MIS18A	psi-mi:“MI:0915”(physical association)	0.560
CNGA3	C2CD2L	psi-mi:“MI:0914”(association)	0.530
CNGA3	HNRNPU	psi-mi:“MI:0915”(physical association)	0.400
ARRB1		psi-mi:“MI:0914”(association)	0.350
CNGA3	MAGEA6	psi-mi:“MI:0914”(association)	0.350
KIF2C	CNGA3	psi-mi:“MI:0914”(association)	0.350
MIS18A	CNGA3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (54): ACBD5 (Affinity Capture-MS), VPS52 (Affinity Capture-MS), SEMG2 (Affinity Capture-MS), C1orf43 (Affinity Capture-MS), ABCB9 (Affinity Capture-MS), SEMG1 (Affinity Capture-MS), PDZD8 (Affinity Capture-MS), ATP2A3 (Affinity Capture-MS), ADCY3 (Affinity Capture-MS), RAB6B (Affinity Capture-MS), SNX14 (Affinity Capture-MS), TMX2 (Affinity Capture-MS), ACVR2B (Affinity Capture-MS), ANKLE2 (Affinity Capture-MS), PKD2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0M3R8G1, A0A0M4FLW6, A9YWR6, B8ALI0, D3GE74, D4AYW0, H6WS93, H6WS94, O81016, O95259, P29973, P45844, P50530, P93025, Q00194, Q00195, Q03720, Q16281, Q28279, Q2PCF1, Q2QV81, Q5W274, Q5Z9S8, Q60603, Q62398, Q62927, Q63472, Q64343, Q7PC84, Q7PC86, Q7PC87, Q84K47, Q8GU83, Q8GU92, Q8H8V7, Q8RWI9, Q8RXN0, Q90805, Q93YS4, Q9C8J8

Diamond homologs: A0A8I5ZN27, A5K0N4, E1AZ71, P29973, P29974, P36600, P55934, Q00194, Q00195, Q03041, Q03611, Q14028, Q16280, Q16281, Q24278, Q28181, Q28279, Q28718, Q29441, Q2K5E1, Q3UW12, Q62398, Q62927, Q64359, Q8I719, Q8IV77, Q8MJD7, Q8TF77, Q90805, Q90980, Q9ER33, Q9JJZ8, Q9JJZ9, Q9NQW8, W7JX98, Q6BZG7, P49605, Q9LD40, A4K2Q6, A6H8H5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

809 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	108
Likely pathogenic	88
Uncertain significance	303
Likely benign	196
Benign	16

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1034766	NM_001298.3(CNGA3):c.1775C>T (p.Pro592Leu)	Pathogenic
1047372	NM_001298.3(CNGA3):c.1001C>T (p.Ser334Phe)	Pathogenic
1056891	NM_001298.3(CNGA3):c.1537G>A (p.Gly513Arg)	Pathogenic
1064462	NM_001298.3(CNGA3):c.1063A>G (p.Ser355Gly)	Pathogenic
1064464	NM_001298.3(CNGA3):c.1115C>T (p.Pro372Leu)	Pathogenic
1064470	NM_001298.3(CNGA3):c.1519del (p.Asp507fs)	Pathogenic
1064474	NM_001298.3(CNGA3):c.1708A>G (p.Ser570Gly)	Pathogenic
1064475	NM_001298.3(CNGA3):c.1717T>C (p.Tyr573His)	Pathogenic
1064483	NM_001298.3(CNGA3):c.464del (p.Lys155fs)	Pathogenic
1065327	NC_000002.12:g.98393909_98399093del	Pathogenic
1070222	NM_001298.3(CNGA3):c.406del (p.Leu136fs)	Pathogenic
1071189	NM_001298.3(CNGA3):c.484del (p.Asp162fs)	Pathogenic
1071996	NM_001298.3(CNGA3):c.542A>G (p.Tyr181Cys)	Pathogenic
1072453	NM_001298.3(CNGA3):c.520del (p.Ala174fs)	Pathogenic
1072948	NM_001298.3(CNGA3):c.673+1G>A	Pathogenic
1073439	NC_000002.11:g.(?98949644)(99013718_?)del	Pathogenic
1074330	NM_001298.3(CNGA3):c.316G>T (p.Glu106Ter)	Pathogenic
1075088	NM_001298.3(CNGA3):c.1495C>T (p.Arg499Ter)	Pathogenic
1299243	NM_001298.3(CNGA3):c.77del (p.Asn26fs)	Pathogenic
1301856	NM_001298.3(CNGA3):c.1749del (p.Leu584fs)	Pathogenic
1348791	NM_001298.3(CNGA3):c.587A>G (p.Gln196Arg)	Pathogenic
1365127	NM_001298.3(CNGA3):c.1641C>G (p.Phe547Leu)	Pathogenic
1366181	NM_001298.3(CNGA3):c.95del (p.Leu32fs)	Pathogenic
1376980	NM_001298.3(CNGA3):c.1319G>C (p.Trp440Ser)	Pathogenic
1444606	NM_001298.3(CNGA3):c.1074G>A (p.Trp358Ter)	Pathogenic
1444626	NM_001298.3(CNGA3):c.1201T>C (p.Ser401Pro)	Pathogenic
1444665	NM_001298.3(CNGA3):c.1541A>T (p.Asp514Val)	Pathogenic
1453201	NM_001298.3(CNGA3):c.1319G>A (p.Trp440Ter)	Pathogenic
1453688	NM_001298.3(CNGA3):c.9del (p.Ile4fs)	Pathogenic
1453825	NM_001298.3(CNGA3):c.1267dup (p.Tyr423fs)	Pathogenic

SpliceAI

1672 predictions. Top by Δscore:

Variant	Effect	Δscore
2:98346533:GG:G	donor_gain	1.0000
2:98346534:GG:G	donor_gain	1.0000
2:98377797:CCAGG:C	donor_loss	1.0000
2:98377798:CAG:C	donor_loss	1.0000
2:98377799:AGGTA:A	donor_loss	1.0000
2:98377800:GGTA:G	donor_loss	1.0000
2:98377802:T:G	donor_loss	1.0000
2:98380174:GGCT:G	acceptor_gain	1.0000
2:98380284:G:GT	donor_gain	1.0000
2:98391967:ACAGG:A	donor_loss	1.0000
2:98391968:CAGGT:C	donor_loss	1.0000
2:98391969:AGG:A	donor_loss	1.0000
2:98391971:G:A	donor_loss	1.0000
2:98391972:T:G	donor_loss	1.0000
2:98395839:TTTA:T	acceptor_loss	1.0000
2:98395840:TTAGG:T	acceptor_loss	1.0000
2:98395841:TA:T	acceptor_loss	1.0000
2:98395842:A:AG	acceptor_gain	1.0000
2:98395842:AGG:A	acceptor_loss	1.0000
2:98395843:G:GG	acceptor_gain	1.0000
2:98346530:GCAGG:G	donor_gain	0.9900
2:98346531:CAGGG:C	donor_loss	0.9900
2:98346532:AGGGT:A	donor_loss	0.9900
2:98346534:GGTAA:G	donor_loss	0.9900
2:98346535:G:GA	donor_loss	0.9900
2:98346536:T:TC	donor_loss	0.9900
2:98369931:C:G	acceptor_gain	0.9900
2:98369932:A:AG	acceptor_gain	0.9900
2:98369933:T:G	acceptor_gain	0.9900
2:98369933:TTTTA:T	acceptor_loss	0.9900

AlphaMissense

4566 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:98396344:T:C	F392L	0.999
2:98396346:T:A	F392L	0.999
2:98396346:T:G	F392L	0.999
2:98396878:A:C	S570R	0.999
2:98396880:C:A	S570R	0.999
2:98396880:C:G	S570R	0.999
2:98396750:T:C	L527P	0.998
2:98396752:G:C	A528P	0.998
2:98396809:T:C	F547L	0.998
2:98396811:C:A	F547L	0.998
2:98396811:C:G	F547L	0.998
2:98396813:G:A	G548E	0.998
2:98396821:A:C	S551R	0.998
2:98396823:C:A	S551R	0.998
2:98396823:C:G	S551R	0.998
2:98396861:G:C	R564T	0.998
2:98396862:G:C	R564S	0.998
2:98396862:G:T	R564S	0.998
2:98396867:C:A	A566D	0.998
2:98396897:T:C	L576P	0.998
2:98396175:G:C	W335C	0.997
2:98396175:G:T	W335C	0.997
2:98396233:A:C	S355R	0.997
2:98396235:T:A	S355R	0.997
2:98396235:T:G	S355R	0.997
2:98396258:T:C	L363P	0.997
2:98396348:C:A	A393D	0.997
2:98396651:T:C	L494P	0.997
2:98396663:T:C	L498P	0.997
2:98396813:G:T	G548V	0.997

dbSNP variants (sampled 300 via entrez): RS1000019826 (2:98388507 G>A), RS1000069756 (2:98351586 C>A), RS1000087979 (2:98387294 A>T), RS1000147424 (2:98382659 T>C), RS1000182977 (2:98386162 G>A,T), RS1000216252 (2:98378576 T>G), RS1000233639 (2:98394226 G>C,T), RS1000235001 (2:98346557 G>A), RS1000295112 (2:98389252 G>A), RS1000320456 (2:98357547 G>A), RS1000349338 (2:98351921 T>G), RS1000361873 (2:98346342 C>T), RS1000385506 (2:98377591 T>G), RS1000483554 (2:98383937 A>G), RS1000497110 (2:98383833 C>T)

Disease associations

OMIM: gene MIM:600053 | disease phenotypes: MIM:216900, MIM:120970, MIM:262300

GenCC curated gene-disease

Disease	Classification	Inheritance
achromatopsia 2	Definitive	Autosomal recessive
cone-rod dystrophy	Supportive	Autosomal dominant
achromatopsia	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
CNGA3-related retinopathy	Definitive	AR

Mondo (10): achromatopsia 2 (MONDO:0009003), inherited retinal dystrophy (MONDO:0019118), achromatopsia (MONDO:0018852), CNGA3-related retinopathy (MONDO:0800102), cone-rod dystrophy (MONDO:0015993), cone dystrophy (MONDO:0000455), retinal disorder (MONDO:0005283), achromatopsia 3 (MONDO:0009875), macular degeneration (MONDO:0003004), optic atrophy (MONDO:0003608)

Orphanet (4): Achromatopsia (Orphanet:49382), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Cone rod dystrophy (Orphanet:1872), Progressive cone dystrophy (Orphanet:1871)

HPO phenotypes

39 total (30 of 39 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000505	Visual impairment
HP:0000529	Progressive visual loss
HP:0000539	Abnormality of refraction
HP:0000540	Hypermetropia
HP:0000543	Optic disc pallor
HP:0000545	Myopia
HP:0000551	Color vision defect
HP:0000603	Central scotoma
HP:0000613	Photophobia
HP:0000639	Nystagmus
HP:0000662	Nyctalopia
HP:0001103	Abnormal macular morphology
HP:0001105	Retinal atrophy
HP:0007641	Dyschromatopsia
HP:0007663	Reduced visual acuity
HP:0007695	Abnormal pupillary light reflex
HP:0007703	Abnormal retinal pigmentation
HP:0007722	Retinal pigment epithelial atrophy
HP:0007737	Spicular pigmentation of the retina
HP:0007750	Hypoplasia of the fovea
HP:0007803	Monochromacy
HP:0007814	Retinal pigment epithelial mottling
HP:0007843	Attenuation of retinal blood vessels
HP:0011463	Childhood onset
HP:0011516	Achromatopsia
HP:0012043	Pendular nystagmus
HP:0012047	Hemeralopia
HP:0012508	Metamorphopsia
HP:0025549	Eccentric visual fixation

GWAS associations

0 associations (top):

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D000077765	Cone Dystrophy	C11.270.151; C11.768.216
D000071700	Cone-Rod Dystrophies	C11.270.152; C11.768.585.658.250; C16.320.290.152
D008268	Macular Degeneration	C11.768.585.439
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D012164	Retinal Diseases	C11.768
D058499	Retinal Dystrophies	C11.768.585.658
C536128	Achromatopsia 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: vgic — Cyclic nucleotide-regulated channels (CNG)

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
cyclic GMP	Agonist	5.6	pKd
cyclic AMP	Agonist	2.88	pKd

CTD chemical–gene interactions

10 total (human), top 10 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
Valproic Acid	increases expression	2
bisphenol A	increases methylation	1
aflatoxin B2	decreases methylation	1
Acetaminophen	increases expression	1
Arsenic	affects methylation	1
Estradiol	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Aflatoxin B1	increases methylation	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

298 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01955135	PHASE4	COMPLETED	Anesthesia for Retinopathy of Prematurity
NCT00312351	PHASE4	TERMINATED	A Clinical Trial to Explore the Safety and Efficacy of Three Different Doses of Pegaptanib Sodium in Patients With Wet Age-Related Macular Degeneration (AMD)
NCT00324116	PHASE4	COMPLETED	Evaluation Of Safety And Efficacy Of 0.3 Mg/Eye Macugen In Patients With Small Age-Related Macular Degeneration Lesions
NCT00327470	PHASE4	TERMINATED	An Open Label Trial to Investigate Macugen for the Preservation of Visual Function in Subjects With Neovascular AMD
NCT00533520	PHASE4	COMPLETED	Evaluation of Dosing Interval of Higher Doses of Ranibizumab
NCT00813891	PHASE4	UNKNOWN	Efficacy of Ranibizumab in Combination With Photodynamic Therapy for Wet Age-Related Macular Degeneration
NCT01006538	PHASE4	COMPLETED	Macular EpiRetinal Brachytherapy Versus Lucentis® Only Treatment (MERLOT)
NCT01213667	PHASE4	UNKNOWN	Genetics in Non-response to Anti-VEGF Treatment in Exudative AMD
NCT01831947	PHASE4	COMPLETED	Efficacy Study of Ranibizumab on Patients With Age-related Macular Degeneration.
NCT02581891	PHASE4	COMPLETED	Managing Neovascular (Known as Wet) Age-related Macular Degeneration Over 2 Years Using Different Treatment Schedules of 2 mg Intravitreal Aflibercept Injected in the Eye
NCT02689518	PHASE4	COMPLETED	EAGLE: Evaluating Genotypes Using Intravitreal Aflibercept Injection
NCT03804099	PHASE4	COMPLETED	Effect Aflibercept on Ocular Perfusion
NCT07367282	PHASE4	NOT_YET_RECRUITING	Evaluate the Efficacy of Faricimab in Patients With Neovascular Age-related Macular Degeneration
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT00000145	PHASE3	COMPLETED	Age-Related Eye Disease Study (AREDS)
NCT00000150	PHASE3	COMPLETED	Submacular Surgery Trials (SST)
NCT00000152	PHASE3	UNKNOWN	Randomized Trial of Beta-Carotene and Macular Degeneration
NCT00000158	PHASE3	UNKNOWN	Macular Photocoagulation Study (MPS)
NCT00000161	PHASE3	UNKNOWN	Randomized Trials of Vitamin Supplements and Eye Disease
NCT00000162	PHASE3	COMPLETED	Branch Vein Occlusion Study
NCT00000167	PHASE3	COMPLETED	Complications of Age-Related Macular Degeneration Prevention Trial
NCT00041483	PHASE3	COMPLETED	Phase 3 Study to Evaluate Anecortave Acetate vs. Visudyne for the Treatment of the Wet Form of AMD
NCT00042211	PHASE3	COMPLETED	Preventing Depression in Patients With Macular Degeneration
NCT00050479	PHASE3	COMPLETED	Laser and Medical Treatment of Diabetic Macular Edema
NCT00051129	PHASE3	COMPLETED	Anecortave Acetate in Subfoveal Choroidal Neovascularization (CNV) Due to Wet Age-Related Macular Degeneration (AMD)
NCT00056836	PHASE3	COMPLETED	A Study to Evaluate rhuFab V2 in Subjects With Minimally Classic or Occult Subfoveal Neovascular Macular Degeneration
NCT00058994	PHASE3	COMPLETED	An Evaluation of Safety and Efficacy of Anecortave Acetate Versus Placebo in Patients With Subfoveal CNV Due to Exudative AMD
NCT00061594	PHASE3	COMPLETED	A Study to Compare rhuFab V2 With Verteporfin Photodynamic in Treating Subfoveal Neovascular Macular Degeneration
NCT00065728	PHASE3	TERMINATED	Open-Label Posterior Juxtascleral Injections of Anecortave Acetate 15mg Dose for Long Term Use in Patients With AMD
NCT00078221	PHASE3	UNKNOWN	Rheopheresis Blood Filtration Study for the Treatment of Dry Age-Related Macular Degeneration (AMD)
NCT00090623	PHASE3	COMPLETED	A Study of rhuFab V2 (Ranibizumab) in Subjects With Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration (AMD)
NCT00095433	PHASE3	COMPLETED	Extension Study of rhuFab V2 in Subjects With Neovascular Age-Related Macular Degeneration (AMD)
NCT00100009	PHASE3	COMPLETED	Triamcinolone Acetonide Plus Laser Therapy to Treat Age-Related Macular Degeneration
NCT00121407	PHASE3	COMPLETED	Visudyne® in Occult (VIO)
NCT00150202	PHASE3	COMPLETED	Clinical Study Of EYE001 For Wet-Type AMD (Age-Related Macular Degeneration)
NCT00157976	PHASE3	UNKNOWN	Double-Masked Study of Photrex (Rostaporfin) Photodynamic Therapy in the Treatment of Age-Related Macular Degeneration
NCT00242580	PHASE3	COMPLETED	A Safety and Efficacy Study Comparing the Combination Treatments of Verteporfin Therapy Plus One of Two Different Doses of Intravitreal Triamcinolone Acetonide and the Verteporfin Therapy Plus Intravitreal Pegaptanib
NCT00299507	PHASE3	COMPLETED	Anecortave Acetate in Patients With Exudative Age-related Macular Degeneration (AMD)
NCT00436553	PHASE3	COMPLETED	Efficacy/Safety of Verteporfin Photodynamic Therapy and Ranibizumab Compared With Ranibizumab in Patients With Subfoveal Choroidal Neovascularization