CNGB3

Summary

CNGB3 (cyclic nucleotide gated channel subunit beta 3, HGNC:2153) is a protein-coding gene on chromosome 8q21.3, encoding Cyclic nucleotide-gated channel beta-3 (Q9NQW8). Pore-forming subunit of the cone cyclic nucleotide-gated channel.

This gene encodes the beta subunit of a cyclic nucleotide-gated ion channel. The encoded beta subunit appears to play a role in modulation of channel function in cone photoreceptors. This heterotetrameric channel is necessary for sensory transduction, and mutations in this gene have been associated with achromatopsia 3, progressive cone dystrophy, and juvenile macular degeneration, also known as Stargardt Disease.

Source: NCBI Gene 54714 — RefSeq curated summary.

At a glance

• Gene–disease (curated): CNGB3-related retinopathy (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 1,388 total — 178 pathogenic, 98 likely-pathogenic
• Phenotypes (HPO): 43
• MANE Select transcript: NM_019098

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2153
Approved symbol	CNGB3
Name	cyclic nucleotide gated channel subunit beta 3
Location	8q21.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000170289
Ensembl biotype	protein_coding
OMIM	605080
Entrez	54714

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding_CDS_not_defined, 2 protein_coding, 1 nonsense_mediated_decay

ENST00000320005, ENST00000517327, ENST00000519777, ENST00000680314, ENST00000681546, ENST00000681746

RefSeq mRNA: 1 — MANE Select: NM_019098 NM_019098

CCDS: CCDS6244

Canonical transcript exons

ENST00000320005 — 18 exons

Exon	Start	End
ENSE00000698483	86666925	86667133
ENSE00000698541	86579106	86579252
ENSE00000698548	86578689	86578863
ENSE00000836170	86668019	86668168
ENSE00001163073	86604093	86604211
ENSE00001195455	86647801	86647887
ENSE00001195460	86654012	86654062
ENSE00001195507	86625983	86626080
ENSE00001195518	86628919	86629078
ENSE00001195526	86632752	86632893
ENSE00001195534	86643751	86643873
ENSE00001195543	86644622	86644686
ENSE00001195576	86670944	86671098
ENSE00001260447	86611588	86611671
ENSE00003511893	86726531	86726657
ENSE00003532076	86739655	86739736
ENSE00003911763	86743499	86743634
ENSE00003913293	86574179	86576130

Expression profiles

Bgee: expression breadth ubiquitous, 161 present calls, max score 82.15.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 7.4793 / max 5695.3072, expressed in 20 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
93825	4.1034	10
93826	2.9269	14
93824	0.0828	4
93827	0.0704	6
93829	0.0701	4
93828	0.0684	6
93830	0.0577	4
93832	0.0516	4
93831	0.0326	4
93823	0.0155	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.15	gold quality
pigmented layer of retina	UBERON:0001782	82.02	gold quality
diaphragm	UBERON:0001103	77.67	gold quality
tongue squamous epithelium	UBERON:0006919	74.99	gold quality
olfactory bulb	UBERON:0002264	71.79	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	71.48	gold quality
hair follicle	UBERON:0002073	70.87	gold quality
CA1 field of hippocampus	UBERON:0003881	70.45	gold quality
type B pancreatic cell	CL:0000169	70.34	gold quality
calcaneal tendon	UBERON:0003701	69.07	gold quality
superficial temporal artery	UBERON:0001614	68.06	gold quality
ventral tegmental area	UBERON:0002691	67.70	gold quality
inferior vagus X ganglion	UBERON:0005363	67.32	gold quality
subthalamic nucleus	UBERON:0001906	67.28	gold quality
dorsal plus ventral thalamus	UBERON:0001897	67.24	gold quality
tongue	UBERON:0001723	67.20	gold quality
cardia of stomach	UBERON:0001162	67.17	gold quality
vena cava	UBERON:0004087	67.04	gold quality
pericardium	UBERON:0002407	66.98	gold quality
male germ cell	CL:0000015	66.94	silver quality
saphenous vein	UBERON:0007318	66.92	gold quality
superior surface of tongue	UBERON:0007371	66.75	gold quality
cerebellar vermis	UBERON:0004720	66.70	gold quality
layer of synovial tissue	UBERON:0007616	66.70	gold quality
vastus lateralis	UBERON:0001379	66.69	gold quality
body of tongue	UBERON:0011876	66.65	gold quality
substantia nigra pars reticulata	UBERON:0001966	66.59	gold quality
pharyngeal mucosa	UBERON:0000355	66.57	gold quality
nipple	UBERON:0002030	66.57	gold quality
lateral globus pallidus	UBERON:0002476	66.50	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-11121	yes	270.80
E-MTAB-7316	yes	27.49
E-ANND-3	yes	6.17

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

97 targeting CNGB3, 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-450A-1-3P	100.00	69.33	1837
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540

Literature-anchored findings (GeneRIF, showing 38)

• NH2- and COOH-terminal calmodulin-binding sites in CNGB3 are functionally important for regulation of cyclic nucleotide-gated channel activity (PMID:12730238)
• CNGB3 has a role in determining ligand sensitivity and pore properties of heteromeric channels (PMID:12815043)
• Novel causative CNGB3 missense mutations found in Achromatopsia patients in the United Kingdom. (PMID:14757870)
• Cone photoreceptor cyclic nucleotide-gated channels are tetrameric assemblies of CNGB3 (B3) subunits. The stoichiometry and arrangement for B3 show pore-forming tetramers and like subunits are positioned adjacent to each other. (PMID:15134637)
• In this study, a novel Arg403Gln mutation was identified, located in the middle of the pore domain of the cone CNG cation channel beta-subunit, which when associated with the nonsense mutation Thr383fs, resulted in progressive cone dystrophy. (PMID:15161866)
• findings indicate that the CNGB3/ACHM3 locus on chromosome 8q21 is the major locus for achromatopsia in patients of European origin or descent (PMID:15657609)
• Out of 36 achromats, 12 (33%) had mutations in CNGB3 (six different mutations including four novel mutations). CNGB3 should be considered as a candidate gene to be evaluated in patients with forms of cone dysfunction, including macular degeneration. (PMID:15712225)
• Mutations in CNGA3 and CNGB3 account for achromatopsia in Hungarian patients including known mutations and a few new CNGB3 mutations. (PMID:16319819)
• We have examined the gating effects of two previously uncharacterized disease-associated mutations in the CNGB3 subunit and found that in each case, the mutations resulted in a gain of function molecular phenotype. (PMID:16379026)
• Phospholipid metabolism and exogenously applied phosphatidylinositol 3,4,5-trisphosphate can modulate heterologously expressed cone CNG channels. (PMID:17018579)
• CNGA3 and CNGB3 mutations are responsible for the substantial majority of achromatopsia. Furthermore, the CNGB3 mutation p.T383fsX is a predominant mutation, results from a founder effect (PMID:17265047)
• Testing confirms the diagnosis at the molecular level and allows for a more precise prognosis of the possible future clinical evolution (PMID:17651254)
• Foveomacular atrophy can occur in CNGB3-affected subjects, and even heterozygous carriers can exhibit maculopathy (PMID:17652762)
• The CNGB3 gene was by far the most important causal gene, and T383IfsX13 the most frequent mutation in complete and incomplete achromatopsia. (PMID:19592100)
• down-regulation of CNGA3 contributes to the pathogenic mechanism by which CNGB3 mutations lead to human cone disease. (PMID:19767295)
• 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)
• Subretinal administration of rAAV5-hCNGB3 with a long version of the red cone opsin promoter in younger animals led to a stable therapeutic effect for at least 33 months. (PMID:20378608)
• 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)
• Missense mutations, nonsense mutations, splice mutations, and small deletions and insertions in the affected genes cause achromatopsia. (PMID:21267001)
• 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)
• Achromatopsia associated F525N and T383fsX mutations in the CNGB3 subunit of cone photoreceptor cyclic nucleotide-gated (CNG) channels increases susceptibility to cell death in photoreceptor-derived cells. (PMID:23805033)
• Data found pathogenic DNA variants in the genes RP1, USH2A, CNGB3, NMNAT1, CHM, and ABCA4, responsible for retinitis pigmentosa, Usher syndrome, achromatopsia, Leber congenital amaurosis, choroideremia, or recessive Stargardt/cone-rod dystrophy cases. (PMID:23940504)
• Genetic testing performed at Carver lab at the University of Iowa confirmed a diagnosis of achromatopsia with identical mutations in the CNGB3 gene. (PMID:24664743)
• 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)
• Eight different mutations were detected in the CNGB3 gene in achromatopsia, including five novel mutations: two splice site mutations, one nonsense substitution, and two frame-shift mutations. (PMID:25558176)
• The degree of residual foveal cone structure varies greatly among subjects with CNGB3-associated ACHM. (PMID:27479814)
• Foveal cone structure showed little or no change in this group of subjects with CNGB3-associated achromatopsia. Over the time scales investigated (6-26 months), achromatopsia seems to be a structurally stable condition, although longer-term follow-up is needed. (PMID:28145975)
• a comprehensive view on the spectrum and prevalence of CNGB3 mutations in achromatopsia patients. (PMID:28795510)
• Although the defect that causes achromatopsia is primarily in the cone photoreceptors, our results reveal an accompanying disruption of rod function that is more severe than has previously been reported. The differential effects on the b-wave relative to the a-wave points to an inner-retinal locus for the disruption of rod function in these patients. (PMID:28929832)
• The results of this study do not support the hypothesis that the focal chorioretinitis seen with high doses of AAV5-PR2.1-hCNGB3 in the initial studies was due to an immune response to human CNGB3. (PMID:29020838)
• Deep-intronic variants in CNGB3 cause achromatopsia by pseudoexon activation. (PMID:31544997)
• Nystagmus and optical coherence tomography findings in CNGB3-associated achromatopsia. (PMID:32151571)
• Identification of disease-causing mutations in CNGB3 in achromatopsia (PMID:32397729)
• Ametropia and Emmetropization in CNGB3 Achromatopsia. (PMID:33560291)
• Disease Progression in CNGA3 and CNGB3 Retinopathy; Characteristics of Slovenian Cohort and Proposed OCT Staging Based on Pooled Data from 126 Patients from 7 Studies. (PMID:34449556)
• A deep intronic substitution in CNGB3 is one of the major causes of achromatopsia among Jewish patients. (PMID:34703197)
• Absent meibomian glands and cone dystrophy in ADULT syndrome: identification by whole exome sequencing of pathogenic variants in two causal genes TP63 and CNGB3. (PMID:37158316)
• Molecular and Clinical Characterization of CNGA3 and CNGB3 Genes in Brazilian Patients Affected with Achromatopsia. (PMID:37372476)

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
danio_rerio	cngb3.1	ENSDARG00000101225
danio_rerio	cngb3.2	ENSDARG00000101368
mus_musculus	Cngb3	ENSMUSG00000056494
rattus_norvegicus	Cngb3	ENSRNOG00000006084
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), CNGA3 (ENSG00000144191), HCN1 (ENSG00000164588), KCNH6 (ENSG00000173826), CNGA2 (ENSG00000183862), KCNH8 (ENSG00000183960), KCNH7 (ENSG00000184611), CNGA1 (ENSG00000198515)

Protein

Protein identifiers

Cyclic nucleotide-gated channel beta-3 — Q9NQW8 (reviewed: Q9NQW8)

Alternative names: Cone photoreceptor cGMP-gated channel subunit beta, Cyclic nucleotide-gated cation channel beta-3, Cyclic nucleotide-gated cation channel modulatory subunit

All UniProt accessions (3): Q9NQW8, A0A5J6DSN8, H0YAZ4

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. 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. Expressed specifically in the retina.

Disease relevance. Stargardt disease 1 (STGD1) [MIM:248200] An autosomal recessive form of Stargardt disease, a retinal degenerative disease characterized by macular dystrophy, progressive bilateral atrophy of the foveal retinal pigment epithelium, and accumulation of fluorescent flecks around the macula and/or in the central and near-peripheral areas of the retina. STGD1 patients typically lose central vision in their first or second decade of life. The disease is caused by variants affecting the gene represented in this entry. Achromatopsia 3 (ACHM3) [MIM:262300] 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. Achromatopsia type 3 patients manifest severe myopia. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. 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. CNGB1 displays an additional charged arginine gate below the central gate to regulate ion permeation.

Similarity. Belongs to the cyclic nucleotide-gated cation channel (TC 1.A.1.5) family. CNGB3 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NQW8-1	1	yes
Q9NQW8-2	2

RefSeq proteins (1): NP_061971* (*=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
IPR050866	CNG_cation_channel	Family

Pfam: PF00027, PF00520

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 (97 total): sequence variant 24, helix 19, strand 18, topological domain 7, transmembrane region 7, region of interest 7, compositionally biased region 5, binding site 4, site 3, chain 1, splice variant 1, turn 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
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-Q9NQW8-F1	68.87	0.34

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 (3): 434 (central gate); 438 (central gate); 442 (occludes the pore below the central gate)

Ligand- & substrate-binding residues (4): 591; 592; 604; 605

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 167 (showing top): PID_CONE_PATHWAY, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, TGANTCA_AP1_C, HNF1_C, GOBP_SENSORY_PERCEPTION, GOCC_NEURON_PROJECTION, GOBP_TRANSMEMBRANE_TRANSPORT, FOXO4_02, TTCNRGNNNNTTC_HSF_Q6, SHEN_SMARCA2_TARGETS_DN, GOCC_CATION_CHANNEL_COMPLEX, GOCC_TRANSPORTER_COMPLEX, GOCC_MEMBRANE_PROTEIN_COMPLEX, GOCC_CILIUM

GO Biological Process (7): monoatomic cation transport (GO:0006812), signal transduction (GO:0007165), visual perception (GO:0007601), monoatomic cation transmembrane transport (GO:0098655), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085)

GO Molecular Function (6): intracellularly cAMP-activated cation channel activity (GO:0005222), intracellularly cGMP-activated cation channel activity (GO:0005223), cGMP binding (GO:0030553), nucleotide binding (GO:0000166), monoatomic ion channel activity (GO:0005216), intracellularly cyclic nucleotide-activated monoatomic cation channel activity (GO:0005221)

GO Cellular Component (5): photoreceptor outer segment (GO:0001750), plasma membrane (GO:0005886), intracellular cyclic nucleotide activated cation channel complex (GO:0017071), transmembrane transporter complex (GO:1902495), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
monoatomic ion transport	2
cellular process	2
transport	2
intracellularly cyclic nucleotide-activated monoatomic cation channel activity	2
cellular anatomical structure	2
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
sensory perception of light stimulus	1
monoatomic cation transport	1
monoatomic ion transmembrane transport	1
transmembrane transport	1
cyclic nucleotide binding	1
guanyl ribonucleotide binding	1
anion 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
ligand-gated monoatomic cation channel activity	1
photoreceptor cell cilium	1
membrane	1
cell periphery	1
cation channel complex	1
membrane protein complex	1
transporter complex	1

Protein interactions and networks

STRING

906 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CNGB3	GNAT2	P19087	988
CNGB3	PDE6C	P51160	983
CNGB3	CNGA3	Q16281	972
CNGB3	PDE6H	Q13956	855
CNGB3	ELOVL4	Q9GZR5	855
CNGB3	ABCA4	P78363	834
CNGB3	OPN4	Q9UHM6	739
CNGB3	RPGR	Q92834	737
CNGB3	GUCY2D	Q02846	715
CNGB3	RPE65	Q16518	698
CNGB3	PDP1	Q9P0J1	686
CNGB3	PDE6A	P16499	656
CNGB3	DECR1	Q16698	650
CNGB3	RPGRIP1	Q96KN7	648
CNGB3	RGS9BP	Q6ZS82	642

IntAct

3 interactions, top by confidence:

A	B	Type	Score
NEK4	E2F8	psi-mi:“MI:0914”(association)	0.350
APBB1	SSPOP	psi-mi:“MI:0914”(association)	0.350

BioGRID (10): CNGA3 (Affinity Capture-Western), CNGB3 (Affinity Capture-MS), CNGB3 (Affinity Capture-MS), CNGB3 (Affinity Capture-MS), SNRPA1 (Cross-Linking-MS (XL-MS)), CNGB3 (Two-hybrid), CNGB3 (Affinity Capture-MS), CNGB3 (Co-fractionation), CNGB3 (Co-fractionation), CNGB3 (Co-fractionation)

ESM2 similar proteins: G5EFJ9, O08703, O08962, O35219, O54852, O54853, O73925, O88457, O95259, O97531, P0C550, P27671, P48994, P56698, P57789, P59111, P70057, P92960, P97414, Q02280, Q0JKV1, Q11122, Q12809, Q38849, Q38998, Q60603, Q63472, Q6K3T2, Q6R5A3, Q8BUW1, Q8GXE6, Q8MJD7, Q8NCM2, Q8WNY2, Q920E3, Q96L42, Q9EPI9, Q9ER47, Q9JJZ9, Q9JK45

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, A0A509AKL0, A0R3F9, A3RL54, A8X6H1, O05581

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1388 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	178
Likely pathogenic	98
Uncertain significance	418
Likely benign	556
Benign	48

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1067152	NM_019098.5(CNGB3):c.1056-1G>C	Pathogenic
1069005	NC_000008.10:g.(?87638201)(87645131_?)del	Pathogenic
1069006	NC_000008.10:g.(?87666240)(87683326_?)dup	Pathogenic
1070082	NM_019098.5(CNGB3):c.1738del (p.Val580fs)	Pathogenic
1072138	NM_019098.5(CNGB3):c.917C>A (p.Ser306Ter)	Pathogenic
1075338	NM_019098.5(CNGB3):c.668T>A (p.Leu223Ter)	Pathogenic
1076826	NM_019098.5(CNGB3):c.826C>T (p.Gln276Ter)	Pathogenic
1322099	NM_019098.5(CNGB3):c.442_446delinsGAAAAT (p.Lys148fs)	Pathogenic
1354843	NM_019098.5(CNGB3):c.2105del (p.Lys702fs)	Pathogenic
1355916	NM_019098.5(CNGB3):c.357del (p.Ala120fs)	Pathogenic
1380448	NM_019098.5(CNGB3):c.223A>T (p.Lys75Ter)	Pathogenic
1386368	NM_019098.5(CNGB3):c.1637T>A (p.Leu546Ter)	Pathogenic
1386651	NM_019098.5(CNGB3):c.1599_1600dup (p.Tyr534fs)	Pathogenic
1397138	NM_019098.5(CNGB3):c.566G>A (p.Trp189Ter)	Pathogenic
1401244	NM_019098.5(CNGB3):c.2184del (p.Glu729fs)	Pathogenic
1407800	NM_019098.5(CNGB3):c.470C>A (p.Ser157Ter)	Pathogenic
1413944	NM_019098.5(CNGB3):c.1370_1371del (p.Ala457fs)	Pathogenic
1431922	NM_019098.5(CNGB3):c.1666G>T (p.Glu556Ter)	Pathogenic
1432544	NM_019098.5(CNGB3):c.1461G>A (p.Trp487Ter)	Pathogenic
1432985	NM_019098.5(CNGB3):c.1250del (p.Leu417fs)	Pathogenic
1437049	NM_019098.5(CNGB3):c.1310T>G (p.Leu437Ter)	Pathogenic
1440503	NM_019098.5(CNGB3):c.1576A>T (p.Lys526Ter)	Pathogenic
1450605	NM_019098.5(CNGB3):c.41_42dup (p.Gly15Ter)	Pathogenic
1451386	NM_019098.5(CNGB3):c.1168G>T (p.Glu390Ter)	Pathogenic
1451538	NC_000008.10:g.(?87679332)(87687741_?)del	Pathogenic
1451933	NM_019098.5(CNGB3):c.381T>G (p.Tyr127Ter)	Pathogenic
1452702	NM_019098.5(CNGB3):c.590T>G (p.Leu197Ter)	Pathogenic
1453089	NM_019098.5(CNGB3):c.1579-2del	Pathogenic
1453998	NM_019098.5(CNGB3):c.250_262del (p.Thr84fs)	Pathogenic
1457526	NC_000008.10:g.(?87738749)(87755865_?)del	Pathogenic

SpliceAI

4276 predictions. Top by Δscore:

Variant	Effect	Δscore
8:86554846:TCTA:T	acceptor_loss	1.0000
8:86554847:CTAG:C	acceptor_loss	1.0000
8:86554849:A:AG	acceptor_gain	1.0000
8:86554849:A:T	acceptor_loss	1.0000
8:86554850:G:A	acceptor_loss	1.0000
8:86554850:G:GG	acceptor_gain	1.0000
8:86554850:GGA:G	acceptor_gain	1.0000
8:86554980:CTTCT:C	donor_gain	1.0000
8:86554981:TTCT:T	donor_gain	1.0000
8:86554982:TCT:T	donor_gain	1.0000
8:86554983:CT:C	donor_gain	1.0000
8:86554984:TG:T	donor_loss	1.0000
8:86554985:G:GG	donor_gain	1.0000
8:86554986:TAAG:T	donor_loss	1.0000
8:86554987:AAGT:A	donor_loss	1.0000
8:86556101:GCAAT:G	acceptor_gain	1.0000
8:86556131:T:TA	acceptor_gain	1.0000
8:86558283:A:AG	acceptor_gain	1.0000
8:86558283:ACAAG:A	acceptor_gain	1.0000
8:86558284:C:G	acceptor_gain	1.0000
8:86558285:A:AG	acceptor_gain	1.0000
8:86558285:AAG:A	acceptor_gain	1.0000
8:86558286:A:G	acceptor_gain	1.0000
8:86578640:A:AC	donor_gain	1.0000
8:86578859:GCACT:G	acceptor_gain	1.0000
8:86578860:CACT:C	acceptor_gain	1.0000
8:86578860:CACTC:C	acceptor_gain	1.0000
8:86578861:ACT:A	acceptor_gain	1.0000
8:86578862:CT:C	acceptor_gain	1.0000
8:86578862:CTC:C	acceptor_gain	1.0000

AlphaMissense

5313 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:86604102:C:T	G591E	0.998
8:86611598:A:T	V551D	0.998
8:86604104:A:C	F590L	0.997
8:86604104:A:T	F590L	0.997
8:86604106:A:G	F590L	0.997
8:86604174:C:T	G567E	0.997
8:86579187:A:G	L616P	0.996
8:86579195:A:C	F613L	0.996
8:86579195:A:T	F613L	0.996
8:86579197:A:G	F613L	0.996
8:86579205:G:T	A610D	0.996
8:86604102:C:A	G591V	0.996
8:86628963:A:T	V479D	0.996
8:86604103:C:G	G591R	0.995
8:86604103:C:T	G591R	0.995
8:86604168:A:T	V569D	0.995
8:86604174:C:A	G567V	0.995
8:86628955:A:G	W482R	0.995
8:86628955:A:T	W482R	0.995
8:86632770:G:C	F434L	0.995
8:86632770:G:T	F434L	0.995
8:86632772:A:G	F434L	0.995
8:86604123:A:G	L584P	0.994
8:86628966:C:G	R478P	0.994
8:86643776:A:G	W385R	0.993
8:86643776:A:T	W385R	0.993
8:86604105:A:C	F590C	0.992
8:86604105:A:G	F590S	0.992
8:86604201:C:T	G558D	0.992
8:86625987:A:G	F525S	0.992

dbSNP variants (sampled 300 via entrez): RS1000021452 (8:86667685 C>T), RS1000022370 (8:86706987 C>G), RS1000025742 (8:86624551 C>T), RS1000057537 (8:86742586 A>G), RS1000064213 (8:86619608 C>T), RS1000074336 (8:86619267 T>G), RS1000090709 (8:86699727 G>T), RS1000118193 (8:86707327 G>A), RS1000146601 (8:86574201 T>C), RS1000172281 (8:86594879 T>A), RS1000190422 (8:86720217 A>C), RS1000191006 (8:86586307 A>C,G), RS1000236314 (8:86673824 T>G), RS1000257289 (8:86631605 G>T), RS1000289014 (8:86592226 C>A,G,T)

Disease associations

OMIM: gene MIM:605080 | disease phenotypes: MIM:248200, MIM:262300, MIM:268000, MIM:204000, MIM:120970

GenCC curated gene-disease

Disease	Classification	Inheritance
achromatopsia 3	Definitive	Autosomal recessive
cone dystrophy	Supportive	Autosomal dominant
achromatopsia	Supportive	Autosomal recessive
severe early-childhood-onset retinal dystrophy	Limited	Unknown

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
CNGB3-related retinopathy	Definitive	AR

Mondo (12): severe early-childhood-onset retinal dystrophy (MONDO:0009549), achromatopsia 3 (MONDO:0009875), achromatopsia (MONDO:0018852), inherited retinal dystrophy (MONDO:0019118), retinitis pigmentosa (MONDO:0019200), Leber congenital amaurosis (MONDO:0018998), CNGB3-related retinopathy (MONDO:0100446), pathologic nystagmus (MONDO:0004843), retinal disorder (MONDO:0005283), optic atrophy (MONDO:0003608), cone-rod dystrophy (MONDO:0015993), cone dystrophy (MONDO:0000455)

Orphanet (7): Severe early-childhood-onset retinal dystrophy (Orphanet:364055), Achromatopsia (Orphanet:49382), Stargardt disease (Orphanet:827), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Retinitis pigmentosa (Orphanet:791), Leber congenital amaurosis (Orphanet:65), Cone rod dystrophy (Orphanet:1872)

HPO phenotypes

43 total (30 of 43 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000493	Abnormal foveal morphology
HP:0000505	Visual impairment
HP:0000512	Abnormal electroretinogram
HP:0000518	Cataract
HP:0000539	Abnormality of refraction
HP:0000540	Hypermetropia
HP:0000545	Myopia
HP:0000551	Color vision defect
HP:0000603	Central scotoma
HP:0000608	Macular degeneration
HP:0000610	Abnormal choroid morphology
HP:0000613	Photophobia
HP:0000639	Nystagmus
HP:0000649	Abnormality of visual evoked potentials
HP:0000662	Nyctalopia
HP:0001103	Abnormal macular morphology
HP:0001141	Severely reduced visual acuity
HP:0007641	Dyschromatopsia
HP:0007663	Reduced visual acuity
HP:0007695	Abnormal pupillary light reflex
HP:0007703	Abnormal retinal pigmentation
HP:0007704	Paroxysmal involuntary eye movements
HP:0007722	Retinal pigment epithelial atrophy
HP:0007750	Hypoplasia of the fovea
HP:0007803	Monochromacy
HP:0007811	Horizontal pendular nystagmus
HP:0007814	Retinal pigment epithelial mottling
HP:0007843	Attenuation of retinal blood vessels
HP:0008002	Abnormal macular pigmentation

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002642_5	Response to simvastatin treatment (PCSK9 protein level change)	5.000000e-06
GCST003542_48	Night sleep phenotypes	6.000000e-06
GCST008559_6	Anxiety and stress-related disorders	9.000000e-07
GCST010002_307	Refractive error	1.000000e-14
GCST010988_304	Adult body size	2.000000e-08
GCST90000047_159	Age at first sexual intercourse	2.000000e-11

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006899	PCSK9 protein measurement
EFO:0010098	stress-related disorder
EFO:0009749	age at first sexual intercourse measurement

MeSH disease descriptors (8)

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
D057130	Leber Congenital Amaurosis	C11.270.516; C11.768.364
D009759	Nystagmus, Pathologic	C10.292.562.675; C11.590.400
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D012164	Retinal Diseases	C11.768
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684

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 (1 total), top 1:

Ligand	Action	Affinity	Parameter
L-(cis)-diltiazem	Antagonist	5.5	pIC50

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	2
bisphenol A	decreases methylation	1
sodium arsenite	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Acetaminophen	decreases expression	1
Copper	affects cotreatment, decreases expression	1
Silver	decreases expression	1
Zinc	decreases expression	1
Aflatoxin B1	increases methylation	1

Cellosaurus cell lines

3 cell lines: 3 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B3UT	1579	Induced pluripotent stem cell	Female
CVCL_B3UU	1580	Induced pluripotent stem cell	Female
CVCL_B3UV	1581	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT05244304	PHASE3	COMPLETED	Phase 3, Randomized, Placebo-Controlled Study of Tinlarebant to Explore Safety and Efficacy in Adolescent Stargardt Disease
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
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT04489511	PHASE2	COMPLETED	Study of STG-001 in Subjects With Stargardt Disease
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa
NCT05392179	PHASE2	COMPLETED	A Study in Subjects With Retinitis Pigmentosa
NCT06627179	PHASE2	RECRUITING	Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
NCT06628947	PHASE2	RECRUITING	A Phase II Study of Intravitreal KIO-301 in Patients With Late-stage Retinitis Pigmentosa
NCT06912633	PHASE2	RECRUITING	Safety of a Single, Intravitreal Injection of 6.0M jCell (Famzeretcel) in Retinitis Pigmentosa (RP)
NCT03772938	PHASE1	UNKNOWN	Stem Cells Therapy in Degenerative Diseases of the Retina