CNGA1

Summary

CNGA1 (cyclic nucleotide gated channel subunit alpha 1, HGNC:2148) is a protein-coding gene on chromosome 4p12, encoding Cyclic nucleotide-gated channel alpha-1 (P29973). Pore-forming subunit of the rod cyclic nucleotide-gated channel.

The protein encoded by this gene is involved in phototransduction. Along with another protein, the encoded protein forms a cGMP-gated cation channel in the plasma membrane, allowing depolarization of rod photoreceptors. This represents the last step in the phototransduction pathway. Defects in this gene are a cause of retinitis pigmentosa autosomal recessive (ARRP) disease. Multiple transcript variants have been found for this gene.

Source: NCBI Gene 1259 — RefSeq curated summary.

At a glance

• Gene–disease (curated): CNGA1-related retinopathy (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 478 total — 40 pathogenic, 19 likely-pathogenic
• Phenotypes (HPO): 37
• MANE Select transcript: NM_001379270

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2148
Approved symbol	CNGA1
Name	cyclic nucleotide gated channel subunit alpha 1
Location	4p12
Locus type	gene with protein product
Status	Approved
Aliases	RCNC1, RCNCa, CNG1, RP49
Ensembl gene	ENSG00000198515
Ensembl biotype	protein_coding
OMIM	123825
Entrez	1259

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 12 protein_coding, 1 retained_intron

ENST00000402813, ENST00000420489, ENST00000504722, ENST00000506118, ENST00000513178, ENST00000514170, ENST00000514520, ENST00000868239, ENST00000868240, ENST00000868241, ENST00000936895, ENST00000959563, ENST00000959564

RefSeq mRNA: 3 — MANE Select: NM_001379270 NM_000087, NM_001142564, NM_001379270

CCDS: CCDS43226

Canonical transcript exons

ENST00000514170 — 11 exons

Exon	Start	End
ENSE00001143810	47943181	47943288
ENSE00001412467	47942041	47942148
ENSE00001414756	47940763	47940869
ENSE00002058206	47981393	47981500
ENSE00002086846	48010794	48010893
ENSE00002087963	48016483	48016681
ENSE00003473022	47952583	47952703
ENSE00003484111	47951353	47951469
ENSE00003553984	47943371	47943412
ENSE00003785175	47949833	47949895
ENSE00003902009	47935977	47937829

Expression profiles

Bgee: expression breadth ubiquitous, 182 present calls, max score 84.07.

FANTOM5 (CAGE): breadth broad, TPM avg 0.8448 / max 48.0503, expressed in 355 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
52057	0.2975	140
52058	0.1965	87
52056	0.1455	73
52054	0.0906	50
52055	0.0743	30
52052	0.0288	4
52049	0.0055	2
52051	0.0032	2
52050	0.0029	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	84.07	gold quality
amniotic fluid	UBERON:0000173	82.92	gold quality
right lobe of liver	UBERON:0001114	82.60	gold quality
sural nerve	UBERON:0015488	80.74	gold quality
epithelial cell of pancreas	CL:0000083	79.44	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.51	gold quality
liver	UBERON:0002107	77.49	gold quality
pancreatic ductal cell	CL:0002079	77.06	silver quality
esophagus mucosa	UBERON:0002469	75.64	gold quality
esophagus squamous epithelium	UBERON:0006920	73.90	gold quality
mucosa of urinary bladder	UBERON:0001259	72.92	silver quality
skin of abdomen	UBERON:0001416	72.40	gold quality
skin of hip	UBERON:0001554	72.38	gold quality
corpus epididymis	UBERON:0004359	72.05	gold quality
skin of leg	UBERON:0001511	71.24	gold quality
hindlimb stylopod muscle	UBERON:0004252	71.22	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	70.36	gold quality
epithelium of esophagus	UBERON:0001976	70.29	gold quality
zone of skin	UBERON:0000014	69.97	gold quality
upper leg skin	UBERON:0004262	69.94	gold quality
right uterine tube	UBERON:0001302	69.68	gold quality
islet of Langerhans	UBERON:0000006	68.98	gold quality
ileal mucosa	UBERON:0000331	68.69	silver quality
rectum	UBERON:0001052	68.07	gold quality
hair follicle	UBERON:0002073	67.90	silver quality
urinary bladder	UBERON:0001255	67.32	gold quality
caput epididymis	UBERON:0004358	67.19	gold quality
tibial nerve	UBERON:0001323	66.78	gold quality
minor salivary gland	UBERON:0001830	66.68	gold quality
squamous epithelium	UBERON:0006914	65.71	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-7316	yes	5954.52
E-GEOD-98556	yes	1718.34
E-GEOD-137537	yes	24.41
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

29 targeting CNGA1, 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-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-5571-5P	99.49	66.99	1764
HSA-MIR-6083	99.47	68.73	2393
HSA-MIR-4735-5P	99.43	68.49	1780
HSA-MIR-208A-5P	99.42	70.83	1913
HSA-MIR-208B-5P	99.42	70.83	1952
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-10522-5P	99.26	68.50	2087
HSA-MIR-4721	99.26	66.05	818
HSA-MIR-664A-3P	99.22	71.08	2696
HSA-MIR-3606-3P	99.11	69.84	3254
HSA-MIR-877-3P	99.09	68.10	1637
HSA-MIR-670-3P	99.03	68.88	2404
HSA-MIR-935	98.82	69.36	1072
HSA-MIR-605-5P	98.79	68.24	1161
HSA-MIR-12125	98.59	67.54	1044
HSA-MIR-6881-3P	98.04	68.24	1777
HSA-MIR-4733-5P	97.75	67.44	866
HSA-MIR-217-3P	95.67	68.42	1000

Literature-anchored findings (GeneRIF, showing 13)

• Novel homozygous mutation R28X truncates CNGA1 very prematurely in patients with autosomal recessive retinitis pigmentosa. (PMID:12362048)
• isolated an endogenous transcript (anti-CNG1) that is antisense to CNG1 mRNA; data suggest the suppression of CNG(alpha)1 expression by anti-CNG1 may play an important role in neuronal functions, especially in synaptic plasticity and cortical development (PMID:12388767)
• The heteromeric cyclic nucleotide-gated channel adopts a 3A:1B stoichiometry (PMID:12432397)
• The autosomal recessive retinitis pigmentosa in this family is caused by a mutation in CNGA1 gene. (PMID:15570217)
• Expressed in a stage- and cell-specific manner in the rat testis. (PMID:15713832)
• Insulin receptor (IR), an integral membrane protein, directly phosphorylates the CNGA1 subunit of CNG channels that in turn affects the function of these channels negatively. CNGA1 is a direct substrate of IR. (PMID:23032687)
• CNGA1 mutations are one of the most frequent autosomal recessive retinitis pigmentosa-causing mutations in the Japanese patients. (PMID:25268133)
• The mut CNGA1 p.(G513R) protein was largely retained inside the cell rather than being targeted to the plasma membrane, suggesting the absence of cGMP-gated cation channels in the plasma membrane (PMID:26802146)
• Compound heterozygous mutations (NM000087, p.Y82X and p.L89fs) in exon 6 of CNGA1are pathogenic mutations in this Chinese family affected with autosomal recessive retinitis pigmentosa. Of which, p.Y82X is firstly reported in patient with autosomal recessive retinitis pigmentosa. (PMID:27391953)
• Identification of a novel homozygous variant in the CNGA1 gene in a Chinese family with autosomal recessive retinitis pigmentosa. (PMID:32705276)
• Genome-wide Association Analysis Across 16,956 Patients Identifies a Novel Genetic Association Between BMP6, NIPAL1, CNGA1 and Spondylosis. (PMID:33332786)
• A case of retinitis pigmentosa homozygous for a rare CNGA1 causal variant. (PMID:33633220)
• Structural basis of the partially open central gate in the human CNGA1/CNGB1 channel explained by additional density for calmodulin in cryo-EM map. (PMID:34971760)

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
danio_rerio	cnga1b	ENSDARG00000012125
danio_rerio	cnga1a	ENSDARG00000029898
mus_musculus	Cnga1	ENSMUSG00000067220
rattus_norvegicus	Cnga1	ENSRNOG00000004778
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), CNGB3 (ENSG00000170289), KCNH6 (ENSG00000173826), CNGA2 (ENSG00000183862), KCNH8 (ENSG00000183960), KCNH7 (ENSG00000184611)

Protein

Protein identifiers

Cyclic nucleotide-gated channel alpha-1 — P29973 (reviewed: P29973)

Alternative names: Cyclic nucleotide-gated channel, photoreceptor, Rod photoreceptor cGMP-gated cation channel subunit alpha, cGMP-gated cation channel alpha-1

All UniProt accessions (3): P29973, D6R978, D6RCF1

UniProt curated annotations — full annotation on UniProt →

Function. Pore-forming subunit of the rod cyclic nucleotide-gated channel. Mediates rod photoresponses at dim 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. The selectivity for Ca(2+) over Na(+) increases with cGMP concentrations, whereas the selectivity among monovalent ions is independent of the cGMP levels.

Subunit / interactions. Forms heterotetrameric channels composed of CNGA1 and CNGB1 subunits with 3:1 stoichiometry. May also form cyclic nucleotide-activated homotetrameric channels, that are efficiently activated by saturating cGMP, but poorly activated by saturating cAMP compared to the heterotetramer with CNGB1. The channel binds Ca(2+)-bound CALM1 via CaM1 and CaM2 regions of the CNGB1 subunit; this interaction modulates the affinity of the channel for cNMPs in response to intracellular Ca(2+) levels.

Subcellular location. Cell membrane.

Tissue specificity. Rod cells in the retina.

Disease relevance. Retinitis pigmentosa 49 (RP49) [MIM:613756] A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Channel opening is activated by cGMP and at a much lesser extent by cAMP. Ca(2+) binding concominantly blocks monovalent cation currents. Inhibited by L-cis-diltiazem.

Domain organisation. The C-terminal coiled-coil domain mediates homotrimerization of CNGA1 subunit. The cyclic nucleotide-binding domain (CNBD) comprises three helices and a beta-roll of eight beta-strands from CNGA1 and CNGB1 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 CNGA1 and CNGB1 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. CNGA1 subfamily.

RefSeq proteins (3): NP_000078, NP_001136036, NP_001366199* (*=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 (84 total): helix 21, strand 12, sequence conflict 8, topological domain 7, transmembrane region 7, region of interest 6, binding site 6, compositionally biased region 4, sequence variant 4, turn 3, site 2, chain 1, coiled-coil region 1, glycosylation site 1, mutagenesis site 1

Structure

Experimental structures (PDB)

19 structures.

PDB	Method	Resolution (Å)
9ZPV	ELECTRON MICROSCOPY	2.07
9ZQ0	ELECTRON MICROSCOPY	2.11
9ZQ1	ELECTRON MICROSCOPY	2.22
9ZPW	ELECTRON MICROSCOPY	2.47
9ZPY	ELECTRON MICROSCOPY	2.48
7LFT	ELECTRON MICROSCOPY	2.6
7RH9	ELECTRON MICROSCOPY	2.61
9ZPX	ELECTRON MICROSCOPY	2.64
9ZPZ	ELECTRON MICROSCOPY	2.64
7LG1	ELECTRON MICROSCOPY	2.7
7RHG	ELECTRON MICROSCOPY	2.88
7RHJ	ELECTRON MICROSCOPY	2.88
7LFW	ELECTRON MICROSCOPY	2.9
7RHL	ELECTRON MICROSCOPY	3.03
7LFX	ELECTRON MICROSCOPY	3.1
7RHK	ELECTRON MICROSCOPY	3.27
7RHH	ELECTRON MICROSCOPY	3.31
7RHI	ELECTRON MICROSCOPY	3.31
7LFY	ELECTRON MICROSCOPY	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P29973-F1	76.88	0.39

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): 385 (central gate); 389 (central gate)

Ligand- & substrate-binding residues (6): 541; 544; 557; 557; 558; 558

Glycosylation sites (1): 325

Mutagenesis-validated functional residues (1):

Position	Phenotype
361	renders the channel voltage-gated in the presence of saturated concentrations of cgmp.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2485179	Activation of the phototransduction cascade
R-HSA-2514859	Inactivation, recovery and regulation of the phototransduction cascade

MSigDB gene sets: 252 (showing top): GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_SENSORY_PERCEPTION_OF_CHEMICAL_STIMULUS, GOBP_MONOATOMIC_CATION_TRANSPORT, chr4p12, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, WANG_RECURRENT_LIVER_CANCER_DN, GOBP_SENSORY_PERCEPTION, GOCC_NEURON_PROJECTION, MODULE_287, GOBP_CALCIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_TRANSMEMBRANE_TRANSPORT, GOBP_SODIUM_ION_TRANSPORT, GOCC_CELL_PROJECTION_MEMBRANE, GOCC_PHOTORECEPTOR_OUTER_SEGMENT_MEMBRANE

GO Biological Process (10): sodium ion transport (GO:0006814), calcium ion transport (GO:0006816), visual perception (GO:0007601), sensory perception of chemical stimulus (GO:0007606), monoatomic cation transmembrane transport (GO:0098655), monoatomic ion transport (GO:0006811), 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 (10): 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), cAMP binding (GO:0030552), cGMP binding (GO:0030553), 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 (6): plasma membrane (GO:0005886), intracellular cyclic nucleotide activated cation channel complex (GO:0017071), photoreceptor outer segment membrane (GO:0042622), rod photoreceptor outer segment (GO:0120200), photoreceptor outer segment (GO:0001750), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
The phototransduction cascade	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
metal ion transport	2
transport	2
monoatomic cation transmembrane transport	2
intracellularly cyclic nucleotide-activated monoatomic cation channel activity	2
monoatomic cation channel activity	2
cyclic nucleotide binding	2
anion binding	2
photoreceptor outer segment	2
cellular anatomical structure	2
sensory perception of light stimulus	1
sensory perception	1
monoatomic cation transport	1
monoatomic ion transmembrane transport	1
monoatomic ion transport	1
transmembrane transport	1
sodium ion transport	1
cellular process	1
calcium ion transport	1
calcium ion transmembrane transporter activity	1
sodium ion transmembrane transporter activity	1
adenyl ribonucleotide binding	1
guanyl ribonucleotide 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
binding	1
membrane	1
cell periphery	1
cation channel complex	1
ciliary membrane	1
photoreceptor cell cilium	1

Protein interactions and networks

STRING

1168 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CNGA1	CNGB1	Q14028	986
CNGA1	PDE6B	P35913	855
CNGA1	PDE6A	P16499	852
CNGA1	CERKL	Q49MI3	800
CNGA1	PDE6G	P18545	798
CNGA1	EYS	Q5T1H1	792
CNGA1	RHO	P08100	782
CNGA1	PRPH2	P23942	776
CNGA1	TULP1	O00294	774
CNGA1	PCARE	A6NGG8	774
CNGA1	PRCD	Q00LT1	774
CNGA1	ROM1	Q03395	769
CNGA1	GUCA1B	Q9UMX6	758
CNGA1	RDH12	Q96NR8	753
CNGA1	IMPG2	Q9BZV3	740

IntAct

8 interactions, top by confidence:

A	B	Type	Score
GRB14	CNGA1	psi-mi:“MI:0915”(physical association)	0.580
CNGA1	Grb14	psi-mi:“MI:0915”(physical association)	0.400
CNGA1	WWC1	psi-mi:“MI:0914”(association)	0.350

BioGRID (5): CNGA1 (Affinity Capture-Western), PNMA2 (Affinity Capture-MS), WWC1 (Affinity Capture-MS), C11orf31 (Affinity Capture-MS), NKX6-2 (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, Q03042, A0A509AKL0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	40
Likely pathogenic	19
Uncertain significance	241
Likely benign	132
Benign	17

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068762	NM_001379270.1(CNGA1):c.1525G>A (p.Gly509Arg)	Pathogenic
1069447	NM_001379270.1(CNGA1):c.1932T>A (p.Tyr644Ter)	Pathogenic
1073264	NM_001379270.1(CNGA1):c.103dup (p.Cys35fs)	Pathogenic
1073339	NM_001379270.1(CNGA1):c.721C>T (p.Gln241Ter)	Pathogenic
1073397	NM_001379270.1(CNGA1):c.1003_1007del (p.Asn334_Asp335insTer)	Pathogenic
1074764	NM_001379270.1(CNGA1):c.1242_1255del (p.Lys414fs)	Pathogenic
1075000	NM_001379270.1(CNGA1):c.1557del (p.Lys519fs)	Pathogenic
1075989	NM_001379270.1(CNGA1):c.1091del (p.Pro364fs)	Pathogenic
1076607	NM_001379270.1(CNGA1):c.1560del (p.Ala521fs)	Pathogenic
1373178	NM_001379270.1(CNGA1):c.85dup (p.Arg29fs)	Pathogenic
1451700	NM_001379270.1(CNGA1):c.148G>T (p.Glu50Ter)	Pathogenic
1454947	NM_001379270.1(CNGA1):c.1415dup (p.Val473fs)	Pathogenic
1459512	NC_000004.11:g.(?47938438)(47954718_?)del	Pathogenic
1460228	NC_000004.11:g.(?47938438)(47945449_?)del	Pathogenic
16930	NM_001379270.1(CNGA1):c.226G>T (p.Glu76Ter)	Pathogenic
16931	NM_001379270.1(CNGA1):c.415A>T (p.Lys139Ter)	Pathogenic
16933	NM_001379270.1(CNGA1):c.1960del (p.Arg654fs)	Pathogenic
2002417	NM_001379270.1(CNGA1):c.1372A>T (p.Arg458Ter)	Pathogenic
2019864	NM_001379270.1(CNGA1):c.432_435del (p.Glu145fs)	Pathogenic
2115312	NM_001379270.1(CNGA1):c.650del (p.Thr217fs)	Pathogenic
2118498	NM_001379270.1(CNGA1):c.664C>T (p.Gln222Ter)	Pathogenic
2118786	NM_001379270.1(CNGA1):c.1635del (p.Asn547fs)	Pathogenic
2131365	NM_001379270.1(CNGA1):c.36del (p.Phe12fs)	Pathogenic
2134241	NM_001379270.1(CNGA1):c.787del (p.Tyr263fs)	Pathogenic
2203541	NM_001379270.1(CNGA1):c.1417del (p.Val473fs)	Pathogenic
242520	NM_001379270.1(CNGA1):c.640C>T (p.Arg214Ter)	Pathogenic
2443933	NM_001379270.1(CNGA1):c.614_615del (p.Ile205fs)	Pathogenic
2443938	NM_001379270.1(CNGA1):c.610G>A (p.Asp204Asn)	Pathogenic
2501675	NM_001379270.1(CNGA1):c.219del (p.Gln74fs)	Pathogenic
2811442	NM_001379270.1(CNGA1):c.825dup (p.Arg276fs)	Pathogenic

SpliceAI

2562 predictions. Top by Δscore:

Variant	Effect	Δscore
4:47940870:C:CC	acceptor_gain	1.0000
4:47942071:A:C	donor_gain	1.0000
4:47943179:A:AC	donor_gain	1.0000
4:47943179:ACT:A	donor_gain	1.0000
4:47943180:C:CC	donor_gain	1.0000
4:47943180:CT:C	donor_gain	1.0000
4:47943180:CTC:C	donor_gain	1.0000
4:47943180:CTCTT:C	donor_gain	1.0000
4:47943285:CTTG:C	acceptor_gain	1.0000
4:47943286:TTG:T	acceptor_gain	1.0000
4:47943287:TG:T	acceptor_gain	1.0000
4:47943289:C:CC	acceptor_gain	1.0000
4:47943365:TCTTA:T	donor_loss	1.0000
4:47943366:CTTA:C	donor_loss	1.0000
4:47943367:TTACC:T	donor_loss	1.0000
4:47943368:TACC:T	donor_loss	1.0000
4:47943370:C:CT	donor_loss	1.0000
4:47943370:CCT:C	donor_gain	1.0000
4:47943413:C:CC	acceptor_gain	1.0000
4:47949824:TATAC:T	donor_loss	1.0000
4:47949825:ATACT:A	donor_loss	1.0000
4:47949826:TACT:T	donor_loss	1.0000
4:47949827:ACTT:A	donor_loss	1.0000
4:47949828:CT:C	donor_loss	1.0000
4:47949829:T:TA	donor_loss	1.0000
4:47949830:TACTG:T	donor_loss	1.0000
4:47949831:A:AC	donor_gain	1.0000
4:47949831:ACT:A	donor_loss	1.0000
4:47949832:C:CA	donor_gain	1.0000
4:47949832:CT:C	donor_gain	1.0000

AlphaMissense

4573 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:47936686:A:G	L603S	1.000
4:47936698:C:T	G599E	1.000
4:47936699:C:A	G599W	1.000
4:47936699:C:G	G599R	1.000
4:47936699:C:T	G599R	1.000
4:47936710:A:G	L595P	1.000
4:47936710:A:T	L595Q	1.000
4:47936740:A:G	L585P	1.000
4:47936744:C:G	A584P	1.000
4:47936752:A:G	L581P	1.000
4:47936767:A:G	L576P	1.000
4:47936767:A:T	L576H	1.000
4:47936776:A:G	L573P	1.000
4:47936776:A:T	L573Q	1.000
4:47936783:A:G	S571P	1.000
4:47936793:A:C	S567R	1.000
4:47936793:A:T	S567R	1.000
4:47936795:T:G	S567R	1.000
4:47936800:A:C	I565S	1.000
4:47936800:A:T	I565N	1.000
4:47936806:G:T	A563D	1.000
4:47936807:C:G	A563P	1.000
4:47936811:T:A	R561S	1.000
4:47936811:T:G	R561S	1.000
4:47936812:C:A	R561I	1.000
4:47936812:C:G	R561T	1.000
4:47936813:T:C	R561G	1.000
4:47936815:C:G	R560P	1.000
4:47936845:A:G	L550P	1.000
4:47936845:A:T	L550H	1.000

dbSNP variants (sampled 300 via entrez): RS1000012308 (4:48011860 G>C), RS1000015827 (4:47969233 A>C,G), RS1000028036 (4:48000302 T>A), RS1000036417 (4:48007404 C>T), RS1000067966 (4:47969551 C>A), RS1000081102 (4:47966272 AT>A,ATT), RS1000166407 (4:47955162 T>A,C), RS1000167843 (4:47948847 A>C), RS1000170004 (4:47945009 A>G), RS1000190190 (4:48007247 G>T), RS1000198094 (4:47940967 C>A,T), RS1000204752 (4:47959169 CAAA>C), RS1000243401 (4:47962311 C>T), RS1000244675 (4:48005506 G>A), RS10002500 (4:47956662 C>T)

Disease associations

OMIM: gene MIM:123825 | disease phenotypes: MIM:613756, MIM:268000, MIM:120970

GenCC curated gene-disease

Disease	Classification	Inheritance
retinitis pigmentosa 49	Definitive	Autosomal recessive
retinitis pigmentosa	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
CNGA1-related retinopathy	Definitive	AR

Mondo (7): retinitis pigmentosa 49 (MONDO:0013405), CNGA1-related retinopathy (MONDO:0800405), retinitis pigmentosa (MONDO:0019200), retinal disorder (MONDO:0005283), cone-rod dystrophy (MONDO:0015993), inherited retinal dystrophy (MONDO:0019118), optic atrophy (MONDO:0003608)

Orphanet (3): Retinitis pigmentosa (Orphanet:791), Cone rod dystrophy (Orphanet:1872), OBSOLETE: Inherited retinal disorder (Orphanet:71862)

HPO phenotypes

37 total (30 of 37 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000501	Glaucoma
HP:0000505	Visual impairment
HP:0000510	Rod-cone dystrophy
HP:0000512	Abnormal electroretinogram
HP:0000543	Optic disc pallor
HP:0000546	Retinal degeneration
HP:0000551	Color vision defect
HP:0000563	Keratoconus
HP:0000602	Ophthalmoplegia
HP:0000613	Photophobia
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000662	Nyctalopia
HP:0000842	Hyperinsulinemia
HP:0001105	Retinal atrophy
HP:0001133	Constriction of peripheral visual field
HP:0001419	X-linked recessive inheritance
HP:0007663	Reduced visual acuity
HP:0007675	Progressive night blindness
HP:0007703	Abnormal retinal pigmentation
HP:0007737	Spicular pigmentation of the retina
HP:0007787	Posterior subcapsular cataract
HP:0007843	Attenuation of retinal blood vessels
HP:0007994	Peripheral visual field loss
HP:0008046	Abnormal retinal vascular morphology

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST012616_2	Spondylosis	4.000000e-07

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D000071700	Cone-Rod Dystrophies	C11.270.152; C11.768.585.658.250; C16.320.290.152
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 (4 total), top 4:

Ligand	Action	Affinity	Parameter
dequalinium	Antagonist	6.7	pIC50
cyclic GMP	Agonist	4.22	pKi
L-(cis)-diltiazem	Antagonist	4.0	pKi
H-8	Antagonist	3.5	pIC50

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	affects expression, decreases expression, decreases methylation	3
Benzo(a)pyrene	increases methylation, decreases expression	2
Nickel	decreases expression	2
Tretinoin	increases expression	2
Valproic Acid	affects expression, decreases expression, decreases methylation	2
methyleugenol	decreases expression	1
bisphenol A	increases methylation	1
sodium arsenite	decreases expression	1
CGP 52608	affects binding, increases reaction	1
JP8 aviation fuel	affects expression	1
(+)-JQ1 compound	increases expression	1
Acetaminophen	decreases expression	1
Endosulfan	decreases expression, decreases reaction	1
Folic Acid	decreases expression	1
Mustard Gas	increases expression	1
Progesterone	increases expression	1
Tetrachlorodibenzodioxin	decreases expression, decreases reaction	1
Tobacco Smoke Pollution	increases expression	1
Cyclosporine	decreases expression	1
Okadaic Acid	decreases expression	1
Nanotubes, Carbon	decreases expression	1

Cellosaurus cell lines

3 cell lines: 2 induced pluripotent stem cell, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D6NM	SJTUGHi002-A	Induced pluripotent stem cell	Male
CVCL_D8J4	Ubigene HCT 116 CNGA1 KO	Cancer cell line	Male
CVCL_F0RI	BTHBIOi001-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

234 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
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
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
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
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline 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
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
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in 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
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
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)
NCT00063765	PHASE1	COMPLETED	Evaluation of Safety of Ciliary Neurotrophic Factor Implants in the Eye
NCT00065455	PHASE1	COMPLETED	Investigating the Effect of Vitamin A Supplementation on Retinitis Pigmentosa
NCT00458575	PHASE1	TERMINATED	A Study to Evaluate the Safety of CNTO 2476 in Patients With Advanced Retinitis Pigmentosa
NCT01068561	PHASE1	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa