CNGA4

Summary

CNGA4 (cyclic nucleotide gated channel subunit alpha 4, HGNC:2152) is a protein-coding gene on chromosome 11p15.4, encoding Cyclic nucleotide-gated channel alpha-4 (Q8IV77). Pore-forming subunit of the olfactory cyclic nucleotide-gated channel.

CNGA4 is a modulatory subunit of vertebrate cyclic nucleotide-gated membrane channels that transduce odorant signals (Munger et al., 2001 [PubMed 11739959]).

Source: NCBI Gene 1262 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 101 total
• MANE Select transcript: NM_001037329

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2152
Approved symbol	CNGA4
Name	cyclic nucleotide gated channel subunit alpha 4
Location	11p15.4
Locus type	gene with protein product
Status	Approved
Aliases	OCNC2, OCNCb, CNG5
Ensembl gene	ENSG00000132259
Ensembl biotype	protein_coding
OMIM	609472
Entrez	1262

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000379936, ENST00000533426, ENST00000872205

RefSeq mRNA: 1 — MANE Select: NM_001037329 NM_001037329

CCDS: CCDS31408

Canonical transcript exons

ENST00000379936 — 6 exons

Exon	Start	End
ENSE00000903290	6239684	6239790
ENSE00001189206	6240066	6240711
ENSE00001483105	6243949	6244479
ENSE00001483107	6241431	6241780
ENSE00002168811	6239089	6239268
ENSE00003486274	6239384	6239485

Expression profiles

Bgee: expression breadth ubiquitous, 151 present calls, max score 95.51.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0834 / max 17.9807, expressed in 37 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
112838	0.0715	32
112837	0.0119	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	95.51	gold quality
right uterine tube	UBERON:0001302	92.99	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.46	gold quality
bronchial epithelial cell	CL:0002328	84.14	gold quality
bronchus	UBERON:0002185	82.19	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	75.24	gold quality
left testis	UBERON:0004533	71.53	gold quality
right testis	UBERON:0004534	70.64	gold quality
testis	UBERON:0000473	69.13	gold quality
fallopian tube	UBERON:0003889	67.54	gold quality
oviduct epithelium	UBERON:0004804	62.08	silver quality
C1 segment of cervical spinal cord	UBERON:0006469	60.73	gold quality
myocardium	UBERON:0002349	60.55	gold quality
right lung	UBERON:0002167	60.30	gold quality
spinal cord	UBERON:0002240	58.86	gold quality
mucosa of paranasal sinus	UBERON:0005030	58.71	gold quality
caudate nucleus	UBERON:0001873	58.25	gold quality
prefrontal cortex	UBERON:0000451	57.76	gold quality
amygdala	UBERON:0001876	57.70	gold quality
granulocyte	CL:0000094	57.44	gold quality
nasal cavity mucosa	UBERON:0001826	57.32	gold quality
Brodmann (1909) area 9	UBERON:0013540	57.13	gold quality
right frontal lobe	UBERON:0002810	56.99	gold quality
hypothalamus	UBERON:0001898	56.75	gold quality
anterior cingulate cortex	UBERON:0009835	55.91	gold quality
lateral nuclear group of thalamus	UBERON:0002736	54.88	gold quality
left uterine tube	UBERON:0001303	54.76	gold quality
nucleus accumbens	UBERON:0001882	54.75	gold quality
putamen	UBERON:0001874	54.62	gold quality
frontal cortex	UBERON:0001870	54.16	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.71

Regulation

Is transcription factor: no

Cross-species orthologs

14 orthologs

Organism	Symbol	Gene ID
danio_rerio	cnga4	ENSDARG00000069383
mus_musculus	Cnga4	ENSMUSG00000030897
rattus_norvegicus	Cnga4	ENSRNOG00000017609
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), KCNH3 (ENSG00000135519), HCN4 (ENSG00000138622), KCNH5 (ENSG00000140015), KCNH1 (ENSG00000143473), HCN3 (ENSG00000143630), CNGA3 (ENSG00000144191), HCN1 (ENSG00000164588), CNGB3 (ENSG00000170289), KCNH6 (ENSG00000173826), CNGA2 (ENSG00000183862), KCNH8 (ENSG00000183960), KCNH7 (ENSG00000184611), CNGA1 (ENSG00000198515)

Protein

Protein identifiers

Cyclic nucleotide-gated channel alpha-4 — Q8IV77 (reviewed: Q8IV77)

Alternative names: Olfactory cyclic nucleotide-gated channel subunit 2

All UniProt accessions (2): Q8IV77, B4DYQ8

UniProt curated annotations — full annotation on UniProt →

Function. Pore-forming subunit of the olfactory cyclic nucleotide-gated channel. Operates in the cilia of olfactory sensory neurons where chemical stimulation of the odorant is converted to an electrical signal. Mediates odorant-induced cAMP-dependent Ca(2+) influx triggering neuron depolarization. The rise of intracellular Ca(2+) levels potentiates the olfactory response by activating Ca(2+)-dependent Cl(-) channels, but it also serves as a negative feedback signal to desensitize the channel for rapid adaptation to odorants. Conducts cAMP- and cGMP-gated ion currents, with permeability for monovalent and divalent cations.

Subunit / interactions. The olfactory cyclic nucleotide-gated channel is an heterotetramer composed of CNGA2, CNGA4 and CNGB1b subunits with 2:1:1 stoichiometry.

Subcellular location. Cell projection. Cilium membrane.

Activity regulation. Ca(2+)-calmodulin exerts its inhibitory effect in cAMP sensitivity by binding to IQ-like motif of CNGA4 and preferably binds to the channel in the closed state. Inhibition by PIP3 of the CNG channel probably occurs via CGNA2 binding.

Domain organisation. The C-terminal coiled-coil domain mediates trimerization of CNGA subunits.

Similarity. Belongs to the cyclic nucleotide-gated cation channel (TC 1.A.1.5) family. CNGA4 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8IV77-1	1	yes
Q8IV77-2	2

RefSeq proteins (1): NP_001032406* (*=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 (36 total): topological domain 7, transmembrane region 7, binding site 6, region of interest 5, splice variant 3, compositionally biased region 2, chain 1, coiled-coil region 1, short sequence motif 1, site 1, sequence variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9UPG	ELECTRON MICROSCOPY	2.87
9UPF	ELECTRON MICROSCOPY	3.59

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IV77-F1	84.01	0.48

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 (1): 258 (central gate)

Ligand- & substrate-binding residues (6): 414; 417; 430; 430; 431; 431

Mutagenesis-validated functional residues (1):

Position	Phenotype
292	loss of inhibition produced by calcium/calmodulin binding.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-381753	Olfactory Signaling Pathway
R-HSA-5620916	VxPx cargo-targeting to cilium

MSigDB gene sets: 79 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, GOBP_SENSORY_PERCEPTION_OF_CHEMICAL_STIMULUS, GOBP_MONOATOMIC_CATION_TRANSPORT, GOCC_GOLGI_ASSOCIATED_VESICLE, KEGG_OLFACTORY_TRANSDUCTION, GOBP_SENSORY_PERCEPTION, GOBP_CALCIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_TRANSMEMBRANE_TRANSPORT, GOBP_SODIUM_ION_TRANSPORT, GOCC_CELL_PROJECTION_MEMBRANE, GOCC_GOLGI_ASSOCIATED_VESICLE_MEMBRANE, GOCC_CATION_CHANNEL_COMPLEX, GOCC_TRANSPORTER_COMPLEX, GOCC_MEMBRANE_PROTEIN_COMPLEX, GOCC_PLASMA_MEMBRANE_REGION

GO Biological Process (10): potassium ion transport (GO:0006813), sodium ion transport (GO:0006814), calcium ion transport (GO:0006816), sensory perception of chemical stimulus (GO:0007606), sensory perception of smell (GO:0007608), monoatomic cation transmembrane transport (GO:0098655), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085), calcium ion transmembrane transport (GO:0070588)

GO Molecular Function (8): intracellularly cAMP-activated cation channel activity (GO:0005222), intracellularly cGMP-activated cation channel activity (GO:0005223), calcium channel activity (GO:0005262), 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)

GO Cellular Component (7): plasma membrane (GO:0005886), intracellular cyclic nucleotide activated cation channel complex (GO:0017071), Golgi-associated vesicle membrane (GO:0030660), ciliary membrane (GO:0060170), non-motile cilium membrane (GO:0098804), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Sensory Perception	1
Cargo trafficking to the periciliary membrane	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
metal ion transport	3
transport	2
intracellularly cyclic nucleotide-activated monoatomic cation channel activity	2
cyclic nucleotide binding	2
anion binding	2
bounding membrane of organelle	2
cellular anatomical structure	2
sensory perception	1
sensory perception of chemical stimulus	1
monoatomic cation transport	1
monoatomic ion transmembrane transport	1
monoatomic ion transport	1
transmembrane transport	1
cellular process	1
calcium ion transport	1
monoatomic cation transmembrane transport	1
monoatomic cation channel activity	1
calcium 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
membrane	1
cell periphery	1
cation channel complex	1
Golgi-associated vesicle	1
cytoplasmic vesicle membrane	1
cilium	1
cell projection membrane	1
ciliary membrane	1
non-motile cilium	1

Protein interactions and networks

STRING

1014 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CNGA4	CNGB1	Q14028	987
CNGA4	CNGA2	Q16280	982
CNGA4	CALM1	P02593	719
CNGA4	CALML6	Q8TD86	708
CNGA4	CALML3	P27482	708
CNGA4	CALML4	Q96GE6	708
CNGA4	CALML5	Q9NZT1	708
CNGA4	RTP2	Q5QGT7	671
CNGA4	ADCY3	O60266	637
CNGA4	ANO2	Q9NQ90	629
CNGA4	OR52W1	Q6IF63	601
CNGA4	RTP1	P59025	595
CNGA4	CNGB3	Q9NQW8	559
CNGA4	OR52B2	Q96RD2	542
CNGA4	PDE1C	Q14123	541

IntAct

4 interactions, top by confidence:

A	B	Type	Score
CNGA4	CCDC22	psi-mi:“MI:0914”(association)	0.350
CNGA4	NPC1	psi-mi:“MI:0914”(association)	0.350

BioGRID (39): HOOK2 (Affinity Capture-MS), PIGO (Affinity Capture-MS), IFT57 (Affinity Capture-MS), TMX2 (Affinity Capture-MS), CEP44 (Affinity Capture-MS), COMMD3 (Affinity Capture-MS), CORO1A (Affinity Capture-MS), OSBPL8 (Affinity Capture-MS), FAM63A (Affinity Capture-MS), LRRC8A (Affinity Capture-MS), ERMP1 (Affinity Capture-MS), GHDC (Affinity Capture-MS), SNAP29 (Affinity Capture-MS), SNAPIN (Affinity Capture-MS), DNAJC18 (Affinity Capture-MS)

ESM2 similar proteins: A0JMD4, B7ZC96, F6RG56, O65718, O73606, P17971, P17972, P70259, P97557, Q00195, Q03041, Q05973, Q0P583, Q16280, Q16281, Q24278, Q28718, Q29441, Q3U2S8, Q3UW12, Q5F4C0, Q5R5V8, Q5RC10, Q60565, Q62398, Q64359, Q6PIU1, Q6Q760, Q6R6I7, Q8AYS8, Q8BWC0, Q8BXR5, Q8BZN2, Q8IV77, Q8IZF0, Q8IZK6, Q8K595, Q8TDD5, Q90980, Q94AS9

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, A0R3F9, A1C9L6, A2R350, O14448

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	90
Likely benign	5
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

838 predictions. Top by Δscore:

Variant	Effect	Δscore
11:6239265:CCAGG:C	donor_loss	1.0000
11:6239266:CAG:C	donor_loss	1.0000
11:6239269:GTG:G	donor_loss	1.0000
11:6239270:T:G	donor_loss	1.0000
11:6239383:GGAA:G	acceptor_gain	1.0000
11:6239484:AG:A	donor_loss	1.0000
11:6239485:GGTAT:G	donor_loss	1.0000
11:6239486:GT:G	donor_loss	1.0000
11:6240651:TGAAG:T	donor_gain	1.0000
11:6241428:CAG:C	acceptor_loss	1.0000
11:6241429:A:T	acceptor_loss	1.0000
11:6241779:AGGT:A	donor_loss	1.0000
11:6241780:GGT:G	donor_loss	1.0000
11:6241781:GTGG:G	donor_loss	1.0000
11:6239264:GCCAG:G	donor_gain	0.9900
11:6239378:TTACA:T	acceptor_loss	0.9900
11:6239379:TACA:T	acceptor_loss	0.9900
11:6239382:A:AG	acceptor_gain	0.9900
11:6239383:G:GG	acceptor_gain	0.9900
11:6239383:GGA:G	acceptor_gain	0.9900
11:6239682:A:AG	acceptor_gain	0.9900
11:6239683:G:GG	acceptor_gain	0.9900
11:6239683:GA:G	acceptor_gain	0.9900
11:6239683:GAGCC:G	acceptor_gain	0.9900
11:6239774:G:GA	donor_gain	0.9900
11:6240652:GAAGA:G	donor_gain	0.9900
11:6240653:AAGAA:A	donor_gain	0.9900
11:6240698:C:T	donor_gain	0.9900
11:6240707:GACTG:G	donor_gain	0.9900
11:6240711:GGT:G	donor_loss	0.9900

AlphaMissense

3748 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:6241750:T:C	F413L	0.999
11:6241752:T:A	F413L	0.999
11:6241752:T:G	F413L	0.999
11:6241762:A:C	S417R	0.999
11:6241764:C:A	S417R	0.999
11:6241764:C:G	S417R	0.999
11:6240566:T:C	F258L	0.998
11:6240568:C:A	F258L	0.998
11:6240568:C:G	F258L	0.998
11:6241754:G:A	G414E	0.998
11:6241754:G:T	G414V	0.998
11:6243969:C:A	R430S	0.998
11:6241753:G:T	G414W	0.997
11:6244030:T:C	L450P	0.997
11:6244096:T:C	L472P	0.997
11:6240344:A:C	S184R	0.996
11:6240346:C:A	S184R	0.996
11:6240346:C:G	S184R	0.996
11:6241559:T:C	F349S	0.996
11:6241685:G:T	G391V	0.996
11:6241693:G:C	A394P	0.996
11:6241753:G:A	G414R	0.996
11:6241753:G:C	G414R	0.996
11:6243949:G:T	G423V	0.996
11:6243967:G:C	R429P	0.996
11:6243982:T:A	I434N	0.996
11:6243987:A:C	S436R	0.996
11:6243989:C:A	S436R	0.996
11:6243989:C:G	S436R	0.996
11:6241558:T:C	F349L	0.995

dbSNP variants (sampled 300 via entrez): RS1000315188 (11:6243698 C>A,T), RS1000389592 (11:6237645 A>G), RS1000423783 (11:6237391 C>T), RS1000750130 (11:6243713 A>G), RS1001025053 (11:6236852 A>G), RS1001578614 (11:6238503 A>G), RS1001790825 (11:6236337 G>A), RS1001864390 (11:6235962 A>T), RS1002003578 (11:6244795 T>G), RS1002008664 (11:6242760 G>A), RS1002009355 (11:6238257 T>A), RS1002521939 (11:6233672 G>C), RS1002716076 (11:6233390 C>A), RS1003476555 (11:6234815 T>A,C), RS1003648836 (11:6241620 C>G)

Disease associations

OMIM: gene MIM:609472 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST008178_11	Early spontaneous preterm birth	2.000000e-06
GCST008832_5	Gastroesophageal reflux disease	2.000000e-08
GCST010725_20	Malaria	4.000000e-69
GCST010725_33	Malaria	2.000000e-67
GCST010725_51	Malaria	1.000000e-55

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006917	spontaneous preterm birth

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)

CTD chemical–gene interactions

14 total (human), top 14 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	3
fluorene-9-bisphenol	decreases expression	1
benzo(e)pyrene	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression	1
CGP 52608	affects binding, increases reaction	1
MT19c compound	decreases expression	1
Acetaminophen	decreases expression	1
Lipopolysaccharides	affects cotreatment, increases expression	1
Methapyrilene	increases methylation	1
Rotenone	decreases expression	1
Silicon Dioxide	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	increases methylation	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_YA43	IDG-HEK293T-CNGA4-V5-OE	Transformed cell line	Female

Clinical trials (associated diseases)

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