HCN2

Summary

HCN2 (hyperpolarization activated cyclic nucleotide gated potassium and sodium channel 2, HGNC:4846) is a protein-coding gene on chromosome 19p13.3, encoding Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 (Q9UL51). Hyperpolarization-activated ion channel that is permeable to sodium and potassium ions.

The protein encoded by this gene is a hyperpolarization-activated cation channel involved in the generation of native pacemaker activity in the heart and in the brain. The encoded protein is activated by cAMP and can produce a fast, large current. Defects in this gene were noted as a possible cause of some forms of epilepsy.

Source: NCBI Gene 610 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 374 total — 9 pathogenic
• Phenotypes (HPO): 6
• Druggable target: yes
• MANE Select transcript: NM_001194

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4846
Approved symbol	HCN2
Name	hyperpolarization activated cyclic nucleotide gated potassium and sodium channel 2
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	BCNG-2, HAC-1
Ensembl gene	ENSG00000099822
Ensembl biotype	protein_coding
OMIM	602781
Entrez	610

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000251287

RefSeq mRNA: 1 — MANE Select: NM_001194 NM_001194

CCDS: CCDS12035

Canonical transcript exons

ENST00000251287 — 8 exons

Exon	Start	End
ENSE00000910025	603544	603967
ENSE00001155482	615795	617159
ENSE00001155487	589881	590577
ENSE00001651475	613852	614016
ENSE00001736795	607964	608182
ENSE00001768049	613248	613488
ENSE00001771431	605061	605222
ENSE00001802093	610259	610405

Expression profiles

Bgee: expression breadth ubiquitous, 177 present calls, max score 96.19.

FANTOM5 (CAGE): breadth broad, TPM avg 1.7015 / max 56.5463, expressed in 507 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
172714	1.2526	438
172716	0.2973	130
172715	0.1516	71

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	96.19	gold quality
right frontal lobe	UBERON:0002810	95.03	gold quality
putamen	UBERON:0001874	94.24	gold quality
nucleus accumbens	UBERON:0001882	93.84	gold quality
anterior cingulate cortex	UBERON:0009835	93.69	gold quality
spinal cord	UBERON:0002240	93.63	gold quality
cingulate cortex	UBERON:0003027	93.63	gold quality
caudate nucleus	UBERON:0001873	93.57	gold quality
Brodmann (1909) area 10	UBERON:0013541	92.92	gold quality
prefrontal cortex	UBERON:0000451	92.12	gold quality
Brodmann (1909) area 9	UBERON:0013540	90.68	gold quality
amygdala	UBERON:0001876	90.56	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	89.50	gold quality
frontal cortex	UBERON:0001870	89.47	gold quality
neocortex	UBERON:0001950	89.21	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.97	gold quality
hypothalamus	UBERON:0001898	88.88	gold quality
telencephalon	UBERON:0001893	88.45	gold quality
substantia nigra	UBERON:0002038	87.69	gold quality
cerebellar cortex	UBERON:0002129	87.56	gold quality
forebrain	UBERON:0001890	87.54	gold quality
cerebellar hemisphere	UBERON:0002245	87.51	gold quality
cerebral cortex	UBERON:0000956	87.23	gold quality
central nervous system	UBERON:0001017	87.08	gold quality
brain	UBERON:0000955	86.87	gold quality
Ammon’s horn	UBERON:0001954	86.86	gold quality
midbrain	UBERON:0001891	86.66	gold quality
endometrium epithelium	UBERON:0004811	86.51	gold quality
cerebellum	UBERON:0002037	86.20	gold quality
middle frontal gyrus	UBERON:0002702	84.12	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.81

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1

miRNA regulators (miRDB)

41 targeting HCN2, 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-4262	100.00	73.26	3931
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-4325	99.49	72.20	1342
HSA-MIR-135A-5P	99.36	71.85	1601
HSA-MIR-135B-5P	99.36	71.63	1613
HSA-MIR-6803-5P	99.19	63.90	1026
HSA-MIR-6815-3P	99.13	68.98	1530
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-3196	98.96	63.91	326
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-6885-5P	98.71	64.33	902

Literature-anchored findings (GeneRIF, showing 30)

• HCN4 activates substantially slower than HCN2 and with a half-maximum activation voltage approximately equal 10 mV less negative, both isoforms activate more positively in myocytes suggesting cell-type specificity (PMID:12194012)
• activation of the fast channel HCN2 is dependent on the S1 segment (PMID:12813043)
• HCN1 and HCN2 expression were measured using in situ hybridization and immunocytochemistry in hippocampi; the expression of HCN isoforms is dynamically regulated in human as well as in experimental hippocampal epilepsy (PMID:12890777)
• Native I(f) channels in atrial myocardium are heteromeric complexes composed of HCN4 and/or HCN2. (PMID:15687126)
• Mutations of a putative cyclic-nucleotide-binding domain (CNBD) can disrupt the function of the hyperpolarization-activated cyclic-nucleotide-gated channel (HCN2). (PMID:15961404)
• an intact F-actin cytoskeleton is a prerequisite for the swelling-induced HCN2 current (PMID:15980171)
• With computer modelling, we show that in channels with relatively slow opening kinetics and fast mode-shift transitions, such as HCN2 and HCN4 channels, the mode shift effects are not readily observable, except in the tail kinetics. (PMID:16777944)
• Noise analysis on macroscopic currents revealed fluctuations whose magnitudes were systematically larger than predicted from the actual single channel current size, consistent with cooperativity between single HCN channels. (PMID:17043149)
• Several functional variants were identified including the amino acid substitution R527Q in HCN2 exon 5. HCN2 channels containing the R527Q variant demonstrated a trend towards a decreased slope of the conductance-voltage relation. (PMID:17931874)
• RPTPalpha plays a critical role in HCN channel function via tyrosine dephosphorylation (PMID:18768480)
• Genetic analysis in 48 Sudden unexpected death in epilepsy cases identified six novel and three previously reported nonsynonymous (amino acid changing) variants in HCN1 , HCN2, HCN3 and HCN4. (PMID:21615589)
• HCN2 channels make an important contribution to the maintenance of spontaneous burst activity in embryonic cortical neuron cultures. (PMID:22094222)
• This is the first evidence in humans for a single-point, homozygous loss-of-function mutation in HCN2 potentially associated with generalized epilepsy with recessive inheritance. (PMID:22131395)
• LBB-injected HCN2/SkM1 potentially provides a more clinically suitable biological pacemaker strategy than other reported constructs. This superiority is attributable to the more negative AP threshold and injection into the LBB (PMID:23395072)
• HCN2 polymorphism may play a role in chronic inflammatory periodontitis but not in peri-implantitis. (PMID:23907424)
• Novel HCN2 mutation contributes to febrile seizures by shifting the channel’s kinetics in a temperature-dependent manner. (PMID:24324597)
• Thermal hyperalgesia under chronic inflammatory conditions is mediated by HCN2 channels. (PMID:24525276)
• Data show that Rab8b-interacting protein TRIP8b does not compete with cyclic AMP for the same binding region of hyperpolarization activated cyclic nucleotide gated potassium channel 2 (HCN2). (PMID:25197093)
• N-glycosylation is not required for HCN2 channels to function. (PMID:25423599)
• Aged patients with sinus rhythm exhibited significantly higher expression levels of HCN2 and HCN4 channel mRNA and protein (P<0.05), but significantly lower expression levels of miR1 and 133, compared with those of adult patients with sinus rhythm. (PMID:26005035)
• promoter methylation status does not appear to be a major determinant of HCN2 expression in normal and adenoid cystic carcinoma ( ACC )tissues. HCN2 hypomethylation is a biomarker of ACC and may play an important role in the carcinogenesis of ACC. (PMID:27212063)
• HCN2 has a role in maturation and processing of the amyloid precursor protein (PMID:28017718)
• TRIP8b competes with a portion of the cAMP-binding site or distorts the binding site by making interactions with the binding pocket, thus acting predominantly as a competitive antagonist that inhibits the cyclic-nucleotide dependence of HCN channels. (PMID:28864772)
• No significant association was found between HCN1/HCN2 alleles, genotypes or haplotypes, and drug resistance in patients, however, it was suggested that HCN2 rs3752158 is involved in the susceptibility to juvenile myoclonic epilepsy. (PMID:29047147)
• beta2-adrenoceptors alone strongly enhanced the activity of HCN2 channels, and co-expression of odorant receptors further diversified the HCN2 channel activity. (PMID:29054409)
• Data suggest that HCN2 variants can confer susceptibility to Genetic generalized epilepsy via a gain-of-function mechanism. (PMID:29064616)
• Effects of HCN2 Mutations on Dendritic Excitability and Synaptic Plasticity: A Computational Study. (PMID:31682955)
• overexpression of TBX3 and HCN2 could reprogram human-induced pluripotent stem cells-derived cardiomyocytes into pacemaker-like cells (PMID:31916853)
• Downregulation of hyperpolarization-activated cyclic nucleotide-gated channels (HCN) in the hippocampus of patients with medial temporal lobe epilepsy and hippocampal sclerosis (MTLE-HS). (PMID:32543742)
• HCN2 channel-induced rescue of brain, eye, heart and gut teratogenesis caused by nicotine, ethanol and aberrant notch signalling. (PMID:35662339)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hcn2	ENSMUSG00000020331
rattus_norvegicus	Hcn2	ENSRNOG00000008831
drosophila_melanogaster	CG6026	FBGN0038676
drosophila_melanogaster	CngA	FBGN0261612
drosophila_melanogaster	CngB	FBGN0266346
caenorhabditis_elegans		WBGENE00000487
caenorhabditis_elegans	tax-2	WBGENE00006525
caenorhabditis_elegans		WBGENE00006526
caenorhabditis_elegans		WBGENE00022295

Paralogs (17): KCNH2 (ENSG00000055118), CNGB1 (ENSG00000070729), KCNH4 (ENSG00000089558), 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), CNGA1 (ENSG00000198515)

Protein

Protein identifiers

Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 — Q9UL51 (reviewed: Q9UL51)

Alternative names: Brain cyclic nucleotide-gated channel 2

All UniProt accessions (1): Q9UL51

UniProt curated annotations — full annotation on UniProt →

Function. Hyperpolarization-activated ion channel that is permeable to sodium and potassium ions. Displays lower selectivity for K(+) over Na(+) ions. Contributes to the native pacemaker currents in heart (If) and in neurons (Ih). Can also transport ammonium in the distal nephron. Involved in the initiation of neuropathic pain in sensory neurons.

Subunit / interactions. Homotetramer. The channel is composed of a homo- or heterotetrameric complex of pore-forming subunits. Heterotetramer with HCN1. Forms an obligate 4:4 complex with accessory subunit PEX5L. Interacts with KCNE2.

Subcellular location. Cell membrane.

Tissue specificity. Highly expressed throughout the brain. Detected at low levels in heart.

Post-translational modifications. Phosphorylation at Ser-668 by PRKG2 shifts the voltage-dependence to more negative voltages, hence counteracting the stimulatory effect of cGMP on gating. S-palmitoylated. N-glycosylated; required for cell surface trafficking of HCN2.

Disease relevance. Epilepsy, idiopathic generalized 17 (EIG17) [MIM:602477] A form of idiopathic generalized epilepsy, a disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Generalized seizures arise diffusely and simultaneously from both hemispheres of the brain. Seizure types include juvenile myoclonic seizures, absence seizures, and generalized tonic-clonic seizures. Both autosomal dominant and autosomal recessive EIG17 inheritance have been reported. Disease susceptibility is associated with variants affecting the gene represented in this entry. Febrile seizures, familial, 2 (FEB2) [MIM:602477] Seizures associated with febrile episodes in childhood without any evidence of intracranial infection or defined pathologic or traumatic cause. It is a common condition, affecting 2-5% of children aged 3 months to 5 years. The majority are simple febrile seizures (generally defined as generalized onset, single seizures with a duration of less than 30 minutes). Complex febrile seizures are characterized by focal onset, duration greater than 30 minutes, and/or more than one seizure in a 24 hour period. The likelihood of developing epilepsy following simple febrile seizures is low. Complex febrile seizures are associated with a moderately increased incidence of epilepsy. FEB2 transmission pattern is consistent with autosomal dominant inheritance. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by cAMP, and at 10-100 times higher concentrations, also by cGMP. cAMP binding causes a conformation change that leads to the assembly of an active tetramer and channel opening. Binding of cAMP removes a tonic inhibition conferred by cyclic nucleotide-binding domain (CNBD) on channel opening. Channel activity is modulated by intracellular chloride ions and pH; acidic pH shifts the activation to more negative voltages. Inhibited by extracellular cesium ions.

Domain organisation. The segment S4 is the voltage-sensor and is characterized by a series of positively charged amino acids at every third position. The ion-conducting pore region is between segment S5 and S6. The cytosolic C-terminal domain contains the cyclic nucleotide-binding domain (CNBD), which mediates modulation by cyclic nucleotides.

Similarity. Belongs to the potassium channel HCN family.

RefSeq proteins (1): NP_001185* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000595	cNMP-bd_dom	Domain
IPR003938	K_chnl_volt-dep_EAG/ELK/ERG	Family
IPR005821	Ion_trans_dom	Domain
IPR013621	Ion_trans_N	Domain
IPR014710	RmlC-like_jellyroll	Homologous_superfamily
IPR018488	cNMP-bd_CS	Conserved_site
IPR018490	cNMP-bd_dom_sf	Homologous_superfamily
IPR051413	K/Na_HCN_channel	Family

Pfam: PF00027, PF00520, PF08412

Catalyzed reactions (Rhea), 3 shown:

• NH4(+)(in) = NH4(+)(out) (RHEA:28747)
• K(+)(in) = K(+)(out) (RHEA:29463)
• Na(+)(in) = Na(+)(out) (RHEA:34963)

UniProt features (79 total): modified residue 10, helix 10, sequence variant 9, strand 9, topological domain 8, binding site 8, transmembrane region 6, sequence conflict 6, compositionally biased region 5, region of interest 3, turn 2, chain 1, intramembrane region 1, glycosylation site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3U10	X-RAY DIFFRACTION	2.3
9R1V	ELECTRON MICROSCOPY	3.53
2MPF	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UL51-F1	72.28	0.38

Functional residue map

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

Ligand- & substrate-binding residues (8): 599; 608; 609; 610; 611; 618; 619; 659

Post-translational modifications (10): 146, 161, 668, 754, 756, 771, 779, 786, 866, 868

Glycosylation sites (1): 407

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1296061	HCN channels

MSigDB gene sets: 183 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, GOBP_POTASSIUM_ION_TRANSPORT, GOBP_MEMBRANE_DEPOLARIZATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_CELLULAR_RESPONSE_TO_LIPID, REACTOME_POTASSIUM_CHANNELS, GOBP_RESPONSE_TO_CORTICOSTEROID, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_MEMBRANE_DEPOLARIZATION_DURING_ACTION_POTENTIAL, GOBP_REGULATION_OF_MEMBRANE_DEPOLARIZATION, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CELL_CELL_SIGNALING, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, GOBP_CELLULAR_RESPONSE_TO_CORTICOSTEROID_STIMULUS

GO Biological Process (19): regulation of membrane depolarization (GO:0003254), cell-cell signaling (GO:0007267), response to xenobiotic stimulus (GO:0009410), sodium ion transmembrane transport (GO:0035725), regulation of membrane potential (GO:0042391), cellular response to cAMP (GO:0071320), cellular response to cGMP (GO:0071321), potassium ion transmembrane transport (GO:0071805), ammonium transmembrane transport (GO:0072488), membrane depolarization during cardiac muscle cell action potential (GO:0086012), sodium ion import across plasma membrane (GO:0098719), cellular response to aldosterone (GO:1904045), potassium ion import across plasma membrane (GO:1990573), monoatomic ion transport (GO:0006811), potassium ion transport (GO:0006813), sodium ion transport (GO:0006814), response to hormone (GO:0009725), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085)

GO Molecular Function (13): intracellularly cAMP-activated cation channel activity (GO:0005222), voltage-gated sodium channel activity (GO:0005248), voltage-gated potassium channel activity (GO:0005249), PDZ domain binding (GO:0030165), cAMP binding (GO:0030552), identical protein binding (GO:0042802), protein-containing complex binding (GO:0044877), molecular adaptor activity (GO:0060090), nucleotide binding (GO:0000166), monoatomic ion channel activity (GO:0005216), potassium channel activity (GO:0005267), sodium channel activity (GO:0005272), protein binding (GO:0005515)

GO Cellular Component (11): plasma membrane (GO:0005886), voltage-gated potassium channel complex (GO:0008076), axon (GO:0030424), dendrite (GO:0030425), dendrite membrane (GO:0032590), neuronal cell body (GO:0043025), dendritic shaft (GO:0043198), HCN channel complex (GO:0098855), membrane (GO:0016020), monoatomic ion channel complex (GO:0034702), somatodendritic compartment (GO:0036477)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Potassium Channels	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	3
cellular anatomical structure	3
response to chemical	2
monoatomic cation transmembrane transport	2
cellular response to nitrogen compound	2
cellular response to oxygen-containing compound	2
transmembrane transport	2
inorganic cation import across plasma membrane	2
transport	2
metal ion transport	2
monoatomic cation channel activity	2
neuron projection	2
dendrite	2
regulation of membrane potential	1
regulation of cellular process	1
membrane depolarization	1
cell communication	1
signaling	1
sodium ion transport	1
monoatomic ion transmembrane transport	1
regulation of biological quality	1
response to cAMP	1
response to cGMP	1
potassium ion transport	1
nitrogen compound transport	1
cardiac muscle cell action potential	1
membrane depolarization during action potential	1
sodium ion transmembrane transport	1
cellular response to mineralocorticoid stimulus	1
cellular response to alcohol	1
cellular response to aldehyde	1
cellular response to ketone	1
response to aldosterone	1
potassium ion transmembrane transport	1
response to endogenous stimulus	1
monoatomic ion transport	1
cellular process	1
intracellularly cyclic nucleotide-activated monoatomic cation channel activity	1
sodium channel activity	1
potassium channel activity	1

Protein interactions and networks

STRING

887 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HCN2	GNAT3	A8MTJ3	659
HCN2	PEX5L	Q8IYB4	586
HCN2	A0A087WUC5	A0A087WUC5	350
HCN2	PCDH11X	Q9BZA7	350
HCN2	CAV3	P56539	345
HCN2	KCNH1	O95259	336
HCN2	KCNJ2	P48049	333
HCN2	ZFX	P17010	322
HCN2	ATRX	P46100	322
HCN2	KCNJ15	Q99712	311
HCN2	KCNN2	Q9H2S1	305
HCN2	KCNE2	Q9Y6J6	304
HCN2	KCNAB1	Q14722	300
HCN2	KCNA2	P16389	295
HCN2	PABPC5	Q96DU9	292

IntAct

197 interactions, top by confidence:

A	B	Type	Score
	HCN2	psi-mi:“MI:0407”(direct interaction)	0.770

BioGRID (19): HCN2 (Affinity Capture-MS), HCN2 (Affinity Capture-Western), HCN2 (Affinity Capture-Western), HCN4 (Affinity Capture-Western), HCN2 (Affinity Capture-Western), HCN2 (Proximity Label-MS), HCN2 (Proximity Label-MS), HCN2 (Proximity Label-MS), HCN2 (Proximity Label-MS), HCN2 (Proximity Label-MS), KCNE2 (Two-hybrid), HCN2 (Two-hybrid), HCN2 (Two-hybrid), HCN1 (Two-hybrid), HCN2 (Affinity Capture-MS)

ESM2 similar proteins: A2APX8, A6H8H5, G5EFJ9, O18868, O18965, O60741, O70507, O88703, O88704, O95259, P04774, P15387, P17970, P35498, P55934, P58391, P58392, Q00194, Q02280, Q03041, Q03611, Q03717, Q14721, Q16281, Q29441, Q4ZHA6, Q60603, Q62897, Q62927, Q63099, Q63472, Q8MJD7, Q8NCM2, Q90805, Q920E3, Q95167, Q9EPI9, Q9ER33, Q9JKA7, Q9JKA8

Diamond homologs: O60741, O70507, O88703, O88704, O88705, P05987, P07278, P31320, P36600, Q2K5E1, Q6BZG7, Q6CPK7, Q6FQL6, Q8MMZ8, Q98GN8, Q9JKA7, Q9JKA8, Q9JKA9, Q9JKB0, Q9MZS1, Q9P1Z3, Q9TV66, Q9UL51, Q9Y3Q4, P9WM60, P9WM61, Q03042, Q03043, A5K0N4, A0A509AKL0, A0R3F9, A3RL54, A8X6H1, O05581, O14448, O42794, O59922, O76360, O77676, P00514

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
SRC	“up-regulates activity”	HCN2	phosphorylation
PRKG2	“down-regulates activity”	HCN2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 91 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Long-term potentiation	6	45.3×	3e-07
Ras activation upon Ca2+ influx through NMDA receptor	5	45.3×	5e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	43.2×	5e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	43.2×	5e-06
Assembly and cell surface presentation of NMDA receptors	10	40.3×	7e-12
Dopamine Neurotransmitter Release Cycle	5	39.4×	7e-06
Neurexins and neuroligins	11	34.4×	5e-12
Protein-protein interactions at synapses	7	29.5×	3e-07

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	10	66.8×	1e-13
protein localization to synapse	6	52.8×	2e-07
receptor clustering	7	50.2×	2e-08
regulation of postsynaptic membrane neurotransmitter receptor levels	7	39.9×	7e-08
cell-cell adhesion	13	15.2×	1e-09
protein-containing complex assembly	9	11.8×	7e-06
establishment of localization in cell	5	9.2×	6e-03
protein localization to plasma membrane	6	7.5×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	0
Uncertain significance	257
Likely benign	54
Benign	24

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
1240010	NM_001194.4(HCN2):c.377C>T (p.Ser126Leu)	Pathogenic
1341477	NM_005035.4(POLRMT):c.2428C>T (p.Pro810Ser)	Pathogenic
1711726	NM_001194.4(HCN2):c.971G>A (p.Arg324His)	Pathogenic
1711727	NM_001194.4(HCN2):c.1088C>T (p.Ala363Val)	Pathogenic
1711729	NM_001194.4(HCN2):c.1478C>T (p.Pro493Leu)	Pathogenic
1711730	NM_001194.4(HCN2):c.1760G>A (p.Gly587Asp)	Pathogenic
1711731	NM_001194.4(HCN2):c.1936_1937insT (p.Pro646fs)	Pathogenic
3024081	NM_001194.4(HCN2):c.1379G>A (p.Gly460Asp)	Pathogenic
3381379	NM_001194.4(HCN2):c.1976G>A (p.Arg659His)	Pathogenic

SpliceAI

2300 predictions. Top by Δscore:

Variant	Effect	Δscore
19:603965:G:GT	donor_gain	1.0000
19:605220:GTG:G	donor_gain	1.0000
19:608170:G:GG	donor_gain	1.0000
19:608180:AAGGT:A	donor_loss	1.0000
19:608182:GG:G	donor_loss	1.0000
19:608190:G:GT	donor_gain	1.0000
19:608191:G:T	donor_gain	1.0000
19:610254:CACA:C	acceptor_loss	1.0000
19:610257:A:AG	acceptor_gain	1.0000
19:610257:A:C	acceptor_loss	1.0000
19:610258:G:C	acceptor_loss	1.0000
19:610258:G:GG	acceptor_gain	1.0000
19:610258:GT:G	acceptor_gain	1.0000
19:610258:GTAC:G	acceptor_gain	1.0000
19:610402:GGAG:G	donor_gain	1.0000
19:610403:G:T	donor_gain	1.0000
19:610403:GAGG:G	donor_gain	1.0000
19:610405:GGTGA:G	donor_loss	1.0000
19:610406:GTGAG:G	donor_loss	1.0000
19:610407:T:A	donor_loss	1.0000
19:613242:CTGCA:C	acceptor_loss	1.0000
19:613243:TGCAG:T	acceptor_loss	1.0000
19:613244:GCAGG:G	acceptor_loss	1.0000
19:613245:CA:C	acceptor_loss	1.0000
19:613246:A:AG	acceptor_gain	1.0000
19:613246:A:C	acceptor_loss	1.0000
19:613246:AG:A	acceptor_gain	1.0000
19:613247:G:GG	acceptor_gain	1.0000
19:613247:GG:G	acceptor_gain	1.0000
19:613247:GGA:G	acceptor_gain	1.0000

AlphaMissense

5787 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:590484:T:C	L180P	1.000
19:590519:G:A	E192K	1.000
19:590529:G:C	R195P	1.000
19:590556:T:A	I204N	1.000
19:590558:C:G	H205D	1.000
19:590559:A:G	H205R	1.000
19:590560:C:A	H205Q	1.000
19:590560:C:G	H205Q	1.000
19:590561:C:A	P206T	1.000
19:590561:C:T	P206S	1.000
19:590562:C:A	P206Q	1.000
19:590562:C:T	P206L	1.000
19:590567:A:C	S208R	1.000
19:590568:G:T	S208I	1.000
19:590569:C:A	S208R	1.000
19:590569:C:G	S208R	1.000
19:590577:G:C	R211T	1.000
19:590577:G:T	R211M	1.000
19:603551:T:A	W214R	1.000
19:603551:T:C	W214R	1.000
19:603567:T:C	L219P	1.000
19:603576:T:A	M222K	1.000
19:603586:C:A	N225K	1.000
19:603586:C:G	N225K	1.000
19:603588:T:A	L226H	1.000
19:603588:T:C	L226P	1.000
19:603599:C:T	P230S	1.000
19:603600:C:A	P230Q	1.000
19:603600:C:G	P230R	1.000
19:603609:T:A	I233N	1.000

dbSNP variants (sampled 300 via entrez): RS1000144396 (19:614440 C>A,T), RS1000198108 (19:611411 C>A,T), RS1000216393 (19:588032 G>A), RS1000244513 (19:587880 T>C), RS1000312482 (19:593549 G>A), RS1000324973 (19:616816 C>G,T), RS1000364751 (19:611480 C>A,T), RS1000408761 (19:599765 G>A,C), RS1000421406 (19:596853 A>G), RS1000537083 (19:610904 G>A,C), RS1000557453 (19:588603 C>G,T), RS1000687055 (19:616348 G>A,T), RS1000759469 (19:616722 G>A), RS1000880755 (19:600107 A>T), RS1000911699 (19:599856 G>A)

Disease associations

OMIM: gene MIM:602781 | disease phenotypes: MIM:602477, MIM:619743

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (3)

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

Disease	Classification	Inheritance
epilepsy	Limited	AD
complex neurodevelopmental disorder	Definitive	AR
complex neurodevelopmental disorder	Definitive	AD

Mondo (6): febrile seizures, familial, 2 (MONDO:0011231), epilepsy, idiopathic generalized, susceptibility to, 17 (MONDO:0100519), generalized epilepsy (MONDO:0100574), combined oxidative phosphorylation deficiency 55 (MONDO:0859228), neurodevelopmental disorder (MONDO:0700092), cardiomyopathy (MONDO:0004994)

Orphanet (1): Rare cardiomyopathy (Orphanet:167848)

HPO phenotypes

6 total (6 of 6 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0002069	Bilateral tonic-clonic seizure
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)
HP:0003593	Infantile onset
HP:0010818	Generalized tonic seizure
HP:0010819	Atonic seizure

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST012490_391	Femur bone mineral density x serum urate levels interaction	4.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D009202	Cardiomyopathies	C14.280.238
D065886	Neurodevelopmental Disorders	F03.625
C566541	Febrile Convulsions, Familial, 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1795172 (SINGLE PROTEIN)

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 (13 total), top 13:

Ligand	Action	Affinity	Parameter
cyclic AMP	Agonist	6.3	pKi
zatebradine	Antagonist	5.7	pIC50
ivabradine	Antagonist	5.6	pIC50
cyclic GMP	Agonist	5.2	pKi
cilobradine	Antagonist	5.1	pIC50
clonidine	Antagonist	5.09	pIC50
PIP2	Activator	4.96	pEC50
MEL57A	Channel blocker	4.9	pEC50
EC18	Channel blocker	4.71	pEC50
cyclic CMP	Activator	4.52	pEC50
ZD7288	Antagonist	4.4	pIC50
Cs+	Antagonist	3.7	pIC50
Mg2+	Channel blocker	3.2	pIC50

ChEMBL bioactivities

1 potent at pChembl≥5 of 3 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.30	IC50	5012	nM	CHEMBL1823882

PubChem BioAssay actives

1 with measured affinity, of 11 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-ethoxy-N-[(1-piperazin-1-ylcyclohexyl)methyl]benzamide	617262: Inhibition of human HCN2 heterologously expressed in HEK-293 cells after 30 mins by VIPR assay	ic50	5.0119	uM

CTD chemical–gene interactions

35 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression, affects cotreatment	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Estradiol	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	decreases methylation, increases expression	2
aristolochic acid I	increases expression	1
bisphenol A	increases methylation	1
cypermethrin	decreases expression	1
butyraldehyde	decreases expression	1
manganese chloride	increases expression, affects cotreatment, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
casticin	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
lipopolysaccharide, Escherichia coli O111 B4	decreases activity	1
abrine	decreases expression	1
Sunitinib	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Cadmium	decreases expression	1
Chloroform	decreases activity	1
Cocaine	increases expression	1
Doxorubicin	affects expression	1
Endosulfan	decreases expression	1
Lead	affects expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Rotenone	decreases methylation, increases expression	1
Smoke	decreases expression	1
Urethane	increases expression	1
Valproic Acid	increases methylation	1
1-Methyl-4-phenylpyridinium	increases expression	1

ChEMBL screening assays

12 unique, capped per target: 6 binding, 4 functional, 2 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1825385	Binding	Inhibition of human HCN2 heterologously expressed in HEK-293 cells after 30 mins by VIPR assay	Discovery of a novel series of selective HCN1 blockers. — Bioorg Med Chem Lett
CHEMBL4039286	ADMET	Inhibition of human HCN2 expressed in CHO cells by automated patch clamp assay	Discovery of N-(5-Fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238): A Novel Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Selected for Clinical Evaluation. — J Med Chem
CHEMBL6194497	Functional	Inhibition of human HCN2 in HCN2 overexpressing HEK293 cells (tetracycline inducible) using Automated patch clamp after a single hyperpolarizing pulse -100 mV (HCN2)	Data for DCP probe RO-275

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_RQ85	PrecisION hHCN2-HEK	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT03590197	PHASE4	COMPLETED	Effect of Melatonin on Seizure Outcome, Neuronal Damage and Quality of Life in Patients With Generalized Epilepsy
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT00150735	PHASE3	COMPLETED	Monotherapy With Levetiracetam in Newly Diagnosed Patients Suffering From Epilepsy
NCT00150748	PHASE3	COMPLETED	Long Term Follow up Treatment With Levetiracetam in Subjects of 4 Years and Older With Generalized Epilepsy
NCT03678753	PHASE3	COMPLETED	Randomized, Double-Blind Study to Evaluate Efficacy and Safety of Cenobamate Adjunctive Therapy in PGTC Seizures
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT06908356	PHASE2	RECRUITING	An Open Label Trial to Evaluate the Efficacy and Safety of PRAX-628 in Adults With Focal Onset or Tonic-Clonic Seizures
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders