HCN1

Summary

HCN1 (hyperpolarization activated cyclic nucleotide gated potassium channel 1, HGNC:4845) is a protein-coding gene on chromosome 5p12, encoding Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 (O60741). Hyperpolarization-activated ion channel that are permeable to sodium and potassium ions.

The membrane protein encoded by this gene is a hyperpolarization-activated cation channel that contributes to the native pacemaker currents in heart and neurons. The encoded protein can homodimerize or heterodimerize with other pore-forming subunits to form a potassium channel. This channel may act as a receptor for sour tastes.

Source: NCBI Gene 348980 — RefSeq curated summary.

At a glance

• Gene–disease (curated): generalized epilepsy with febrile seizures plus (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 30
• Clinical variants (ClinVar): 1,174 total — 19 pathogenic, 22 likely-pathogenic
• Phenotypes (HPO): 80
• Druggable target: yes
• MANE Select transcript: NM_021072

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4845
Approved symbol	HCN1
Name	hyperpolarization activated cyclic nucleotide gated potassium channel 1
Location	5p12
Locus type	gene with protein product
Status	Approved
Aliases	BCNG-1, HAC-2
Ensembl gene	ENSG00000164588
Ensembl biotype	protein_coding
OMIM	602780
Entrez	348980

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000303230, ENST00000634658, ENST00000637256, ENST00000637305, ENST00000638054, ENST00000673735, ENST00000947598

RefSeq mRNA: 1 — MANE Select: NM_021072 NM_021072

CCDS: CCDS3952

Canonical transcript exons

ENST00000303230 — 8 exons

Exon	Start	End
ENSE00001085689	45267089	45267253
ENSE00001085691	45303599	45303839
ENSE00001146224	45353100	45353246
ENSE00001146248	45645185	45645608
ENSE00001292063	45695669	45696380
ENSE00001299697	45396492	45396710
ENSE00001317576	45254948	45262810
ENSE00001327253	45461846	45462007

Expression profiles

Bgee: expression breadth ubiquitous, 147 present calls, max score 96.17.

FANTOM5 (CAGE): breadth broad, TPM avg 3.0602 / max 161.6797, expressed in 216 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
61596	2.3602	184
61595	0.5954	141
61597	0.0534	37
203544	0.0323	19
61594	0.0188	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	96.17	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.86	gold quality
primary visual cortex	UBERON:0002436	91.27	gold quality
occipital lobe	UBERON:0002021	91.04	gold quality
trigeminal ganglion	UBERON:0001675	89.10	gold quality
Brodmann (1909) area 46	UBERON:0006483	87.71	gold quality
dorsal root ganglion	UBERON:0000044	86.94	gold quality
prefrontal cortex	UBERON:0000451	86.60	gold quality
superior frontal gyrus	UBERON:0002661	85.46	gold quality
middle temporal gyrus	UBERON:0002771	85.40	gold quality
parietal lobe	UBERON:0001872	84.36	gold quality
frontal cortex	UBERON:0001870	84.22	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	83.90	gold quality
Brodmann (1909) area 9	UBERON:0013540	83.57	gold quality
pons	UBERON:0000988	83.37	gold quality
postcentral gyrus	UBERON:0002581	83.35	gold quality
neocortex	UBERON:0001950	82.91	gold quality
cortical plate	UBERON:0005343	82.05	gold quality
cerebral cortex	UBERON:0000956	81.35	gold quality
entorhinal cortex	UBERON:0002728	80.52	gold quality
cerebellar vermis	UBERON:0004720	80.35	silver quality
right frontal lobe	UBERON:0002810	78.84	gold quality
anterior cingulate cortex	UBERON:0009835	78.38	gold quality
cerebellum	UBERON:0002037	76.94	gold quality
cerebellar cortex	UBERON:0002129	76.44	gold quality
cerebellar hemisphere	UBERON:0002245	76.31	gold quality
tibial nerve	UBERON:0001323	76.23	gold quality
right hemisphere of cerebellum	UBERON:0014890	76.00	gold quality
sural nerve	UBERON:0015488	74.84	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.87	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	78.32
E-HCAD-25	yes	38.00
E-ANND-3	yes	6.02
E-GEOD-111727	no	104.30

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): REST

miRNA regulators (miRDB)

313 targeting HCN1, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616

Literature-anchored findings (GeneRIF, showing 31)

• Helical secondary structure of the external S3-S4 linker of this pacemaker channel is examined and affects its activation (PMID:12668666)
• 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)
• In HCN1, the amino acid substitution A881T was identified in one idiopathic generalized epilepsy patient. (PMID:17931874)
• The polymorphism rs10941679 near HCN1/MRPS30 was also associated with percent dense area in breast cancer. (PMID:19232126)
• Human HCN1 hyperpolarization activated current (Ih) amplitude is rapidly enhanced after establishment of the whole-cell configuration in HEK293 cells. (PMID:20806410)
• increasing cAMP levels in cells antagonized the up-regulation of HCN1 channels mediated by a TRIP8b construct binding the CNBD exclusively. (PMID:21504900)
• Hyperpolarization-activated currents are smaller and slower, input resistances are higher, and membrane time constants are longer in HCN1-deficient than in HCN1-expressing neurons of the ventral cochlear nucleus. (PMID:21562186)
• 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)
• HCN1 channels make an important contribution to the maintenance of spontaneous burst activity in embryonic cortical neuron cultures. (PMID:22094222)
• Studies suggest that HCN1 channels may be therapeutic targets for treatment of depressive disorders. (PMID:23033536)
• Wild-type presynaptic HCN1 channel function is persistently decreased following seizures. (PMID:23077068)
• acute abrogation of HCN1-FLNa interaction in neurons, with the use of decoy peptides that mimic the FLNa-binding domain of HCN1, abolishes the punctate distribution of HCN1 channels in neuronal cell bodies (PMID:24403084)
• de novo HCN1 point mutations cause a recognizable early-onset epileptic encephalopathy in humans (PMID:24747641)
• A new mode of regulating HCN1 trafficking: through the use of a di-arginine ER retention signal that monitors processing of the channel in the early secretory pathway. (PMID:25142030)
• Study presents cryo-electron microscopy structures of the human HCN1 channel in the absence and presence of cAMP at 3.5 A resolution. HCN channels contain a K(+) channel selectivity filter-forming sequence from which the amino acids create a unique structure that explains Na(+) and K(+) permeability. (PMID:28086084)
• Polymorphism of HCN1 is associated with breast cancer. (PMID:28178648)
• 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)
• Mechanical transduction of cytoplasmic-to-transmembrane-domain movements in a hyperpolarization-activated cyclic nucleotide-gated cation channel. (PMID:29936413)
• The results expand the clinical spectrum related to HCN1 variants to include common generalized epilepsy phenotypes and further illustrate how HCN1 has a pivotal function in brain development and control of neuronal excitability. (PMID:30351409)
• Study found stronger h-channel (HCN1)-related membrane properties in supragranular pyramidal neurons in human temporal cortex, compared to mouse supragranular pyramidal neurons in temporal association area. H-channels contribute to between-species differences in a fundamental neuronal property. (PMID:30392798)
• this study provides evidence that the HCN1 is candidate genes for Dravet and Dravet-like phenotypes. (PMID:30776697)
• All-atom molecular dynamics simulations (~20 mus) of HCN1 channel under hyperpolarization reveals an initial downward movement of the S4 voltage-sensor but following the transfer of last gating charge, the S4 breaks into two sub-helices with the lower sub-helix becoming parallel to the membrane. (PMID:31774399)
• Mutating two residues of HCN1 located at the interface between the voltage sensor and the pore domain resulted in the open state upon depolarization instead of hyperpolarization. (PMID:32184399)
• 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)
• HCN1 channels: A versatile tool for signal processing by primary sensory neurons. (PMID:34197835)
• Biophysical analysis of an HCN1 epilepsy variant suggests a critical role for S5 helix Met-305 in voltage sensor to pore domain coupling. (PMID:34298002)
• Do the functional properties of HCN1 mutants correlate with the clinical features in epileptic patients? (PMID:34310985)
• Developmental HCN channelopathy results in decreased neural progenitor proliferation and microcephaly in mice. (PMID:34429357)
• The Impact of Altered HCN1 Expression on Brain Function and Its Relationship with Epileptogenesis. (PMID:37366350)
• HCN1 pathogenic variants associated with childhood epilepsy in a cohort of Chinese patients. (PMID:38009841)
• Structural basis for hyperpolarization-dependent opening of human HCN1 channel. (PMID:38890331)

Cross-species orthologs

14 orthologs

Organism	Symbol	Gene ID
danio_rerio	hcn1	ENSDARG00000104480
mus_musculus	Hcn1	ENSMUSG00000021730
rattus_norvegicus	Hcn1	ENSRNOG00000055382
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), CNGB3 (ENSG00000170289), KCNH6 (ENSG00000173826), CNGA2 (ENSG00000183862), KCNH8 (ENSG00000183960), KCNH7 (ENSG00000184611), CNGA1 (ENSG00000198515)

Protein

Protein identifiers

Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 — O60741 (reviewed: O60741)

Alternative names: Brain cyclic nucleotide-gated channel 1

All UniProt accessions (3): A0A0U1RQR7, A0A669KB45, O60741

UniProt curated annotations — full annotation on UniProt →

Function. Hyperpolarization-activated ion channel that are 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 the generation of the I(h) current which controls neuron excitability. Participates in cerebellar mechanisms of motor learning. May mediate responses to sour stimuli.

Subunit / interactions. Homotetramer. Heterotetramer with HCN2. The potassium channel is composed of a homo- or heterotetrameric complex of pore-forming subunits. Interacts with KCNE2. Interacts with the SH3 domain of CSK.

Subcellular location. Cell membrane.

Tissue specificity. Detected in brain, in particular in amygdala and hippocampus, while expression in caudate nucleus, corpus callosum, substantia nigra, subthalamic nucleus and thalamus is very low or not detectable. Detected at very low levels in muscle and pancreas.

Disease relevance. Developmental and epileptic encephalopathy 24 (DEE24) [MIM:615871] A disease characterized by early-onset seizures, intellectual disability of varying degrees, and behavioral disturbances or autistic features in most individuals. The disease is caused by variants affecting the gene represented in this entry. Generalized epilepsy with febrile seizures plus 10 (GEFSP10) [MIM:618482] An autosomal dominant neurologic disorder with incomplete penetrance, characterized by variable types of seizures including absence, tonic-clonic, febrile, focal, and eyelid myoclonia. Some patients have normal neurologic development. Others have mild-to-moderate intellectual disability or autism spectrum disorder. 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 promotes tetramerization and formation of an active channel. Compared to other family members, cAMP has less stimulatory effect on HCN1 because part of the molecules already contain bound cAMP and form homotetramers when cAMP levels are low, this inherent tetramerization in HCN1 results in a weaker response to increased cAMP. Inhibited by Cs(1+), zatebradine, capsazepine and ZD7288.

Domain organisation. The segment S4 is probably the voltage-sensor and is characterized by a series of positively charged amino acids at every third position.

Similarity. Belongs to the potassium channel HCN family.

RefSeq proteins (1): NP_066550* (*=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), 2 shown:

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

UniProt features (117 total): sequence variant 32, helix 26, strand 14, topological domain 8, compositionally biased region 7, binding site 7, transmembrane region 6, sequence conflict 5, region of interest 4, turn 4, chain 1, intramembrane region 1, short sequence motif 1, glycosylation site 1

Structure

Experimental structures (PDB)

17 structures.

PDB	Method	Resolution (Å)
9BC6	ELECTRON MICROSCOPY	2.5
9PXN	ELECTRON MICROSCOPY	2.5
9Z6T	ELECTRON MICROSCOPY	2.6
8UC7	ELECTRON MICROSCOPY	2.9
8UC8	ELECTRON MICROSCOPY	3
6UQF	ELECTRON MICROSCOPY	3.04
8T4M	ELECTRON MICROSCOPY	3.16
8Y60	ELECTRON MICROSCOPY	3.23
9BC7	ELECTRON MICROSCOPY	3.3
9R1T	ELECTRON MICROSCOPY	3.34
5U6O	ELECTRON MICROSCOPY	3.5
5U6P	ELECTRON MICROSCOPY	3.51
9R1V	ELECTRON MICROSCOPY	3.53
6UQG	ELECTRON MICROSCOPY	3.54
8T4Y	ELECTRON MICROSCOPY	3.58
8T50	ELECTRON MICROSCOPY	3.6
9R1U	ELECTRON MICROSCOPY	3.92

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60741-F1	70.61	0.41

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 (7): 539; 540; 542; 549; 550; 590; 593

Glycosylation sites (1): 338

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1296061	HCN channels

MSigDB gene sets: 0 (showing top):

GO Biological Process (28): regulation of membrane depolarization (GO:0003254), neuronal action potential (GO:0019228), cellular response to interferon-beta (GO:0035458), sodium ion transmembrane transport (GO:0035725), regulation of membrane potential (GO:0042391), maternal behavior (GO:0042711), apical protein localization (GO:0045176), negative regulation of action potential (GO:0045759), retinal cone cell development (GO:0046549), protein homotetramerization (GO:0051289), response to calcium ion (GO:0051592), general adaptation syndrome, behavioral process (GO:0051867), negative regulation of synaptic transmission, glutamatergic (GO:0051967), cellular response to cAMP (GO:0071320), potassium ion transmembrane transport (GO:0071805), regulation of heart rate by cardiac conduction (GO:0086091), sodium ion import across plasma membrane (GO:0098719), regulation of SA node cell action potential (GO:0098907), response to L-glutamate (GO:1902065), positive regulation of membrane hyperpolarization (GO:1902632), potassium ion import across plasma membrane (GO:1990573), monoatomic ion transport (GO:0006811), potassium ion transport (GO:0006813), sodium ion transport (GO:0006814), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085), regulation of postsynaptic membrane potential (GO:0060078), regulation of membrane hyperpolarization (GO:1902630)

GO Molecular Function (14): intracellularly cAMP-activated cation channel activity (GO:0005222), voltage-gated sodium channel activity (GO:0005248), voltage-gated potassium channel activity (GO:0005249), potassium channel activity (GO:0005267), phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), phosphatidylinositol-3,4,5-trisphosphate binding (GO:0005547), voltage-gated monoatomic cation channel activity (GO:0022843), cAMP binding (GO:0030552), identical protein binding (GO:0042802), obsolete intracellular cAMP-activated cation channel activity involved in regulation of presynaptic membrane potential (GO:0140232), nucleotide binding (GO:0000166), monoatomic ion channel activity (GO:0005216), sodium channel activity (GO:0005272), protein binding (GO:0005515)

GO Cellular Component (17): plasma membrane (GO:0005886), cell surface (GO:0009986), basolateral plasma membrane (GO:0016323), axon (GO:0030424), dendrite (GO:0030425), dendrite membrane (GO:0032590), neuronal cell body (GO:0043025), dendritic shaft (GO:0043198), axon terminus (GO:0043679), postsynaptic membrane (GO:0045211), presynaptic active zone membrane (GO:0048787), apical dendrite (GO:0097440), HCN channel complex (GO:0098855), glutamatergic synapse (GO:0098978), 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
cellular anatomical structure	4
monoatomic cation channel activity	3
dendrite	3
action potential	2
monoatomic cation transmembrane transport	2
phosphatidylinositol phosphate binding	2
anion binding	2
neuron projection	2
synaptic membrane	2
regulation of membrane potential	1
regulation of cellular process	1
membrane depolarization	1
transmission of nerve impulse	1
response to interferon-beta	1
cellular response to cytokine stimulus	1
sodium ion transport	1
monoatomic ion transmembrane transport	1
regulation of biological quality	1
parental behavior	1
intracellular protein localization	1
negative regulation of biological process	1
regulation of action potential	1
eye photoreceptor cell development	1
retinal cone cell differentiation	1
protein homooligomerization	1
protein tetramerization	1
response to metal ion	1
behavior	1
general adaptation syndrome	1
synaptic transmission, glutamatergic	1
negative regulation of synaptic transmission	1
regulation of synaptic transmission, glutamatergic	1
response to cAMP	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
potassium ion transport	1
regulation of heart rate	1
cardiac conduction	1
sodium ion transmembrane transport	1
inorganic cation import across plasma membrane	1

Protein interactions and networks

STRING

622 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HCN1	PEX5L	Q8IYB4	664
HCN1	GNAT3	A8MTJ3	660
HCN1	KCNA2	P16389	493
HCN1	KCNT1	Q5JUK3	414
HCN1	P3H3	Q8IVL6	409
HCN1	KCNH1	O95259	346
HCN1	ASPA	P45381	345
HCN1	KCNB1	Q14721	338
HCN1	A0A590UK56	A0A590UK56	309
HCN1	KCNJ3	P48549	284
HCN1	ASTN1	O14525	283
HCN1	AP3B2	Q13367	282
HCN1	NPTX2	P47972	272
HCN1	CAV3	P56539	272
HCN1	KCTD3	Q9Y597	271

IntAct

32 interactions, top by confidence:

A	B	Type	Score
HCN1	HCN4	psi-mi:“MI:0915”(physical association)	0.620
HCN4	HCN1	psi-mi:“MI:0915”(physical association)	0.620
HCN1	C3	psi-mi:“MI:0915”(physical association)	0.620
Shank3	HCN1	psi-mi:“MI:0915”(physical association)	0.520
HCN1	SEMA4C	psi-mi:“MI:0915”(physical association)	0.500
HCN1	MARK3	psi-mi:“MI:0915”(physical association)	0.500
HCN1	SRPK2	psi-mi:“MI:0915”(physical association)	0.500
HCN1	INA	psi-mi:“MI:0915”(physical association)	0.500
HCN1	SYNGAP1	psi-mi:“MI:0915”(physical association)	0.500
HCN1	AKAP11	psi-mi:“MI:0915”(physical association)	0.500
HCN1	PYGB	psi-mi:“MI:0915”(physical association)	0.500
HCN1	ARID3B	psi-mi:“MI:0915”(physical association)	0.500
HCN1	PARP1	psi-mi:“MI:0915”(physical association)	0.500
MARK3	HCN1	psi-mi:“MI:0915”(physical association)	0.500
SRPK2	HCN1	psi-mi:“MI:0915”(physical association)	0.500
INA	HCN1	psi-mi:“MI:0915”(physical association)	0.500
PCDHA2	HCN1	psi-mi:“MI:0915”(physical association)	0.500
SEMA4C	HCN1	psi-mi:“MI:0915”(physical association)	0.500
HNRNPA2B1	HCN1	psi-mi:“MI:0915”(physical association)	0.500
FMR1	HCN1	psi-mi:“MI:0915”(physical association)	0.500
SLC25A11	HCN1	psi-mi:“MI:0915”(physical association)	0.400
ITM2B	ILVBL	psi-mi:“MI:0914”(association)	0.350
HCN1	USP27X	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350

BioGRID (72): HCN1 (Affinity Capture-MS), HCN2 (Affinity Capture-Western), HCN3 (Affinity Capture-Western), HCN4 (Affinity Capture-Western), HCN1 (Synthetic Lethality), HCN1 (Reconstituted Complex), HCN4 (Affinity Capture-Western), HCN1 (Affinity Capture-Western), NDRG2 (Affinity Capture-MS), SERPINA3 (Affinity Capture-MS), TYMP (Affinity Capture-MS), HCN1 (Two-hybrid), HCN2 (Two-hybrid), HCN1 (Two-hybrid), HIST2H3PS2 (Affinity Capture-MS)

ESM2 similar proteins: A0JPH4, A1DWM3, A4QN56, A6H8H5, B0UYT5, B3MG58, B3NSE1, B4GAP7, B4KR05, B4LPX5, B4QBN2, O18868, O60741, P08911, P11483, P15387, P20309, P41984, P59995, Q03717, Q0P5V9, Q14721, Q1LUC3, Q1LUQ4, Q291H8, Q4V887, Q4ZHA6, Q5BKX6, Q5VW38, Q62897, Q63099, Q63881, Q6ZSS7, Q8C145, Q8CBH5, Q8HYZ1, Q91WD0, Q92953, Q95167, Q95L11

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

1 interactions.

A	Effect	B	Mechanism
REST	“down-regulates quantity by repression”	HCN1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

1174 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	19
Likely pathogenic	22
Uncertain significance	612
Likely benign	420
Benign	22

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1074847	NM_021072.4(HCN1):c.1172G>T (p.Gly391Val)	Pathogenic
1341556	NM_021072.4(HCN1):c.737A>C (p.Glu246Ala)	Pathogenic
1342978	NM_021072.4(HCN1):c.1184C>G (p.Ala395Gly)	Pathogenic
1342979	NM_021072.4(HCN1):c.1138A>T (p.Ile380Phe)	Pathogenic
1342980	NM_021072.4(HCN1):c.1169T>C (p.Val390Ala)	Pathogenic
139573	NM_021072.4(HCN1):c.814T>C (p.Ser272Pro)	Pathogenic
139574	NM_021072.4(HCN1):c.890G>C (p.Arg297Thr)	Pathogenic
2128837	NM_021072.4(HCN1):c.585G>T (p.Arg195Ser)	Pathogenic
2729721	NM_021072.4(HCN1):c.1160C>G (p.Ala387Gly)	Pathogenic
3358955	NM_021072.4(HCN1):c.1171G>T (p.Gly391Cys)	Pathogenic
461375	NM_021072.4(HCN1):c.701A>T (p.Tyr234Phe)	Pathogenic
635188	NM_021072.4(HCN1):c.728T>G (p.Met243Arg)	Pathogenic
635189	NM_021072.4(HCN1):c.1171G>A (p.Gly391Ser)	Pathogenic
635190	NM_021072.4(HCN1):c.1769G>A (p.Arg590Gln)	Pathogenic
635191	NM_021072.4(HCN1):c.986G>C (p.Cys329Ser)	Pathogenic
635192	NM_021072.4(HCN1):c.1240G>A (p.Val414Met)	Pathogenic
635193	NM_021072.4(HCN1):c.469C>G (p.Leu157Val)	Pathogenic
658809	NM_021072.4(HCN1):c.790A>T (p.Ser264Cys)	Pathogenic
976076	NM_021072.4(HCN1):c.1562G>T (p.Gly521Val)	Pathogenic
1298993	NM_021072.4(HCN1):c.1191C>G (p.Ile397Met)	Likely pathogenic
1298994	NM_021072.4(HCN1):c.858C>A (p.His286Gln)	Likely pathogenic
1308642	NM_021072.4(HCN1):c.628C>T (p.Pro210Ser)	Likely pathogenic
1328701	NM_021072.4(HCN1):c.1148C>T (p.Ala383Val)	Likely pathogenic
1342977	NM_021072.4(HCN1):c.2128_2129dup (p.Ser710fs)	Likely pathogenic
1480620	NM_021072.4(HCN1):c.1159G>C (p.Ala387Pro)	Likely pathogenic
1741776	NM_021072.4(HCN1):c.459G>T (p.Met153Ile)	Likely pathogenic
1803035	NM_021072.4(HCN1):c.794T>A (p.Leu265His)	Likely pathogenic
1803037	NM_021072.4(HCN1):c.535A>T (p.Asn179Tyr)	Likely pathogenic
2014403	NM_021072.4(HCN1):c.908G>T (p.Gly303Val)	Likely pathogenic
2027999	NM_021072.4(HCN1):c.1159G>A (p.Ala387Thr)	Likely pathogenic

SpliceAI

3707 predictions. Top by Δscore:

Variant	Effect	Δscore
5:45267085:GTAC:G	donor_loss	1.0000
5:45267086:TA:T	donor_loss	1.0000
5:45267087:A:AT	donor_loss	1.0000
5:45267091:A:AC	donor_gain	1.0000
5:45267091:ATT:A	donor_gain	1.0000
5:45267092:T:C	donor_gain	1.0000
5:45267131:T:A	donor_gain	1.0000
5:45267249:AATCT:A	acceptor_gain	1.0000
5:45267250:ATCT:A	acceptor_gain	1.0000
5:45267252:CT:C	acceptor_gain	1.0000
5:45267253:TC:T	acceptor_loss	1.0000
5:45267254:C:CA	acceptor_loss	1.0000
5:45267254:C:CC	acceptor_gain	1.0000
5:45267256:A:AC	acceptor_gain	1.0000
5:45267256:A:C	acceptor_gain	1.0000
5:45267263:C:CT	acceptor_gain	1.0000
5:45303837:CTC:C	acceptor_gain	1.0000
5:45303839:CCTAA:C	acceptor_loss	1.0000
5:45303840:C:CG	acceptor_loss	1.0000
5:45303841:T:A	acceptor_loss	1.0000
5:45303846:A:C	acceptor_gain	1.0000
5:45303850:C:CT	acceptor_gain	1.0000
5:45353095:CTTA:C	donor_loss	1.0000
5:45353096:TTA:T	donor_loss	1.0000
5:45353097:TACCT:T	donor_loss	1.0000
5:45353098:A:AC	donor_gain	1.0000
5:45353098:ACCTC:A	donor_loss	1.0000
5:45353099:C:CC	donor_gain	1.0000
5:45353099:C:CG	donor_loss	1.0000
5:45353099:CCT:C	donor_gain	1.0000

AlphaMissense

5840 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:45267094:C:G	R593P	1.000
5:45267100:A:G	L591P	1.000
5:45267103:C:G	R590P	1.000
5:45267104:G:C	R590G	1.000
5:45267112:G:T	A587D	1.000
5:45267113:C:G	A587P	1.000
5:45267115:A:T	V586D	1.000
5:45267120:C:A	E584D	1.000
5:45267120:C:G	E584D	1.000
5:45267123:A:C	F583L	1.000
5:45267123:A:T	F583L	1.000
5:45267124:A:C	F583C	1.000
5:45267124:A:G	F583S	1.000
5:45267125:A:G	F583L	1.000
5:45267127:G:T	A582D	1.000
5:45267128:C:G	A582P	1.000
5:45267132:C:A	R580S	1.000
5:45267132:C:G	R580S	1.000
5:45267133:C:A	R580M	1.000
5:45267133:C:G	R580T	1.000
5:45267136:A:C	M579R	1.000
5:45267136:A:G	M579T	1.000
5:45267136:A:T	M579K	1.000
5:45267142:G:T	P577Q	1.000
5:45267154:A:C	L573R	1.000
5:45267154:A:G	L573P	1.000
5:45267154:A:T	L573Q	1.000
5:45267157:A:T	V572D	1.000
5:45267165:G:C	F569L	1.000
5:45267165:G:T	F569L	1.000

dbSNP variants (sampled 300 via entrez): RS1000004371 (5:45429161 A>G), RS1000019645 (5:45637011 G>A), RS1000024275 (5:45511026 G>A), RS1000025852 (5:45633306 A>T), RS1000026869 (5:45566983 G>A,C,T), RS1000027920 (5:45271053 A>G), RS1000030669 (5:45600322 C>A,G), RS1000036477 (5:45349203 C>G,T), RS1000040821 (5:45342732 G>A,T), RS1000041570 (5:45514335 T>C,G), RS1000044825 (5:45345215 A>C), RS1000053273 (5:45478060 A>C), RS1000057062 (5:45280077 T>G), RS1000064679 (5:45654702 C>T), RS1000067260 (5:45521212 C>A)

Disease associations

OMIM: gene MIM:602780 | disease phenotypes: MIM:618482, MIM:615871, MIM:613123

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy, 24	Definitive	Autosomal dominant
generalized epilepsy with febrile seizures plus, type 10	Strong	Autosomal dominant
generalized epilepsy with febrile seizures plus	Supportive	Autosomal dominant
undetermined early-onset epileptic encephalopathy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
generalized epilepsy with febrile seizures plus	Definitive	AD

Mondo (9): generalized epilepsy with febrile seizures plus, type 10 (MONDO:0032777), early-infantile DEE (MONDO:0800491), developmental and epileptic encephalopathy (MONDO:0100620), developmental and epileptic encephalopathy, 24 (MONDO:0014377), intellectual disability (MONDO:0001071), epilepsy (MONDO:0005027), Brugada syndrome 8 (MONDO:0013148), generalized epilepsy with febrile seizures plus (MONDO:0018214), undetermined early-onset epileptic encephalopathy (MONDO:0018614)

Orphanet (5): Early infantile developmental and epileptic encephalopathy (Orphanet:1934), Non-specific early-onset epileptic encephalopathy (Orphanet:442835), Brugada syndrome (Orphanet:130), Early myoclonic encephalopathy (Orphanet:1935), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

80 total (30 of 80 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000252	Microcephaly
HP:0000348	High forehead
HP:0000494	Downslanted palpebral fissures
HP:0000504	Abnormality of vision
HP:0000508	Ptosis
HP:0000546	Retinal degeneration
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000668	Hypodontia
HP:0000708	Atypical behavior
HP:0000717	Autism
HP:0000729	Autistic behavior
HP:0000739	Anxiety
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001268	Mental deterioration
HP:0001273	Abnormal corpus callosum morphology
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001315	Reduced tendon reflexes
HP:0001336	Myoclonus
HP:0001337	Tremor

GWAS associations

30 associations (top):

Study	Trait	p-value
GCST002539_56	Schizophrenia	5.000000e-09
GCST002820_9	Survival in microsatellite instability low/stable colorectal cancer	9.000000e-06
GCST002822_3	Survival in colon cancer	3.000000e-06
GCST003264_253	Post bronchodilator FEV1/FVC ratio	4.000000e-06
GCST003795_4	Age at first birth	2.000000e-10
GCST003804_3	Non-response to bupropion and depression	7.000000e-07
GCST004521_285	Autism spectrum disorder or schizophrenia	5.000000e-08
GCST004750_73	Squamous cell lung carcinoma	3.000000e-06
GCST004826_16	P wave duration	4.000000e-12
GCST004826_7	P wave duration	1.000000e-11
GCST004946_130	Schizophrenia	4.000000e-11
GCST006045_6	Age at first birth	4.000000e-08
GCST006803_101	Schizophrenia	6.000000e-11
GCST006941_65	Irritable mood	3.000000e-09
GCST006947_54	Feeling fed-up	2.000000e-09
GCST007201_344	Schizophrenia	1.000000e-06
GCST007201_472	Schizophrenia	1.000000e-09
GCST007324_81	Adventurousness	4.000000e-09
GCST007325_280	General risk tolerance (MTAG)	8.000000e-13
GCST007326_16	Number of sexual partners	3.000000e-08
GCST007335_13	Age at first sexual intercourse	3.000000e-12
GCST008595_156	Cognitive ability, years of educational attainment or schizophrenia (pleiotropy)	3.000000e-10
GCST009307_1	Spatial memory	8.000000e-08
GCST009600_19	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	4.000000e-08
GCST010002_24	Refractive error	1.000000e-13
GCST010320_104	PR interval	1.000000e-20
GCST010321_215	PR interval	3.000000e-23
GCST011010_40	Electrocardiographic traits (multivariate)	1.000000e-11
GCST90000047_98	Age at first sexual intercourse	1.000000e-15
GCST90000050_35	Age at first birth	6.000000e-10

EFO canonical traits (14, from GWAS)

EFO ID	Trait name
EFO:0007054	microsatellite instability measurement
EFO:0000638	overall survival
EFO:0004713	FEV/FVC ratio
EFO:0009101	age at first birth measurement
EFO:0005094	P wave duration
EFO:0009594	irritability measurement
EFO:0009588	feeling “fed-up” measurement
EFO:0008579	risk-taking behaviour
EFO:0009749	age at first sexual intercourse measurement
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0004874	memory performance
EFO:0004462	PR interval
EFO:0004327	electrocardiography

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C567732	Brugada Syndrome 8 (supp.)
C565808	Generalized Epilepsy with Febrile Seizures Plus (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1795171 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs79983226	Metabolism/PK	3	o-desmethyltramadol;tramadol

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs79983226	HCN1	3	1.50	1	o-desmethyltramadol;tramadol

GtoPdb / IUPHAR curated pharmacology

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

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

Most potent curated ligand interactions (11 total), top 11:

Ligand	Action	Affinity	Parameter
cyclic AMP	Agonist	7.2	pKd
MEL57A	Channel blocker	6.49	pEC50
cilobradine	Antagonist	5.9	pIC50
zatebradine	Antagonist	5.7	pIC50
ivabradine	Antagonist	5.7	pIC50
propofol	Channel blocker	5.2	pIC50
ZD7288	Antagonist	4.7	pIC50
EC18	Channel blocker	4.68	pEC50
clonidine	Antagonist	4.4	pIC50
Cs+	Antagonist	3.7	pIC50
Mg2+	Channel blocker	3.3	pIC50

ChEMBL bioactivities

30 potent at pChembl≥5 of 45 total, top 25 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.80	IC50	15.85	nM	CHEMBL1823874
7.50	IC50	31.62	nM	CHEMBL1823875
7.50	IC50	31.62	nM	CHEMBL1823878
7.37	IC50	43	nM	CHEMBL6195028
7.34	IC50	46	nM	CHEMBL6195028
7.32	IC50	48	nM	CHEMBL6195028
7.31	IC50	49	nM	CHEMBL6195028
7.30	IC50	50.12	nM	CHEMBL1823879
7.10	IC50	79.43	nM	CHEMBL1823880
6.90	IC50	125.9	nM	CHEMBL1823677
6.80	IC50	158.5	nM	CHEMBL2052019
6.70	IC50	199.5	nM	CHEMBL1823881
6.60	IC50	251.2	nM	CHEMBL1823876
6.57	IC50	269	nM	CHEMBL6195028
6.50	IC50	316.2	nM	CHEMBL1823887
6.40	IC50	398.1	nM	CHEMBL1823666
6.40	IC50	398.1	nM	CHEMBL1435630
6.40	IC50	398.1	nM	CHEMBL1823882
6.40	IC50	398.1	nM	CHEMBL1823886
6.20	IC50	631	nM	CHEMBL1823667
6.20	IC50	631	nM	CHEMBL1823674
6.20	IC50	631	nM	CHEMBL1823888
5.90	IC50	1259	nM	CHEMBL1823665
5.80	IC50	1585	nM	CHEMBL1823885
5.60	IC50	2512	nM	CHEMBL1823889

PubChem BioAssay actives

20 with measured affinity, of 48 total; 20 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-(4-propan-2-ylpiperazin-1-yl)cyclohexyl]methyl]benzamide	617259: Inhibition of human HCN1 heterologously expressed in HEK-293 cells after 30 mins by VIPR assay	ic50	0.0158	uM
2-ethoxy-N-[[1-(4-ethylpiperazin-1-yl)cyclohexyl]methyl]benzamide	617259: Inhibition of human HCN1 heterologously expressed in HEK-293 cells after 30 mins by VIPR assay	ic50	0.0316	uM
2-methoxy-N-[[1-(4-propan-2-ylpiperazin-1-yl)cyclohexyl]methyl]benzamide	617259: Inhibition of human HCN1 heterologously expressed in HEK-293 cells after 30 mins by VIPR assay	ic50	0.0316	uM
N-[[1-(4-cyclopropylpiperazin-1-yl)cyclohexyl]methyl]-2-ethoxybenzamide	617259: Inhibition of human HCN1 heterologously expressed in HEK-293 cells after 30 mins by VIPR assay	ic50	0.0501	uM
N-[[1-(4-cyclobutylpiperazin-1-yl)cyclohexyl]methyl]-2-ethoxybenzamide	617259: Inhibition of human HCN1 heterologously expressed in HEK-293 cells after 30 mins by VIPR assay	ic50	0.0794	uM
2-ethoxy-N-[[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl]benzamide	617259: Inhibition of human HCN1 heterologously expressed in HEK-293 cells after 30 mins by VIPR assay	ic50	0.1259	uM
4-N-ethyl-6-N,1,2-trimethyl-4-N-phenylpyrimidin-1-ium-4,6-diamine chloride	617259: Inhibition of human HCN1 heterologously expressed in HEK-293 cells after 30 mins by VIPR assay	ic50	0.1585	uM
N-[[1-(4-cyclopentylpiperazin-1-yl)cyclohexyl]methyl]-2-ethoxybenzamide	617259: Inhibition of human HCN1 heterologously expressed in HEK-293 cells after 30 mins by VIPR assay	ic50	0.1995	uM
2-propan-2-yloxy-N-[[1-(4-propan-2-ylpiperazin-1-yl)cyclohexyl]methyl]benzamide	617259: Inhibition of human HCN1 heterologously expressed in HEK-293 cells after 30 mins by VIPR assay	ic50	0.2512	uM
2-ethoxy-N-[[4-(4-propan-2-ylpiperazin-1-yl)oxan-4-yl]methyl]benzamide	617259: Inhibition of human HCN1 heterologously expressed in HEK-293 cells after 30 mins by VIPR assay	ic50	0.3162	uM
2-methoxy-N-[[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl]benzamide	617259: Inhibition of human HCN1 heterologously expressed in HEK-293 cells after 30 mins by VIPR assay	ic50	0.3981	uM
2-ethoxy-N-[(1-piperazin-1-ylcyclohexyl)methyl]benzamide	617259: Inhibition of human HCN1 heterologously expressed in HEK-293 cells after 30 mins by VIPR assay	ic50	0.3981	uM
2-ethoxy-N-[[1-(4-methylpiperazin-1-yl)cyclopentyl]methyl]benzamide	617259: Inhibition of human HCN1 heterologously expressed in HEK-293 cells after 30 mins by VIPR assay	ic50	0.3981	uM
2-ethoxy-N-[[2-(4-methylpiperazin-1-yl)-1,3-dihydroinden-2-yl]methyl]benzamide	617259: Inhibition of human HCN1 heterologously expressed in HEK-293 cells after 30 mins by VIPR assay	ic50	0.3981	uM
N-[[2-(4-methylpiperazin-1-yl)-1,3-dihydroinden-2-yl]methyl]-2-phenylmethoxybenzamide	617259: Inhibition of human HCN1 heterologously expressed in HEK-293 cells after 30 mins by VIPR assay	ic50	0.6310	uM
2-ethoxy-N-[[2-(4-propan-2-ylpiperazin-1-yl)-1,3-dihydroinden-2-yl]methyl]benzamide	617259: Inhibition of human HCN1 heterologously expressed in HEK-293 cells after 30 mins by VIPR assay	ic50	0.6310	uM
2-methoxy-N-[[1-phenyl-4-(4-propan-2-ylpiperazin-1-yl)piperidin-4-yl]methyl]benzamide	617259: Inhibition of human HCN1 heterologously expressed in HEK-293 cells after 30 mins by VIPR assay	ic50	0.6310	uM
2-methoxy-N-[[2-(4-methylpiperazin-1-yl)-1,3-dihydroinden-2-yl]methyl]benzamide	617259: Inhibition of human HCN1 heterologously expressed in HEK-293 cells after 30 mins by VIPR assay	ic50	1.2589	uM
2-methoxy-N-[[2-(4-methylpiperazin-1-yl)-3,4-dihydro-1H-naphthalen-2-yl]methyl]benzamide	617259: Inhibition of human HCN1 heterologously expressed in HEK-293 cells after 30 mins by VIPR assay	ic50	1.5849	uM
2-methoxy-N-[2-(4-methylphenyl)-2-(4-methylpiperazin-1-yl)ethyl]benzamide	617259: Inhibition of human HCN1 heterologously expressed in HEK-293 cells after 30 mins by VIPR assay	ic50	2.5119	uM

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation, increases mutagenesis	3
geldanamycin	increases expression	1
trichostatin A	increases expression	1
triadimefon	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	increases expression	1
Amiodarone	increases expression	1
Vehicle Emissions	decreases methylation	1
Cadmium	decreases expression, increases abundance	1
Doxorubicin	decreases expression	1
Oxygen	increases expression	1
Triclosan	decreases expression	1
Valproic Acid	increases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	decreases expression, increases abundance	1

ChEMBL screening assays

21 unique, capped per target: 12 binding, 8 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1825382	Binding	Inhibition of human HCN1 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
CHEMBL4407443	ADMET	Inhibition of HCN1 (unknown origin) at 3 uM relative to control	Discovery of 3,4,6-Trisubstituted Piperidine Derivatives as Orally Active, Low hERG Blocking Akt Inhibitors via Conformational Restriction and Structure-Based Design. — J Med Chem
CHEMBL6194489	Functional	Inhibition of human HCN1 in HCN1 overexpressing HEK293 cells (tetracycline inducible) using Automated patch clamp after a single hyperpolarizing pulse -80 mV (HCN1)	Data for DCP probe RO-275

Cellosaurus cell lines

2 cell lines: 1 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8WI	Abcam MCF-7 HCN1 KO	Cancer cell line	Female
CVCL_RQ84	PrecisION hHCN1-HEK	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT03347526	PHASE3	SUSPENDED	A Novel Approach to Infantile Spasms
NCT03421496	PHASE3	TERMINATED	A Study to Assess Cannabidiol Oral Solution With Vigabatrin as Initial Therapy in Participants With Infantile Spasms
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT04289467	PHASE2	RECRUITING	Treatment of Refractory Infantile Spasms With Fenfluramine
NCT05626634	PHASE2	COMPLETED	Open-label, Long-term Safety Study of LP352 in Subjects With Developmental and Epileptic Encephalopathy
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT04727970	PHASE1	COMPLETED	Tricaprilin Infantile Spasms Pilot Study
NCT06700811	PHASE1	RECRUITING	Ketogenic Diet for Prevention of Epileptic Spasms in Infantile Onset Genetic Epilepsies
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT00006191	Not specified	COMPLETED	Effect of Levetiracetam on Brain Excitability
NCT02960347	Not specified	COMPLETED	Examining the Efficacy of tDCS in the Attenuation of Epileptic Paroxysmal Discharges and Clinical Seizures
NCT06938542	Not specified	ENROLLING_BY_INVITATION	Palliative Care Needs of Children With Rare Diseases and Their Families
NCT07585643	Not specified	NOT_YET_RECRUITING	IBIS - Investigating Reliability of BIS and SEDLINE Monitoring in Children With Developmental and Epileptic Encephalopathies (DEE).
NCT03876444	PHASE2/PHASE3	UNKNOWN	Intravenous Methylprednisolone Versus Oral Prednisolone for Infantile Spasms
NCT05279118	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Ketogenic Diet vs ACTH for the Treatment of Children With West Syndrome
NCT05364021	PHASE1/PHASE2	COMPLETED	Study to Investigate LP352 in Subjects With Developmental and Epileptic Encephalopathies
NCT06983158	PHASE1/PHASE2	SUSPENDED	A Clinical Trial of CAP-002 Gene Therapy in Pediatric Patients With Syntaxin-Binding Protein 1 (STXBP1) Encephalopathy
NCT04937062	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Phenylbutyrate for Monogenetic Developmental and Epileptic Encephalopathy
NCT04302116	Not specified	RECRUITING	Vigabatrin With High Dose Prednisolone Combination Therapy vs Vigabatrin Alone for Infantile Spasm
NCT05538936	Not specified	COMPLETED	The Effect of Spa and Massage on Babies on Colic Symptoms
NCT06149663	Not specified	AVAILABLE	Intermediate-Size Expanded Access Protocol (EAP) for LP352
NCT06266234	Not specified	RECRUITING	Characterization by Automated System on Infantile Spasmes
NCT06380192	Not specified	RECRUITING	Developmental and Epileptic Encephalopathy of Genetic Etiology: Natural History Through Reuse of Clinical Data
NCT07396883	Not specified	NOT_YET_RECRUITING	Developmental and Epileptic Encephalopathies Diagnosed Via Long-read Genome Sequencing
NCT07413211	Not specified	RECRUITING	Genetic Developmental and Epileptic Encephalopathy Natural History Study for Clinical Trial Readiness
NCT07531511	Not specified	NOT_YET_RECRUITING	SLC6A1-NDD Prospective Longitudinal Natural History Study
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome