HCN1

Chr 5AD

hyperpolarization activated cyclic nucleotide gated potassium channel 1

ENSG00000164588UniProt: O60741

Hyperpolarization-activated ion channel that are permeable to sodium and potassium ions (PubMed:15351778, PubMed:28086084). Displays lower selectivity for K(+) over Na(+) ions (PubMed:28086084). Contributes to the native pacemaker currents in heart (If) and in the generation of the I(h) current which controls neuron excitability (PubMed:29936235, PubMed:30351409). Participates in cerebellar mechanisms of motor learning (By similarity). May mediate responses to sour stimuli (By similarity)

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 24MIM #615871
AD
Generalized epilepsy with febrile seizures plus, type 10MIM #618482
AD
592
ClinVar variants
19
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— HCN1
🧬
Gene-Disease Validity (ClinGen)
generalized epilepsy with febrile seizures plus · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
19 Pathogenic / Likely Pathogenic· 353 VUS of 592 total submissions
Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.18LOEUF
pLI 1.000
Z-score 5.15
OE 0.06 (0.02–0.18)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
3.66Z-score
OE missense 0.53 (0.48–0.59)
261 obs / 489.1 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.06 (0.02–0.18)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.53 (0.48–0.59)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.21
0≤1.21.6
LoF obs/exp: 2 / 34.8Missense obs/exp: 261 / 489.1Syn Z: -2.32

ClinVar Variant Classifications

592 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5
Likely Pathogenic14
VUS353
Likely Benign206
Benign5
Conflicting9
5
Pathogenic
14
Likely Pathogenic
353
VUS
206
Likely Benign
5
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
3
2
0
5
Likely Pathogenic
0
12
2
0
14
VUS
19
284
48
2
353
Likely Benign
0
11
58
137
206
Benign
0
0
3
2
5
Conflicting
—9
Total19310113141592

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

HCN1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

HCN1-related epileptic encephalopathy, early infantile

definitive
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Developmental and epileptic encephalopathy 24

MIM #615871

Molecular basis of disorder known

Autosomal dominant

Generalized epilepsy with febrile seizures plus, type 10

MIM #618482

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Deep posteromedial cortical rhythm in dissociation.
Vesuna S et al.·Nature
2020
HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond.
Marini C et al.·Brain
2018
HCN channels and absence seizures.
Crunelli V et al.·Neurobiol Dis
2023Review
HCN1 epilepsy: From genetics and mechanisms to precision therapies.
Bleakley LE et al.·J Neurochem
2024Review
Cardiac and neuronal HCN channelopathies.
Rivolta I et al.·Pflugers Arch
2020Review
Identification of HCN1 as a 14-3-3 client.
Lankford C et al.·PLoS One
2022
Extracellular activation of HCN4 by a subtype-specific nanobody.
Sharifzadeh AS et al.·Nat Commun
2025
Dravet syndrome and its mimics: Beyond SCN1A.
Steel D et al.·Epilepsia
2017Review
Retinal Dysfunction in a Mouse Model of HCN1 Genetic Epilepsy.
Zhao D et al.·J Neurosci
2023Functional
Org 34167 rescues voltage dependence of mutant channels and normalizes hyperexcitability in HCN1 epilepsy.
Bleakley LE et al.·Epilepsia
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools