HCN4

Chr 15AD

hyperpolarization activated cyclic nucleotide gated potassium channel 4

Also known as: BRGDA8, EIG18, SSS2

NCBI Gene: 10021 ENSG00000138622 UniProt: Q9Y3Q4 OMIM: 605206

This gene encodes a member of the hyperpolarization-activated cyclic nucleotide-gated potassium channels. The encoded protein shows slow kinetics of activation and inactivation, and is necessary for the cardiac pacemaking process. This channel may also mediate responses to sour stimuli. Mutations in this gene have been linked to sick sinus syndrome 2, also known as atrial fibrillation with bradyarrhythmia or familial sinus bradycardia. Two pseudogenes have been identified on chromosome 15. [provided by RefSeq, Oct 2008]

GeneReviews OMIM Research

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

{Epilepsy, idiopathic generalized, susceptibility to, 18}MIM #619521

Brugada syndrome 8MIM #613123

Sick sinus syndrome 2MIM #163800

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.24

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

📖

GeneReview available — HCN4

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.24LOEUF

pLI 0.999

Z-score 4.79

OE 0.09 (0.04–0.24)

Highly constrained

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

Missense Constraint?

2.75Z-score

OE missense 0.70 (0.65–0.76)

478 obs / 679.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.09 (0.04–0.24)

0≤0.351.4

Missense OE?0.70 (0.65–0.76)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 3 / 32.5Missense obs/exp: 478 / 679.5Syn Z: 0.63

Background carrier burden — how many people carry a rare variant somewhere in HCN4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 46

1,520 rare PASS variants

Rare truncating (LoF)

1 in 1,400

119 rare PASS variants

Rare synonymous (reference)

1 in 37

813 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for HCN4. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 62	1 in 1,600
South Asian	~43k	1 in 42	1 in 1,100
Remaining (unassigned)	~30k	1 in 38	1 in 1,200
European (Finnish)	~27k	1 in 110	1 in 630
Admixed American	~22k	1 in 34	1 in 940
African / African American	~21k	1 in 38	1 in 860
East Asian	~20k	1 in 43	1 in 1,900
Ashkenazi Jewish	~13k	1 in 110	1 in 1,700
Middle Eastern	~2,884	1 in 35	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 7 of 8 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 8.? see exons ↓