HCN3

Chr 1

hyperpolarization activated cyclic nucleotide gated potassium channel 3

This gene encodes a multi-pass membrane protein that functions as a voltage gated cation channel. The encoded protein is a member of a family of closely related cyclic adenosine monophosphate-binding channel proteins. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

ResearchGenerating clinical summary…
MultiplemechanismLOEUF 0.74
Clinical SummaryHCN3
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint?
0.74LOEUF
pLI 0.000
Z-score 2.57
OE 0.46 (0.290.74)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?
1.52Z-score
OE missense 0.81 (0.750.88)
424 obs / 521.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?
LoF OE?0.46 (0.290.74)
00.351.4
Missense OE?0.81 (0.750.88)
00.61.4
Synonymous OE?0.90
01.21.6
LoF obs/exp: 12 / 26.2Missense obs/exp: 424 / 521.7Syn Z: 1.13

This gene — mechanism propensity

DN
0.83top 10%
GOF
0.88top 5%
LOF
0.2678th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median
DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

HCN3 · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

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