KCNJ4
Chr 22potassium inwardly rectifying channel subfamily J member 4
Also known as: HIR, HIRK2, HRK1, IRK-3, IRK3, Kir2.3
The protein is an inwardly rectifying potassium channel that preferentially allows potassium flow into cells rather than out, playing a key role in neuronal and muscle cell excitability. This gene is highly constrained against loss-of-function variants (pLI 0.96, LOEUF 0.29), suggesting that mutations likely cause severe developmental phenotypes, though specific associated diseases have not yet been definitively established in the literature. The high constraint scores indicate that pathogenic variants in this gene would be expected to cause significant clinical consequences.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Highly missense-constrained (top ~0.1%)
This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
63 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 19 | 0 | 19 |
Likely Pathogenic | 0 | 0 | 3 | 0 | 3 |
VUS | 0 | 34 | 2 | 0 | 36 |
Likely Benign | 0 | 0 | 0 | 1 | 1 |
Benign | 0 | 0 | 1 | 1 | 2 |
Conflicting | — | 1 | |||
| Total | 0 | 34 | 25 | 2 | 62 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
KCNJ4 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools