KCNJ4

Chr 22

potassium inwardly rectifying channel subfamily J member 4

Also known as: HIR, HIRK2, HRK1, IRK-3, IRK3, Kir2.3

NCBI Gene: 3761 ENSG00000168135 UniProt: P48050 OMIM: 600504

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.

OMIM ResearchSummary from RefSeq, UniProt

Several different potassium channels are known to be involved with electrical signaling in the nervous system. One class is activated by depolarization whereas a second class is not. The latter are referred to as inwardly rectifying K+ channels, and they have a greater tendency to allow potassium to flow into the cell rather than out of it. This asymmetry in potassium ion conductance plays a key role in the excitability of muscle cells and neurons. The protein encoded by this gene is an integral membrane protein and member of the inward rectifier potassium channel family. The encoded protein has a small unitary conductance compared to other members of this protein family. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.29

Clinical Summary— KCNJ4

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.96). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.29LOEUF

pLI 0.965

Z-score 2.99

OE 0.00 (0.00–0.29)

Highly constrained

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

Missense Constraint?

3.97Z-score

OE missense 0.39 (0.33–0.45)

128 obs / 331.3 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.29)

0≤0.351.4

Missense OE?0.39 (0.33–0.45)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 0 / 10.4Missense obs/exp: 128 / 331.3Syn Z: 0.31

This gene — mechanism propensity

0.5378th %ile

GOF

0.78top 25%

LOF

0.55top 25%

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.

LOFLOEUF 0.29

GOFprediction 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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.