KCNJ2

Chr 17AD

potassium inwardly rectifying channel subfamily J member 2

Also known as: ATFB9, HHBIRK1, HHIRK1, IRK1, KIR2.1, LQT7, SQT3

NCBI Gene: 3759 ENSG00000123700 UniProt: P63252 OMIM: 600681

The protein is an inward-rectifier potassium channel that allows potassium to flow preferentially into cells and participates in establishing action potential waveform and excitability of neuronal and muscle tissues. Mutations cause autosomal dominant Andersen syndrome characterized by periodic paralysis, cardiac arrhythmias, and dysmorphic features, as well as familial atrial fibrillation and short QT syndrome. The predicted mechanism is gain-of-function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. The encoded protein, which has a greater tendency to allow potassium to flow into a cell rather than out of a cell, probably participates in establishing action potential waveform and excitability of neuronal and muscle tissues. Mutations in this gene have been associated with Andersen syndrome, which is characterized by periodic paralysis, cardiac arrhythmias, and dysmorphic features. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.613 OMIM phenotypes

Clinical Summary— KCNJ2

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Gene-Disease Validity (ClinGen)

congenital heart disease · UDNo Known Disease Relationship

No known disease relationship

4 total gene-disease associations curated

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.

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ClinVar Variants

67 unique Pathogenic / Likely Pathogenic· 330 VUS of 685 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — KCNJ2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.61LOEUF

pLI 0.307

Z-score 2.51

OE 0.24 (0.11–0.61)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.75Z-score

OE missense 0.50 (0.43–0.58)

121 obs / 240.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.24 (0.11–0.61)

0≤0.351.4

Missense OE?0.50 (0.43–0.58)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 3 / 12.6Missense obs/exp: 121 / 240.9Syn Z: -0.95

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedKCNJ2-related long QT syndromeOTHERAD

limitedKCNJ2-related catecholaminergic polymorphic ventricular tachycardiaOTHERAD

definitiveKCNJ2-related Andersen-related Tawil syndromeOTHERAD

moderateKCNJ2-related short QT syndromeOTHERAD

This gene — mechanism propensity

0.7327th %ile

GOF

0.84top 5%

LOF

0.3066th %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 · 1 literature citation · 84% of P/LP are missense

DNprediction above median · 1 literature citation

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.

Literature Evidence

DNCharacterization of a novel, dominant negative KCNJ2 mutation associated with Andersen-Tawil syndrome.1

GOFA novel gain-of-function KCNJ2 mutation associated with short-QT syndrome impairs inward rectification of Kir2.1 currents.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

685 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic41

Likely Pathogenic26

VUS330

Likely Benign179

Benign26

Conflicting64

Pathogenic

Likely Pathogenic

330

VUS

179

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	9	30	2	0	41
Likely Pathogenic	0	26	0	0	26
VUS	9	262	59	0	330
Likely Benign	0	3	14	162	179
Benign	0	1	23	2	26
Conflicting	—				64
Total	18	322	98	164	666

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap KCNJ2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →