KCNK3

Chr 2AD

potassium two pore domain channel subfamily K member 3

Also known as: DDSA, K2p3.1, OAT1, PPH4, TASK, TASK-1, TASK1, TBAK1

NCBI Gene: 3777 ENSG00000171303 UniProt: O14649 OMIM: 603220

This gene encodes a pH-sensitive potassium channel that conducts outward rectifying currents and is involved in regulating neuronal excitability, respiratory chemoreflexes, and vascular tone. Mutations cause autosomal dominant developmental delay with sleep apnea and primary pulmonary hypertension, affecting respiratory and cardiovascular systems. The gene has an associated GeneReviews entry indicating its clinical significance in pediatric practice.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismADLOEUF 0.402 OMIM phenotypes

Clinical Summary— KCNK3

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Gene-Disease Validity (ClinGen)

pulmonary arterial hypertension · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.90). 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

0.40LOEUF

pLI 0.900

Z-score 2.92

OE 0.08 (0.03–0.40)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

3.55Z-score

OE missense 0.39 (0.33–0.46)

103 obs / 266.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.08 (0.03–0.40)

0≤0.351.4

Missense OE0.39 (0.33–0.46)

0≤0.61.4

Synonymous OE0.62

0≤1.21.6

LoF obs/exp: 1 / 11.8Missense obs/exp: 103 / 266.1Syn Z: 3.49

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongKCNK3-related developmental delay with sleep apneaOTHERAD

0.7131th %ile

GOF

0.85top 5%

LOF

0.4628th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, loss-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

LOF1 literature citation · LOEUF 0.40

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.

Literature Evidence

GOFDefective X-gating caused by de novo gain-of-function mutations in KCNK3 underlies a developmental disorder with sleep apneaPMID:PPR380292

LOFHeterozygous loss of function mutations in the KCNK3 gene cause hereditary pulmonary arterial hypertension (PAH).PMID:28889099

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