KCNK12

Chr 2

potassium two pore domain channel subfamily K member 12

Also known as: K2p12.1, THIK-2, THIK2

NCBI Gene: 56660 ENSG00000184261 UniProt: Q9HB15

The protein forms potassium channels that conduct outward K+ currents at the plasma membrane, either as homodimers or by heterodimerizing with KCNK13. Mutations cause autosomal dominant developmental delay with intellectual disability, autism spectrum disorder, and seizures, typically with onset in infancy or early childhood. This gene is highly constrained against loss-of-function mutations (pLI 0.92, LOEUF 0.37), indicating that haploinsufficiency is likely not well-tolerated.

Summary from RefSeq, UniProt

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Active trials

Pubs (1 yr)

P/LP submissions

P/LP missense

0.37

LOEUF

Multiple*

Mechanism· predicted

Clinical Summary— KCNK12

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.92). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

16 unique Pathogenic / Likely Pathogenic· 42 VUS of 100 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.37LOEUF

pLI 0.919

Z-score 2.63

OE 0.00 (0.00–0.37)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

3.65Z-score

OE missense 0.28 (0.23–0.35)

58 obs / 204.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.00 (0.00–0.37)

0≤0.351.4

Missense OE0.28 (0.23–0.35)

0≤0.61.4

Synonymous OE0.84

0≤1.21.6

LoF obs/exp: 0 / 8.0Missense obs/exp: 58 / 204.9Syn Z: 1.24

0.6549th %ile

GOF

0.87top 5%

LOF

0.4726th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, dominant-negative and loss-of-function). 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

LOFLOEUF 0.37

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.