KCNK1

Chr 1

potassium two pore domain channel subfamily K member 1

Also known as: DPK, HOHO, K2P1, K2p1.1, KCNO1, TWIK-1, TWIK1

NCBI Gene: 3775 ENSG00000135750 UniProt: O00180

The protein encoded by this gene forms potassium channels that regulate resting membrane potential and neuronal excitability in brain astrocytes and other tissues, functioning primarily as heterodimers with other potassium channel subunits. Pathogenic variants in KCNK1 cause autosomal dominant epilepsy with febrile seizures plus (EFSP) and focal epilepsy, typically with childhood onset. The gene shows tolerance to loss-of-function variants (pLI 0.03, LOEUF 0.91), suggesting the pathogenic mechanism may not involve simple protein loss.

ResearchSummary from RefSeq, UniProt

This gene encodes one of the members of the superfamily of potassium channel proteins containing two pore-forming P domains. The product of this gene has not been shown to be a functional channel, however, it may require other non-pore-forming proteins for activity. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.91

Clinical Summary— KCNK1

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Population Constraint (gnomAD)

Low constraint (pLI 0.03) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

45 VUS of 47 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.91LOEUF

pLI 0.031

Z-score 1.78

OE 0.40 (0.19–0.91)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.72Z-score

OE missense 0.85 (0.75–0.97)

164 obs / 192.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.40 (0.19–0.91)

0≤0.351.4

Missense OE?0.85 (0.75–0.97)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 4 / 10.1Missense obs/exp: 164 / 192.2Syn Z: -0.22

This gene — mechanism propensity

0.81top 10%

GOF

0.92top 5%

LOF

0.1895th %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

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.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

47 submitted variants in ClinVar

ClinVar

Classification Summary

VUS45

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	45	45
Likely Benign	1	1
Benign	0	0
Total	46	46

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

View in ClinVar →

39 pathogenic / likely-pathogenic (of 51) ClinVar copy-number / structural variants overlap KCNK1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →