KCNK4

Chr 11AD

potassium two pore domain channel subfamily K member 4

Also known as: FHEIG, K2p4.1, TRAAK, TRAAK1

NCBI Gene: 50801ENSG00000182450UniProt: Q9NYG8

This gene encodes a member of the TWIK-related arachidonic acid-stimulated two pore potassium channel subfamily. The encoded protein homodimerizes and functions as an outwardly rectifying channel. This channel is regulated by polyunsaturated fatty acids, temperature and mechanical deformation of the lipid membrane. This protein is expressed primarily in neural tissues and may be involved in regulating the noxious input threshold in dorsal root ganglia neurons. Alternate splicing results in multiple transcript variants. Naturally occurring read-through transcripts also exist between this gene and the downstream testis expressed 40 (TEX40) gene, as represented in GeneID: 106780802. [provided by RefSeq, Nov 2015]

Primary Disease Associations & Inheritance

Facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndromeMIM #618381
AD
488
ClinVar variants
14
Pathogenic / LP
0.01
pLI score
0
Active trials
Clinical Summary— KCNK4
🧬
Gene-Disease Validity (ClinGen)
facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndrome · ADModerate

Moderate evidence — consider for supplementary testing

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
14 Pathogenic / Likely Pathogenic· 228 VUS of 488 total submissions
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.83LOEUF
pLI 0.006
Z-score 2.03
OE 0.42 (0.23–0.83)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.75Z-score
OE missense 0.86 (0.77–0.97)
197 obs / 229.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.42 (0.23–0.83)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.86 (0.77–0.97)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.10
0≤1.21.6
LoF obs/exp: 6 / 14.3Missense obs/exp: 197 / 229.1Syn Z: -0.81

ClinVar Variant Classifications

488 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8
Likely Pathogenic6
VUS228
Likely Benign199
Benign19
Conflicting28
8
Pathogenic
6
Likely Pathogenic
228
VUS
199
Likely Benign
19
Benign
28
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
2
6
0
8
Likely Pathogenic
0
4
2
0
6
VUS
14
186
25
3
228
Likely Benign
2
49
29
119
199
Benign
0
9
5
5
19
Conflicting
—28
Total1625067127488

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

View in ClinVar →

Protein Context — Lollipop Plot

KCNK4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

KCNK4-related facial dysmorphism, hypertrichosis, epilepsy, intellectual and developmental delay, and gingival overgrowth syndrome

limited
ADGain Of FunctionAltered Gene Product Structure
Dev. DisordersSkin
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndrome

MIM #618381

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — KCNK4
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
A recurrent KCNK4 variant in a dominant pedigree with hypertrichosis and gingival fibromatosis syndrome: Variable phenotypic expressivity and insights on patients' dental management.
Elhossini RM et al.·Am J Med Genet A
2024Cohort
ATP6V1B2-related epileptic encephalopathy.
Inuzuka LM et al.·Epileptic Disord
2020Case report
The epilepsy phenotype of KCNK4-related neurodevelopmental disease.
Krygier M et al.·Seizure
2024Case report
Syndromic disorders caused by gain-of-function variants in KCNH1, KCNK4, and KCNN3-a subgroup of K(+) channelopathies.
Gripp KW et al.·Eur J Hum Genet
2021Case report
Gain-of-Function Mutations in KCNN3 Encoding the Small-Conductance Ca(2+)-Activated K(+) Channel SK3 Cause Zimmermann-Laband Syndrome.
Bauer CK et al.·Am J Hum Genet
2019
A novel SCN8A variant of unknown significance in pediatric epilepsy: a case report.
Bouzroud W et al.·J Int Med Res
2023Case report
Cantú syndrome versus Zimmermann-Laband syndrome: Report of nine individuals with ABCC9 variants.
Kortüm F et al.·Eur J Med Genet
2020Case report
Genetics and postsurgical neuropathic pain: An ancillary study of a multicentre survey.
Blanc P et al.·Eur J Anaesthesiol
2019
A novel sarcoidosis risk locus for Europeans on chromosome 11q13.1.
Fischer A et al.·Am J Respir Crit Care Med
2012
Hereditary gingival fibromatosis associated with the missense mutation of the KCNK4 gene.
Mariani P et al.·Oral Surg Oral Med Oral Pathol Oral Radiol
2021Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools