KCNMA1

Chr 10ADAR

potassium calcium-activated channel subfamily M alpha 1

Also known as: BKTM, CADEDS, IEG16, KCa1.1, LIWAS, MaxiK, PNKD3, SAKCA

NCBI Gene: 3778ENSG00000156113UniProt: Q12791

This gene encodes the alpha subunit of calcium-activated BK channel. The encoded protein is involved in several physiological processes including smooth muscle contraction, neurotransmitter release and neuronal excitability. Mutations in this gene are associated with a spectrum of neurological disorders including Paroxysmal Nonkinesigenic Dyskinesia 3, Idiopathic Generalized Epilepsy 16 and Liang-Wang syndrome. [provided by RefSeq, Aug 2022]

Primary Disease Associations & Inheritance

{Epilepsy, idiopathic generalized, susceptibility to, 16}MIM #618596
AD
Cerebellar atrophy, developmental delay, and seizuresMIM #617643
AR
Liang-Wang syndromeMIM #618729
AD
Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsyMIM #609446
AD
UniProtParoxysmal non-kinesigenic dyskinesia 3 with or without generalized epilepsy
577
ClinVar variants
26
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— KCNMA1
🧬
Gene-Disease Validity (ClinGen)
generalized epilepsy-paroxysmal dyskinesia syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
26 Pathogenic / Likely Pathogenic· 347 VUS of 577 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.28LOEUF
pLI 0.997
Z-score 6.08
OE 0.16 (0.10–0.28)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.
5.06Z-score
OE missense 0.46 (0.41–0.50)
311 obs / 683.4 exp
Constrained

Extremely missense-constrained (top ~0.01%)

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.0.16 (0.10–0.28)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.46 (0.41–0.50)
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.1.18
0≤1.21.6
LoF obs/exp: 10 / 61.5Missense obs/exp: 311 / 683.4Syn Z: -2.35

ClinVar Variant Classifications

577 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12
Likely Pathogenic14
VUS347
Likely Benign159
Benign34
Conflicting11
12
Pathogenic
14
Likely Pathogenic
347
VUS
159
Likely Benign
34
Benign
11
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
3
4
0
12
Likely Pathogenic
9
3
2
0
14
VUS
8
279
53
7
347
Likely Benign
0
6
69
84
159
Benign
0
1
31
2
34
Conflicting
—11
Total2229215993577

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

View in ClinVar →

Protein Context — Lollipop Plot

KCNMA1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

KCNMA1-related generalized epilepsy and paroxysmal dyskinesia

definitive
ADGain Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗

KCNMA1-related developmental delay, seizures and cerebellar atrophy

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Epilepsy, idiopathic generalized, susceptibility to, 16}

MIM #618596

Molecular basis of disorder known

Autosomal dominant

Cerebellar atrophy, developmental delay, and seizures

MIM #617643

Molecular basis of disorder known

Autosomal recessive

Liang-Wang syndrome

MIM #618729

Molecular basis of disorder known

Autosomal dominant

Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy

MIM #609446

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — KCNMA1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
BK Channelopathies and KCNMA1-Linked Disease Models.
Meredith AL·Annu Rev Physiol
2024Review
An emerging spectrum of variants and clinical features in KCNMA1-linked channelopathy.
Miller JP et al.·Channels (Austin)
2021Review
Solving the Etiology of Developmental and Epileptic Encephalopathy with Spike-Wave Activation in Sleep (D/EE-SWAS).
Viswanathan S et al.·Ann Neurol
2024
Paroxysmal Dyskinesias.
McGuire S et al.·Semin Pediatr Neurol
2018Review
KCNMA1-related refractory status epilepticus responding to vagal nerve stimulation: Case report and literature review.
Al-Attas AA et al.·Neurosciences (Riyadh)
2022Review
Hepatic stellate cell-specific Kcnma1 deletion mitigates metabolic dysfunction-associated steatotic liver disease progression via upregulating Amphiregulin secretion.
Zou Y et al.·Mol Metab
2025
Genetic Diversity and Expanded Phenotypes in Dystonia: Insights From Large-Scale Exome Sequencing.
Thomsen M et al.·Ann Clin Transl Neurol
2025
Polymicrogyria in a child with KCNMA1-related channelopathy.
Graber D et al.·Brain Dev
2022Case report
KCNMA1-Related Episodes of Behavioral Arrest and Loss of Postural Reflexes: A Critical Reappraisal.
Roze E et al.·Mov Disord Clin Pract
2025
Unraveling genetic risk contributions to nonverbal status in autism spectrum disorder probands.
Liu H et al.·Behav Brain Funct
2025
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
Rare DisordersUndiagnosed DisordersDisorders of Unknown Prevalence

Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford

RECRUITING
NCT01793168Sanford HealthStarted 2010-07

External Resources

Links to major genomics databases and tools