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: 3778 ENSG00000156113 UniProt: Q12791 OMIM: 600150

This gene encodes the alpha subunit of calcium-activated BK channels, which regulate smooth muscle contraction, neurotransmitter release, and neuronal excitability. Mutations cause a spectrum of autosomal dominant and autosomal recessive neurological disorders including generalized epilepsy, paroxysmal nonkinesigenic dyskinesia, cerebellar atrophy with developmental delay, and Liang-Wang syndrome. Disease mechanisms vary by variant type, with the gene showing high constraint against loss-of-function variants.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

GOF/LOFmechanismAD/ARLOEUF 0.284 OMIM phenotypes

Clinical Summary— KCNMA1

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Gene-Disease Validity (ClinGen)

generalized epilepsy-paroxysmal dyskinesia syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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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.

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ClinVar Variants

11 unique Pathogenic / Likely Pathogenic· 110 VUS of 200 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — KCNMA1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

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

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

LoF OE0.16 (0.10–0.28)

0≤0.351.4

Missense OE0.46 (0.41–0.50)

0≤0.61.4

Synonymous OE1.18

0≤1.21.6

LoF obs/exp: 10 / 61.5Missense obs/exp: 311 / 683.4Syn Z: -2.35

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveKCNMA1-related generalized epilepsy and paroxysmal dyskinesiaGOFAD

strongKCNMA1-related developmental delay, seizures and cerebellar atrophyLOFAR

Mechanism Note (variant-dependent)

GOFLOF— mechanism depends on specific variant

BK channel (KCa1.1). D434G is well-characterized GOF causing GEPD. Other monoallelic variants cause LOF. Biallelic LOF variants cause cerebellar ataxia. Mechanism is variant-specific.

References:PMID:15529566

0.4785th %ile

GOF

0.6052th %ile

LOF

0.67top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 73% of P/LP variants are LoF · LOEUF 0.28

GOF1 literature citation

DN1 literature citation

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

DNIt is however also possible that some KCNMA1 missense LoF variants confer a higher degree of penetrance by a dominant negative mechanism by impacting multiple subunits and binding proteins of the BK channel Î±-subunit (2,20).PMID:31152168

GOFLoF variants of KCNMA1 cause a new syndrome distinctly different from gain-of-function variants in the same gene.PMID:31152168

LOFDe novo loss-of-function KCNMA1 variants are associated with a new multiple malformation syndrome and a broad spectrum of developmental and neurological phenotypesPMID:31152168

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