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

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

{Epilepsy, idiopathic generalized, susceptibility to, 16}MIM #618596

Cerebellar atrophy, developmental delay, and seizuresMIM #617643

Liang-Wang syndromeMIM #618729

Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsyMIM #609446

UniProtParoxysmal non-kinesigenic dyskinesia 3 with or without generalized epilepsy

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · generalized epilepsy-paroxysmal dyskinesia syndrome · AD · ClinGen 2022
Strong · Liang-Wang syndrome · AD · Ambry Genetics
Strong · cerebellar atrophy, developmental delay, and seizures · AR · Labcorp Genetics (formerly Invitae)

Interpreting a novel variant

The dominant disease is caused by gain-of-function changes and the recessive disease by loss of function (Gene2Phenotype). A single heterozygous truncating variant therefore fits the recessive disease and does not by itself explain a dominant presentation; a novel missense has to be read against the dominant mechanism.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.28

LOEUF· LoF intol.

GOF/LOF*

Mechanism· annotated

📖

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 OE?0.16 (0.10–0.28)

0≤0.351.4

Missense OE?0.46 (0.41–0.50)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

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

Background carrier burden — how many people carry a rare variant somewhere in KCNMA1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 44

1,512 rare PASS variants

Rare truncating (LoF)

1 in 350

169 rare PASS variants

Rare synonymous (reference)

1 in 49

849 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for KCNMA1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 58	1 in 360
South Asian	~43k	1 in 40	1 in 600
Remaining (unassigned)	~30k	1 in 34	1 in 360
European (Finnish)	~27k	1 in 140	1 in 1,500
Admixed American	~22k	1 in 43	1 in 750
African / African American	~21k	1 in 43	1 in 480
East Asian	~20k	1 in 50	1 in 330
Ashkenazi Jewish	~13k	1 in 150	1 in 2,100
Middle Eastern	~2,884	1 in 49	≈ 1 in 620

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 14 of 28 coding exons well covered in gnomAD exomes; exons 3, 4, 5, 6, 7 and 9 more marginal. Genomes: all 28.? see exons ↓