KCNA2

Chr 1AD

potassium voltage-gated channel subfamily A member 2

Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain and the central nervous system, but also in the cardiovascular system. Prevents aberrant action potential firing and regulates neuronal output. Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient. The channel alternates between opened and closed conformations in response to the voltage difference across the membrane (PubMed:11211111, PubMed:19912772, PubMed:23769686, PubMed:8495559). Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA5, KCNA6, KCNA7, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel (PubMed:20220134, PubMed:8495559). Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation of delayed rectifier potassium channels. In vivo, membranes probably contain a mixture of heteromeric potassium channel complexes, making it difficult to assign currents observed in intact tissues to any particular potassium channel family member. Homotetrameric KCNA2 forms a delayed-rectifier potassium channel that opens in response to membrane depolarization, followed by slow spontaneous channel closure (PubMed:19912772, PubMed:23769686). In contrast, a heteromultimer formed by KCNA2 and KCNA4 shows rapid inactivation (PubMed:8495559). Regulates neuronal excitability and plays a role as pacemaker in the regulation of neuronal action potentials (By similarity). KCNA2-containing channels play a presynaptic role and prevent hyperexcitability and aberrant action potential firing (By similarity). Response to toxins that are selective for KCNA2-containing potassium channels suggests that in Purkinje cells, dendritic subthreshold KCNA2-containing potassium channels prevent random spontaneous calcium spikes, suppressing dendritic hyperexcitability without hindering the generation of somatic action potentials, and thereby play an important role in motor coordination (By similarity). Plays a role in the induction of long-term potentiation of neuron excitability in the CA3 layer of the hippocampus (By similarity). May function as down-stream effector for G protein-coupled receptors and inhibit GABAergic inputs to basolateral amygdala neurons (By similarity). May contribute to the regulation of neurotransmitter release, such as gamma-aminobutyric acid (GABA) (By similarity). Contributes to the regulation of the axonal release of the neurotransmitter dopamine (By similarity). Reduced KCNA2 expression plays a role in the perception of neuropathic pain after peripheral nerve injury, but not acute pain (By similarity). Plays a role in the regulation of the time spent in non-rapid eye movement (NREM) sleep (By similarity)

OMIMResearchGenerating clinical summary…
GOF/LOFmechanismADLOEUF 0.381 OMIM phenotype
Clinical SummaryKCNA2
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Gene-Disease Validity (ClinGen)
genetic developmental and epileptic encephalopathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.91). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
65 unique Pathogenic / Likely Pathogenic· 303 VUS of 579 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Dual constrained — LoF & missense intolerant
LoF Constraint?
0.38LOEUF
pLI 0.911
Z-score 3.32
OE 0.12 (0.050.38)
Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?
3.83Z-score
OE missense 0.35 (0.300.42)
99 obs / 279.1 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?
LoF OE?0.12 (0.050.38)
00.351.4
Missense OE?0.35 (0.300.42)
00.61.4
Synonymous OE?1.00
01.21.6
LoF obs/exp: 2 / 16.6Missense obs/exp: 99 / 279.1Syn Z: -0.03
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveKCNA2-related epileptic encephalopathyGOFAD
definitiveKCNA2-related epileptic encephalopathyLOFAD
Mechanism Note (variant-dependent)
GOFLOF— mechanism depends on specific variant

Kv1.2 is tetrameric, but functional studies show mechanism is variant-specific. GOF variants cause DEE with increased current. LOF variants cause ataxia/ID with reduced current.1

This gene — mechanism propensity

DN
0.6357th %ile
GOF
0.78top 25%
LOF
0.4726th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, dominant-negative and loss-of-function). 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 · 1 literature citation · 78% of P/LP are missense
DNprediction above median · 1 literature citation
LOF20% of P/LP variants are LoF · LOEUF 0.38

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

DNRecently, de novo mutations in the gene KCNA2, causing either a dominant-negative loss-of-function or a gain-of-function of the voltage-gated K+ channel Kv1.2, were described to cause a new molecular entity within the epileptic encephalopathies.2
GOFThey carried mutations inducing a drastic gain-of-function effect leading to permanently open channels.3

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

ClinVar Variant Classifications

579 submitted variants in ClinVar

Classification Summary

Pathogenic27
Likely Pathogenic38
VUS303
Likely Benign166
Benign24
Conflicting19
27
Pathogenic
38
Likely Pathogenic
303
VUS
166
Likely Benign
24
Benign
19
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
7
19
1
0
27
Likely Pathogenic
6
32
0
0
38
VUS
27
272
3
1
303
Likely Benign
0
13
14
139
166
Benign
0
1
20
3
24
Conflicting
19
Total4033738143577

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap KCNA2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

KCNA2 · protein map & ClinVar variants

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