KCNA5

Chr 12AD

potassium voltage-gated channel subfamily A member 5

Also known as: ATFB7, HCK1, HK2, HPCN1, KV1.5, PCN1

KCNA5 encodes a voltage-gated potassium channel that forms tetrameric channels mediating potassium transport across excitable membranes and regulating membrane potential in cardiac and pancreatic cells. Mutations cause familial atrial fibrillation type 7, a cardiac arrhythmia disorder with autosomal dominant inheritance. The gene shows low constraint against loss-of-function variants (pLI 0.001, LOEUF 0.919), suggesting tolerance to heterozygous inactivation.

Summary from RefSeq, OMIM, UniProt
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Primary Disease Associations & Inheritance

Atrial fibrillation, familial, 7MIM #612240
AD
0
Active trials
10
Pubs (1 yr)
0
P/LP submissions
P/LP missense
0.92
LOEUF
Multiple*
Mechanism· predicted
Clinical SummaryKCNA5
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint
0.92LOEUF
pLI 0.001
Z-score 1.79
OE 0.49 (0.280.92)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
-0.05Z-score
OE missense 1.01 (0.931.09)
401 obs / 398.0 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.49 (0.280.92)
00.351.4
Missense OE1.01 (0.931.09)
00.61.4
Synonymous OE1.15
01.21.6
LoF obs/exp: 7 / 14.3Missense obs/exp: 401 / 398.0Syn Z: -1.58
DN
0.79top 25%
GOF
0.88top 5%
LOF
0.2678th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). 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
DNprediction above median

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

GOFThe mutant proteins Y155C, D469E, and P488S displayed decreased surface expression and loss-of-function in patch-clamp studies, whereas E48G, A305T, and D322H showed preserved surface expression and gain-of-function for KV1.5.PMID:23264583

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

KCNA5 · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

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Clinical Literature
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