KCNA5

Chr 12AD

potassium voltage-gated channel subfamily A member 5

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

NCBI Gene: 3741 ENSG00000130037 UniProt: P22460 OMIM: 176267

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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Potassium channels represent the most complex class of voltage-gated ino channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the delayed rectifier class, the function of which could restore the resting membrane potential of beta cells after depolarization and thereby contribute to the regulation of insulin secretion. This gene is intronless, and the gene is clustered with genes KCNA1 and KCNA6 on chromosome 12. Defects in this gene are a cause of familial atrial fibrillation type 7 (ATFB7). [provided by RefSeq, May 2012]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.921 OMIM phenotype

Clinical Summary— KCNA5

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 430 VUS of 595 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.92LOEUF

pLI 0.001

Z-score 1.79

OE 0.49 (0.28–0.92)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.05Z-score

OE missense 1.01 (0.93–1.09)

401 obs / 398.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.49 (0.28–0.92)

0≤0.351.4

Missense OE?1.01 (0.93–1.09)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 7 / 14.3Missense obs/exp: 401 / 398.0Syn Z: -1.58

This gene — mechanism propensity

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 KV1.5.1

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

References

1.PMID 23264583 ↗

ClinVar Variant Classifications

595 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

VUS430

Likely Benign120

Benign13

Conflicting29

Pathogenic

430

VUS

120

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	2	0	0	3
Likely Pathogenic	0	0	0	0	0
VUS	20	360	14	36	430
Likely Benign	0	10	4	106	120
Benign	0	0	6	7	13
Conflicting	—				29
Total	21	372	24	149	595

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

View in ClinVar →

56 pathogenic / likely-pathogenic (of 70) ClinVar copy-number / structural variants overlap KCNA5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →