KCNE3

Chr 11

potassium voltage-gated channel subfamily E regulatory subunit 3

Also known as: BRGDA6, HOKPP, HYPP, MiRP2

NCBI Gene: 10008 ENSG00000175538 UniProt: Q9Y6H6

KCNE3 encodes a beta subunit that modulates the gating kinetics and enhances stability of voltage-gated potassium channel complexes, including channels that establish resting membrane potential in skeletal muscle and regulate chloride secretion in the intestine. Mutations cause Brugada syndrome 6, a cardiac arrhythmia disorder, and have been associated with hypokalemic periodic paralysis. This gene follows autosomal recessive inheritance and is not highly constrained against loss-of-function variants.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion 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. This gene encodes a member of the potassium channel, voltage-gated, isk-related subfamily. This member is a type I membrane protein, and a beta subunit that assembles with a potassium channel alpha-subunit to modulate the gating kinetics and enhance stability of the multimeric complex. This gene is prominently expressed in the kidney. A missense mutation in this gene is associated with hypokalemic periodic paralysis. [provided by RefSeq, Jul 2008]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtBrugada syndrome 6

Clinical highlights

Gene–disease validity (ClinGen)

Disputed · Brugada syndrome · AD · ClinGen 2025

evidence questions this relationship

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.49

LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — KCNE3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.49LOEUF

pLI 0.468

Z-score 1.19

OE 0.00 (0.00–1.49)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.24Z-score

OE missense 0.92 (0.75–1.14)

62 obs / 67.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–1.49)

0≤0.351.4

Missense OE?0.92 (0.75–1.14)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 0 / 1.7Missense obs/exp: 62 / 67.5Syn Z: 0.55

Background carrier burden — how many people carry a rare variant somewhere in KCNE3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 420

136 rare PASS variants

Rare truncating (LoF)

1 in 6,900

16 rare PASS variants

Rare synonymous (reference)

1 in 2,100

47 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for KCNE3. 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 480	1 in 6,200
South Asian	~43k	1 in 220	≈ 1 in 43,000
Remaining (unassigned)	~30k	1 in 360	1 in 6,000
European (Finnish)	~27k	1 in 2,400	none seen
Admixed American	~22k	1 in 410	≈ 1 in 11,000
African / African American	~21k	1 in 360	1 in 2,400
East Asian	~20k	1 in 340	≈ 1 in 20,000
Ashkenazi Jewish	~13k	1 in 290	none seen
Middle Eastern	~2,884	1 in 210	≈ 1 in 2,900

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): All 1 coding exons well covered in gnomAD exomes and genomes.? see exons ↓