KCNE3

Summary

KCNE3 (potassium voltage-gated channel subfamily E regulatory subunit 3, HGNC:6243) is a protein-coding gene on chromosome 11q13.4, encoding Potassium voltage-gated channel subfamily E member 3 (Q9Y6H6). Ancillary protein that functions as a regulatory subunit of the voltage-gated potassium (Kv) channel complex composed of pore-forming and potassium-conducting alpha subunits and of regulatory beta subunits.

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.

Source: NCBI Gene 10008 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Brugada syndrome 6 (Limited, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 132 total
• Phenotypes (HPO): 35
• MANE Select transcript: NM_005472

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6243
Approved symbol	KCNE3
Name	potassium voltage-gated channel subfamily E regulatory subunit 3
Location	11q13.4
Locus type	gene with protein product
Status	Approved
Aliases	MiRP2, HOKPP
Ensembl gene	ENSG00000175538
Ensembl biotype	protein_coding
OMIM	604433
Entrez	10008

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 11 protein_coding

ENST00000310128, ENST00000525550, ENST00000526855, ENST00000529425, ENST00000531854, ENST00000532569, ENST00000875764, ENST00000875765, ENST00000929452, ENST00000929453, ENST00000929454

RefSeq mRNA: 1 — MANE Select: NM_005472 NM_005472

CCDS: CCDS8232

Canonical transcript exons

ENST00000310128 — 3 exons

Exon	Start	End
ENSE00001184057	74461955	74462103
ENSE00001184073	74454841	74457603
ENSE00002197944	74467398	74467549

Expression profiles

Bgee: expression breadth ubiquitous, 227 present calls, max score 98.64.

FANTOM5 (CAGE): breadth broad, TPM avg 5.9740 / max 284.3269, expressed in 662 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
121316	4.0702	495
121318	1.8367	394
121317	0.0671	32

Top tissues by expression

256 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
nasal cavity epithelium	UBERON:0005384	98.64	gold quality
monocyte	CL:0000576	96.85	gold quality
leukocyte	CL:0000738	96.57	gold quality
ileal mucosa	UBERON:0000331	96.02	gold quality
duodenum	UBERON:0002114	95.04	gold quality
bronchial epithelial cell	CL:0002328	94.57	gold quality
mucosa of sigmoid colon	UBERON:0004993	94.54	gold quality
pancreatic ductal cell	CL:0002079	94.13	gold quality
pylorus	UBERON:0001166	94.03	gold quality
bronchus	UBERON:0002185	93.80	gold quality
rectum	UBERON:0001052	93.59	gold quality
blood	UBERON:0000178	93.17	gold quality
trabecular bone tissue	UBERON:0002483	92.77	gold quality
kidney epithelium	UBERON:0004819	92.12	gold quality
colonic mucosa	UBERON:0000317	91.88	gold quality
jejunal mucosa	UBERON:0000399	91.56	gold quality
gall bladder	UBERON:0002110	90.38	gold quality
granulocyte	CL:0000094	90.04	gold quality
nasal cavity mucosa	UBERON:0001826	88.85	gold quality
vermiform appendix	UBERON:0001154	87.79	gold quality
palpebral conjunctiva	UBERON:0001812	86.72	gold quality
caecum	UBERON:0001153	86.45	gold quality
mucosa of paranasal sinus	UBERON:0005030	85.68	gold quality
bone marrow	UBERON:0002371	85.11	gold quality
small intestine	UBERON:0002108	83.83	gold quality
eye	UBERON:0000970	83.69	gold quality
cortex of kidney	UBERON:0001225	83.44	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	83.37	gold quality
adult mammalian kidney	UBERON:0000082	83.35	gold quality
small intestine Peyer’s patch	UBERON:0003454	83.12	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.50

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

86 targeting KCNE3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085

Literature-anchored findings (GeneRIF, showing 24)

• Ectopic expression of KCNE3 accelerates cardiac repolarization and abbreviates the QT interval. (PMID:11956246)
• The authors found MiRP2-R83H in 3 of 321 control subjects and in 5 unaffected related individuals. Provocation of an unaffected carrier with glucose or KCl did not induce weakness. (PMID:15037716)
• interaction of MiRP2-72 with KCNQ1-338; and MinK-59,58 with KCNQ1-339, 340 (PMID:16308347)
• The result indicates that 112G/A SNP in the KCNE1 gene and 198T/C SNP in the KCNE3 gene could determine an increased susceptibility to develop MD. (PMID:16374062)
• The characterization of a missense mutation in MiRP2 that affects its phosphorylation and consequent interactions with Kv3.4 is reported. (PMID:16449802)
• KCNE3 also inhibits currents generated by Kv4.3 in complex with the accessory subunit KChIP2 (PMID:16782062)
• Up-regulation and incrased activity of KV3.4 channels and their accessory subunit Mirp2 induced by amyloid peptide are involved in apoptotic neuronal death. (PMID:17495071)
• Abnormalities in the KCNE3 gene is a potential genetic risk factor for initiation and/or maintenance of atrial fibrillation. (PMID:18209471)
• KCNE variants reveal a critical role of the beta subunit carboxyl terminus in PKA-dependent regulation of the IKs potassium channel, KCNQ1. (PMID:19077539)
• KCNE3 plays a functional role in the modulation of I(to) in the human heart and suggest that mutations in KCNE3 can underlie the development of BrS. (PMID:19122847)
• The KCNE3 protein within the micellesis in monomeric form and acquires mainly alpha-helical conformation. (PMID:19961415)
• data show that SNPs in KCNE1 and KCNE3 are not associated with Meniere disease in Caucasians (PMID:20034061)
• 2 of the 8 MiRP2 extracellular domain acidic residues (D54 and D55) are important for KCNQ1-MiRP2 constitutive activation. (PMID:20040519)
• Allele frequencies are studied for 11 known variants of KCNE3 gene, of which two (F66F and R83H) are polymorphic but are not associated with chronic tinnitus. (PMID:21899751)
• The results of this study indicated that Kv7.5 contributes to the spatial regulation. (PMID:22190306)
• A KCNE3 T4A mutation was identified in a Japanese patient presenting Brugada-pattern ECG and neurally mediated syncope. (PMID:22987075)
• KCNE1 and KCNE3: The yin and yang of voltage-gated K(+) channel regulation (PMID:26410412)
• Data show that voltage-gated potassium channel KCNE3 directly affects the S4 movement in potassium channel KCNQ1. (PMID:26668384)
• KCNQ1/KCNE3 channels make only a small contribution to basolateral conductance in normal colonic crypts, with increased channel activity in UC appearing insufficient to prevent colonic cell depolarization in this disease. (PMID:26718405)
• Based on current evidence from published studies, neither of the two variants from KCNE was significantly associated with the risk of Meniere’s disease–{REVIEW} (PMID:26890422)
• Reported here are previously undiscovered protein-coding regions in exon 1 of hKCNE3 and hKCNE4 that extend their encoded extracellular domains by 44 and 51 residues, which yields full-length proteins of 147 and 221 residues, respectively. (PMID:27162025)
• Structural, computational, biochemical, and electrophysiological studies lead to an atomically explicit integrative structural model of the KCNE3-KCNQ1 complex that explains how KCNE3 induces the constitutive activation of KCNQ1 channel activity, a crucial component in K(+) recycling. (PMID:27626070)
• Regulation of human cardiac potassium channels by full-length KCNE3 and KCNE4 has been reported. (PMID:27922120)
• Comparing the structural dynamics of the human KCNE3 in reconstituted micelle and lipid bilayered vesicle environments. (PMID:35716725)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Kcne3	ENSMUSG00000035165
rattus_norvegicus	Kcne3	ENSRNOG00000063050

Paralogs (1): KCNE5 (ENSG00000176076)

Protein

Protein identifiers

Potassium voltage-gated channel subfamily E member 3 — Q9Y6H6 (reviewed: Q9Y6H6)

Alternative names: MinK-related peptide 2, Minimum potassium ion channel-related peptide 2, Potassium channel subunit beta MiRP2

All UniProt accessions (6): Q9Y6H6, E9PJQ7, E9PJV9, E9PN03, Q2N1I1, Q6IAE6

UniProt curated annotations — full annotation on UniProt →

Function. Ancillary protein that functions as a regulatory subunit of the voltage-gated potassium (Kv) channel complex composed of pore-forming and potassium-conducting alpha subunits and of regulatory beta subunits. KCNE3 beta subunit modulates the gating kinetics and enhances stability of the channel complex. Alters the gating of the delayed rectifier Kv channel containing KCNB1 alpha subunit. Associates with KCNC4/Kv3.4 alpha subunit to form the subthreshold Kv channel in skeletal muscle and to establish the resting membrane potential (RMP) in muscle cells. Association with KCNQ1/KCLQT1 alpha subunit may form the intestinal cAMP-stimulated potassium channel involved in chloride secretion that produces a current with nearly instantaneous activation with a linear current-voltage relationship.

Subunit / interactions. Interacts with KCNB1. Interacts with KCNC2. Associates with KCNC4/Kv3.4. Interacts with KCNQ1; associates with a KCNQ1:KCNE3 stoichiometry of 4:4; produces a current with nearly instantaneous activation with a linear current-voltage relationship and alters membrane raft localization; affects KCNQ1 structure and gating properties.

Subcellular location. Cell membrane. Cytoplasm. Perikaryon. Cell projection. Dendrite. Membrane raft.

Tissue specificity. Expressed in hippocampal neurons (at protein level). Widely expressed with highest levels in kidney and moderate levels in small intestine.

Disease relevance. Brugada syndrome 6 (BRGDA6) [MIM:613119] A tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs, the individual will faint and may die in a few minutes if the heart is not reset. The gene represented in this entry may be involved in disease pathogenesis.

Similarity. Belongs to the potassium channel KCNE family.

RefSeq proteins (1): NP_005463* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000369	K_chnl_KCNE	Family
IPR005426	K_chnl_volt-dep_bsu_KCNE3	Family

Pfam: PF02060

UniProt features (17 total): sequence variant 4, helix 3, glycosylation site 3, region of interest 2, chain 1, transmembrane region 1, mutagenesis site 1, topological domain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
6V00	ELECTRON MICROSCOPY	3.1
6V01	ELECTRON MICROSCOPY	3.9
9WD8	ELECTRON MICROSCOPY	3.9
2NDJ	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y6H6-F1	71.28	0.25

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Glycosylation sites (3): 5, 22, 41

Mutagenesis-validated functional residues (1):

Position	Phenotype
90	decreases current 4-fold in kcnh2/kcne3 channel.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-5576890	Phase 3 - rapid repolarisation
R-HSA-5576893	Phase 2 - plateau phase
R-HSA-397014	Muscle contraction
R-HSA-5576891	Cardiac conduction

MSigDB gene sets: 283 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, GOBP_POTASSIUM_ION_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_TRANSPORTER_ACTIVITY, GOBP_CIRCULATORY_SYSTEM_PROCESS, chr11q13, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_REGULATION_OF_CARDIAC_MUSCLE_CELL_MEMBRANE_REPOLARIZATION, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_POTASSIUM_ION_TRANSPORT, GOBP_MUSCLE_CONTRACTION, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1, GOBP_REGULATION_OF_HEART_RATE, GOBP_INTRACELLULAR_MONOATOMIC_ANION_HOMEOSTASIS, GOBP_MONOATOMIC_ANION_HOMEOSTASIS

GO Biological Process (16): sodium ion transport (GO:0006814), intracellular chloride ion homeostasis (GO:0030644), regulation of ventricular cardiac muscle cell membrane repolarization (GO:0060307), ventricular cardiac muscle cell action potential (GO:0086005), membrane repolarization during action potential (GO:0086011), regulation of heart rate by cardiac conduction (GO:0086091), potassium ion export across plasma membrane (GO:0097623), membrane repolarization during ventricular cardiac muscle cell action potential (GO:0098915), negative regulation of delayed rectifier potassium channel activity (GO:1902260), negative regulation of potassium ion export across plasma membrane (GO:1903765), negative regulation of membrane repolarization during ventricular cardiac muscle cell action potential (GO:1905025), monoatomic ion transport (GO:0006811), potassium ion transport (GO:0006813), monoatomic ion transmembrane transport (GO:0034220), regulation of potassium ion transport (GO:0043266), potassium ion transmembrane transport (GO:0071805)

GO Molecular Function (6): voltage-gated potassium channel activity (GO:0005249), potassium channel regulator activity (GO:0015459), transmembrane transporter binding (GO:0044325), delayed rectifier potassium channel activity (GO:0005251), protein binding (GO:0005515), voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization (GO:1902282)

GO Cellular Component (11): cytoplasm (GO:0005737), plasma membrane (GO:0005886), voltage-gated potassium channel complex (GO:0008076), dendrite (GO:0030425), vesicle (GO:0031982), neuronal cell body membrane (GO:0032809), perikaryon (GO:0043204), membrane raft (GO:0045121), basolateral part of cell (GO:1990794), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Cardiac conduction	2
Muscle contraction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
metal ion transport	2
ventricular cardiac muscle cell membrane repolarization	2
membrane repolarization during ventricular cardiac muscle cell action potential	2
potassium ion transport	2
potassium channel activity	2
neuronal cell body	2
intracellular monoatomic anion homeostasis	1
chloride ion homeostasis	1
regulation of cardiac muscle cell membrane repolarization	1
cardiac muscle cell action potential involved in contraction	1
action potential	1
membrane repolarization	1
regulation of heart rate	1
cardiac conduction	1
potassium ion transmembrane transport	1
export across plasma membrane	1
ventricular cardiac muscle cell action potential	1
membrane repolarization during cardiac muscle cell action potential	1
delayed rectifier potassium channel activity	1
regulation of delayed rectifier potassium channel activity	1
negative regulation of voltage-gated potassium channel activity	1
potassium ion export across plasma membrane	1
negative regulation of potassium ion transmembrane transport	1
regulation of potassium ion export across plasma membrane	1
regulation of membrane repolarization during ventricular cardiac muscle cell action potential	1
negative regulation of membrane repolarization during cardiac muscle cell action potential	1
transport	1
monoatomic ion transport	1
transmembrane transport	1
regulation of metal ion transport	1
monoatomic cation transmembrane transport	1
voltage-gated monoatomic cation channel activity	1
ion channel regulator activity	1
protein binding	1
voltage-gated potassium channel activity	1
binding	1
voltage-gated potassium channel activity involved in cardiac muscle cell action potential repolarization	1
intracellular anatomical structure	1
membrane	1

Protein interactions and networks

STRING

1160 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNE3	KCNQ1	P51787	996
KCNE3	KCNE1	P15382	970
KCNE3	KCNE2	Q9Y6J6	965
KCNE3	KCNE4	Q8WWG9	951
KCNE3	KCND3	Q9UK17	945
KCNE3	KCNC4	Q03721	909
KCNE3	KCNH2	Q12809	906
KCNE3	GPD1L	Q8N335	904
KCNE3	SCN5A	Q14524	892
KCNE3	SCN3B	Q9NY72	890
KCNE3	SCN1B	Q07699	885
KCNE3	CACNB2	Q08289	841
KCNE3	KCNQ4	P56696	836
KCNE3	KCNE5	Q9UJ90	828
KCNE3	AKAP9	Q99996	827

IntAct

13 interactions, top by confidence:

A	B	Type	Score
KCNE3	RIOK3	psi-mi:“MI:0914”(association)	0.530
C11orf68	KCNE3	psi-mi:“MI:0915”(physical association)	0.370
LRIF1	KCNE3	psi-mi:“MI:0915”(physical association)	0.370
KCNE3	EEF1A1	psi-mi:“MI:0915”(physical association)	0.370
KCNE3	GAPDH	psi-mi:“MI:0915”(physical association)	0.370
KCNE3	GOLM1	psi-mi:“MI:0915”(physical association)	0.370
KIF5A	KCNE3	psi-mi:“MI:0915”(physical association)	0.370
POLA2	KCNE3	psi-mi:“MI:0915”(physical association)	0.370
QARS1	KCNE3	psi-mi:“MI:0915”(physical association)	0.370
RASSF1	KCNE3	psi-mi:“MI:0915”(physical association)	0.370
SLC44A1	KCNE3	psi-mi:“MI:0915”(physical association)	0.370
KCNE3	PIK3R2	psi-mi:“MI:0914”(association)	0.350
KCNE3	TMEM131L	psi-mi:“MI:0914”(association)	0.350

BioGRID (294): KCNE3 (Affinity Capture-RNA), RAB9A (Affinity Capture-MS), MYADM (Affinity Capture-MS), KIAA0895 (Affinity Capture-MS), FIBP (Affinity Capture-MS), GOLGA2 (Affinity Capture-MS), CBX2 (Affinity Capture-MS), AGBL5 (Affinity Capture-MS), DST (Affinity Capture-MS), PIK3R3 (Affinity Capture-MS), PKP4 (Affinity Capture-MS), SLC43A1 (Affinity Capture-MS), NFRKB (Affinity Capture-MS), OSBPL9 (Affinity Capture-MS), OSBPL6 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GW64, A2AFR3, A4IFL2, A6QLZ5, A8MVS5, A8MWV9, E1BBQ2, E9Q2Z6, O54693, O73612, P01134, P0C8R9, P18519, P48030, P52795, P52796, P98172, Q0VAQ4, Q0VBP7, Q14CM0, Q15223, Q3MHZ5, Q4FZH1, Q4R566, Q5JRV8, Q5R8M2, Q5RB29, Q5T1S8, Q5T292, Q5VX71, Q6AYP5, Q7TPF1, Q8BHW5, Q8BR63, Q8CA71, Q8IVY1, Q8R5M8, Q91WM6, Q91XV6, Q96DD7

Diamond homologs: Q9JJV7, Q9QZ26, Q9UJ90, Q9WTW2, Q9Y6H6, P15383, Q9TUH9, Q9XSP1

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
KCNE3	“down-regulates quantity”	potassium(1+)	relocalization
KCNE3	“up-regulates activity”	KCNQ1	binding
PRKCD	“up-regulates activity”	KCNE3	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

132 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	70
Likely benign	27
Benign	13

Top pathogenic / likely-pathogenic (0)

SpliceAI

454 predictions. Top by Δscore:

Variant	Effect	Δscore
11:74461954:CCAGA:C	donor_gain	1.0000
11:74457601:GCTC:G	acceptor_loss	0.9900
11:74457602:CT:C	acceptor_gain	0.9900
11:74457603:TC:T	acceptor_loss	0.9900
11:74457603:TCTG:T	acceptor_gain	0.9900
11:74457605:T:A	acceptor_loss	0.9900
11:74457607:G:GC	acceptor_gain	0.9900
11:74457611:C:CT	acceptor_gain	0.9900
11:74461946:AAGAC:A	donor_loss	0.9900
11:74461947:AGACT:A	donor_loss	0.9900
11:74461948:GAC:G	donor_loss	0.9900
11:74461949:ACT:A	donor_loss	0.9900
11:74461950:CTCA:C	donor_loss	0.9900
11:74461951:T:TA	donor_loss	0.9900
11:74461952:C:CC	donor_loss	0.9900
11:74461953:A:G	donor_loss	0.9900
11:74461954:C:CG	donor_loss	0.9900
11:74467392:CCTTA:C	donor_loss	0.9900
11:74467393:CTTA:C	donor_loss	0.9900
11:74467394:TTA:T	donor_loss	0.9900
11:74467395:TAC:T	donor_loss	0.9900
11:74467396:A:C	donor_loss	0.9900
11:74467397:C:A	donor_loss	0.9900
11:74467397:CCTG:C	donor_gain	0.9900
11:74457599:AAGCT:A	acceptor_gain	0.9800
11:74457600:AGCT:A	acceptor_gain	0.9800
11:74457601:GCT:G	acceptor_gain	0.9800
11:74457602:CTC:C	acceptor_gain	0.9800
11:74457604:C:A	acceptor_gain	0.9800
11:74457604:C:CC	acceptor_gain	0.9800

AlphaMissense

671 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:74457342:G:C	S74R	0.996
11:74457342:G:T	S74R	0.996
11:74457344:T:G	S74R	0.996
11:74457347:C:G	G73R	0.992
11:74457346:C:T	G73D	0.990
11:74457340:A:T	L75H	0.986
11:74457358:G:T	A69D	0.986
11:74457360:A:C	F68L	0.985
11:74457360:A:T	F68L	0.985
11:74457362:A:G	F68L	0.985
11:74457277:A:G	I96T	0.980
11:74457340:A:G	L75P	0.980
11:74457295:T:C	D90G	0.978
11:74457277:A:T	I96N	0.976
11:74457277:A:C	I96S	0.975
11:74457340:A:C	L75R	0.965
11:74457290:A:C	Y92D	0.963
11:74457364:A:C	L67R	0.960
11:74457370:A:T	M65K	0.960
11:74457290:A:T	Y92N	0.958
11:74457332:C:G	G78R	0.956
11:74457332:C:T	G78R	0.956
11:74457337:A:T	I76N	0.956
11:74457290:A:G	Y92H	0.954
11:74457294:G:C	D90E	0.954
11:74457294:G:T	D90E	0.954
11:74457370:A:C	M65R	0.954
11:74457295:T:A	D90V	0.953
11:74457361:A:C	F68C	0.953
11:74457362:A:T	F68I	0.953

dbSNP variants (sampled 300 via entrez): RS1000400371 (11:74464772 T>C), RS1000414645 (11:74462707 T>C), RS1000667033 (11:74469319 A>C), RS1000899300 (11:74465120 G>GTGTA), RS1001038148 (11:74456895 T>C), RS1001232625 (11:74463635 G>A), RS1001422983 (11:74460914 T>C), RS1001471663 (11:74461256 C>T), RS1001595592 (11:74467785 C>T), RS1001638986 (11:74455169 T>C), RS1001968273 (11:74462179 C>G), RS1002000841 (11:74462434 C>T), RS1002006323 (11:74454837 C>A,T), RS1002124923 (11:74468675 C>A,T), RS1002446652 (11:74459637 T>C)

Disease associations

OMIM: gene MIM:604433 | disease phenotypes: MIM:613119, MIM:617668, MIM:601144

GenCC curated gene-disease

Disease	Classification	Inheritance
Brugada syndrome 6	Limited	Unknown

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Brugada syndrome	Disputed	AD

Mondo (7): long QT syndrome (MONDO:0002442), Brugada syndrome 6 (MONDO:0013145), encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities (MONDO:0060562), ventricular fibrillation (MONDO:0000190), cardiomyopathy (MONDO:0004994), periodic paralysis (MONDO:0016122), Brugada syndrome (MONDO:0015263)

Orphanet (4): Brugada syndrome (Orphanet:130), Lipoyl transferase 2 deficiency (Orphanet:447795), Rare cardiomyopathy (Orphanet:167848), Periodic paralysis (Orphanet:206976)

HPO phenotypes

35 total (30 of 35 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001279	Syncope
HP:0001315	Reduced tendon reflexes
HP:0001649	Tachycardia
HP:0001663	Ventricular fibrillation
HP:0001695	Cardiac arrest
HP:0002203	Respiratory paralysis
HP:0002486	Myotonia
HP:0002747	Respiratory insufficiency due to muscle weakness
HP:0003394	Muscle spasm
HP:0003457	EMG abnormality
HP:0003470	Paralysis
HP:0003694	Late-onset proximal muscle weakness
HP:0003752	Episodic flaccid weakness
HP:0004303	Abnormal muscle fiber morphology
HP:0004308	Ventricular arrhythmia
HP:0004751	Paroxysmal ventricular tachycardia
HP:0004755	Supraventricular tachycardia
HP:0006670	Impaired myocardial contractility
HP:0008153	Periodic hypokalemic paresis
HP:0008180	Mildly elevated creatine kinase
HP:0008256	Adrenocortical adenoma
HP:0009020	Exercise-induced muscle fatigue
HP:0011675	Arrhythmia
HP:0011704	Sick sinus syndrome
HP:0011705	First degree atrioventricular block
HP:0011712	Complete right bundle branch block
HP:0011715	Trifascicular block
HP:0011998	Postprandial hyperglycemia
HP:0012240	Increased intramyocellular lipid droplets

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001339_6	Corneal astigmatism	5.000000e-06
GCST008829_1	Neuritic plaque	1.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006798	neuritic plaque measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D053840	Brugada Syndrome	C14.280.067.322; C14.280.123.250; C16.320.100
D009202	Cardiomyopathies	C14.280.238
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
D014693	Ventricular Fibrillation	C14.280.067.922; C23.550.073.922
C567735	Brugada Syndrome 6 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

40 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	2
entinostat	increases expression, affects cotreatment	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
aminomethylphosphonic acid (AMPA)	increases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	decreases methylation	1
beta-lapachone	decreases expression	1
butyraldehyde	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases expression, decreases reaction	1
pentanal	decreases expression	1
CGP 52608	affects binding, increases reaction	1
7,8-benzoquinoline	increases activity	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	increases expression, affects cotreatment	1
gardiquimod	decreases expression, decreases reaction	1
theaflavin-3,3’-digallate	affects expression	1
Leflunomide	increases expression	1
Anions	affects secretion	1
Arsenic	affects methylation	1
Cisplatin	increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Lipopolysaccharides	decreases expression, decreases reaction	1
Phenylmercuric Acetate	affects cotreatment, increases expression	1
Progesterone	affects cotreatment, decreases expression	1
Silicon Dioxide	decreases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Tretinoin	increases expression	1
Triclosan	increases expression	1
Urethane	decreases expression	1

Clinical trials (associated diseases)

297 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT00147277	PHASE4	COMPLETED	ADVANCE-D: Antitachycardia Pacing (ATP) Delivery for Painless Implantable Cardioverter Defibrillator (ICD) Therapy
NCT00147290	PHASE4	COMPLETED	ADVANCE CRT - D: Antitachycardia Pacing (ATP) Delivery for Painless Implantable Cardioverter Defibrillator (ICD) Therapy
NCT00180427	PHASE4	COMPLETED	VERRARI - Are Ventricular Arrhythmic Episodes Reduced by Rate Response in ICDs?
NCT00401466	PHASE4	COMPLETED	Remote Follow-up of Patients Receiving Implantable Cardioverter Defibrillator for Prophylactic Therapy
NCT00538356	PHASE4	COMPLETED	Influence of Home Monitoring on the Clinical Status of Heart Failure Patients With an Impaired Left Ventricular Function
NCT00787800	PHASE4	COMPLETED	The Use of Dual Chamber ICD With Special Programmed Features to Lower the Risk of Inappropriate Shock
NCT03826524	PHASE4	RECRUITING	Epinephrine Dose: Optimal Versus Standard Evaluation Trial
NCT03855826	PHASE4	UNKNOWN	Evaluation of the Efficacy and Safety of Nifekalant Hydrochloride (NIF) Injection.
NCT00348530	PHASE4	UNKNOWN	Carvedilol Versus Verapamil in Chronic Heart Failure Secondary to Non-Ischemic Cardiomyopathy
NCT00371891	PHASE4	COMPLETED	Ontario Multidetector Computed Tomographic (MDCT) Coronary Angiography Study (OMCAS)
NCT00401856	PHASE4	COMPLETED	CMR to Assess Fibrosis in Cardiomyopathy Using Eplerenone
NCT00559338	PHASE4	COMPLETED	Impact of Nesiritide Infusion for Decompensated Heart Failure in the Emergency Department
NCT00606775	PHASE4	UNKNOWN	The Preventive Efficacy of Carvedilol on Cardiac Dysfunction in Duchenne Muscular Dystrophy
NCT00658203	PHASE4	COMPLETED	Clinical Evaluation on Advanced Resynchronization
NCT00701220	PHASE4	COMPLETED	Statin Therapy for Ischemic and Nonischemic Cardiomyopathy
NCT00800761	PHASE4	COMPLETED	Intensive Combined Chelation Therapy for Iron-Induced Cardiac Disease in Patients With Thalassemia Major
NCT00806390	PHASE4	TERMINATED	Prevention of Anthracycline or Trastuzumab Induced Cardiomyopathy by Metoprolol
NCT01006473	PHASE4	COMPLETED	Exercise Training in Chagas Cardiomyopathy
NCT01261065	PHASE4	COMPLETED	Mechanisms of Improvement With Beta-Blocker Treatment in Heart Failure
NCT01345188	PHASE4	COMPLETED	Ranolazine in Ischemic Cardiomyopathy
NCT01868841	PHASE4	COMPLETED	123-I mIBG (AdreView) Heart-to-Mediastinal (H/M) Ratio and SPECT Imaging on a Small Field of View-High Efficiency Cardiac SPECT System
NCT02640846	PHASE4	UNKNOWN	Effects of Levosimendan, Milrinone and Norepinephrine on Left and Right Ventricular Function in Septic Shock
NCT03228823	PHASE4	UNKNOWN	Prospective Assessment of Premature Ventricular Contractions Suppression in Cardiomyopathy(PAPS)
NCT04323852	PHASE4	COMPLETED	Can Vitamin D Reduce Heart Muscle Damage After Bypass Surgery?
NCT05034432	PHASE4	RECRUITING	The PIVATAL Study -Study of Ventricular Arrhythmia (VTA) Ablation in Left Ventricular Assist Device (LVAD) Patients
NCT05718128	PHASE4	RECRUITING	Clinical Study of Endocardial Myocardial Biopsy
NCT06964464	PHASE4	RECRUITING	Comparative Effectiveness of Carvedilol Versus Metoprolol Succinate in Heart Failure Patients With an Implantable Cardioverter Defibrillator
NCT00000464	PHASE3	COMPLETED	Cardiac Arrest in Seattle: Conventional Versus Amiodarone Drug Evaluation (CASCADE)
NCT00000492	PHASE3	COMPLETED	Beta-Blocker Heart Attack Trial (BHAT)
NCT00000502	PHASE3	COMPLETED	Evaluation of SC-V Versus Conventional CPR
NCT00000518	PHASE3	COMPLETED	Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM)
NCT00000531	PHASE3	COMPLETED	Antiarrhythmics Versus Implantable Defibrillators (AVID)
NCT00004559	PHASE3	COMPLETED	Fatty Acid Antiarrhythmia Trial (FAAT)
NCT00004560	PHASE3	COMPLETED	Public Access Defibrillation (PAD) Community Trial
NCT00139542	PHASE3	COMPLETED	AED Use in Out-of-Hospital Cardiac Arrest: A New Algorithm Named One Shock Per Minute
NCT00429611	PHASE3	UNKNOWN	High Low Biphasic Energy Defibrillation (HiLoBED)