KCNG2

Summary

KCNG2 (potassium voltage-gated channel modifier subfamily G member 2, HGNC:6249) is a protein-coding gene on chromosome 18q23, encoding Voltage-gated potassium channel regulatory subunit KCNG2 (Q9UJ96). Regulatory alpha-subunit of the voltage-gated potassium (Kv) channel which, when coassembled with KCNB1, can modulate the kinetics and conductance-voltage relationship.

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, subfamily G. This member is a gamma subunit of the voltage-gated potassium channel. The delayed-rectifier type channels containing this subunit may contribute to cardiac action potential repolarization.

Source: NCBI Gene 26251 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 91 total — 1 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_012283

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6249
Approved symbol	KCNG2
Name	potassium voltage-gated channel modifier subfamily G member 2
Location	18q23
Locus type	gene with protein product
Status	Approved
Aliases	Kv6.2, KCNF2
Ensembl gene	ENSG00000178342
Ensembl biotype	protein_coding
OMIM	605696
Entrez	26251

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000316249, ENST00000590307, ENST00000958293, ENST00000958294

RefSeq mRNA: 1 — MANE Select: NM_012283 NM_012283

CCDS: CCDS12019

Canonical transcript exons

ENST00000316249 — 4 exons

Exon	Start	End
ENSE00001275081	79899040	79900100
ENSE00001275089	79863628	79864291
ENSE00003927495	79856379	79856452
ENSE00003932351	79797938	79798014

Expression profiles

Bgee: expression breadth ubiquitous, 130 present calls, max score 65.88.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	65.88	gold quality
anterior cingulate cortex	UBERON:0009835	63.91	gold quality
secondary oocyte	CL:0000655	63.72	silver quality
bone marrow cell	CL:0002092	59.33	gold quality
nucleus accumbens	UBERON:0001882	58.68	gold quality
Ammon’s horn	UBERON:0001954	58.23	gold quality
Brodmann (1909) area 9	UBERON:0013540	58.17	gold quality
esophagus squamous epithelium	UBERON:0006920	57.48	gold quality
amygdala	UBERON:0001876	56.99	gold quality
gastrocnemius	UBERON:0001388	56.53	gold quality
right frontal lobe	UBERON:0002810	56.37	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	55.58	gold quality
blood	UBERON:0000178	54.97	gold quality
monocyte	CL:0000576	54.81	gold quality
putamen	UBERON:0001874	54.78	gold quality
leukocyte	CL:0000738	54.64	gold quality
muscle of leg	UBERON:0001383	53.85	gold quality
neocortex	UBERON:0001950	53.69	gold quality
heart right ventricle	UBERON:0002080	53.69	gold quality
cerebral cortex	UBERON:0000956	53.66	gold quality
granulocyte	CL:0000094	53.37	gold quality
medial globus pallidus	UBERON:0002477	53.11	gold quality
adult mammalian kidney	UBERON:0000082	52.60	gold quality
forebrain	UBERON:0001890	52.40	gold quality
cortical plate	UBERON:0005343	52.21	silver quality
caudate nucleus	UBERON:0001873	52.16	gold quality
prefrontal cortex	UBERON:0000451	51.52	gold quality
frontal cortex	UBERON:0001870	51.45	gold quality
mucosa of sigmoid colon	UBERON:0004993	51.12	gold quality
brain	UBERON:0000955	50.91	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.19

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1I2

Literature-anchored findings (GeneRIF, showing 1)

• Whole genome sequencing identifies a deletion mutation in the unknown-functional KCNG2 from familial sick sinus syndrome. (PMID:35285753)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	kcng2	ENSDARG00000035961
mus_musculus	Kcng2	ENSMUSG00000059852
rattus_norvegicus	Kcng2	ENSRNOG00000053640

Paralogs (31): KCNG1 (ENSG00000026559), KCNQ1 (ENSG00000053918), KCNQ2 (ENSG00000075043), KCND1 (ENSG00000102057), KCNA7 (ENSG00000104848), KCNA1 (ENSG00000111262), KCNC4 (ENSG00000116396), KCNQ4 (ENSG00000117013), KCNS1 (ENSG00000124134), KCNC1 (ENSG00000129159), KCNA5 (ENSG00000130037), KCNC3 (ENSG00000131398), KCNA10 (ENSG00000143105), KCNA6 (ENSG00000151079), KCNS2 (ENSG00000156486), KCNB1 (ENSG00000158445), KCNF1 (ENSG00000162975), KCNV1 (ENSG00000164794), KCNC2 (ENSG00000166006), KCNV2 (ENSG00000168263), KCNG4 (ENSG00000168418), KCNS3 (ENSG00000170745), KCNG3 (ENSG00000171126), KCND3 (ENSG00000171385), KCNA3 (ENSG00000177272), KCNA2 (ENSG00000177301), KCNA4 (ENSG00000182255), KCNB2 (ENSG00000182674), KCNQ3 (ENSG00000184156), KCND2 (ENSG00000184408), KCNQ5 (ENSG00000185760)

Protein

Protein identifiers

Voltage-gated potassium channel regulatory subunit KCNG2 — Q9UJ96 (reviewed: Q9UJ96)

Alternative names: Cardiac potassium channel subunit, Potassium voltage-gated channel subfamily G member 2, Voltage-gated potassium channel subunit Kv6.2

All UniProt accessions (1): Q9UJ96

UniProt curated annotations — full annotation on UniProt →

Function. Regulatory alpha-subunit of the voltage-gated potassium (Kv) channel which, when coassembled with KCNB1, can modulate the kinetics and conductance-voltage relationship. Modulates channel activity by shifting the threshold and the half-maximal activation to more negative values. Potassium channel subunit that does not form functional channels by itself.

Subunit / interactions. Heterodimer with KCNB1.

Subcellular location. Cell membrane.

Tissue specificity. Highly expressed in heart, liver, skeletal muscle, kidney and pancreas. Detected at low levels in brain, lung and placenta.

Miscellaneous. Heterodimers with KCNB1 are highly sensitive to inhibition by tetraethylammonium (TEA) and propafenone.

Similarity. Belongs to the potassium channel family. G (TC 1.A.1.2) subfamily. Kv6.2/KCNG2 sub-subfamily.

RefSeq proteins (1): NP_036415* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR003131	T1-type_BTB	Domain
IPR003968	K_chnl_volt-dep_Kv	Family
IPR003969	K_chnl_volt-dep_Kv6	Family
IPR005821	Ion_trans_dom	Domain
IPR011333	SKP1/BTB/POZ_sf	Homologous_superfamily
IPR027359	Volt_channel_dom_sf	Homologous_superfamily
IPR028325	VG_K_chnl	Family

Pfam: PF00520, PF02214

UniProt features (22 total): topological domain 8, transmembrane region 6, intramembrane region 2, region of interest 2, compositionally biased region 2, chain 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UJ96-F1	80.41	0.36

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1296072	Voltage gated Potassium channels
R-HSA-381676	Glucagon-like Peptide-1 (GLP1) regulates insulin secretion
R-HSA-112316	Neuronal System
R-HSA-1296071	Potassium Channels
R-HSA-1430728	Metabolism
R-HSA-163685	Integration of energy metabolism
R-HSA-422356	Regulation of insulin secretion

MSigDB gene sets: 67 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, REACTOME_VOLTAGE_GATED_POTASSIUM_CHANNELS, REACTOME_POTASSIUM_CHANNELS, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_PROTEIN_HOMOOLIGOMERIZATION, GOBP_REGULATION_OF_TRANSPORT, GOBP_REGULATION_OF_MONOATOMIC_ION_TRANSPORT, GOBP_TRANSMEMBRANE_TRANSPORT, GOBP_REGULATION_OF_POTASSIUM_ION_TRANSPORT, REACTOME_INTEGRATION_OF_ENERGY_METABOLISM, GOCC_POTASSIUM_CHANNEL_COMPLEX, GOBP_REGULATION_OF_MEMBRANE_POTENTIAL, GOCC_CATION_CHANNEL_COMPLEX, GOCC_TRANSPORTER_COMPLEX, GOCC_MEMBRANE_PROTEIN_COMPLEX

GO Biological Process (8): action potential (GO:0001508), regulation of potassium ion transport (GO:0043266), protein homooligomerization (GO:0051260), potassium ion transmembrane transport (GO:0071805), monoatomic ion transport (GO:0006811), potassium ion transport (GO:0006813), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085)

GO Molecular Function (5): voltage-gated potassium channel activity (GO:0005249), potassium channel regulator activity (GO:0015459), monoatomic ion channel activity (GO:0005216), potassium channel activity (GO:0005267), protein binding (GO:0005515)

GO Cellular Component (5): plasma membrane (GO:0005886), voltage-gated potassium channel complex (GO:0008076), membrane (GO:0016020), extracellular exosome (GO:0070062), monoatomic ion channel complex (GO:0034702)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Potassium Channels	1
Regulation of insulin secretion	1
Neuronal System	1
Metabolism	1
Integration of energy metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
potassium ion transport	2
transport	2
potassium channel activity	2
regulation of membrane potential	1
regulation of metal ion transport	1
protein complex oligomerization	1
monoatomic cation transmembrane transport	1
metal ion transport	1
monoatomic ion transport	1
transmembrane transport	1
cellular process	1
voltage-gated monoatomic cation channel activity	1
ion channel regulator activity	1
monoatomic ion transmembrane transporter activity	1
channel activity	1
monoatomic cation channel activity	1
potassium ion transmembrane transporter activity	1
binding	1
membrane	1
cell periphery	1
potassium channel complex	1
plasma membrane protein complex	1
cellular anatomical structure	1
extracellular vesicle	1
transmembrane transporter complex	1

Protein interactions and networks

STRING

1350 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNG2	CNIH3	Q8TBE1	748
KCNG2	PARVA	Q9NVD7	517
KCNG2	SCN5A	Q14524	515
KCNG2	SCN10A	Q9Y5Y9	508
KCNG2	KCNH7	Q9NS40	507
KCNG2	CACNA1D	Q01668	490
KCNG2	KCNC1	P48547	476
KCNG2	SLC66A2	Q8N2U9	452
KCNG2	APBB2	Q92870	448
KCNG2	RGMA	Q96B86	439
KCNG2	ADNP2	Q6IQ32	431
KCNG2	KCNH3	Q9ULD8	425
KCNG2	BEND4	Q6ZU67	410
KCNG2	KCNJ3	P48549	395
KCNG2	OPRM1	P35372	394

IntAct

0 interactions, top by confidence:

BioGRID (3): KCNB1 (Two-hybrid), KCNG2 (Negative Genetic), KCNG2 (Affinity Capture-RNA)

ESM2 similar proteins: A6NGC4, A6NKX4, A6NM10, D3YZZ2, O35595, O46547, O60391, O77808, O95528, P30518, P43119, P46092, P46095, P48044, P48748, Q14626, Q3SYU3, Q3ZAV1, Q4U2R8, Q4W8A3, Q5RF19, Q5U419, Q64385, Q684M3, Q6UXD7, Q6UXT9, Q6YNI2, Q863Y8, Q86SM5, Q8CFZ5, Q8IXF9, Q8WUG5, Q91X56, Q924U0, Q96S37, Q99MF4, Q9BGL8, Q9BZ11, Q9H1Z9, Q9H228

Diamond homologs: A2BDX4, A4K2M4, A4K2N8, A4K2P6, A4K2Q6, A4K2R3, A4K2S2, A4K2T1, A4K2V2, A4K2W6, A4K2X4, A4K2Y2, A6H8H5, D4AD53, D4ADX7, G5EFC3, O18868, O35173, O35174, O73606, O88758, O88759, P10499, P15384, P15385, P15387, P15388, P16388, P16390, P17970, P17971, P17972, P22001, P22459, P22739, P25122, P48547, P59053, P59994, P59995

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	83
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2571020	GRCh37/hg19 18q22.3-23(chr18:71740696-78005231)x1	Pathogenic

SpliceAI

632 predictions. Top by Δscore:

Variant	Effect	Δscore
18:79864283:G:GT	donor_gain	1.0000
18:79864288:GCGG:G	donor_gain	1.0000
18:79899039:GGGC:G	acceptor_gain	1.0000
18:79864290:GG:G	donor_gain	0.9900
18:79864291:GG:G	donor_gain	0.9900
18:79864292:G:GC	donor_loss	0.9900
18:79864292:G:GG	donor_gain	0.9900
18:79864293:T:A	donor_loss	0.9900
18:79884721:G:T	donor_gain	0.9900
18:79899034:CCGCA:C	acceptor_loss	0.9900
18:79899035:CGCA:C	acceptor_loss	0.9900
18:79899036:GCAG:G	acceptor_loss	0.9900
18:79899037:CA:C	acceptor_loss	0.9900
18:79899038:A:AG	acceptor_gain	0.9900
18:79899038:AG:A	acceptor_gain	0.9900
18:79899038:AGGGC:A	acceptor_gain	0.9900
18:79899039:G:GA	acceptor_loss	0.9900
18:79899039:G:GG	acceptor_gain	0.9900
18:79899039:GG:G	acceptor_gain	0.9900
18:79899039:GGGCG:G	acceptor_gain	0.9900
18:79884721:G:GT	donor_gain	0.9800
18:79899038:AGG:A	acceptor_gain	0.9800
18:79899039:GGG:G	acceptor_gain	0.9800
18:79899035:C:CA	acceptor_gain	0.9600
18:79883183:G:GT	donor_gain	0.9500
18:79864287:A:T	donor_gain	0.9400
18:79864625:C:G	donor_gain	0.9100
18:79864287:AGCGG:A	donor_gain	0.8900
18:79864288:GCGGG:G	donor_gain	0.8900
18:79864294:GA:G	donor_loss	0.8600

AlphaMissense

2948 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:79863879:T:C	F71S	0.998
18:79863991:G:C	W108C	0.998
18:79863991:G:T	W108C	0.998
18:79863875:T:C	F70L	0.997
18:79863877:C:A	F70L	0.997
18:79863877:C:G	F70L	0.997
18:79863989:T:A	W108R	0.997
18:79863989:T:C	W108R	0.997
18:79899100:T:C	F229L	0.997
18:79899102:C:A	F229L	0.997
18:79899102:C:G	F229L	0.997
18:79899580:A:C	S389R	0.997
18:79899582:C:A	S389R	0.997
18:79899582:C:G	S389R	0.997
18:79899589:A:C	S392R	0.997
18:79899591:C:A	S392R	0.997
18:79899591:C:G	S392R	0.997
18:79899637:T:C	F408L	0.997
18:79899639:T:A	F408L	0.997
18:79899639:T:G	F408L	0.997
18:79863733:C:A	N22K	0.996
18:79863733:C:G	N22K	0.996
18:79863734:G:A	V23M	0.996
18:79899499:T:A	W362R	0.996
18:79899499:T:C	W362R	0.996
18:79899512:C:A	S366Y	0.996
18:79899512:C:T	S366F	0.996
18:79899521:C:T	T369I	0.996
18:79899533:G:T	G373V	0.996
18:79863846:A:T	D60V	0.995

dbSNP variants (sampled 300 via entrez): RS1000033736 (18:79823407 T>A,C), RS1000039171 (18:79873559 C>T), RS1000057266 (18:79863521 G>A), RS1000095094 (18:79818180 G>A), RS1000141420 (18:79871287 C>A,T), RS1000173225 (18:79839551 T>C), RS1000196301 (18:79871162 T>C,G), RS1000206098 (18:79870972 G>A,T), RS1000223303 (18:79829734 C>T), RS1000244041 (18:79845496 CTT>C), RS1000244997 (18:79894817 T>C), RS1000249033 (18:79835895 C>T), RS1000300331 (18:79851832 G>A), RS1000313853 (18:79819519 G>A), RS1000343123 (18:79862612 G>A)

Disease associations

OMIM: gene MIM:605696 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST002235_3	Opioid sensitivity	4.000000e-10
GCST004946_106	Schizophrenia	5.000000e-10
GCST004946_28	Schizophrenia	2.000000e-08
GCST007201_260	Schizophrenia	5.000000e-09
GCST007201_451	Schizophrenia	3.000000e-06
GCST007326_73	Number of sexual partners	1.000000e-08
GCST007327_144	Smoking status (ever vs never smokers)	4.000000e-09
GCST90000047_233	Age at first sexual intercourse	4.000000e-16
GCST90026414_1	Severe insulin-resistant type 2 diabetes	4.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004318	smoking behavior
EFO:0009749	age at first sexual intercourse measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2362996 (PROTEIN FAMILY)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: vgic — Voltage-gated potassium channels (K_v)

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.82	Ki	0.15	nM	CHEMBL5722941
9.74	IC50	0.18	nM	CHEMBL5722941

PubChem BioAssay actives

2 with measured affinity, of 34 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3-[(1R,2aS,4S,5aS,8aS,10S,11aR,14aS,16S,17aS,19S,20aS,22S,23aS,25S,26aS,28S,29aS,31R,32aS,35aS,36R,38aS,39S,41aS,42S,44aS,45S,48R,50aS,51S,53aS,54S,56aS,57S,59aS,60S,63S,66S,69S,72S,75S,78S,87R,93S,96S,99S)-17a,20a,23a,53a,63-pentakis(4-aminobutyl)-31-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-5-carbamimidamido-2-[[(2S)-5-carbamimidamido-2-[[(2S)-1-[(2S)-5-oxopyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]pentanoyl]amino]pentanoyl]amino]hexanoyl]amino]-4-methylpentanoyl]amino]-16,29a,72,78-tetrakis(2-amino-2-oxoethyl)-14a,26a-bis(3-amino-3-oxopropyl)-2a,38a,66-tribenzyl-28,50a,57-tris[(2S)-butan-2-yl]-4,5a,19,42,45,69-hexakis(3-carbamimidamidopropyl)-51,54-bis(2-carboxyethyl)-56a,99-bis(carboxymethyl)-36-[[(2S,3S)-1-(carboxymethylamino)-3-methyl-1-oxopentan-2-yl]carbamoyl]-39,60-bis[(1R)-1-hydroxyethyl]-75,93-bis(hydroxymethyl)-32a,35a,59a-tris[(4-hydroxyphenyl)methyl]-22-(1H-imidazol-4-ylmethyl)-96-(1H-indol-3-ylmethyl)-41a-methyl-25-(2-methylpropyl)-1a,3,4a,6,7a,9,10a,13a,15,16a,18,19a,21,22a,24,25a,27,28a,30,31a,34a,37a,38,40a,41,43a,44,47,49a,50,52a,53,55a,56,58a,59,61a,62,65,68,71,74,77,80,83,86,89,92,95,98-pentacontaoxo-33,34,63a,64a,67a,68a-hexathia-a,2,3a,5,6a,8,9a,12a,14,15a,17,18a,20,21a,23,24a,26,27a,29,30a,33a,36a,37,39a,40,42a,43,46,48a,49,51a,52,54a,55,57a,58,60a,61,64,67,70,73,76,79,82,85,88,91,94,97-pentacontazapentacyclo[85.74.4.448,111.010,14.0144,148]nonahexacontahectan-8a-yl]propanoic acid	2198828: Binding affinity to KV channel (unknown origin) assessed as inhibition constant	ki	0.0001	uM

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	decreases methylation, increases expression	2
daidzein	affects cotreatment, increases expression	1
bisphenol A	affects methylation	1
glycitein	affects cotreatment, increases expression	1
CGP 52608	affects binding, increases reaction	1
licochalcone B	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects methylation	1
Benzo(a)pyrene	decreases methylation	1
Diethylhexyl Phthalate	increases expression	1
Formaldehyde	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Smoke	increases expression	1
Valproic Acid	increases methylation	1
Cyclosporine	increases methylation	1
Aflatoxin B1	decreases methylation	1
Genistein	affects cotreatment, increases expression	1
Particulate Matter	decreases expression, increases abundance	1
Coal Ash	increases expression	1

ChEMBL screening assays

21 unique, capped per target: 20 binding, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1787442	Binding	Inhibition of human recombinant Kv channel at 10 uM by radioligand binding assay	Structure-activity relationships of pyrrole based S-nitrosoglutathione reductase inhibitors: pyrrole regioisomers and propionic acid replacement. — Bioorg Med Chem Lett
CHEMBL5522525	Toxicity	Inhibition of human K+ channel by automated electrophysiology	Discovery of Clinical Candidate AZD5462, a Selective Oral Allosteric RXFP1 Agonist for Treatment of Heart Failure. — J Med Chem

Clinical trials (associated diseases)

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