KCNG4

Summary

KCNG4 (potassium voltage-gated channel modifier subfamily G member 4, HGNC:19697) is a protein-coding gene on chromosome 16q24.1, encoding Voltage-gated potassium channel regulatory subunit KCNG4 (Q8TDN1). Regulatory subunit of the voltage-gated potassium (Kv) channel which, when coassembled with KCNB1, modulates the kinetics parameters of the heterotetrameric channel namely the time course of activation, deactivation and inactivation and on the voltage-dependence of activation.

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 functions as a modulatory subunit. The gene has strong expression in brain. Multiple alternatively spliced variants have been found in normal and cancerous tissues.

Source: NCBI Gene 93107 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 134 total
• GTEx eGene: eQTL in 12 tissues, sQTL in 0 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.47 (unconstrained)
• MANE Select transcript: NM_172347
• Notable: 134 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19697
Approved symbol	KCNG4
Name	potassium voltage-gated channel modifier subfamily G member 4
Location	16q24.1
Locus type	gene with protein product
Status	Approved
Aliases	Kv6.4
Ensembl gene	ENSG00000168418
Ensembl biotype	protein_coding
OMIM	607603
Entrez	93107

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

MANE Select: ENST00000308251

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2

ENST00000308251, ENST00000568181, ENST00001134045

RefSeq mRNA: 1 — MANE Select: NM_172347 NM_172347

CCDS: CCDS10945

Canonical transcript exons

ENST00000308251 — 3 exons

Exon	Start	End
ENSE00001190857	84236730	84237525
ENSE00001190862	84218657	84223020
ENSE00001860611	84239670	84240012

Expression profiles

Bgee: expression breadth broad, 40 present calls, max score 68.81.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0170 / max 5.1472, expressed in 8 samples.

Highest expression (Bgee): male germ line stem cell (sensu Vertebrata) in testis, endothelial cell, epithelium of nasopharynx, secondary oocyte, sperm.

Genetic regulation across tissues (GTEx eQTL / sQTL)

KCNG4 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 12 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

12 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Brain Cortex	eqtl	9.6e-12	-0.61	16:84199401:C:G
Brain Cerebellum	eqtl	1.1e-08	+0.51	16:84253066:T:C
Brain Frontal Cortex BA9	eqtl	3.9e-07	-0.44	16:84199990:C:T
Pituitary	eqtl	7.8e-07	-0.42	16:84307499:T:C
Brain Cerebellar Hemisphere	eqtl	9.0e-06	+0.35	16:84253047:T:A
Brain Nucleus accumbens basal ganglia	eqtl	9.8e-06	-0.39	16:84225633:G:T
Brain Amygdala	eqtl	1.6e-05	-0.49	16:84196770:T:C
Brain Anterior cingulate cortex BA24	eqtl	7.5e-05	-0.39	16:84199401:C:G
Brain Hippocampus	eqtl	7.2e-04	-0.29	16:84197697:A:T
Brain Putamen basal ganglia	eqtl	1.2e-03	-0.37	16:84229800:T:C
Brain Hypothalamus	eqtl	4.2e-03	+0.33	16:84228025:G:T
Brain Caudate basal ganglia	eqtl	1.7e-02	-0.31	16:84239777:G:GA

FANTOM5 promoters

1 alternative TSS:

Promoter ID	TPM avg	Samples expressed
158343	0.0170	8

Top tissues by expression

showing 100 of 244 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	68.81	silver quality
endothelial cell	CL:0000115	59.89	gold quality
epithelium of nasopharynx	UBERON:0001951	59.67	gold quality
secondary oocyte	CL:0000655	58.28	gold quality
sperm	CL:0000019	54.97	gold quality
skin of hip	UBERON:0001554	54.37	silver quality
amygdala	UBERON:0001876	50.97	gold quality
substantia nigra	UBERON:0002038	49.76	gold quality
midbrain	UBERON:0001891	48.92	gold quality
hypothalamus	UBERON:0001898	48.17	gold quality
lateral globus pallidus	UBERON:0002476	47.79	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	47.18	gold quality
oocyte	CL:0000023	46.59	gold quality
spinal cord	UBERON:0002240	46.51	gold quality
temporal lobe	UBERON:0001871	46.26	gold quality
buccal mucosa cell	CL:0002336	46.12	gold quality
prefrontal cortex	UBERON:0000451	46.04	gold quality
saphenous vein	UBERON:0007318	45.76	gold quality
Ammon’s horn	UBERON:0001954	45.73	gold quality
upper leg skin	UBERON:0004262	44.77	silver quality
putamen	UBERON:0001874	44.34	gold quality
bone marrow cell	CL:0002092	44.12	gold quality
amniotic fluid	UBERON:0000173	43.90	gold quality
anterior cingulate cortex	UBERON:0009835	43.56	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
nipple	UBERON:0002030	43.01	gold quality
trigeminal ganglion	UBERON:0001675	42.99	gold quality
sural nerve	UBERON:0015488	42.80	gold quality
trachea	UBERON:0003126	42.77	gold quality
neocortex	UBERON:0001950	42.42	gold quality
frontal cortex	UBERON:0001870	42.36	gold quality
cerebral cortex	UBERON:0000956	42.31	gold quality
globus pallidus	UBERON:0001875	42.28	gold quality
brain	UBERON:0000955	42.21	gold quality
nucleus accumbens	UBERON:0001882	42.21	silver quality
inferior vagus X ganglion	UBERON:0005363	42.12	gold quality
forebrain	UBERON:0001890	42.07	gold quality
ganglionic eminence	UBERON:0004023	42.07	gold quality
occipital lobe	UBERON:0002021	41.85	gold quality
ventral tegmental area	UBERON:0002691	41.82	gold quality
medial globus pallidus	UBERON:0002477	41.57	gold quality
vastus lateralis	UBERON:0001379	41.41	gold quality
quadriceps femoris	UBERON:0001377	41.37	gold quality
superficial temporal artery	UBERON:0001614	41.33	gold quality
bone marrow	UBERON:0002371	41.16	gold quality
biceps brachii	UBERON:0001507	41.12	gold quality
palpebral conjunctiva	UBERON:0001812	41.10	gold quality
primary visual cortex	UBERON:0002436	41.01	gold quality
mucosa of paranasal sinus	UBERON:0005030	40.98	gold quality
caudate nucleus	UBERON:0001873	40.82	gold quality
left adrenal gland cortex	UBERON:0035825	40.82	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	40.73	gold quality
cerebellum	UBERON:0002037	40.65	silver quality
jejunal mucosa	UBERON:0000399	40.59	gold quality
mammary duct	UBERON:0001765	40.48	gold quality
myocardium	UBERON:0002349	40.45	gold quality
superior frontal gyrus	UBERON:0002661	40.45	gold quality
gingival epithelium	UBERON:0001949	40.43	gold quality
cerebellar cortex	UBERON:0002129	40.40	silver quality
germinal epithelium of ovary	UBERON:0001304	40.33	gold quality
esophagus squamous epithelium	UBERON:0006920	40.29	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	40.27	gold quality
Brodmann (1909) area 9	UBERON:0013540	40.23	silver quality
cerebellar hemisphere	UBERON:0002245	40.22	silver quality
jejunum	UBERON:0002115	40.18	gold quality
parietal lobe	UBERON:0001872	40.07	gold quality
cartilage tissue	UBERON:0002418	40.06	gold quality
oviduct epithelium	UBERON:0004804	40.03	gold quality
mucosa of sigmoid colon	UBERON:0004993	39.95	gold quality
cortical plate	UBERON:0005343	39.88	gold quality
colonic mucosa	UBERON:0000317	39.87	gold quality
right hemisphere of cerebellum	UBERON:0014890	39.85	gold quality
bronchial epithelial cell	CL:0002328	39.83	gold quality
deltoid	UBERON:0001476	39.83	gold quality
parotid gland	UBERON:0001831	39.81	gold quality
bronchus	UBERON:0002185	39.81	gold quality
urethra	UBERON:0000057	39.80	gold quality
heart right ventricle	UBERON:0002080	39.79	gold quality
mammalian vulva	UBERON:0000997	39.78	gold quality
pericardium	UBERON:0002407	39.77	gold quality
layer of synovial tissue	UBERON:0007616	39.77	gold quality
adrenal cortex	UBERON:0001235	39.72	gold quality
synovial joint	UBERON:0002217	39.70	gold quality
dorsal root ganglion	UBERON:0000044	39.68	gold quality
decidua	UBERON:0002450	39.65	gold quality
penis	UBERON:0000989	39.64	gold quality
gingiva	UBERON:0001828	39.64	gold quality
tendon of biceps brachii	UBERON:0008188	39.60	gold quality
superior surface of tongue	UBERON:0007371	39.56	gold quality
pylorus	UBERON:0001166	39.55	gold quality
renal medulla	UBERON:0000362	39.53	gold quality
pons	UBERON:0000988	39.51	gold quality
thymus	UBERON:0002370	39.50	gold quality
skeletal muscle tissue	UBERON:0001134	39.48	gold quality
medulla oblongata	UBERON:0001896	39.48	gold quality
adrenal gland	UBERON:0002369	39.48	gold quality
superior vestibular nucleus	UBERON:0007227	39.47	gold quality
cardia of stomach	UBERON:0001162	39.46	gold quality
parietal pleura	UBERON:0002400	39.45	gold quality
Brodmann (1909) area 23	UBERON:0013554	39.40	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.59

HPA expression

RNA tissue specificity: Tissue enriched

42 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Spinal cord	tissue	7.1
Thalamus	tissue	4.6
Frontal cortex	tissue	4.5
Medulla oblongata	tissue	4.3
Superior colliculi	tissue	4.0
Retina	tissue	3.6
Cerebellum	tissue	3.6
Midbrain	tissue	3.3
Periaqueductal gray	tissue	3.3
Hippocampus	tissue	2.7
Locus coeruleus	tissue	2.5
Substantia nigra	tissue	2.3
Postcentral gyrus	tissue	2.2
Nucleus accumbens	tissue	2.1
Choroid plexus	tissue	2.1
Pons	tissue	1.5
Caudate putamen	tissue	1.4
Cerebral cortex	tissue	1.1
Somatosensory cortex	tissue	1.1
Temporal cortex	tissue	1.1
Occipital cortex	tissue	1.1
Hypothalamus	tissue	0.9
Motor cortex	tissue	0.8
Hippocampal formation	tissue	0.7
Entorhinal cortex	tissue	0.7
Retrosplenial and cingulate cortex	tissue	0.7
Insular cortex	tissue	0.7
Prefrontal cortex	tissue	0.6
Amygdala	tissue	0.6
Ventral forebrain	tissue	0.6
Septum	tissue	0.6
Retrosplenial cortex	tissue	0.6
Putamen	tissue	0.4
Adrenal gland	tissue	0.3
Olfactory bulb	tissue	0.3
Skin 1	tissue	0.2
Corpus callosum	tissue	0.2
Bone marrow	tissue	0.2
Adipose tissue	tissue	0.1
Skeletal muscle	tissue	0.1
Epididymis	tissue	0.1
Basal ganglia	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 188; highest nTPM — Nucleus cuneatus (8.4), Cerebellar nuclei (8.2), Ventral spinal cord (7.1), Spinal trigeminal nucleus, caudal (6.7), Spinal trigeminal nucleus, oral (6.4).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1

miRNA regulators (miRDB)

Targeting KCNG4 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 67 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-4524A-5P	99.57	71.73	1193

Functional genomics

gnomAD constraint: pLI 3.25e-13, LOEUF 1.47, missense Z -2 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000308251 — one region, missense o/e 1.23.

Literature-anchored findings (GeneRIF, showing 7)

• Obligatory heterotetramerization of three previously uncharacterized Kv channel subunits identified in human genome (Kv6.3)(Kv10.1) (Kv11.1) (PMID:12060745)
• This study suggests that the silent behaviour of Kv6.3 is largely caused by the C-terminal part of its sixth transmembrane domain that causes ER retention of the subunit. (PMID:16096342)
• Mutation of histidine 105 in the T1 domain of the potassium channel Kv2.1 disrupts heteromerization with Kv6.3 and Kv6.4. (PMID:19074135)
• KCNE5 subunits may affect Kv2.1 homotetramers and Kv2.1/Kv6.4 heterotetramers in vivo, resulting in more tissue-specific fine-tuning mechanisms. (PMID:26242757)
• KvS subunits modify the pharmacological response of Kv2 subunits when assembled in heterotetramers and illustrate the potential of KvS subunits to provide unique properties to the heterotetramers, as is the case for 4-AP on Kv2.1/Kv6.4 channels. (PMID:26505474)
• Human Labor Pain Is Influenced by the Voltage-Gated Potassium Channel KV6.4 Subunit. (PMID:32697988)
• KCNG4 Genetic Variant Linked to Migraine Prevents Expression of KCNB1. (PMID:39201645)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	kcng4b	ENSDARG00000051892
danio_rerio	kcng4a	ENSDARG00000062967
mus_musculus	Kcng4	ENSMUSG00000045246
rattus_norvegicus	Kcng4	ENSRNOG00000015746

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), KCNS3 (ENSG00000170745), KCNG3 (ENSG00000171126), KCND3 (ENSG00000171385), KCNA3 (ENSG00000177272), KCNA2 (ENSG00000177301), KCNG2 (ENSG00000178342), KCNA4 (ENSG00000182255), KCNB2 (ENSG00000182674), KCNQ3 (ENSG00000184156), KCND2 (ENSG00000184408), KCNQ5 (ENSG00000185760)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1913983) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 17 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal spermatogenesis	1
hydrocephaly	1
male infertility	1
abnormal spermiogenesis	1
abnormal brain morphology	1
asthenozoospermia	1
oligozoospermia	1
increased circulating aspartate transaminase level	1
teratozoospermia	1
abnormal sperm head morphology	1
small sperm head	1
short sperm flagellum	1
necrospermia	1
abnormal sperm midpiece morphology	1
abnormal elongated spermatid morphology	1
decreased elongated spermatid number	1
decreased sperm progressive motility	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pongo abelii	Q5RC10	100.0%	Diamond
Macaca fascicularis	Q9GKU7	100.0%	Diamond
Macaca mulatta	A4K2T1	99.8%	Diamond
Chlorocebus aethiops	A4K2Y2	99.8%	Diamond
Pan troglodytes	A4K2N8	99.4%	Diamond
Papio anubis	A4K2M4	99.2%	Diamond
Gorilla gorilla gorilla	A4K2R3	99.2%	Diamond
Oryctolagus cuniculus	Q9TTT5	99.1%	Diamond
Mesocricetus auratus	Q60565	99.0%	Diamond
Colobus guereza	A4K2P6	98.9%	Diamond
Aotus nancymaae	A4K2W6	98.1%	Diamond
Saimiri boliviensis boliviensis	A4K2X4	98.1%	Diamond
Sus scrofa	O18868	97.3%	Diamond
Bos taurus	Q0P583	96.8%	Diamond
Otolemur garnettii	A4K2Q6	93.4%	Diamond
Lemur catta	A4K2S2	93.4%	Diamond
Canis lupus familiaris	Q95167	92.0%	Diamond
Mesorhizobium japonicum MAFF 303099	Q98GN8	73.5%	Diamond
Drosophila melanogaster	P17971	72.9%	Diamond
Gallus gallus	O73606	68.3%	Diamond
Caenorhabditis elegans	G5EFC3	64.1%	Diamond
Arabidopsis thaliana	Q8LBL1	58.2%	Diamond
Bacillus subtilis subsp. subtilis str. 168	Q795M8	50.0%	Diamond
Escherichia coli K-12	P31069	37.9%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
ADAD2	protein-coding	161931
WFDC1	protein-coding	58189
ADAD2-AS1	ncRNA	654780
DNAAF1	protein-coding	123872
HSDL1	protein-coding	83693
TAF1C	protein-coding	9013
ATP2C2-AS1	ncRNA	105371374
ATP2C2	protein-coding	9914

Protein

Protein identifiers

Voltage-gated potassium channel regulatory subunit KCNG4 — Q8TDN1 (reviewed: Q8TDN1)

Alternative names: Potassium voltage-gated channel subfamily G member 4, Voltage-gated potassium channel subunit Kv6.3, Voltage-gated potassium channel subunit Kv6.4

All UniProt accessions (2): Q8TDN1, Q547S7

UniProt curated annotations — full annotation on UniProt →

Function. Regulatory subunit of the voltage-gated potassium (Kv) channel which, when coassembled with KCNB1, modulates the kinetics parameters of the heterotetrameric channel namely the time course of activation, deactivation and inactivation and on the voltage-dependence of activation. Potassium channel subunit that does not form functional channels by itself. Reduces the deactivation rate. Modulates the threshold for activation by shifting by approximately 20 mV in hyperpolarizing direction. Markedly changes the inactivation by shifting the voltage dependence of inactivation by approximately 40 mV in hyperpolarizing direction. Acceleratee activation and enhances the time course of activation.

Subunit / interactions. Heterotetramer with KCNB1. Does not form homomultimer.

Subcellular location. Cell membrane.

Tissue specificity. Highly expressed in brain, and at lower levels in liver, small intestine and colon.

Domain organisation. The transmembrane segment S4 functions as a voltage-sensor and is characterized by a series of positively charged amino acids at every third position. Channel opening and closing is effected by a conformation change that affects the position and orientation of the voltage-sensor paddle formed by S3 and S4 within the membrane. A transmembrane electric field that is positive inside would push the positively charged S4 segment outwards, thereby opening the pore, while a field that is negative inside would pull the S4 segment inwards and close the pore. Changes in the position and orientation of S4 are then transmitted to the activation gate formed by the inner helix bundle via the S4-S5 linker region.

Similarity. Belongs to the potassium channel family. G (TC 1.A.1.2) subfamily. Kv6.4/KCNG4 sub-subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8TDN1-1	1	yes
Q8TDN1-2	2

RefSeq proteins (1): NP_758857* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003131	T1-type_BTB	Domain
IPR003968	K_chnl_volt-dep_Kv	Family
IPR003971	K_chnl_volt-dep_Kv5/Kv9	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 (27 total): topological domain 8, transmembrane region 6, sequence variant 6, intramembrane region 2, splice variant 2, chain 1, region of interest 1, short sequence motif 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TDN1-F1	78.07	0.33

Human Protein Atlas

Protein class: Transporters, Transporter channels and pores, Voltage-gated ion channels, Voltage-Gated Potassium Channels, Predicted membrane proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): plasma membrane; nucleoplasm

Antibody reliability (HPA): IF supported

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

ID	Pathway	Evidence
R-HSA-1296072	Voltage gated Potassium channels	curated
R-HSA-112316	Neuronal System	—
R-HSA-1296071	Potassium Channels	—

MSigDB gene sets: 84 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, REACTOME_VOLTAGE_GATED_POTASSIUM_CHANNELS, REACTOME_POTASSIUM_CHANNELS, TGACCTY_ERR1_Q2, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_PROTEIN_HOMOOLIGOMERIZATION, GOBP_REGULATION_OF_TRANSPORT, GOBP_REGULATION_OF_MONOATOMIC_ION_TRANSPORT, GOBP_TRANSMEMBRANE_TRANSPORT, TGACCTTG_SF1_Q6, GOBP_REGULATION_OF_POTASSIUM_ION_TRANSPORT, AP4_01, GOBP_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, LEIN_PONS_MARKERS, LEIN_MEDULLA_MARKERS

GO Biological Process (9): action potential (GO:0001508), regulation of potassium ion transport (GO:0043266), protein homooligomerization (GO:0051260), potassium ion transmembrane transport (GO:0071805), regulation of potassium ion transmembrane transport (GO:1901379), 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), transmembrane transporter binding (GO:0044325), monoatomic ion channel activity (GO:0005216), potassium channel activity (GO:0005267)

GO Cellular Component (4): plasma membrane (GO:0005886), voltage-gated potassium channel complex (GO:0008076), membrane (GO:0016020), monoatomic ion channel complex (GO:0034702)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Potassium Channels	1
Neuronal System	1

GO top-level categories

27 GO namespaces:

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
regulation of potassium ion transport	1
potassium ion transmembrane transport	1
regulation of 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
protein binding	1
monoatomic ion transmembrane transporter activity	1
channel activity	1
monoatomic cation channel activity	1
potassium ion transmembrane transporter activity	1
membrane	1
cell periphery	1
potassium channel complex	1
plasma membrane protein complex	1
cellular anatomical structure	1
transmembrane transporter complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 6 of 18 annotations. The rest are phylogenetic / computational / electronic (IEA).

6 experimentally-supported GO terms:

GO term	NS	Evidence
regulation of potassium ion transmembrane transport	BP	direct assay
regulation of potassium ion transport	BP	direct assay
plasma membrane	CC	direct assay
voltage-gated potassium channel complex	CC	direct assay
potassium channel regulator activity	MF	direct assay
transmembrane transporter binding	MF	physical interaction

Protein interactions and networks

STRING

showing 16 of 1,180 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNG4	TYW3	Q6IPR3	573
KCNG4	SCN4B	Q8IWT1	543
KCNG4	CABP7	Q86V35	446
KCNG4	OPN4	Q9UHM6	435
KCNG4	KCNB1	Q14721	421
KCNG4	SDK2	Q58EX2	407
KCNG4	CARTPT	Q16568	398
KCNG4	KCNAB1	Q14722	396
KCNG4	LRRTM1	Q86UE6	394
KCNG4	KCNJ14	Q9UNX9	378
KCNG4	PTPDC1	A2A3K4	373
KCNG4	KCNH8	Q96L42	373
KCNG4	KCNT2	Q6UVM3	371
KCNG4	GLRB	P48167	370
KCNG4	KATNA1	O75449	370
KCNG4	PIK3C2G	O75747	370

IntAct

Human interaction partners of KCNG4 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

2 partners by confidence:

Partner	Interaction type	MIscore	Records
KCNB2	physical association	0.400	1
CA1	association	0.350	1

BioGRID (26 interactions; top human partners by supporting records): KCNB1 (FRET; 5 records), KCNB2 (Affinity Capture-MS; 3 records), CST1 (Affinity Capture-MS; 2 records), CST2 (Affinity Capture-MS; 2 records), CST4 (Affinity Capture-MS; 2 records), ATF6 (Affinity Capture-MS), AXL (Affinity Capture-MS), CA1 (Affinity Capture-MS), DCAKD (Affinity Capture-MS), KCNE1L (FRET), PDZD8 (Affinity Capture-MS), POLI (Reconstituted Complex), PPP1R15B (Affinity Capture-MS), RNF123 (Affinity Capture-MS), SREBF1 (Affinity Capture-MS)

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
★ KCNB1-KCNG4 complex	2	KCNB1, KCNG4

Disease & clinical

Genetic variants

Variant evidence for KCNG4: 134 ClinVar records (0 pathogenic / likely pathogenic); 3 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	123
Likely benign	5
Benign	5

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 16 predictions of 301):

Position(s)	Effect	Δscore	Sites
16:84239669	donor_loss	1.0000	2
16:84237534–84237535	acceptor_gain	0.9900	2
16:84239668	donor_loss	0.9900
16:84239669	donor_loss	0.9800
16:84239668	donor_loss	0.9700
16:84222216	donor_gain	0.8800
16:84236728–84236729	donor_loss	0.8800	5
16:84222221	donor_gain	0.8700
16:84236728	donor_loss	0.8700
16:84239672	donor_gain	0.8500

AlphaMissense

1,117 missense substitutions predicted likely pathogenic (of 3,393 scored), across 277 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D299	8	0.992	0.997
D423	8	0.973	0.987
F273	8	0.971	0.998
F113	8	0.967	0.992
F457	8	0.960	0.997
F120	8	0.944	0.987
F377	8	0.943	0.989
F402	8	0.933	0.997
D102	8	0.931	0.973
F448	8	0.928	0.982
F454	8	0.918	0.991
D114	8	0.916	0.964
F223	8	0.914	0.983
H353	8	0.904	0.974
M416	8	0.849	0.983
D103	8	0.763	0.880
W150	7	0.985	0.995
W411	7	0.984	0.998
F290	7	0.975	0.996
E276	7	0.967	0.989

HPA cancer prognostics

RNA cancer specificity: Not detected

Disease associations

OMIM: gene MIM:607603 | disease phenotypes:

GWAS associations

3 associations:

Study	Trait	p-value
GCST011891_12	Systolic blood pressure (baseline)	2e-8
GCST003830_46	Response to bronchodilator in chronic obstructive pulmonary disease (change in FEV1)	7e-7
GCST001523_23	Visceral adipose tissue adjusted for BMI	6e-6

EFO canonical traits (from GWAS)

3 canonical traits:

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0005921	FEV change measurement
EFO:0006335	systolic blood pressure

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2362996 (PROTEIN FAMILY)

PharmGKB: 1 entry (CPIC guideline: no)

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

10 total (human), top 10 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Resveratrol	affects cotreatment, decreases expression	2
bisphenol A	decreases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
bisphenol S	decreases methylation	1
Acetaminophen	increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Copper	affects cotreatment, decreases expression	1
Lipopolysaccharides	increases expression, decreases expression, affects response to substance	1
Plant Extracts	affects cotreatment, decreases expression	1
Valproic Acid	increases methylation	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*

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_YA61	IDG-HEK293T-KCNG4-V5-OE	Transformed cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.