GJD4

Summary

GJD4 (gap junction protein delta 4, HGNC:23296) is a protein-coding gene on chromosome 10p11.21, encoding Gap junction delta-4 protein (Q96KN9). One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.

Connexins, such as GJD4, are involved in the formation of gap junctions, intercellular conduits that directly connect the cytoplasms of contacting cells. Each gap junction channel is formed by docking of 2 hemichannels, each of which contains 6 connexin subunits (Sohl et al., 2003 [PubMed 12881038]).

Source: NCBI Gene 219770 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 83 total
• MANE Select transcript: NM_153368

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23296
Approved symbol	GJD4
Name	gap junction protein delta 4
Location	10p11.21
Locus type	gene with protein product
Status	Approved
Aliases	CX40.1, FLJ90023
Ensembl gene	ENSG00000177291
Ensembl biotype	protein_coding
OMIM	611922
Entrez	219770

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000321660

RefSeq mRNA: 1 — MANE Select: NM_153368 NM_153368

CCDS: CCDS7191

Canonical transcript exons

ENST00000321660 — 2 exons

Exon	Start	End
ENSE00001242724	35607578	35608935
ENSE00001242732	35605341	35605631

Expression profiles

Bgee: expression breadth broad, 31 present calls, max score 84.65.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0208 / max 14.7441, expressed in 8 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
104696	0.0109	3
104695	0.0099	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.65	gold quality
kidney epithelium	UBERON:0004819	82.27	gold quality
cardiac muscle of right atrium	UBERON:0003379	79.02	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	78.80	gold quality
left ventricle myocardium	UBERON:0006566	78.63	gold quality
upper arm skin	UBERON:0004263	78.47	gold quality
myocardium	UBERON:0002349	73.62	gold quality
nasal cavity epithelium	UBERON:0005384	72.65	gold quality
heart right ventricle	UBERON:0002080	70.08	gold quality
vastus lateralis	UBERON:0001379	70.02	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	69.52	gold quality
germinal epithelium of ovary	UBERON:0001304	69.33	gold quality
quadriceps femoris	UBERON:0001377	68.87	gold quality
vena cava	UBERON:0004087	67.32	silver quality
mucosa of paranasal sinus	UBERON:0005030	66.76	gold quality
biceps brachii	UBERON:0001507	64.66	gold quality
parotid gland	UBERON:0001831	64.62	gold quality
gingival epithelium	UBERON:0001949	64.58	gold quality
epithelial cell of pancreas	CL:0000083	64.30	gold quality
superficial temporal artery	UBERON:0001614	63.98	gold quality
gingiva	UBERON:0001828	63.87	gold quality
layer of synovial tissue	UBERON:0007616	63.68	gold quality
lateral nuclear group of thalamus	UBERON:0002736	63.19	gold quality
cartilage tissue	UBERON:0002418	62.82	gold quality
epithelium of mammary gland	UBERON:0003244	62.01	gold quality
secondary oocyte	CL:0000655	61.97	gold quality
mammary duct	UBERON:0001765	61.88	gold quality
subthalamic nucleus	UBERON:0001906	61.81	gold quality
postcentral gyrus	UBERON:0002581	61.72	gold quality
body of tongue	UBERON:0011876	61.72	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.81

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

15 targeting GJD4, 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-4425	100.00	67.59	1049
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-6832-5P	99.58	64.82	1132
HSA-MIR-4735-5P	99.43	68.49	1780
HSA-MIR-6809-5P	99.13	68.45	1223
HSA-MIR-371A-5P	99.08	66.51	1914
HSA-MIR-5089-5P	98.45	66.06	1388
HSA-MIR-1304-3P	98.29	66.44	1207
HSA-MIR-660-3P	98.14	66.04	1434
HSA-MIR-1182	96.41	64.89	336
HSA-MIR-635	96.00	65.54	687
HSA-MIR-6774-5P	95.94	65.18	722

Literature-anchored findings (GeneRIF, showing 4)

• expression patterns differ from mouse orthologs [Cx30.2; Cx40.1] (PMID:12881038)
• The data show that induced expression of either Cx37 or Cx40 in Cx43-expressing cells can selectively alter the intercellular exchange of some molecules without affecting the transfer of others. (PMID:22729648)
• Connexin40 regulates platelet function. (PMID:24096827)
• Human deltoid muscle biopsies of 5 Chilean dysferlinopathy patients exhibited the presence of muscular connexins (Cx40.1, Cx43 and Cx45). (PMID:27229680)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000116895
mus_musculus	Gjd4	ENSMUSG00000036855
rattus_norvegicus	Gjd4	ENSRNOG00000018407

Paralogs (20): GJA8 (ENSG00000121634), GJB6 (ENSG00000121742), GJA3 (ENSG00000121743), GJA9 (ENSG00000131233), GJA10 (ENSG00000135355), GJA1 (ENSG00000152661), GJD2 (ENSG00000159248), GJB7 (ENSG00000164411), GJB2 (ENSG00000165474), GJB1 (ENSG00000169562), GJC3 (ENSG00000176402), GJC1 (ENSG00000182963), GJD3 (ENSG00000183153), GJA4 (ENSG00000187513), GJB3 (ENSG00000188910), GJB5 (ENSG00000189280), GJB4 (ENSG00000189433), GJC2 (ENSG00000198835), GJE1 (ENSG00000203733), GJA5 (ENSG00000265107)

Protein

Protein identifiers

Gap junction delta-4 protein — Q96KN9 (reviewed: Q96KN9)

Alternative names: Connexin-40.1

All UniProt accessions (1): Q96KN9

UniProt curated annotations — full annotation on UniProt →

Function. One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.

Subunit / interactions. A connexon is composed of a hexamer of connexins.

Subcellular location. Cell membrane. Cell junction. Gap junction.

Tissue specificity. Expressed in pancreas, kidney, skeletal muscle, liver, placenta, and heart.

Similarity. Belongs to the connexin family. Delta-type subfamily.

RefSeq proteins (1): NP_699199* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000500	Connexin	Family
IPR013092	Connexin_N	Domain
IPR017990	Connexin_CS	Conserved_site
IPR019570	Connexin_CCC	Domain
IPR038359	Connexin_N_sf	Homologous_superfamily

Pfam: PF00029

UniProt features (33 total): helix 10, topological domain 5, transmembrane region 4, strand 4, sequence variant 3, compositionally biased region 2, turn 2, chain 1, region of interest 1, sequence conflict 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
8GN7	ELECTRON MICROSCOPY	3
8GN8	ELECTRON MICROSCOPY	3.5
8GNB	ELECTRON MICROSCOPY	3.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96KN9-F1	68.92	0.38

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-190861	Gap junction assembly

MSigDB gene sets: 49 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_SKELETAL_MUSCLE_TISSUE_REGENERATION, MIDORIKAWA_AMPLIFIED_IN_LIVER_CANCER, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_GROWTH, GOBP_REGENERATION, REACTOME_MEMBRANE_TRAFFICKING, GOBP_CELL_CELL_SIGNALING, GOBP_TISSUE_REGENERATION, GOBP_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, REACTOME_GAP_JUNCTION_ASSEMBLY, GOCC_CELL_CELL_JUNCTION, GOBP_TRANSMEMBRANE_TRANSPORT, GOBP_REGULATION_OF_GROWTH, GOCC_MEMBRANE_PROTEIN_COMPLEX

GO Biological Process (4): cell-cell signaling (GO:0007267), regulation of satellite cell activation involved in skeletal muscle regeneration (GO:0014717), cell communication (GO:0007154), transmembrane transport (GO:0055085)

GO Molecular Function (1): gap junction channel activity (GO:0005243)

GO Cellular Component (5): connexin complex (GO:0005922), plasma membrane (GO:0005886), gap junction (GO:0005921), membrane (GO:0016020), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Gap junction trafficking	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	2
cell communication	1
signaling	1
satellite cell activation involved in skeletal muscle regeneration	1
regulation of skeletal muscle tissue regeneration	1
regulation of cell activation	1
transport	1
wide pore channel activity	1
gap junction	1
plasma membrane protein complex	1
membrane	1
cell periphery	1
cell-cell junction	1
cellular anatomical structure	1
cell junction	1

Protein interactions and networks

STRING

446 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GJD4	FXYD4	P59646	961
GJD4	ZBBX	A8MT70	524
GJD4	TBC1D22B	Q9NU19	512
GJD4	NRSN2	Q9GZP1	480
GJD4	PLCD4	Q9BRC7	462
GJD4	CALHM1	Q8IU99	450
GJD4	FSTL5	Q8N475	449
GJD4	CHRNA2	Q15822	433
GJD4	SYCP2	Q9BX26	429
GJD4	WDR49	Q8IV35	395
GJD4	GJE1	A6NN92	375
GJD4	RASL11A	Q6T310	365
GJD4	SLC38A11	Q08AI6	364
GJD4	FAM78A	Q5JUQ0	359
GJD4	PHYHIP	Q92561	358

IntAct

126 interactions, top by confidence:

A	B	Type	Score
	GJD4	psi-mi:“MI:0915”(physical association)	0.560
GJD4	TJP2	psi-mi:“MI:0407”(direct interaction)	0.440
GJD4	PDZD2	psi-mi:“MI:0407”(direct interaction)	0.440
GJD4	HTRA3	psi-mi:“MI:0407”(direct interaction)	0.440
GJD4	GORASP2	psi-mi:“MI:0407”(direct interaction)	0.440
GJD4	PATJ	psi-mi:“MI:0407”(direct interaction)	0.440
GJD4	LNX2	psi-mi:“MI:0407”(direct interaction)	0.440
GJD4	GORASP1	psi-mi:“MI:0407”(direct interaction)	0.440
GJD4	TJP1	psi-mi:“MI:0407”(direct interaction)	0.440
GJD4	NOS1	psi-mi:“MI:0407”(direct interaction)	0.440
GJD4	RADIL	psi-mi:“MI:0407”(direct interaction)	0.440
GJD4	APBA1	psi-mi:“MI:0407”(direct interaction)	0.440
GJD4	TJP3	psi-mi:“MI:0407”(direct interaction)	0.440
GJD4	HTRA4	psi-mi:“MI:0407”(direct interaction)	0.440
SNX27	GJD4	psi-mi:“MI:0407”(direct interaction)	0.440
GJD4	HTRA1	psi-mi:“MI:0407”(direct interaction)	0.440
GJD4	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
GJD4	FRMPD2	psi-mi:“MI:0407”(direct interaction)	0.440
GJD4	SYNJ2BP	psi-mi:“MI:0407”(direct interaction)	0.440
GJD4	DLG1	psi-mi:“MI:0407”(direct interaction)	0.440
GJD4	DLG2	psi-mi:“MI:0407”(direct interaction)	0.440
GJD4	ERBIN	psi-mi:“MI:0407”(direct interaction)	0.440
DLG4	GJD4	psi-mi:“MI:0407”(direct interaction)	0.440
TIAM2	GJD4	psi-mi:“MI:0407”(direct interaction)	0.440
GJD4	PDZK1	psi-mi:“MI:0407”(direct interaction)	0.440
GJD4	NHERF4	psi-mi:“MI:0407”(direct interaction)	0.440
GJD4	MPDZ	psi-mi:“MI:0407”(direct interaction)	0.440
GJD4	GRIP2	psi-mi:“MI:0407”(direct interaction)	0.440
GJD4	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (13): TMEM31 (Two-hybrid), GJD4 (Affinity Capture-MS), GJD4 (Affinity Capture-MS), PTER (Affinity Capture-MS), GJD4 (Affinity Capture-MS), STXBP3 (Affinity Capture-MS), STXBP1 (Affinity Capture-MS), MBLAC2 (Affinity Capture-MS), FOXK2 (Affinity Capture-MS), DPP9 (Affinity Capture-MS), STXBP2 (Affinity Capture-MS), GJD4 (Affinity Capture-MS), GJD4 (Two-hybrid)

ESM2 similar proteins: A0A0U1RQ45, A0A0U1RQS6, A0A2R8YCJ5, A2A699, A2AEV7, A6NGB7, A6NJG2, A6NKF7, A6NKL6, A6NL88, A8MVW0, A9JSM3, B2RU40, B8ZZ34, C9JH25, D4A9R4, J3QNX5, P0CG09, P98077, Q0VD38, Q14761, Q17QH7, Q29RK8, Q2KJ18, Q2M3V2, Q3SX20, Q5BJT1, Q5HZJ5, Q5RKR3, Q5T442, Q64697, Q69YZ2, Q6PB97, Q6PCT2, Q6UXK2, Q6ZMQ8, Q6ZVH7, Q6ZW31, Q80XF7, Q8BLS7

Diamond homologs: A2VE67, A3KN25, A4GG66, A4GVD1, A4IFL1, A6XKM2, O18968, O57474, O93533, O95377, O95452, P08033, P08034, P08050, P08983, P14154, P16863, P16864, P17302, P18246, P18860, P18861, P21994, P23242, P25305, P28228, P28229, P28230, P28231, P28232, P28233, P28234, P28235, P28236, P29033, P29414, P29415, P33725, P35212, P36381

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 81 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Assembly and cell surface presentation of NMDA receptors	8	38.3×	2e-09
Neurexins and neuroligins	10	37.1×	2e-11
Protein-protein interactions at synapses	6	30.1×	3e-06
RHOA GTPase cycle	5	7.0×	7e-03
Neuronal System	6	5.0×	9e-03
Signaling by Rho GTPases	7	4.5×	8e-03
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	7	4.4×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	10	75.5×	2e-14
protein localization to synapse	6	59.7×	9e-08
receptor clustering	6	48.6×	2e-07
regulation of postsynaptic membrane neurotransmitter receptor levels	7	45.1×	4e-08
protein-containing complex assembly	9	13.3×	2e-06
cell-cell adhesion	9	11.9×	4e-06
chemical synaptic transmission	7	7.0×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	75
Likely benign	6
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

192 predictions. Top by Δscore:

Variant	Effect	Δscore
10:35605628:GTGG:G	donor_gain	1.0000
10:35605632:G:GG	donor_gain	1.0000
10:35605630:GG:G	donor_gain	0.9900
10:35605631:GG:G	donor_gain	0.9900
10:35605632:GTGA:G	donor_loss	0.9900
10:35605633:T:TG	donor_loss	0.9900
10:35605634:GAG:G	donor_loss	0.9900
10:35605629:TGG:T	donor_gain	0.9800
10:35605630:GGG:G	donor_gain	0.9800
10:35605636:G:C	donor_loss	0.9800
10:35607572:TTCCA:T	acceptor_loss	0.9800
10:35607573:TCCA:T	acceptor_loss	0.9800
10:35607574:CCAG:C	acceptor_loss	0.9800
10:35607575:CA:C	acceptor_loss	0.9800
10:35607576:A:AG	acceptor_gain	0.9800
10:35607576:A:AT	acceptor_loss	0.9800
10:35607577:G:A	acceptor_loss	0.9800
10:35607577:G:GG	acceptor_gain	0.9800
10:35607577:GGAAA:G	acceptor_gain	0.9800
10:35607576:AG:A	acceptor_gain	0.9700
10:35607577:GG:G	acceptor_gain	0.9700
10:35607577:GGA:G	acceptor_gain	0.9700
10:35607577:GGAA:G	acceptor_gain	0.9700
10:35605563:G:GT	donor_gain	0.8800
10:35605979:A:T	donor_gain	0.8300
10:35605934:T:TA	donor_gain	0.8100
10:35605984:G:GT	donor_gain	0.8100
10:35605571:G:GT	donor_gain	0.7600
10:35605854:G:GT	donor_gain	0.7600
10:35605978:G:GT	donor_gain	0.7400

AlphaMissense

2343 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:35607668:T:G	F52C	0.998
10:35607667:T:C	F52L	0.994
10:35607669:T:A	F52L	0.994
10:35607669:T:G	F52L	0.994
10:35607668:T:C	F52S	0.992
10:35607673:T:A	C54S	0.989
10:35607674:G:C	C54S	0.989
10:35607708:C:G	C65W	0.989
10:35607674:G:A	C54Y	0.988
10:35607707:G:A	C65Y	0.987
10:35607718:T:C	F69L	0.987
10:35607720:C:A	F69L	0.987
10:35607720:C:G	F69L	0.987
10:35608071:C:G	C186W	0.986
10:35607706:T:A	C65S	0.985
10:35607707:G:C	C65S	0.985
10:35607776:C:G	P88R	0.985
10:35607790:A:C	S93R	0.985
10:35607792:C:A	S93R	0.985
10:35607792:C:G	S93R	0.985
10:35607677:A:T	N55I	0.984
10:35607694:T:A	C61S	0.984
10:35607695:G:C	C61S	0.984
10:35608095:G:C	K194N	0.984
10:35608095:G:T	K194N	0.984
10:35607787:T:C	F92L	0.983
10:35607789:C:A	F92L	0.983
10:35607789:C:G	F92L	0.983
10:35607678:C:A	N55K	0.982
10:35607678:C:G	N55K	0.982

dbSNP variants (sampled 300 via entrez): RS1001272049 (10:35605280 G>A), RS1001723246 (10:35605014 A>C), RS1002046905 (10:35608801 A>C,G), RS1002329257 (10:35603604 G>A,C), RS1002682144 (10:35603829 T>C), RS1003355656 (10:35606468 T>C), RS1003443232 (10:35607248 A>C,G), RS1003754276 (10:35606918 A>G), RS1004018827 (10:35603880 T>C), RS1004069618 (10:35606604 G>A), RS1004578246 (10:35609171 A>G), RS1006575891 (10:35605179 G>C), RS1007180092 (10:35605877 C>G), RS1007416087 (10:35608853 A>C,G), RS1007468516 (10:35609129 C>A,T)

Disease associations

OMIM: gene MIM:611922 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: other ic — Connexins and Pannexins

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
incobotulinumtoxinA	decreases expression	1
theaflavin-3,3’-digallate	affects expression	1
Resveratrol	affects cotreatment, decreases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Hydralazine	affects cotreatment, increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Valproic Acid	increases expression, affects cotreatment	1

Clinical trials (associated diseases)

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