DLG5

Summary

DLG5 (discs large MAGUK scaffold protein 5, HGNC:2904) is a protein-coding gene on chromosome 10q22.3, encoding Disks large homolog 5 (Q8TDM6). Acts as a regulator of the Hippo signaling pathway. It is a selective cancer dependency (DepMap: 10.3% of cell lines).

This gene encodes a member of the family of discs large (DLG) homologs, a subset of the membrane-associated guanylate kinase (MAGUK) superfamily. The MAGUK proteins are composed of a catalytically inactive guanylate kinase domain, in addition to PDZ and SH3 domains, and are thought to function as scaffolding molecules at sites of cell-cell contact. The protein encoded by this gene localizes to the plasma membrane and cytoplasm, and interacts with components of adherens junctions and the cytoskeleton. It is proposed to function in the transmission of extracellular signals to the cytoskeleton and in the maintenance of epithelial cell structure. Alternative splice variants have been described but their biological nature has not been determined.

Source: NCBI Gene 9231 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Yuksel-Vogel-Bauer syndrome (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 16
• Clinical variants (ClinVar): 361 total — 3 pathogenic
• Phenotypes (HPO): 20
• Cancer dependency (DepMap): dependent in 10.3% of screened cell lines
• MANE Select transcript: NM_004747

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2904
Approved symbol	DLG5
Name	discs large MAGUK scaffold protein 5
Location	10q22.3
Locus type	gene with protein product
Status	Approved
Aliases	P-dlg, KIAA0583
Ensembl gene	ENSG00000151208
Ensembl biotype	protein_coding
OMIM	604090
Entrez	9231

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 5 protein_coding, 4 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000372391, ENST00000424842, ENST00000459739, ENST00000463362, ENST00000466198, ENST00000468332, ENST00000475613, ENST00000476354, ENST00000484525, ENST00000489547, ENST00000928379, ENST00000928380, ENST00000962015

RefSeq mRNA: 1 — MANE Select: NM_004747 NM_004747

CCDS: CCDS7353

Canonical transcript exons

ENST00000372391 — 32 exons

Exon	Start	End
ENSE00001211398	77853354	77853537
ENSE00001211401	77854227	77854370
ENSE00001241369	77856730	77856892
ENSE00001729213	77869129	77869197
ENSE00001942599	77926217	77926755
ENSE00003459855	77830741	77830873
ENSE00003461437	77841881	77842193
ENSE00003461862	77817007	77817096
ENSE00003461901	77809547	77809730
ENSE00003468284	77829355	77829530
ENSE00003479974	77807796	77807944
ENSE00003480899	77819895	77820018
ENSE00003505653	77796451	77796594
ENSE00003530838	77796061	77796188
ENSE00003560239	77805665	77805861
ENSE00003565078	77790791	77792543
ENSE00003572983	77794008	77794117
ENSE00003574061	77794849	77794958
ENSE00003591234	77830217	77830344
ENSE00003594026	77833914	77834039
ENSE00003595801	77819321	77819465
ENSE00003604495	77824384	77824476
ENSE00003612509	77812215	77812377
ENSE00003625794	77811924	77812057
ENSE00003636356	77816551	77816701
ENSE00003640390	77821082	77822101
ENSE00003648462	77811094	77811234
ENSE00003649042	77806758	77806928
ENSE00003665326	77828882	77828985
ENSE00003670318	77835738	77835922
ENSE00003673210	77817777	77817889
ENSE00003680486	77843447	77843706

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 96.42.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.6130 / max 54.2742, expressed in 1543 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
110206	4.6315	1458
110189	1.2865	781
110207	0.6163	360
110205	0.0536	29
205909	0.0172	7
205910	0.0078	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	96.42	gold quality
left adrenal gland cortex	UBERON:0035825	96.10	gold quality
right adrenal gland cortex	UBERON:0035827	96.08	gold quality
ganglionic eminence	UBERON:0004023	95.79	gold quality
right adrenal gland	UBERON:0001233	95.46	gold quality
left adrenal gland	UBERON:0001234	95.35	gold quality
placenta	UBERON:0001987	95.04	gold quality
adrenal gland	UBERON:0002369	94.43	gold quality
stromal cell of endometrium	CL:0002255	93.94	gold quality
pituitary gland	UBERON:0000007	93.87	gold quality
skin of abdomen	UBERON:0001416	93.56	gold quality
prostate gland	UBERON:0002367	93.54	gold quality
zone of skin	UBERON:0000014	93.48	gold quality
skin of leg	UBERON:0001511	93.35	gold quality
cortical plate	UBERON:0005343	93.34	gold quality
adenohypophysis	UBERON:0002196	92.81	gold quality
lower esophagus muscularis layer	UBERON:0035833	92.61	gold quality
lower esophagus	UBERON:0013473	92.57	gold quality
mucosa of stomach	UBERON:0001199	92.07	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.03	gold quality
muscle layer of sigmoid colon	UBERON:0035805	91.99	gold quality
thyroid gland	UBERON:0002046	91.89	gold quality
right lobe of thyroid gland	UBERON:0001119	91.56	gold quality
left lobe of thyroid gland	UBERON:0001120	91.52	gold quality
ectocervix	UBERON:0012249	91.51	gold quality
vagina	UBERON:0000996	91.41	gold quality
endocervix	UBERON:0000458	91.36	gold quality
uterine cervix	UBERON:0000002	91.34	gold quality
body of uterus	UBERON:0009853	91.29	gold quality
left ovary	UBERON:0002119	90.73	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.99
E-GEOD-99795	no	43.39

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

132 targeting DLG5, 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-3646	100.00	73.56	5283
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-6508-5P	99.92	70.67	2465

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 10.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• findings suggest that lp-dlg/KIAA0583 is a novel scaffolding protein that can link the vinexin-vinculin complex and beta-catenin at sites of cell-cell contact (PMID:12657639)
• Genetic variation in DLG5 is associated with inflammatory bowel disease (PMID:15107852)
• Collaboration of RAB6KIFL and DLG5 is likely to be involved in pancreatic cancer. (PMID:15665285)
• DLG5 constitutes a true inflammatory bowel diseases risk factor of modest effect (PMID:15841097)
• Genetic variation in DLG5 is associated with inflammatory bowel disease (PMID:15930978)
• there are significant population allele frequency differences at the DLG5 gene [letter] (PMID:16391570)
• The G113A polymorphism of the DLG5 gene was completely absent in Greek Crohn disease cases as well as the Greek healthy population (PMID:16437728)
• R30Q variant constitutes a susceptibility factor for Crohn disease (CD) in men. (PMID:16446977)
• The results indicate a role for DLG5 variants in inflammatory bowel disease (IBD) susceptibility. (PMID:16450402)
• The initial report of DLG5 as a novel inflammatory bowel disease (IBD) susceptibility gene sparked a multitude of studies concerning its role in the aetiology of Crohn disease and IBD. (PMID:16773680)
• The R30Q variant in the DLG5 gene does not appear to be associated with an overall increase in the risk of disease in a British IBD cohort (PMID:16944184)
• DLG5 has a gender-specific role in the susceptibility of pediatric CD. Significant negative association found between DLG5 R30Q and CD in female children suggests DLG5 may have a protective effect in CD susceptibility for female children. (PMID:17156146)
• DLG5 gene missense mutation is associated with increased susceptibility to inflammatory bowel diseases in children. (PMID:17307543)
• polymorphism exerts a weak influence on Crohn’s disease phenotype (PMID:17451203)
• the DLG5 haplotype A is associated with reduced risk of inflammatory bowel disease in the New Zealand Caucasian population (PMID:17455201)
• polymorphisms 3020insC in CARD15 and SNP rs2165047 in DLG5 may have a role in pediatric-onset Crohn’s disease (PMID:17476680)
• DLG5 30Q is associated with a small reduction in risk of Crohn disease in women in a Caucasian cohort. (PMID:17693570)
• Results provide evidence that the scaffolding protein DLG5 belongs to the CARD protein family. (PMID:18335190)
• findings show that the inflammatory bowel disease-susceptibility gene DLG5 is also associated with gluten-sensitive enteropathy (PMID:18559397)
• In the studied population, DLG5 R30Q was associated with all forms of IBD. An elevated presence of the R30Q variant was observed in all members of a familial IBD registry (PMID:20037206)
• Increased expression of discs large homolog 5 gene is associated with ulcerative colitis. (PMID:21674725)
• Examined the genetic association of DLG5 SNP P1371Q with inflammatory bowel disease and its interaction with R30Q in disease susceptibility. P1371Q is complementary to R30Q, with R30Q exhibiting a dominant effect in IBD susceptibility. (PMID:22065243)
• Polymorphisms in the DLG5 gene were found to be associated with Crohn’s disease patients in Malaysia. (PMID:22118696)
• Overexpression of Dlg5 enhances the degradation of TGFBRI. (PMID:23624079)
• Findings demonstrate that Dlg5 interacts with and inhibits the activity of Girdin, thereby suppressing the migration of prostate cancer cells. (PMID:24662825)
• DLG5 plays a role in cell migration, cell adhesion, precursor cell division, cell proliferation, epithelial cell polarity maintenance, and transmission of extracellular signals to the membrane and cytoskeleton. (PMID:24910533)
• These data suggest that inhibition of Dlg5 by DNA hypermethylation contributes to provoke invasive phenotypes in bladder tumor. (PMID:25478998)
• study has identified several new proteins like RHOC, DLG5, UGDH, TMOD3 in addition to known chemoresistance associated proteins in non-small cell lung carcinoma. (PMID:26898345)
• Pooled data indicated no significant association between DLG5113G/A gene polymorphism and the development of Crohn’s disease (PMID:27309475)
• G113A variant may be significantly associated with Crohn’s disease risk in children and colonic involvement (Meta-Analysis) (PMID:27338058)
• both polymorphisms of DLG5 are correlated with inflammatory bowel disease susceptibility in an ethnic-specific manner. (PMID:27633114)
• Low expression of DLG5 is associated with Crohn’s disease. (PMID:27760079)
• DLG5 inhibits the association between MST1/2 and large tumor suppressor homologs 1/2 (LATS1/2), uses its scaffolding function to link MST1/2 with MARK3, and inhibits MST1/2 kinase activity (PMID:28087714)
• Loss of DLG5 expression promoted breast cancer progression by inactivating the Hippo signaling pathway and increasing nuclear YAP. (PMID:28169360)
• Data found that Dlg5 expression was significantly lower in human hepatocellular carcinoma (HCC) tissues and indicate that Dlg5 acts as a novel regulator of invadopodium-associated invasion via Girdin and by interfering with the interaction between Girdin and Tks5, which might be important for Tks5 phosphorylation in HCC cells. (PMID:28390157)
• Down-regulated DLG5 expression increases the stemness of breast cancer cells by enhancing TAZ expression, contributing to TAM resistance in breast cancer. (PMID:30450766)
• DLG5 variants are associated with multiple congenital anomalies including ciliopathy phenotypes. (PMID:32631816)
• The scaffolding protein DLG5 promotes glioblastoma growth by controlling Sonic Hedgehog signaling in tumor stem cells. (PMID:34984467)
• Recent Hints on the Dual Role of Discs Large MAGUK Scaffold Protein 5 in Cancers and in Hepatocellular Carcinoma. (PMID:35638431)
• A double-edged sword: DLG5 in diseases. (PMID:37001186)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	dlg5a	ENSDARG00000074059
danio_rerio	dlg5b.1	ENSDARG00000090949
		ENSDARG00000109235
mus_musculus	Dlg5	ENSMUSG00000021782
rattus_norvegicus	Dlg5	ENSRNOG00000005783
drosophila_melanogaster	Dlg5	FBGN0032363
caenorhabditis_elegans		WBGENE00009678

Paralogs (3): TJP1 (ENSG00000104067), TJP3 (ENSG00000105289), TJP2 (ENSG00000119139)

Protein

Protein identifiers

Disks large homolog 5 — Q8TDM6 (reviewed: Q8TDM6)

Alternative names: Discs large protein P-dlg, Placenta and prostate DLG

All UniProt accessions (3): Q8TDM6, A0A0A0MSL1, R4GMQ2

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a regulator of the Hippo signaling pathway. Negatively regulates the Hippo signaling pathway by mediating the interaction of MARK3 with STK3/4, bringing them together to promote MARK3-dependent hyperphosphorylation and inactivation of STK3 kinase activity toward LATS1. Positively regulates the Hippo signaling pathway by mediating the interaction of SCRIB with STK4/MST1 and LATS1 which is important for the activation of the Hippo signaling pathway. Involved in regulating cell proliferation, maintenance of epithelial polarity, epithelial-mesenchymal transition (EMT), cell migration and invasion. Plays an important role in dendritic spine formation and synaptogenesis in cortical neurons; regulates synaptogenesis by enhancing the cell surface localization of N-cadherin. Acts as a positive regulator of hedgehog (Hh) signaling pathway. Plays a critical role in the early point of the SMO activity cycle by interacting with SMO at the ciliary base to induce the accumulation of KIF7 and GLI2 at the ciliary tip for GLI2 activation.

Subunit / interactions. Interacts with MPP1. Interacts with CTNNB1 and with the third SH3 domain of SORBS3 to form a ternary complex. Interacts (via coiled-coil domain) with MARK3. Interacts (via PDZ domain 3) with STK3/MST2 and STK4/MST1. Interacts with SCRIB. Interacts with CTNB1, SMO and (via PDZ4 or guanylate kinase-like domain) with KIF7.

Subcellular location. Cell junction. Cell membrane. Postsynaptic density. Cytoplasm. Cytoskeleton. Cilium basal body.

Tissue specificity. Highly expressed in normal breast tissues and low-grade breast cancer tissues (at protein level). Highly expressed in the placenta and prostate. Expressed at a lower level in the thyroid, spinal cord, trachea, adrenal gland, skeletal muscle, pancreas, heart, brain, liver and kidney. A short splice product shows more limited expression, being absent from at least the brain.

Disease relevance. Yuksel-Vogel-Bauer syndrome (YUVOB) [MIM:620703] An autosomal recessive disorder characterized by multisystemic manifestations including cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The guanylate kinase-like domain interacts with the SH3 domain.

Similarity. Belongs to the MAGUK family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q8TDM6-1	1	yes
Q8TDM6-2	2
Q8TDM6-3	3
Q8TDM6-4	4
Q8TDM6-5	5

RefSeq proteins (1): NP_004738* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001315	CARD	Domain
IPR001452	SH3_domain	Domain
IPR001478	PDZ	Domain
IPR006907	DLG5_N	Domain
IPR008144	Guanylate_kin-like_dom	Domain
IPR008145	GK/Ca_channel_bsu	Domain
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR035537	DLG5_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily
IPR053004	MAGUK_Signaling_Regulators	Family

Pfam: PF00595, PF00625, PF04822, PF16610

UniProt features (54 total): modified residue 12, sequence variant 8, region of interest 7, domain 6, compositionally biased region 6, splice variant 6, strand 4, helix 2, chain 1, coiled-coil region 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1UIT	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TDM6-F1	63.25	0.15

Functional residue map

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

Post-translational modifications (12): 264, 295, 900, 984, 1000, 1011, 1021, 1183, 1209, 1263, 1334, 1666

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-9013420	RHOU GTPase cycle
R-HSA-9013424	RHOV GTPase cycle
R-HSA-9696264	RND3 GTPase cycle
R-HSA-9696270	RND2 GTPase cycle
R-HSA-9696273	RND1 GTPase cycle

MSigDB gene sets: 349 (showing top): GOBP_APICAL_PROTEIN_LOCALIZATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_DENDRITE_DEVELOPMENT, GGGACCA_MIR133A_MIR133B, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_METANEPHROS_DEVELOPMENT, GOBP_SYNAPSE_ASSEMBLY, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_EPITHELIAL_TUBE_BRANCHING_INVOLVED_IN_LUNG_MORPHOGENESIS, GOBP_APICAL_JUNCTION_ASSEMBLY, GOBP_DENDRITIC_SPINE_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_SYNAPSE_ASSEMBLY

GO Biological Process (32): epithelial to mesenchymal transition (GO:0001837), signal transduction (GO:0007165), negative regulation of cell population proliferation (GO:0008285), glial cell differentiation (GO:0010001), maintenance of cell polarity (GO:0030011), negative regulation of cell migration (GO:0030336), polarized epithelial cell differentiation (GO:0030859), midbrain development (GO:0030901), negative regulation of hippo signaling (GO:0035331), positive regulation of hippo signaling (GO:0035332), intracellular signal transduction (GO:0035556), negative regulation of T cell proliferation (GO:0042130), regulation of apoptotic process (GO:0042981), apical protein localization (GO:0045176), zonula adherens assembly (GO:0045186), establishment or maintenance of epithelial cell apical/basal polarity (GO:0045197), positive regulation of smoothened signaling pathway (GO:0045880), positive regulation of synapse assembly (GO:0051965), epithelial tube branching involved in lung morphogenesis (GO:0060441), neuroepithelial cell differentiation (GO:0060563), positive regulation of dendritic spine development (GO:0060999), protein-containing complex assembly (GO:0065003), protein localization to adherens junction (GO:0071896), metanephric collecting duct development (GO:0072205), cell-cell adhesion (GO:0098609), postsynapse organization (GO:0099173), establishment or maintenance of cell polarity (GO:0007163), tissue development (GO:0009888), positive regulation of signal transduction (GO:0009967), cell differentiation (GO:0030154), animal organ development (GO:0048513), regulation of multicellular organismal process (GO:0051239)

GO Molecular Function (4): beta-catenin binding (GO:0008013), cytoskeletal protein binding (GO:0008092), signaling receptor complex adaptor activity (GO:0030159), protein binding (GO:0005515)

GO Cellular Component (12): cytoplasm (GO:0005737), plasma membrane (GO:0005886), adherens junction (GO:0005912), postsynaptic density (GO:0014069), cell junction (GO:0030054), ciliary basal body (GO:0036064), glutamatergic synapse (GO:0098978), cytoskeleton (GO:0005856), membrane (GO:0016020), cell projection (GO:0042995), synapse (GO:0045202), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
RHO GTPase cycle	5

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
hippo signaling	2
regulation of hippo signaling	2
intracellular anatomical structure	2
protein binding	2
cell junction	2
mesenchymal cell differentiation	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
cell differentiation	1
gliogenesis	1
establishment or maintenance of cell polarity	1
cell migration	1
regulation of cell migration	1
negative regulation of cell motility	1
morphogenesis of a polarized epithelium	1
epithelial cell differentiation	1
brain development	1
anatomical structure development	1
negative regulation of intracellular signal transduction	1
positive regulation of intracellular signal transduction	1
signal transduction	1
T cell proliferation	1
regulation of T cell proliferation	1
negative regulation of lymphocyte proliferation	1
negative regulation of T cell activation	1
apoptotic process	1
regulation of programmed cell death	1
intracellular protein localization	1
adherens junction assembly	1
apical junction assembly	1
establishment or maintenance of apical/basal cell polarity	1
smoothened signaling pathway	1
regulation of smoothened signaling pathway	1

Protein interactions and networks

STRING

1764 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DLG5	NOD2	Q9HC29	890
DLG5	SORBS3	O60504	888
DLG5	STX4	Q12846	739
DLG5	NKX2-3	Q8TAU0	668
DLG5	PGLYRP1	O75594	656
DLG5	SLC22A4	Q9H015	655
DLG5	NOD1	Q9Y239	610
DLG5	MPP1	Q00013	566
DLG5	EVC2	Q86UK5	531
DLG5	CTNNB1	P35222	528
DLG5	SCRIB	Q14160	512
DLG5	SLC22A5	O76082	506
DLG5	IQCE	Q6IPM2	503
DLG5	CDH2	P19022	502
DLG5	MARK2	Q7KZI7	496

IntAct

565 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:2364”(proximity)	0.900
DYNLL1	BLTP3B	psi-mi:“MI:0914”(association)	0.730
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
DYNLL2	BLTP3B	psi-mi:“MI:0914”(association)	0.640
NCK2	SH3PXD2B	psi-mi:“MI:0914”(association)	0.640
TGIF2LY	PGP	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
CEP104	CCDC66	psi-mi:“MI:2364”(proximity)	0.540
Tax	DLG5	psi-mi:“MI:0915”(physical association)	0.540
NET1	DLG5	psi-mi:“MI:0915”(physical association)	0.540
E6	DLG5	psi-mi:“MI:0915”(physical association)	0.540
E	DLG5	psi-mi:“MI:0915”(physical association)	0.540
E6	DLG5	psi-mi:“MI:0407”(direct interaction)	0.540
E	DLG5	psi-mi:“MI:0407”(direct interaction)	0.540
DLG5	NET1	psi-mi:“MI:0407”(direct interaction)	0.540
Tax	DLG5	psi-mi:“MI:0407”(direct interaction)	0.540
YWHAQ	IGLC7	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
NCK1	SH3PXD2B	psi-mi:“MI:0914”(association)	0.530
EPS8L1	DHPS	psi-mi:“MI:0914”(association)	0.530
PNMA2	CCDC85C	psi-mi:“MI:0914”(association)	0.530
RPL13	RRP8	psi-mi:“MI:0914”(association)	0.530
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
YWHAQ	PLEKHG3	psi-mi:“MI:0914”(association)	0.480

BioGRID (215): DLG5 (Affinity Capture-MS), DLG5 (Affinity Capture-MS), DLG5 (Proximity Label-MS), DLG5 (Proximity Label-MS), DLG5 (Proximity Label-MS), DLG5 (Proximity Label-MS), DLG5 (Proximity Label-MS), DLG5 (Proximity Label-MS), DLG5 (Proximity Label-MS), DLG5 (Proximity Label-MS), DLG5 (Proximity Label-MS), DLG5 (Proximity Label-MS), DLG5 (Proximity Label-MS), DLG5 (Proximity Label-MS), DLG5 (Affinity Capture-MS)

ESM2 similar proteins: A0JM23, A0M8T3, A1X154, A6H7D1, A7MBF6, A8Y5U1, B1WC10, E9Q9R9, F1M649, F1MHT9, O00750, O88480, O95876, P0CI65, P50851, Q008S8, Q00PJ3, Q07E17, Q07E30, Q07E43, Q09YN0, Q108U1, Q15052, Q2IBF5, Q2IBG0, Q2QLA4, Q2QLB5, Q32NR4, Q32NR9, Q3UP24, Q3V129, Q4V7F0, Q5XXR3, Q5ZLR6, Q692V3, Q6AZT7, Q6P2S7, Q6P3V7, Q6PIY5, Q6ZS30

Diamond homologs: E9Q9R9, F1MAD2, O61967, Q3MHQ0, Q4H4B6, Q63ZW7, Q8TDM6, Q9ES64, Q9Y6N9, A0A8C0TYJ0, A0A8P0N4K0, O14907, O15085, O62683, P31007, P31016, P70175, P78352, Q09506, Q12959, Q14160, Q15700, Q28C55, Q5EBL8, Q5IS48, Q5PYH5, Q5PYH6, Q5PYH7, Q5ZIK2, Q62108, Q62936, Q63622, Q6NXB2, Q6R005, Q7KRY7, Q80U72, Q8TEW0, Q91XM9, Q92796, Q9DBG9

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
DLG5	“form complex”	Scribble_complex_DLG5-LLGL2_variant	binding
DLG5	“form complex”	Scribble_complex_DLG5-LLGL1_variant	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 202 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
Activation of BAD and translocation to mitochondria	6	32.2×	1e-06
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	28.4×	2e-06
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	28.4×	2e-06
Activation of BH3-only proteins	6	21.0×	1e-05
Signaling by Hippo	5	19.1×	1e-04
Signaling by RAS mutants	5	14.9×	4e-04
Transcriptional and post-translational regulation of MITF-M expression and activity	11	13.8×	7e-08
RHO GTPases activate PKNs	6	13.4×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
peptidyl-tyrosine phosphorylation	6	13.7×	4e-03
cell surface receptor protein tyrosine kinase signaling pathway	8	7.5×	5e-03
small GTPase-mediated signal transduction	7	6.9×	8e-03
MAPK cascade	8	6.6×	8e-03
protein autophosphorylation	8	6.3×	8e-03
regulation of small GTPase mediated signal transduction	8	6.2×	8e-03
positive regulation of neuron projection development	8	5.9×	8e-03
protein localization to plasma membrane	9	5.3×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	272
Likely benign	33
Benign	16

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
2071701	NM_004747.4(DLG5):c.154A>T (p.Lys52Ter)	Pathogenic
2692349	NM_004747.4(DLG5):c.3081_3106del (p.Arg1027fs)	Pathogenic
2692350	NM_004747.4(DLG5):c.2461C>T (p.Arg821Ter)	Pathogenic

SpliceAI

5910 predictions. Top by Δscore:

Variant	Effect	Δscore
10:77794003:CCTA:C	donor_loss	1.0000
10:77794004:CTAC:C	donor_loss	1.0000
10:77794005:TA:T	donor_loss	1.0000
10:77794007:C:A	donor_loss	1.0000
10:77794114:CTCC:C	acceptor_gain	1.0000
10:77794115:TCC:T	acceptor_gain	1.0000
10:77794116:CC:C	acceptor_gain	1.0000
10:77794116:CCC:C	acceptor_gain	1.0000
10:77794116:CCCTG:C	acceptor_loss	1.0000
10:77794117:CC:C	acceptor_gain	1.0000
10:77794118:C:CC	acceptor_gain	1.0000
10:77794118:CT:C	acceptor_loss	1.0000
10:77794844:CCTA:C	donor_gain	1.0000
10:77794847:A:AC	donor_gain	1.0000
10:77794848:C:CC	donor_gain	1.0000
10:77794954:CGGTT:C	acceptor_gain	1.0000
10:77794957:TTC:T	acceptor_loss	1.0000
10:77794959:C:CC	acceptor_gain	1.0000
10:77794959:CTG:C	acceptor_loss	1.0000
10:77794960:T:C	acceptor_loss	1.0000
10:77796056:GGTAC:G	donor_loss	1.0000
10:77796057:GTAC:G	donor_loss	1.0000
10:77796058:TACCT:T	donor_loss	1.0000
10:77796059:A:AG	donor_loss	1.0000
10:77796060:C:T	donor_loss	1.0000
10:77796074:T:TA	donor_gain	1.0000
10:77796184:CACCT:C	acceptor_gain	1.0000
10:77796185:ACCT:A	acceptor_gain	1.0000
10:77796186:CCTC:C	acceptor_gain	1.0000
10:77796187:CT:C	acceptor_gain	1.0000

AlphaMissense

12597 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:77812282:A:T	V1374D	1.000
10:77829522:T:A	D673V	1.000
10:77829522:T:C	D673G	1.000
10:77829522:T:G	D673A	1.000
10:77829523:C:G	D673H	1.000
10:77830220:A:G	L669S	1.000
10:77830259:A:T	V656D	1.000
10:77833989:A:G	L558P	1.000
10:77834002:C:G	A554P	1.000
10:77834010:C:G	R551P	1.000
10:77834022:A:G	L547P	1.000
10:77842002:C:G	R439P	1.000
10:77792463:A:G	W1913R	0.999
10:77792463:A:T	W1913R	0.999
10:77794912:A:G	L1828P	0.999
10:77796134:A:G	F1788S	0.999
10:77796534:A:T	V1742D	0.999
10:77806866:A:G	L1620P	0.999
10:77812041:A:G	L1402P	0.999
10:77812222:A:G	L1394S	0.999
10:77812255:G:T	A1383D	0.999
10:77812260:G:C	S1381R	0.999
10:77812260:G:T	S1381R	0.999
10:77812262:T:G	S1381R	0.999
10:77829417:C:G	R708P	0.999
10:77829420:C:G	R707P	0.999
10:77829523:C:A	D673Y	0.999
10:77830232:G:T	A665D	0.999
10:77830316:A:G	F637S	0.999
10:77830776:A:G	W616R	0.999

dbSNP variants (sampled 300 via entrez): RS1000035458 (10:77791204 T>C), RS1000060953 (10:77798723 C>T), RS1000061729 (10:77803950 C>T), RS1000110622 (10:77874239 G>A), RS1000114871 (10:77835054 T>C,G), RS1000116782 (10:77923112 T>C), RS1000119493 (10:77864558 A>T), RS1000156782 (10:77921987 A>G), RS1000162382 (10:77902958 AAAAT>A,AAAATAAAT,AAAATAAATAAATAAATAAAT), RS1000169637 (10:77904986 G>A,T), RS1000172475 (10:77864342 C>G,T), RS1000181050 (10:77862594 C>A), RS1000198418 (10:77820144 A>G), RS1000271078 (10:77858089 G>A,T), RS1000307124 (10:77836497 C>T)

Disease associations

OMIM: gene MIM:604090 | disease phenotypes: MIM:609446, MIM:606170, MIM:620703

GenCC curated gene-disease

Disease	Classification	Inheritance
Yuksel-Vogel-Bauer syndrome	Strong	Autosomal recessive
congenital anomaly of kidney and urinary tract	Limited	Autosomal recessive
ciliopathy	Limited	Autosomal dominant

Mondo (5): generalized epilepsy-paroxysmal dyskinesia syndrome (MONDO:0012276), genitopatellar syndrome (MONDO:0011640), Yuksel-Vogel-Bauer syndrome (MONDO:0958205), congenital anomaly of kidney and urinary tract (MONDO:0019719), ciliopathy (MONDO:0005308)

Orphanet (2): Generalized epilepsy-paroxysmal dyskinesia syndrome (Orphanet:79137), Genitopatellar syndrome (Orphanet:85201)

HPO phenotypes

20 total (20 of 20 shown, HPO-id order):

HPO	Term
HP:0000003	Multicystic kidney dysplasia
HP:0000007	Autosomal recessive inheritance
HP:0000126	Hydronephrosis
HP:0000127	Renal salt wasting
HP:0000175	Cleft palate
HP:0000280	Coarse facial features
HP:0001169	Broad palm
HP:0001171	Split hand
HP:0001263	Global developmental delay
HP:0001332	Dystonia
HP:0001334	Communicating hydrocephalus
HP:0001629	Ventricular septal defect
HP:0001631	Atrial septal defect
HP:0001769	Broad foot
HP:0003577	Congenital onset
HP:0009473	Joint contracture of the hand
HP:0010953	Noncommunicating hydrocephalus
HP:0030674	Antenatal onset
HP:0033132	Renal cortical hyperechogenicity
HP:0410030	Cleft lip

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST001277_15	Liver enzyme levels (gamma-glutamyl transferase)	6.000000e-10
GCST001762_85	Obesity-related traits	4.000000e-06
GCST005998_20	Alanine transaminase levels	1.000000e-08
GCST006019_2	Gamma glutamyl transferase levels	5.000000e-26
GCST006976_59	Macular thickness	4.000000e-10
GCST009959_25	Retinal detachment or retinal break	2.000000e-07
GCST011349_15	Gamma glutamyl transferase levels	8.000000e-28
GCST011352_35	Alanine aminotransferase levels	2.000000e-09
GCST90011898_76	Alanine aminotransferase levels	5.000000e-27
GCST90011899_40	Aspartate aminotransferase levels	1.000000e-16
GCST90011900_50	Serum alkaline phosphatase levels	2.000000e-16
GCST90013405_135	Liver enzyme levels (alanine transaminase)	1.000000e-37
GCST90013406_56	Liver enzyme levels (alkaline phosphatase)	7.000000e-34
GCST90013407_50	Liver enzyme levels (gamma-glutamyl transferase)	7.000000e-192
GCST90013663_97	Alanine aminotransferase levels	3.000000e-33
GCST90013664_57	Aspartate aminotransferase levels	2.000000e-18

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004532	serum gamma-glutamyl transferase measurement
EFO:0003940	physical activity
EFO:0010698	retinal break
EFO:0004736	aspartate aminotransferase measurement
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
C566906	Cakut (supp.)
C563719	Generalized Epilepsy and Paroxysmal Dyskinesia (supp.)
C565255	Genitopatellar Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2289310	Efficacy	3	capecitabine;fluorouracil	Metastatic neoplasm

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2289310	DLG5	3	0.00	1	capecitabine;fluorouracil

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects cotreatment, increases expression	3
sodium arsenite	increases abundance, increases expression, decreases expression	2
Acetaminophen	increases expression	2
Arsenic	affects methylation, increases abundance, increases expression	2
Progesterone	affects cotreatment, increases expression	2
Valproic Acid	affects expression, decreases methylation	2
Medroxyprogesterone Acetate	increases expression	2
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	increases activity, increases expression, affects binding	1
lead acetate	decreases expression	1
trichostatin A	affects expression	1
methoxyacetic acid	increases expression, increases reaction	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	increases methylation	1
cupric chloride	decreases expression	1
coumarin	increases phosphorylation	1
cupric oxide	decreases expression	1
1-hydroxypyrene	affects cotreatment, decreases methylation	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
abrine	increases expression	1
Atrazine	increases expression	1
Caffeine	affects phosphorylation	1
Cisplatin	increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04115345	PHASE1	COMPLETED	A Study of a Renal Autologous Cell Therapy (REACT) in Patients With Chronic Kidney Disease (CKD) From Congenital Anomalies of the Kidney and Urinary Tract (CAKUT).
NCT05694169	PHASE1	TERMINATED	A Study of Participants With Chronic Kidney Disease Previously Treated With REACT
NCT04537364	Not specified	COMPLETED	Prediction of Renal Parenchymal Damage of CAKUT
NCT06921733	Not specified	RECRUITING	Ultrasound Localization Microscopy in Patient With Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)
NCT00068224	Not specified	COMPLETED	Clinical and Molecular Investigations Into Ciliopathies
NCT04874909	Not specified	COMPLETED	Classification, Functional Stratification and Biomarkers in Ciliopathy (CILLICORIRCM)