DENND4B

Summary

DENND4B (DENN domain containing 4B, HGNC:29044) is a protein-coding gene on chromosome 1q21.3, encoding DENN domain-containing protein 4B (O75064). Guanine nucleotide exchange factor (GEF) which may activate RAB10.

Enables guanyl-nucleotide exchange factor activity. Involved in regulation of Rab protein signal transduction. Located in Golgi apparatus and nucleoplasm.

Source: NCBI Gene 9909 — RefSeq curated summary.

At a glance

• Gene–disease (curated): isolated cleft palate (Limited, GenCC)
• GWAS associations: 20
• Clinical variants (ClinVar): 243 total — 1 likely-pathogenic
• MANE Select transcript: NM_014856

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29044
Approved symbol	DENND4B
Name	DENN domain containing 4B
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000198837
Ensembl biotype	protein_coding
OMIM	619843
Entrez	9909

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 14 protein_coding, 9 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000361217, ENST00000368646, ENST00000462423, ENST00000464048, ENST00000472932, ENST00000474386, ENST00000477746, ENST00000480340, ENST00000483561, ENST00000485359, ENST00000492898, ENST00000494683, ENST00000531748, ENST00000877427, ENST00000877428, ENST00000877429, ENST00000877430, ENST00000877431, ENST00000912806, ENST00000912807, ENST00000912808, ENST00000912809, ENST00000912810, ENST00000912811

RefSeq mRNA: 2 — MANE Select: NM_014856 NM_001367466, NM_014856

CCDS: CCDS44228

Canonical transcript exons

ENST00000361217 — 28 exons

Exon	Start	End
ENSE00000895325	153941231	153941289
ENSE00000895326	153940904	153941048
ENSE00000895327	153940431	153940606
ENSE00000895328	153940156	153940256
ENSE00000895331	153939589	153939804
ENSE00000895333	153938900	153939045
ENSE00000895337	153937724	153937863
ENSE00000895339	153937488	153937614
ENSE00000895340	153936542	153936748
ENSE00000895343	153936060	153936188
ENSE00000895345	153934760	153934964
ENSE00000895346	153934135	153934302
ENSE00000895352	153933483	153933871
ENSE00000895354	153933197	153933319
ENSE00000895364	153930692	153930857
ENSE00001415598	153946301	153946718
ENSE00001628292	153942878	153943130
ENSE00001632044	153941869	153942113
ENSE00001637288	153942187	153942356
ENSE00001781243	153942556	153942625
ENSE00003518623	153930539	153930603
ENSE00003529328	153941374	153941440
ENSE00003551811	153932204	153932440
ENSE00003594328	153944058	153944397
ENSE00003622759	153932642	153932777
ENSE00003646558	153930947	153931064
ENSE00003681888	153929501	153930442
ENSE00003791413	153932861	153933030

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 98.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.0887 / max 580.1176, expressed in 1754 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14737	5.3714	584
14740	4.4488	1534
14739	2.7547	1358
14736	0.9765	312
14734	0.3171	143
14741	0.1696	53
14735	0.0506	23

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	98.60	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.42	gold quality
spleen	UBERON:0002106	97.33	gold quality
cerebellar hemisphere	UBERON:0002245	96.71	gold quality
cerebellar cortex	UBERON:0002129	96.66	gold quality
lymph node	UBERON:0000029	96.36	gold quality
cerebellum	UBERON:0002037	96.09	gold quality
right frontal lobe	UBERON:0002810	95.84	gold quality
upper lobe of left lung	UBERON:0008952	95.69	gold quality
blood	UBERON:0000178	95.63	gold quality
right ovary	UBERON:0002118	95.53	gold quality
apex of heart	UBERON:0002098	95.42	gold quality
upper lobe of lung	UBERON:0008948	95.26	gold quality
vermiform appendix	UBERON:0001154	95.18	gold quality
monocyte	CL:0000576	94.97	gold quality
mononuclear cell	CL:0000842	94.96	gold quality
leukocyte	CL:0000738	94.93	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.91	gold quality
gastrocnemius	UBERON:0001388	94.90	gold quality
body of uterus	UBERON:0009853	94.80	gold quality
left ovary	UBERON:0002119	94.79	gold quality
metanephros cortex	UBERON:0010533	94.74	gold quality
tibial nerve	UBERON:0001323	94.63	gold quality
endocervix	UBERON:0000458	94.60	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	94.57	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.51	gold quality
olfactory bulb	UBERON:0002264	94.40	silver quality
muscle of leg	UBERON:0001383	94.30	gold quality
postcentral gyrus	UBERON:0002581	94.22	gold quality
omental fat pad	UBERON:0010414	94.18	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

53 targeting DENND4B, 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-5692A	100.00	74.40	6850
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-6126	99.62	68.09	996
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-208A-5P	99.42	70.83	1913
HSA-MIR-208B-5P	99.42	70.83	1952
HSA-MIR-548B-3P	99.38	67.26	1000
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-6734-3P	99.15	66.27	1627

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dennd4b	ENSDARG00000102914
mus_musculus	Dennd4b	ENSMUSG00000042404
rattus_norvegicus	Dennd4b	ENSRNOG00000022373
drosophila_melanogaster	Crag	FBGN0025864
caenorhabditis_elegans		WBGENE00018681

Paralogs (3): DENND3 (ENSG00000105339), DENND4C (ENSG00000137145), DENND4A (ENSG00000174485)

Protein

Protein identifiers

DENN domain-containing protein 4B — O75064 (reviewed: O75064)

All UniProt accessions (3): O75064, E9PAK5, H0YEF0

UniProt curated annotations — full annotation on UniProt →

Function. Guanine nucleotide exchange factor (GEF) which may activate RAB10. Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab proteins into their active GTP-bound form.

Subcellular location. Golgi apparatus.

RefSeq proteins (2): NP_001354395, NP_055671* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001194	cDENN_dom	Domain
IPR002885	PPR_rpt	Repeat
IPR005112	dDENN_dom	Domain
IPR005113	uDENN_dom	Domain
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR023341	MABP	Domain
IPR037516	Tripartite_DENN	Domain
IPR043153	DENN_C	Homologous_superfamily
IPR051696	DENN_Domain_GEFs	Family

Pfam: PF02141, PF03455, PF03456

UniProt features (20 total): compositionally biased region 6, region of interest 5, domain 4, modified residue 2, repeat 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75064-F1	73.32	0.35

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 (2): 953, 1092

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8876198	RAB GEFs exchange GTP for GDP on RABs

MSigDB gene sets: 108 (showing top): MODULE_45, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, REACTOME_MEMBRANE_TRAFFICKING, GOBP_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, MODULE_47, GINESTIER_BREAST_CANCER_ZNF217_AMPLIFIED_DN, chr1q21, GOMF_GUANYL_NUCLEOTIDE_EXCHANGE_FACTOR_ACTIVITY, GOMF_NUCLEOSIDE_TRIPHOSPHATASE_REGULATOR_ACTIVITY, GOMF_ENZYME_REGULATOR_ACTIVITY, CHEN_METABOLIC_SYNDROM_NETWORK, KIM_ALL_DISORDERS_OLIGODENDROCYTE_NUMBER_CORR_UP, KIM_BIPOLAR_DISORDER_OLIGODENDROCYTE_DENSITY_CORR_UP, WANG_RESPONSE_TO_GSK3_INHIBITOR_SB216763_UP, GOBP_RAB_PROTEIN_SIGNAL_TRANSDUCTION

GO Biological Process (1): regulation of Rab protein signal transduction (GO:0032483)

GO Molecular Function (2): guanyl-nucleotide exchange factor activity (GO:0005085), protein binding (GO:0005515)

GO Cellular Component (5): nucleoplasm (GO:0005654), Golgi apparatus (GO:0005794), cytosol (GO:0005829), cytoplasmic vesicle (GO:0031410), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Rab regulation of trafficking	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	3
Rab protein signal transduction	1
regulation of small GTPase mediated signal transduction	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
binding	1
nuclear lumen	1
endomembrane system	1
intracellular membrane-bounded organelle	1
intracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

596 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DENND4B	CRTC2	Q53ET0	565
DENND4B	RAB10	P61026	432
DENND4B	DENND1C	Q8IV53	420
DENND4B	DENND5B	Q6ZUT9	414
DENND4B	TMEM160	Q9NX00	413
DENND4B	DENND1A	Q8TEH3	402
DENND4B	AVL9	Q8NBF6	401
DENND4B	C9orf43	Q8TAL5	400
DENND4B	ZNF709	Q8N972	392
DENND4B	RIC1	Q4ADV7	380
DENND4B	FAM219B	Q5XKK7	370
DENND4B	KRABD2	Q6ZNG9	370
DENND4B	RAB3IL1	Q8TBN0	370
DENND4B	ZNF665	Q9H7R5	348
DENND4B	SLC39A1	Q9NY26	348

IntAct

11 interactions, top by confidence:

A	B	Type	Score
ZMAT5	DENND4B	psi-mi:“MI:0914”(association)	0.530
PLEKHJ1	AP3B1	psi-mi:“MI:0914”(association)	0.350
PLEKHJ1	DENND4B	psi-mi:“MI:0914”(association)	0.350
CALM1	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350
DENND4B	rpoB	psi-mi:“MI:0915”(physical association)	0.000
	DENND4B	psi-mi:“MI:0915”(physical association)	0.000
DENND4B	manY	psi-mi:“MI:0915”(physical association)	0.000
argE	DENND4B	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (22): DENND4B (Affinity Capture-MS), DENND4B (Affinity Capture-MS), DENND4B (Proximity Label-MS), DENND4B (Proximity Label-MS), DENND4B (Proximity Label-MS), DENND4B (Proximity Label-MS), DENND4B (Proximity Label-MS), DENND4B (Proximity Label-MS), DENND4B (Proximity Label-MS), DENND4B (Proximity Label-MS), DENND4B (Proximity Label-MS), DENND4B (Proximity Label-MS), DENND4B (Affinity Capture-RNA), DENND4B (Affinity Capture-MS), DENND4B (Affinity Capture-MS)

ESM2 similar proteins: A0A061IR73, A0A7N9VSG0, A7YSY2, D3KCC4, D3ZU57, D4A2B7, O08644, O15197, O19179, O43542, O75064, O95382, P0C0K6, P0C0K7, P51840, P52785, P52824, P54777, Q02846, Q05932, Q13470, Q13608, Q1HG60, Q3ZBE0, Q4KM32, Q5JZY3, Q643R3, Q6MG64, Q6NVG1, Q6ZPS2, Q76MJ5, Q7TNJ2, Q80SX8, Q8BYG9, Q8IZY2, Q8NFF5, Q8R5G7, Q8TDZ2, Q8WWN8, Q91V24

Diamond homologs: A6H8H2, G2WWH6, O75064, Q3U1Y4, Q5VZ89, Q7Z401, Q9W3D3, E9PXF8, I1RQE2, O02626, O95248, P78524, Q3U1T9, Q68D51, Q68F67, Q6NTN5, Q6P3S1, Q6ZPE2, Q86WG5, Q8C4S8, Q8CFK6, Q8IV53, Q8K382, Q8TEH3, Q91VV4, Q924W7, Q9H6A0, Q9TXP3, Q9ULE3, Q9Y7Q7, X0JZ91, Q80U28, Q9VXY2, O08873, Q8WXG6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	175
Likely benign	24
Benign	6

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
599505	NM_014856.3(DENND4B):c.1825C>T (p.Leu609Phe)	Likely pathogenic

SpliceAI

4137 predictions. Top by Δscore:

Variant	Effect	Δscore
1:153930438:GGCCA:G	acceptor_gain	1.0000
1:153930439:GCCA:G	acceptor_gain	1.0000
1:153930440:CCA:C	acceptor_gain	1.0000
1:153930440:CCAC:C	acceptor_gain	1.0000
1:153930441:CA:C	acceptor_gain	1.0000
1:153930441:CAC:C	acceptor_gain	1.0000
1:153930442:AC:A	acceptor_loss	1.0000
1:153930443:C:CC	acceptor_gain	1.0000
1:153930443:CTAG:C	acceptor_loss	1.0000
1:153930602:CCCTT:C	acceptor_gain	1.0000
1:153930603:CCTT:C	acceptor_gain	1.0000
1:153930691:CCT:C	donor_gain	1.0000
1:153930853:CTGGC:C	acceptor_gain	1.0000
1:153930858:C:CC	acceptor_gain	1.0000
1:153930862:A:AC	acceptor_gain	1.0000
1:153930862:A:C	acceptor_gain	1.0000
1:153932640:AC:A	donor_gain	1.0000
1:153932640:ACC:A	donor_gain	1.0000
1:153932640:ACCC:A	donor_gain	1.0000
1:153932641:CC:C	donor_gain	1.0000
1:153932641:CCC:C	donor_gain	1.0000
1:153932641:CCCC:C	donor_gain	1.0000
1:153932774:GACA:G	acceptor_gain	1.0000
1:153932776:CA:C	acceptor_gain	1.0000
1:153932778:C:CC	acceptor_gain	1.0000
1:153933195:A:AC	donor_gain	1.0000
1:153933196:C:CC	donor_gain	1.0000
1:153933198:T:TA	donor_gain	1.0000
1:153934133:A:AC	donor_gain	1.0000
1:153934134:C:CT	donor_gain	1.0000

AlphaMissense

9494 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:153932289:A:G	L1304P	0.999
1:153932364:A:G	L1279P	0.999
1:153932373:A:G	L1276P	0.999
1:153932385:A:G	L1272P	0.999
1:153932396:G:C	S1268R	0.999
1:153932396:G:T	S1268R	0.999
1:153932398:T:G	S1268R	0.999
1:153932925:A:G	C1187R	0.999
1:153932958:A:G	W1176R	0.999
1:153932958:A:T	W1176R	0.999
1:153933006:A:G	C1160R	0.999
1:153936658:A:G	W775R	0.999
1:153936658:A:T	W775R	0.999
1:153940513:C:G	G474R	0.999
1:153941381:A:G	L372P	0.999
1:153941384:A:G	I371T	0.999
1:153941384:A:T	I371N	0.999
1:153941426:A:G	F357S	0.999
1:153941435:A:T	I354N	0.999
1:153942289:G:C	F236L	0.999
1:153942289:G:T	F236L	0.999
1:153942291:A:G	F236L	0.999
1:153930425:A:C	Y1455D	0.998
1:153931006:T:A	D1352V	0.998
1:153932291:G:C	N1303K	0.998
1:153932291:G:T	N1303K	0.998
1:153932377:C:T	E1275K	0.998
1:153932378:C:A	K1274N	0.998
1:153932378:C:G	K1274N	0.998
1:153932394:G:C	P1269R	0.998

dbSNP variants (sampled 300 via entrez): RS1000021969 (1:153943317 C>T), RS1000054409 (1:153943669 CTCTG>C), RS1000595720 (1:153948499 T>C,G), RS1001146282 (1:153935070 A>T), RS1001588165 (1:153947776 G>A,C), RS1001699815 (1:153941494 C>G), RS1001730887 (1:153941804 C>G,T), RS1002022604 (1:153934428 T>TGTTG), RS1002064838 (1:153940079 T>C,G), RS1002170933 (1:153943193 G>A,C,T), RS1002309124 (1:153932055 C>G,T), RS1002515614 (1:153936771 C>G), RS1002592007 (1:153935193 C>T), RS1002674572 (1:153929904 C>G), RS1002680399 (1:153947142 G>A)

Disease associations

OMIM: gene MIM:619843 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
isolated cleft palate	Limited	Unknown

Mondo (1): isolated cleft palate (MONDO:0007336)

Orphanet (0):

HPO phenotypes

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

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST001640_7	Lentiform nucleus volume	5.000000e-06
GCST003795_1	Age at first birth	6.000000e-10
GCST005751_3	Empathy quotient	3.000000e-07
GCST006044_1	Age at first birth	3.000000e-07
GCST006045_3	Age at first birth	5.000000e-06
GCST006083_15	Prostate cancer (advanced)	8.000000e-07
GCST006085_110	Prostate cancer	5.000000e-14
GCST010136_18	Fruit consumption	3.000000e-08
GCST010137_3	Cooked vegetable consumption	3.000000e-09
GCST010138_14	Raw vegetable consumption	5.000000e-11
GCST010142_60	Fish- and plant-related diet	4.000000e-09
GCST010142_92	Fish- and plant-related diet	6.000000e-14
GCST010696_22	Cortical thickness (min-P)	4.000000e-10
GCST010697_50	Cortical surface area (min-P)	1.000000e-12
GCST010698_81	Subcortical volume (min-P)	1.000000e-23
GCST010699_7	Brain morphology (min-P)	1.000000e-10
GCST010700_11	Cortical thickness (MOSTest)	4.000000e-13
GCST010701_73	Cortical surface area (MOSTest)	4.000000e-09
GCST010702_45	Subcortical volume (MOSTest)	4.000000e-10
GCST010703_276	Brain morphology (MOSTest)	2.000000e-15

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0009101	age at first birth measurement
EFO:0009183	empathy measurement
EFO:0008111	diet measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs8450	CRTC2, DENND4B	3	5.25	1	cyclosporine;tacrolimus

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	2
Valproic Acid	affects expression, increases methylation	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	decreases expression	1
trichostatin A	increases expression	1
butyraldehyde	decreases expression	1
tetrabromobisphenol A	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
2-palmitoylglycerol	increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
(+)-JQ1 compound	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Bortezomib	increases expression	1
Sunitinib	increases expression	1
Vorinostat	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Doxorubicin	decreases expression	1
Ozone	increases abundance, affects expression	1
Smoke	decreases expression	1
Tretinoin	increases expression	1
Urethane	decreases expression	1
Cyclosporine	increases expression	1
Cadmium Chloride	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1PZ	Abcam HeLa DENND4B KO	Cancer cell line	Female

Clinical trials (associated diseases)

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