DENND2A

Summary

DENND2A (DENN domain containing 2A, HGNC:22212) is a protein-coding gene on chromosome 7q34, encoding DENN domain-containing protein 2A (Q9ULE3). Guanine nucleotide exchange factor (GEF) which may activate RAB9A and RAB9B.

Enables guanyl-nucleotide exchange factor activity. Involved in retrograde transport, endosome to Golgi. Located in actin cytoskeleton.

Source: NCBI Gene 27147 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 172 total
• MANE Select transcript: NM_015689

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:22212
Approved symbol	DENND2A
Name	DENN domain containing 2A
Location	7q34
Locus type	gene with protein product
Status	Approved
Aliases	FAM31D
Ensembl gene	ENSG00000146966
Ensembl biotype	protein_coding
OMIM	620120
Entrez	27147

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 15 protein_coding, 1 nonsense_mediated_decay

ENST00000275884, ENST00000461883, ENST00000469373, ENST00000475837, ENST00000477488, ENST00000489552, ENST00000491728, ENST00000492720, ENST00000496613, ENST00000537639, ENST00000923108, ENST00000923109, ENST00000945287, ENST00000945288, ENST00000945289, ENST00000945290

RefSeq mRNA: 4 — MANE Select: NM_015689 NM_001318052, NM_001318053, NM_001362678, NM_015689

CCDS: CCDS43659, CCDS83233

Canonical transcript exons

ENST00000496613 — 20 exons

Exon	Start	End
ENSE00000360203	140567086	140567273
ENSE00000727196	140568763	140568813
ENSE00000727210	140573808	140574008
ENSE00000872142	140527318	140527495
ENSE00000909473	140546799	140546939
ENSE00000909474	140555636	140555713
ENSE00000909475	140558143	140558212
ENSE00000909476	140559708	140559817
ENSE00001207714	140601403	140602542
ENSE00001635824	140544618	140544766
ENSE00001839852	140605705	140605806
ENSE00001907146	140640504	140640813
ENSE00001919051	140518420	140518738
ENSE00003468283	140521855	140522100
ENSE00003476494	140525751	140525792
ENSE00003508644	140523307	140523424
ENSE00003509501	140569645	140569738
ENSE00003512874	140519632	140519718
ENSE00003582444	140585589	140585710
ENSE00003615443	140587653	140587780

Expression profiles

Bgee: expression breadth ubiquitous, 236 present calls, max score 91.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.6277 / max 84.5843, expressed in 933 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
86563	6.4000	925
86562	0.1201	49
86564	0.0676	19
86565	0.0401	17

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left uterine tube	UBERON:0001303	91.87	gold quality
ventricular zone	UBERON:0003053	91.43	gold quality
sural nerve	UBERON:0015488	91.12	gold quality
lower esophagus muscularis layer	UBERON:0035833	90.54	gold quality
lower esophagus	UBERON:0013473	90.44	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	90.12	gold quality
adenohypophysis	UBERON:0002196	88.85	gold quality
body of uterus	UBERON:0009853	88.73	gold quality
pituitary gland	UBERON:0000007	88.26	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	88.14	gold quality
endocervix	UBERON:0000458	87.96	gold quality
amygdala	UBERON:0001876	87.95	gold quality
apex of heart	UBERON:0002098	87.36	gold quality
substantia nigra	UBERON:0002038	87.33	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	87.30	gold quality
putamen	UBERON:0001874	87.20	gold quality
right ovary	UBERON:0002118	87.09	gold quality
left ovary	UBERON:0002119	86.87	gold quality
ganglionic eminence	UBERON:0004023	86.85	gold quality
spinal cord	UBERON:0002240	86.25	gold quality
midbrain	UBERON:0001891	86.19	gold quality
mucosa of stomach	UBERON:0001199	86.18	gold quality
medial globus pallidus	UBERON:0002477	85.34	gold quality
hypothalamus	UBERON:0001898	85.21	gold quality
inferior olivary complex	UBERON:0002127	85.17	gold quality
caudate nucleus	UBERON:0001873	85.03	gold quality
anterior cingulate cortex	UBERON:0009835	84.62	gold quality
cingulate cortex	UBERON:0003027	84.56	gold quality
colonic mucosa	UBERON:0000317	84.53	gold quality
nucleus accumbens	UBERON:0001882	84.10	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.73

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

11 targeting DENND2A, 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-577	99.78	69.13	2479
HSA-MIR-623	99.76	68.16	1170
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-889-3P	99.40	69.76	2103
HSA-MIR-548AS-3P	99.12	69.12	2294
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-4733-3P	98.35	65.20	994
HSA-MIR-6072	98.00	66.47	804
HSA-MIR-7113-5P	97.88	67.33	1735

Literature-anchored findings (GeneRIF, showing 1)

• DOCK11 and DENND2A play pivotal roles in the maintenance of hepatitis B virus in host cells. (PMID:33539396)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Dennd2a	ENSMUSG00000038456
rattus_norvegicus	Dennd2a	ENSRNOG00000026748

Paralogs (3): DENND2D (ENSG00000162777), DENND2B (ENSG00000166444), DENND2C (ENSG00000175984)

Protein

Protein identifiers

DENN domain-containing protein 2A — Q9ULE3 (reviewed: Q9ULE3)

All UniProt accessions (7): Q9ULE3, C9IY76, C9IYZ8, C9JAA0, C9JD15, F8WAT8, H7C5K8

UniProt curated annotations — full annotation on UniProt →

Function. Guanine nucleotide exchange factor (GEF) which may activate RAB9A and RAB9B. Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab proteins into their active GTP-bound form. May play a role in late endosomes back to trans-Golgi network/TGN transport.

Subcellular location. Cytoplasm. Cytoskeleton.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9ULE3-1	1	yes
Q9ULE3-2	2

RefSeq proteins (4): NP_001304981, NP_001304982, NP_001349607, NP_056504* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001194	cDENN_dom	Domain
IPR005112	dDENN_dom	Domain
IPR005113	uDENN_dom	Domain
IPR037516	Tripartite_DENN	Domain
IPR043153	DENN_C	Homologous_superfamily
IPR051942	DENN_domain_containing_2	Family

Pfam: PF02141, PF03455, PF03456

UniProt features (23 total): compositionally biased region 7, region of interest 4, domain 3, sequence variant 3, splice variant 2, sequence conflict 2, chain 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9ULE3-F1	61.16	0.28

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 (1): 551

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: 71 (showing top): GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, GOBP_RETROGRADE_TRANSPORT_ENDOSOME_TO_GOLGI, GOBP_CYTOSOLIC_TRANSPORT, GOMF_GUANYL_NUCLEOTIDE_EXCHANGE_FACTOR_ACTIVITY, NUYTTEN_NIPP1_TARGETS_DN, GOMF_NUCLEOSIDE_TRIPHOSPHATASE_REGULATOR_ACTIVITY, GOMF_ENZYME_REGULATOR_ACTIVITY, VERHAAK_GLIOBLASTOMA_CLASSICAL, LU_EZH2_TARGETS_UP, GOBP_ENDOSOMAL_TRANSPORT, GOBP_INTRACELLULAR_TRANSPORT, FORTSCHEGGER_PHF8_TARGETS_DN, ODONNELL_METASTASIS_UP, CSR_LATE_UP.V1_DN

GO Biological Process (2): protein transport (GO:0015031), retrograde transport, endosome to Golgi (GO:0042147)

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

GO Cellular Component (4): cytosol (GO:0005829), actin cytoskeleton (GO:0015629), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

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	2
transport	1
intracellular protein localization	1
establishment of protein localization	1
intercellular transport	1
endosomal transport	1
cytosolic transport	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
binding	1
cytoplasm	1
cytoskeleton	1
intracellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

384 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DENND2A	RAB9A	P51151	574
DENND2A	RAB9B	Q9NP90	539
DENND2A	RHOBTB3	O94955	506
DENND2A	AVL9	Q8NBF6	395
DENND2A	RAB13	P51153	381
DENND2A	RIC1	Q4ADV7	360
DENND2A	KDM7A	Q6ZMT4	357
DENND2A	SHISAL1	Q3SXP7	355
DENND2A	JADE3	Q92613	347
DENND2A	AARSD1	Q9BTE6	328
DENND2A	HAUS8	Q9BT25	314
DENND2A	ZCCHC10	Q8TBK6	306
DENND2A	RAB15	P59190	303
DENND2A	SLC35B3	Q9H1N7	302
DENND2A	NMT1	P30419	301

IntAct

4 interactions, top by confidence:

A	B	Type	Score
DENND2A	Dlg4	psi-mi:“MI:0407”(direct interaction)	0.440
DENND2A	H1-5	psi-mi:“MI:0915”(physical association)	0.400
FYN	DENND2A	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (5): DENND2A (Proximity Label-MS), SH3KBP1 (Two-hybrid), DENND2A (Proximity Label-MS), DENND2A (Affinity Capture-RNA), DENND2A (Affinity Capture-MS)

ESM2 similar proteins: A0A8I3NFE2, A0FI79, A1A5B6, A4D2P6, D7PF45, F1LXF1, O15357, O60346, O75808, P11274, P49796, P52734, P53349, P59672, P70268, P78524, P98174, Q0QWG9, Q13233, Q13905, Q16825, Q3MII6, Q50H33, Q5RDA9, Q62925, Q63433, Q6NS60, Q6P549, Q6PDJ6, Q6WVG3, Q7Z5H3, Q8BL80, Q8BUP8, Q8N2R8, Q8TF61, Q8VHK2, Q8WXD9, Q924W7, Q92625, Q96CX2

Diamond homologs: E9PXF8, G2WWH6, I1RQE2, O02626, O75064, O95248, P78524, Q3U1T9, Q3U1Y4, Q5VZ89, Q68D51, Q68F67, Q6NTN5, Q6P3S1, Q6ZPE2, Q7Z401, Q86WG5, Q8C4S8, Q8CFK6, Q8IV53, Q8K382, Q8TEH3, Q91VV4, Q924W7, Q9H6A0, Q9TXP3, Q9ULE3, Q9Y7Q7, X0JZ91, A2RSQ0, C8YR32, G3V7Q0, Q6IQ26, Q6NXD8, Q6PAL8, Q6ZUT9, Q8IVV2, Q8RXA7, A6H8H2, O08873

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	149
Likely benign	6
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3655 predictions. Top by Δscore:

Variant	Effect	Δscore
7:140518860:ATC:A	donor_gain	1.0000
7:140518862:C:A	donor_gain	1.0000
7:140519714:CAGAC:C	acceptor_gain	1.0000
7:140519718:CCTGT:C	acceptor_loss	1.0000
7:140519719:C:CA	acceptor_loss	1.0000
7:140519719:C:CC	acceptor_gain	1.0000
7:140519720:T:C	acceptor_loss	1.0000
7:140521849:CCTCA:C	donor_loss	1.0000
7:140521850:CTCAC:C	donor_loss	1.0000
7:140521851:TCACC:T	donor_loss	1.0000
7:140521852:CACCT:C	donor_loss	1.0000
7:140521853:A:AC	donor_gain	1.0000
7:140521853:AC:A	donor_gain	1.0000
7:140521854:C:CC	donor_gain	1.0000
7:140521854:CC:C	donor_gain	1.0000
7:140521854:CCT:C	donor_gain	1.0000
7:140522105:G:C	acceptor_gain	1.0000
7:140522105:G:GC	acceptor_gain	1.0000
7:140523304:TA:T	donor_loss	1.0000
7:140523305:A:AC	donor_gain	1.0000
7:140523305:AC:A	donor_gain	1.0000
7:140523306:C:CT	donor_gain	1.0000
7:140523306:CC:C	donor_gain	1.0000
7:140523306:CCG:C	donor_gain	1.0000
7:140523306:CCGT:C	donor_gain	1.0000
7:140523306:CCGTG:C	donor_gain	1.0000
7:140523420:TCCAT:T	acceptor_gain	1.0000
7:140523421:CCAT:C	acceptor_gain	1.0000
7:140523421:CCATC:C	acceptor_gain	1.0000
7:140523422:CAT:C	acceptor_gain	1.0000

AlphaMissense

6581 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:140558155:G:C	C649W	1.000
7:140527367:C:T	G819E	0.999
7:140546893:A:T	V695D	0.999
7:140555666:G:C	S669R	0.999
7:140555666:G:T	S669R	0.999
7:140555667:C:A	S669I	0.999
7:140555668:T:G	S669R	0.999
7:140555675:G:C	C666W	0.999
7:140555676:C:T	C666Y	0.999
7:140555677:A:G	C666R	0.999
7:140558153:C:G	R650P	0.999
7:140558156:C:T	C649Y	0.999
7:140558157:A:G	C649R	0.999
7:140558162:C:T	G647D	0.999
7:140558197:A:C	F635L	0.999
7:140558197:A:T	F635L	0.999
7:140558198:A:G	F635S	0.999
7:140558199:A:G	F635L	0.999
7:140558203:G:C	F633L	0.999
7:140558203:G:T	F633L	0.999
7:140558205:A:G	F633L	0.999
7:140559749:A:C	F616L	0.999
7:140559749:A:T	F616L	0.999
7:140559750:A:G	F616S	0.999
7:140559751:A:G	F616L	0.999
7:140559752:A:C	C615W	0.999
7:140559753:C:T	C615Y	0.999
7:140559754:A:G	C615R	0.999
7:140559755:G:C	F614L	0.999
7:140559755:G:T	F614L	0.999

dbSNP variants (sampled 300 via entrez): RS1000029420 (7:140594555 C>T), RS1000033141 (7:140631045 T>C), RS1000039766 (7:140522815 C>T), RS1000056817 (7:140530642 A>G), RS1000097702 (7:140593222 C>A,T), RS1000114322 (7:140576884 C>G,T), RS1000133761 (7:140641245 G>A,C,T), RS1000174358 (7:140539748 C>T), RS1000201307 (7:140533231 T>G), RS1000234266 (7:140642461 G>A), RS1000269742 (7:140588811 T>C), RS1000278757 (7:140545226 C>T), RS1000291861 (7:140607711 T>G), RS1000343615 (7:140607426 T>C), RS1000350846 (7:140624377 C>G,T)

Disease associations

OMIM: gene MIM:620120 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000659_8	Optic nerve measurement (cup area)	4.000000e-06
GCST006624_83	Systolic blood pressure	1.000000e-09
GCST90000025_314	Appendicular lean mass	1.000000e-12
GCST90002400_61	Plateletcrit	4.000000e-10
GCST90002401_496	Platelet distribution width	2.000000e-18

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0004980	appendicular lean mass
EFO:0007985	platelet crit
EFO:0007984	platelet component distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, increases methylation	5
trichostatin A	affects cotreatment, decreases expression	3
sodium arsenite	decreases expression, increases abundance, increases expression	2
entinostat	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Doxorubicin	affects response to substance, decreases expression	2
FR900359	decreases phosphorylation	1
bisphenol A	increases expression, affects cotreatment	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
NSC 689534	affects binding, decreases expression	1
(+)-JQ1 compound	decreases expression	1
bisphenol AF	decreases expression	1
Temozolomide	increases expression	1
Zoledronic Acid	decreases expression	1
Fulvestrant	increases methylation	1
Acetaminophen	increases expression	1
Arsenic	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Copper	affects binding, decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Indomethacin	increases expression, affects cotreatment	1
Oxygen	increases expression	1
Progesterone	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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