DENND2C

Summary

DENND2C (DENN domain containing 2C, HGNC:24748) is a protein-coding gene on chromosome 1p13.2, encoding DENN domain-containing protein 2C (Q68D51). Guanine nucleotide exchange factor (GEF) which may activate RAB9A and RAB9B.

Enables guanyl-nucleotide exchange factor activity. Located in nucleoplasm.

Source: NCBI Gene 163259 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 138 total
• MANE Select transcript: NM_001256404

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24748
Approved symbol	DENND2C
Name	DENN domain containing 2C
Location	1p13.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ37099, DKFZp686G0351, DKFZp779P1149, dJ1156J9.1, RP5-1156J9.1
Ensembl gene	ENSG00000175984
Ensembl biotype	protein_coding
Entrez	163259

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000393274, ENST00000393276, ENST00000481894, ENST00000493549, ENST00000495031, ENST00000935533, ENST00000970986, ENST00000970987

RefSeq mRNA: 2 — MANE Select: NM_001256404 NM_001256404, NM_198459

CCDS: CCDS58018, CCDS875

Canonical transcript exons

ENST00000393274 — 21 exons

Exon	Start	End
ENSE00001411242	114623507	114623643
ENSE00001450295	114625179	114626188
ENSE00001514682	114582850	114585631
ENSE00001514683	114645448	114645559
ENSE00001514684	114654505	114654761
ENSE00001514685	114669983	114670049
ENSE00003495984	114601508	114601585
ENSE00003505484	114600820	114600960
ENSE00003523251	114622987	114623099
ENSE00003524590	114608686	114608873
ENSE00003525833	114594473	114594578
ENSE00003534876	114587716	114587952
ENSE00003547731	114587387	114587473
ENSE00003557762	114600204	114600352
ENSE00003561785	114621895	114622065
ENSE00003562849	114599274	114599451
ENSE00003590144	114604922	114605031
ENSE00003600573	114618386	114618482
ENSE00003611051	114611073	114611117
ENSE00003681109	114602125	114602194
ENSE00003685879	114595832	114595873

Expression profiles

Bgee: expression breadth ubiquitous, 213 present calls, max score 95.84.

FANTOM5 (CAGE): breadth broad, TPM avg 1.8175 / max 80.0054, expressed in 735 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
13951	1.2962	592
13950	0.3826	180
13952	0.1387	51

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
esophagus squamous epithelium	UBERON:0006920	95.84	gold quality
buccal mucosa cell	CL:0002336	95.78	gold quality
upper arm skin	UBERON:0004263	94.36	gold quality
lower esophagus mucosa	UBERON:0035834	93.77	gold quality
vastus lateralis	UBERON:0001379	92.26	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	92.13	gold quality
quadriceps femoris	UBERON:0001377	91.49	gold quality
amniotic fluid	UBERON:0000173	91.41	gold quality
tibialis anterior	UBERON:0001385	91.02	gold quality
gingival epithelium	UBERON:0001949	90.70	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.39	gold quality
deltoid	UBERON:0001476	90.32	gold quality
skeletal muscle tissue	UBERON:0001134	90.06	gold quality
gingiva	UBERON:0001828	90.04	gold quality
upper leg skin	UBERON:0004262	90.04	gold quality
pancreatic ductal cell	CL:0002079	89.96	gold quality
esophagus mucosa	UBERON:0002469	89.66	gold quality
hindlimb stylopod muscle	UBERON:0004252	88.80	gold quality
oral cavity	UBERON:0000167	88.26	gold quality
muscle of leg	UBERON:0001383	87.20	gold quality
skin of leg	UBERON:0001511	87.16	gold quality
skin of abdomen	UBERON:0001416	86.95	gold quality
zone of skin	UBERON:0000014	86.75	gold quality
pharyngeal mucosa	UBERON:0000355	86.68	gold quality
gastrocnemius	UBERON:0001388	86.57	gold quality
muscle tissue	UBERON:0002385	86.56	gold quality
biceps brachii	UBERON:0001507	85.83	gold quality
penis	UBERON:0000989	85.00	gold quality
vagina	UBERON:0000996	83.49	gold quality
skin of hip	UBERON:0001554	83.35	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	116.28
E-CURD-114	yes	67.09
E-ANND-3	yes	15.24

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

71 targeting DENND2C, 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-6833-3P	100.00	70.63	3197
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
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-195-5P	99.90	72.81	2805
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-4694-3P	99.79	69.53	2640

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	dennd2c	ENSDARG00000073738
mus_musculus	Dennd2c	ENSMUSG00000007379
rattus_norvegicus	Dennd2c	ENSRNOG00000018716

Paralogs (3): DENND2A (ENSG00000146966), DENND2D (ENSG00000162777), DENND2B (ENSG00000166444)

Protein

Protein identifiers

DENN domain-containing protein 2C — Q68D51 (reviewed: Q68D51)

All UniProt accessions (1): Q68D51

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.

Isoforms (3)

UniProt ID	Names	Canonical?
Q68D51-1	1	yes
Q68D51-2	2
Q68D51-3	3

RefSeq proteins (2): NP_001243333, NP_940861 (=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 (16 total): domain 3, sequence conflict 3, region of interest 3, splice variant 2, sequence variant 2, chain 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q68D51-F1	61.31	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): 271

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: 117 (showing top): REACTOME_MEMBRANE_TRAFFICKING, BILD_HRAS_ONCOGENIC_SIGNATURE, CCANNAGRKGGC_UNKNOWN, SOX9_B1, FREAC3_01, SOX5_01, SHAFFER_IRF4_MULTIPLE_MYELOMA_PROGRAM, MASSARWEH_TAMOXIFEN_RESISTANCE_UP, GOMF_GUANYL_NUCLEOTIDE_EXCHANGE_FACTOR_ACTIVITY, GOMF_NUCLEOSIDE_TRIPHOSPHATASE_REGULATOR_ACTIVITY, GOMF_ENZYME_REGULATOR_ACTIVITY, DODD_NASOPHARYNGEAL_CARCINOMA_DN, MIKKELSEN_ES_ICP_WITH_H3K4ME3, WIERENGA_STAT5A_TARGETS_DN, PILON_KLF1_TARGETS_UP

GO Biological Process (0):

GO Molecular Function (1): guanyl-nucleotide exchange factor activity (GO:0005085)

GO Cellular Component (1): nucleoplasm (GO:0005654)

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
GTP binding	1
GDP binding	1
GTPase regulator activity	1
nuclear lumen	1
cellular anatomical structure	1

Protein interactions and networks

STRING

382 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DENND2C	CFAP20DC	Q6ZVT6	543
DENND2C	AMPD1	P23109	507
DENND2C	CSDE1	O75534	465
DENND2C	ARHGAP26	Q9UNA1	464
DENND2C	RAB9A	P51151	449
DENND2C	RHOBTB3	O94955	435
DENND2C	FYCO1	Q9BQS8	427
DENND2C	GSTM3	P21266	425
DENND2C	KIF2B	Q8N4N8	419
DENND2C	ZNF567	Q8N184	419
DENND2C	SYTL1	Q8IYJ3	413
DENND2C	SYCE1L	A8MT33	412
DENND2C	RAB9B	Q9NP90	407
DENND2C	OLFML3	Q9NRN5	405
DENND2C	NRAS	P01111	400

IntAct

8 interactions, top by confidence:

A	B	Type	Score
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAQ	IGLC7	psi-mi:“MI:0914”(association)	0.530
DENND2C	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
YWHAG	C1orf226	psi-mi:“MI:0914”(association)	0.350
KCNE3	PIK3R2	psi-mi:“MI:0914”(association)	0.350
DENND2C	ARHGAP42	psi-mi:“MI:0914”(association)	0.350

BioGRID (16): HID1 (Affinity Capture-MS), ARHGAP42 (Affinity Capture-MS), YES1 (Two-hybrid), DENND2C (Proximity Label-MS), HIST1H2BH (Proximity Label-MS), DENND2C (Proximity Label-MS), YWHAB (Affinity Capture-MS), HID1 (Affinity Capture-MS), YWHAH (Affinity Capture-MS), YWHAG (Affinity Capture-MS), ARHGAP42 (Affinity Capture-MS), YWHAQ (Affinity Capture-MS), DENND2C (Affinity Capture-MS), Nudt21 (Two-hybrid), PDIA4 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0JPH7, A4QNA8, A5D7P0, A7MBD1, D2HHP1, E1BTE1, F7EA39, O35589, O57473, O94988, P30304, P30305, P30306, P30307, P30308, P30309, P30310, P30311, P47817, P48964, P48965, P48966, P48967, P48968, Q08D35, Q13506, Q28FA8, Q29029, Q3TLR7, Q3UWM4, Q4KM37, Q4V7W5, Q5RHD1, Q5XIX3, Q61122, Q62722, Q68D51, Q6A098, Q6DFE0, Q6P1H6

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, A6H8H2, O08873, Q6NXD8, Q6P9P8, Q6ZUT9, Q80U28, Q8WXG6, A0JMK5, A2BGG1, A2RSQ0, A4FU01

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	123
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

3307 predictions. Top by Δscore:

Variant	Effect	Δscore
1:114587711:CTGA:C	donor_loss	1.0000
1:114587712:TGAC:T	donor_loss	1.0000
1:114587713:GAC:G	donor_loss	1.0000
1:114587714:A:AC	donor_gain	1.0000
1:114587715:C:CC	donor_gain	1.0000
1:114587715:C:CG	donor_loss	1.0000
1:114587953:CTG:C	acceptor_gain	1.0000
1:114587954:TG:T	acceptor_gain	1.0000
1:114587959:CAACA:C	acceptor_gain	1.0000
1:114587962:C:CT	acceptor_gain	1.0000
1:114587963:A:AC	acceptor_gain	1.0000
1:114587963:A:C	acceptor_gain	1.0000
1:114594468:CATA:C	donor_loss	1.0000
1:114594470:TA:T	donor_loss	1.0000
1:114594471:A:C	donor_loss	1.0000
1:114594472:C:CT	donor_loss	1.0000
1:114594580:T:C	acceptor_gain	1.0000
1:114599450:TG:T	acceptor_gain	1.0000
1:114599452:C:CC	acceptor_gain	1.0000
1:114599457:C:CT	acceptor_gain	1.0000
1:114599457:C:T	acceptor_gain	1.0000
1:114599458:A:T	acceptor_gain	1.0000
1:114600349:TGGA:T	acceptor_gain	1.0000
1:114600353:C:CC	acceptor_gain	1.0000
1:114600816:TTACC:T	donor_loss	1.0000
1:114600817:TAC:T	donor_loss	1.0000
1:114600818:A:AC	donor_gain	1.0000
1:114600818:A:AT	donor_loss	1.0000
1:114600819:C:CC	donor_gain	1.0000
1:114600819:C:CG	donor_loss	1.0000

AlphaMissense

6110 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:114587754:A:G	F877S	0.999
1:114599399:A:G	W720R	0.999
1:114599399:A:T	W720R	0.999
1:114601538:A:C	S595R	0.999
1:114601538:A:T	S595R	0.999
1:114601540:T:G	S595R	0.999
1:114587753:G:C	F877L	0.998
1:114587753:G:T	F877L	0.998
1:114587755:A:G	F877L	0.998
1:114600234:C:G	R692P	0.998
1:114600237:T:A	E691V	0.998
1:114600875:G:T	P634Q	0.998
1:114602137:A:C	C575W	0.998
1:114587762:A:C	F874L	0.997
1:114587762:A:T	F874L	0.997
1:114587763:A:G	F874S	0.997
1:114587764:A:G	F874L	0.997
1:114587790:A:G	L865P	0.997
1:114587829:A:G	F852S	0.997
1:114587844:A:G	F847S	0.997
1:114599404:A:G	F718S	0.997
1:114600851:A:T	V642D	0.997
1:114601539:C:A	S595I	0.997
1:114602144:C:T	G573D	0.997
1:114602179:A:C	F561L	0.997
1:114602179:A:T	F561L	0.997
1:114602181:A:G	F561L	0.997
1:114587742:C:G	R881P	0.996
1:114595863:A:T	V765D	0.996
1:114599331:G:C	F742L	0.996

dbSNP variants (sampled 300 via entrez): RS1000019960 (1:114595276 C>T), RS1000027087 (1:114647482 C>T), RS1000036654 (1:114588305 T>C), RS1000115171 (1:114592601 G>A), RS1000119486 (1:114614129 G>A), RS1000138582 (1:114635360 T>C), RS1000172276 (1:114614389 T>C), RS1000202401 (1:114642279 G>A), RS1000211881 (1:114653774 T>C), RS1000254690 (1:114659272 G>A), RS1000310833 (1:114647243 T>C), RS1000337036 (1:114659767 TCTTC>T,TCTTCCTTC), RS1000370753 (1:114614477 G>C), RS1000372618 (1:114586046 A>G), RS1000389552 (1:114659966 T>C)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002268_9	Autism	3.000000e-08
GCST009379_29	Type 2 diabetes	3.000000e-08
GCST90002395_319	Mean platelet volume	6.000000e-22
GCST90002395_320	Mean platelet volume	2.000000e-20
GCST90002401_356	Platelet distribution width	1.000000e-41
GCST90002401_357	Platelet distribution width	7.000000e-48

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
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

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	6
entinostat	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
trichostatin A	affects expression	1
beta-lapachone	increases expression	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
potassium chromate(VI)	increases expression, affects cotreatment	1
epigallocatechin gallate	affects cotreatment, increases expression	1
pentanal	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	decreases expression	1
NSC 689534	affects binding, increases expression	1
(+)-JQ1 compound	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Aldehydes	increases expression	1
Arsenic	affects methylation	1
Cadmium	decreases expression	1

Clinical trials (associated diseases)

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