DENND1C

Summary

DENND1C (DENN domain containing 1C, HGNC:26225) is a protein-coding gene on chromosome 19p13.3, encoding DENN domain-containing protein 1C (Q8IV53). Guanine nucleotide exchange factor (GEF) which may activate RAB8A, RAB13 and RAB35.

The protein encoded by this gene functions as a guanine nucleotide exchange factor for the early endosomal small GTPase RAB35, which regulates endosomal membrane trafficking and is involved in actin polymerization. The encoded protein activates RAB35 by promoting the exchange of RAB35-bound GDP for GTP. This gene may play a role in linking RAB35 activation with the clathrin machinery.

Source: NCBI Gene 79958 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 142 total
• MANE Select transcript: NM_024898

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26225
Approved symbol	DENND1C
Name	DENN domain containing 1C
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ22757
Ensembl gene	ENSG00000205744
Ensembl biotype	protein_coding
OMIM	613634
Entrez	79958

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 7 protein_coding, 6 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000381480, ENST00000543576, ENST00000586046, ENST00000588421, ENST00000588988, ENST00000589491, ENST00000590173, ENST00000590444, ENST00000590473, ENST00000590818, ENST00000590867, ENST00000591030, ENST00000591795, ENST00000592543, ENST00000871258, ENST00000871259

RefSeq mRNA: 2 — MANE Select: NM_024898 NM_001290331, NM_024898

CCDS: CCDS45938, CCDS77225

Canonical transcript exons

ENST00000381480 — 23 exons

Exon	Start	End
ENSE00001488740	6475484	6475585
ENSE00001488742	6475706	6475751
ENSE00001488743	6475837	6475937
ENSE00001488745	6476857	6476967
ENSE00002744131	6481679	6481787
ENSE00003465647	6469596	6469640
ENSE00003474056	6468846	6468953
ENSE00003477721	6478783	6478852
ENSE00003541469	6479859	6479902
ENSE00003556519	6478937	6479056
ENSE00003558130	6479669	6479718
ENSE00003562700	6477074	6477127
ENSE00003565388	6479987	6480051
ENSE00003613593	6468578	6468645
ENSE00003618151	6470295	6470366
ENSE00003620433	6472889	6472993
ENSE00003632228	6467207	6468118
ENSE00003635806	6471265	6471305
ENSE00003639100	6477378	6477458
ENSE00003662374	6468234	6468441
ENSE00003664331	6475274	6475399
ENSE00003694631	6471406	6471496
ENSE00003784953	6477218	6477283

Expression profiles

Bgee: expression breadth ubiquitous, 180 present calls, max score 97.83.

FANTOM5 (CAGE): breadth broad, TPM avg 8.2528 / max 177.5732, expressed in 633 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
178649	7.2644	501
178648	0.7519	219
178647	0.2365	147

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	97.83	gold quality
spleen	UBERON:0002106	93.48	gold quality
mucosa of transverse colon	UBERON:0004991	92.80	gold quality
lymph node	UBERON:0000029	92.74	gold quality
rectum	UBERON:0001052	92.12	gold quality
blood	UBERON:0000178	92.02	gold quality
leukocyte	CL:0000738	90.24	gold quality
monocyte	CL:0000576	89.85	gold quality
mononuclear cell	CL:0000842	89.82	gold quality
vermiform appendix	UBERON:0001154	89.75	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.87	gold quality
lower esophagus mucosa	UBERON:0035834	88.72	gold quality
islet of Langerhans	UBERON:0000006	87.76	gold quality
upper lobe of left lung	UBERON:0008952	87.31	gold quality
small intestine	UBERON:0002108	86.75	gold quality
body of pancreas	UBERON:0001150	86.56	gold quality
skin of leg	UBERON:0001511	86.55	gold quality
bone marrow cell	CL:0002092	86.09	gold quality
pancreas	UBERON:0001264	85.68	gold quality
transverse colon	UBERON:0001157	85.54	gold quality
skin of abdomen	UBERON:0001416	85.53	gold quality
upper lobe of lung	UBERON:0008948	85.48	gold quality
caecum	UBERON:0001153	85.39	gold quality
body of stomach	UBERON:0001161	85.36	gold quality
esophagus mucosa	UBERON:0002469	85.36	gold quality
right lobe of liver	UBERON:0001114	84.94	gold quality
metanephros cortex	UBERON:0010533	84.94	gold quality
gall bladder	UBERON:0002110	84.85	gold quality
right lung	UBERON:0002167	84.21	gold quality
minor salivary gland	UBERON:0001830	84.02	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.35

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

25 targeting DENND1C, 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-4487	99.96	64.58	1252
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-4320	99.75	65.80	793
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-3125	99.14	68.49	2269
HSA-MIR-4504	99.10	69.14	1328
HSA-MIR-3916	98.99	68.04	2155
HSA-MIR-5006-5P	98.79	66.92	1246
HSA-MIR-6769B-5P	98.73	64.91	1092
HSA-MIR-4733-3P	98.35	65.20	994
HSA-MIR-876-5P	97.99	68.49	1345
HSA-MIR-3650	97.88	64.89	693
HSA-MIR-4456	97.50	64.88	1678
HSA-MIR-10400-3P	97.29	64.66	597
HSA-MIR-4674	97.29	64.62	597
HSA-MIR-6515-5P	97.08	65.48	1219
HSA-MIR-4474-3P	96.97	65.87	870
HSA-MIR-3616-3P	96.96	65.45	983
HSA-MIR-3126-5P	96.87	65.83	912
HSA-MIR-6875-5P	96.87	65.49	958
HSA-MIR-3167	96.81	67.09	1236
HSA-MIR-3139	96.68	66.77	652
HSA-MIR-6834-5P	96.25	64.88	823

Literature-anchored findings (GeneRIF, showing 1)

• whereas connecdenn 1 and 2 activate Rab35 for endosomal trafficking, connecdenn 3 uniquely activates Rab35 for its role in actin regulation (PMID:22072793)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dennd1c	ENSDARG00000078503
mus_musculus	Dennd1c	ENSMUSG00000002668
rattus_norvegicus	Dennd1c	ENSRNOG00000046050
drosophila_melanogaster	CG18659	FBGN0027561
caenorhabditis_elegans		WBGENE00004375

Paralogs (2): DENND1A (ENSG00000119522), DENND1B (ENSG00000213047)

Protein

Protein identifiers

DENN domain-containing protein 1C — Q8IV53 (reviewed: Q8IV53)

Alternative names: Connecdenn 3, Protein FAM31C

All UniProt accessions (6): Q8IV53, K7EKL5, K7EM30, K7EM80, K7EMN9, K7ENM0

UniProt curated annotations — full annotation on UniProt →

Function. Guanine nucleotide exchange factor (GEF) which may activate RAB8A, RAB13 and RAB35. Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab proteins into their active GTP-bound form.

Subunit / interactions. Exhibits low nucleotide-independent RAB35-binding activity. Interacts with clathrin heavy chain/CLTC and with AP2A2, but not with AP2B1.

Subcellular location. Cytoplasm. Cytosol. Cytoplasmic vesicle. Clathrin-coated vesicle.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8IV53-1	1	yes
Q8IV53-2	2

RefSeq proteins (2): NP_001277260, NP_079174* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001194	cDENN_dom	Domain
IPR005112	dDENN_dom	Domain
IPR005113	uDENN_dom	Domain
IPR037516	Tripartite_DENN	Domain
IPR040032	DENND1A/B/C	Family
IPR043153	DENN_C	Homologous_superfamily

Pfam: PF02141, PF03455, PF03456

UniProt features (24 total): compositionally biased region 8, domain 3, sequence variant 3, sequence conflict 3, region of interest 2, short sequence motif 2, chain 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IV53-F1	63.79	0.41

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): 553

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: 129 (showing top): GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, BOYLAN_MULTIPLE_MYELOMA_D_DN, GOCC_COATED_VESICLE, GOBP_ENDOCYTIC_RECYCLING, GOBP_LOCALIZATION_WITHIN_MEMBRANE, GOBP_IMPORT_INTO_CELL, GOBP_ENDOCYTOSIS, GOCC_CLATHRIN_COATED_VESICLE, GOMF_GUANYL_NUCLEOTIDE_EXCHANGE_FACTOR_ACTIVITY, chr19p13, GOMF_PHOSPHATIDYLINOSITOL_PHOSPHATE_BINDING, GOMF_PHOSPHATIDYLINOSITOL_BINDING, GOMF_NUCLEOSIDE_TRIPHOSPHATASE_REGULATOR_ACTIVITY, GOMF_ENZYME_REGULATOR_ACTIVITY

GO Biological Process (2): endocytosis (GO:0006897), endocytic recycling (GO:0032456)

GO Molecular Function (3): guanyl-nucleotide exchange factor activity (GO:0005085), phosphatidylinositol phosphate binding (GO:1901981), protein binding (GO:0005515)

GO Cellular Component (6): nucleoplasm (GO:0005654), centrosome (GO:0005813), cytosol (GO:0005829), clathrin-coated vesicle (GO:0030136), cytoplasm (GO:0005737), cytoplasmic vesicle (GO:0031410)

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	2
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
endosomal transport	1
vesicle-mediated transport to the plasma membrane	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
phospholipid binding	1
binding	1
nuclear lumen	1
centriole	1
microtubule organizing center	1
coated vesicle	1
intracellular anatomical structure	1
intracellular vesicle	1

Protein interactions and networks

STRING

698 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DENND1C	RAB35	Q15286	930
DENND1C	CLTC	Q00610	726
DENND1C	RAB13	P51153	589
DENND1C	RAB28	P51157	448
DENND1C	MADD	Q8WXG6	438
DENND1C	RAB21	Q9UL25	432
DENND1C	SYP	P08247	427
DENND1C	DENND4B	O75064	420
DENND1C	DENND5B	Q6ZUT9	412
DENND1C	DENND3	A2RUS2	401
DENND1C	RAB22A	Q9UL26	398
DENND1C	AVL9	Q8NBF6	394
DENND1C	RABIF	P47224	386
DENND1C	WDR83OS	Q9Y284	375
DENND1C	SLC37A3	Q8NCC5	369

IntAct

8 interactions, top by confidence:

A	B	Type	Score
DENND1C	SNAPIN	psi-mi:“MI:0915”(physical association)	0.560
SNAPIN	DENND1C	psi-mi:“MI:0915”(physical association)	0.560
DENND1C	DAPK1	psi-mi:“MI:0407”(direct interaction)	0.440
DENND1C	HSPA8	psi-mi:“MI:0915”(physical association)	0.400
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350
DENND1C	cysJ	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (8): DENND1C (Reconstituted Complex), DENND1C (Affinity Capture-MS), DENND1C (Two-hybrid), DENND1C (Proximity Label-MS), DENND1C (Affinity Capture-RNA), DENND1C (Affinity Capture-MS), DENND1C (Affinity Capture-RNA), APP (Reconstituted Complex)

ESM2 similar proteins: A1L3T7, A2CI98, A2CJ06, A2VCK2, D3ZQL6, E1BBG2, M3WHG5, O15037, O43918, O70303, O75333, P48778, P59729, Q32PJ7, Q3KP66, Q3T191, Q5JYT7, Q5T124, Q5U4F0, Q5XIS1, Q6AXX1, Q6VYH9, Q7TSI1, Q80U38, Q8BGT6, Q8BHW9, Q8BWG4, Q8BWQ5, Q8BZ33, Q8BZW2, Q8C0J6, Q8C2K5, Q8CFK6, Q8IV53, Q8IY33, Q8IZW8, Q8K1S6, Q8K330, Q8N3F8, Q8TB24

Diamond homologs: A2RSQ0, C8YR32, G3V7Q0, Q5FVJ0, Q6IQ26, Q6NXD8, Q6P3S1, Q6PAL8, Q6ZUT9, Q8BIJ7, Q8C4S8, Q8CFK6, Q8IV53, Q8IVV2, Q8RXA7, Q8WXG6, Q96T51, Q9TXP3, E9PXF8, G2WWH6, I1RQE2, O02626, O75064, O95248, P78524, Q3U1T9, Q3U1Y4, Q5VZ89, Q68D51, Q68F67, Q6NTN5, Q6ZPE2, Q7Z401, Q86WG5, Q8K382, Q8TEH3, Q91VV4, Q924W7, Q9H6A0, Q9ULE3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	111
Likely benign	13
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3428 predictions. Top by Δscore:

Variant	Effect	Δscore
19:6468119:C:CC	acceptor_gain	1.0000
19:6468442:C:CC	acceptor_gain	1.0000
19:6468949:CCATC:C	acceptor_gain	1.0000
19:6468950:CATC:C	acceptor_gain	1.0000
19:6468950:CATCC:C	acceptor_gain	1.0000
19:6468952:TC:T	acceptor_gain	1.0000
19:6468953:CC:C	acceptor_gain	1.0000
19:6468953:CCTA:C	acceptor_loss	1.0000
19:6468954:C:CA	acceptor_loss	1.0000
19:6468954:C:CC	acceptor_gain	1.0000
19:6468955:T:C	acceptor_loss	1.0000
19:6470287:AG:A	donor_gain	1.0000
19:6471400:GCTCA:G	donor_loss	1.0000
19:6471401:CTCA:C	donor_loss	1.0000
19:6471402:TCA:T	donor_loss	1.0000
19:6471403:CA:C	donor_loss	1.0000
19:6471405:C:CT	donor_loss	1.0000
19:6471493:TGAA:T	acceptor_gain	1.0000
19:6471497:C:CC	acceptor_gain	1.0000
19:6471511:A:T	acceptor_gain	1.0000
19:6471518:C:CT	acceptor_gain	1.0000
19:6472993:CCTGG:C	acceptor_loss	1.0000
19:6475273:CCGGG:C	donor_gain	1.0000
19:6475480:TGACC:T	donor_loss	1.0000
19:6475481:GAC:G	donor_loss	1.0000
19:6475482:A:AC	donor_gain	1.0000
19:6475482:A:C	donor_loss	1.0000
19:6475483:C:CC	donor_gain	1.0000
19:6475483:CCA:C	donor_gain	1.0000
19:6475483:CCACG:C	donor_gain	1.0000

AlphaMissense

5183 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:6475887:C:A	W243C	0.999
19:6475887:C:G	W243C	0.999
19:6475889:A:G	W243R	0.999
19:6475889:A:T	W243R	0.999
19:6475728:C:T	G268E	0.998
19:6475734:A:G	L266P	0.998
19:6475738:A:C	Y265D	0.998
19:6476888:C:A	R216I	0.998
19:6476891:C:A	R215I	0.998
19:6479692:G:C	F51L	0.998
19:6479692:G:T	F51L	0.998
19:6479694:A:G	F51L	0.998
19:6476888:C:G	R216T	0.997
19:6476890:T:A	R215S	0.997
19:6476890:T:G	R215S	0.997
19:6476891:C:G	R215T	0.997
19:6476894:T:A	E214V	0.997
19:6475332:A:G	F332S	0.996
19:6475888:C:G	W243S	0.996
19:6476885:A:T	V217D	0.996
19:6476960:A:G	L192P	0.996
19:6478981:G:C	F84L	0.996
19:6478981:G:T	F84L	0.996
19:6478983:A:G	F84L	0.996
19:6479020:G:C	F71L	0.996
19:6479020:G:T	F71L	0.996
19:6479022:A:G	F71L	0.996
19:6475873:A:G	I248T	0.995
19:6476887:T:A	R216S	0.995
19:6476887:T:G	R216S	0.995

dbSNP variants (sampled 300 via entrez): RS1000017818 (19:6470674 T>C), RS1000244407 (19:6473064 T>A,C), RS1000418310 (19:6468643 G>A), RS1000468877 (19:6478460 C>G,T), RS1000490393 (19:6483771 C>A,G), RS1000744647 (19:6477940 T>G), RS1000798769 (19:6478734 G>A,C,T), RS1000878555 (19:6468890 C>G,T), RS1000987700 (19:6472733 C>T), RS1001054973 (19:6478486 C>T), RS1001332012 (19:6472531 T>C), RS1001421289 (19:6467408 T>C,G), RS1001430626 (19:6470623 T>TTTTTTG), RS1001896818 (19:6470478 C>T), RS1001915954 (19:6474520 G>C)

Disease associations

OMIM: gene MIM:613634 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002002_3	Adverse response to chemotherapy (neutropenia/leucopenia) (cyclophosphamide)	8.000000e-06
GCST90002393_637	Monocyte count	1.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005091	monocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	increases expression, decreases expression	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
sodium arsenite	increases expression	1
perfluorooctanoic acid	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
entinostat	increases expression	1
perfluorohexanesulfonic acid	decreases expression	1
jinfukang	increases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Calcitriol	increases expression, affects cotreatment	1
Coumestrol	decreases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Estradiol	affects cotreatment, decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Methyl Methanesulfonate	increases expression	1
Nickel	increases expression	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression	1
Testosterone	affects cotreatment, increases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	increases expression	1
Aflatoxin B1	increases expression	1

Clinical trials (associated diseases)

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