DENND6A

Summary

DENND6A (DENN domain containing 6A, HGNC:26635) is a protein-coding gene on chromosome 3p14.3, encoding Protein DENND6A (Q8IWF6). Guanine nucleotide exchange factor (GEF) for RAB14.

Enables guanyl-nucleotide exchange factor activity. Involved in positive regulation of cell-cell adhesion mediated by cadherin. Located in recycling endosome.

Source: NCBI Gene 201627 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 65 total
• MANE Select transcript: NM_152678

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26635
Approved symbol	DENND6A
Name	DENN domain containing 6A
Location	3p14.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ34969, AFI1A
Ensembl gene	ENSG00000174839
Ensembl biotype	protein_coding
OMIM	620561
Entrez	201627

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 3 retained_intron

ENST00000311128, ENST00000464875, ENST00000471531, ENST00000477344, ENST00000480710, ENST00000487662, ENST00000892345, ENST00000892346, ENST00000972142, ENST00000972143

RefSeq mRNA: 1 — MANE Select: NM_152678 NM_152678

CCDS: CCDS33773

Canonical transcript exons

ENST00000311128 — 20 exons

Exon	Start	End
ENSE00001180641	57628811	57628885
ENSE00001180645	57630421	57630523
ENSE00001180650	57630715	57630824
ENSE00001180654	57630925	57630978
ENSE00001180658	57633265	57633354
ENSE00001180662	57634558	57634622
ENSE00001180673	57641653	57641747
ENSE00001180680	57645661	57645756
ENSE00001180685	57646316	57646438
ENSE00001180691	57657680	57657735
ENSE00001180714	57666123	57666235
ENSE00001180904	57692782	57693077
ENSE00001823599	57625454	57628345
ENSE00003465436	57672400	57672438
ENSE00003608956	57661446	57661551
ENSE00003623360	57659118	57659180
ENSE00003624056	57660760	57660839
ENSE00003656277	57672256	57672298
ENSE00003660017	57663636	57663716
ENSE00003791565	57634704	57634769

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 98.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.1077 / max 505.7435, expressed in 1801 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42666	20.1077	1801

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
germinal epithelium of ovary	UBERON:0001304	98.00	gold quality
parietal pleura	UBERON:0002400	96.72	gold quality
palpebral conjunctiva	UBERON:0001812	96.39	gold quality
visceral pleura	UBERON:0002401	96.27	gold quality
cardiac muscle of right atrium	UBERON:0003379	96.21	gold quality
left ventricle myocardium	UBERON:0006566	95.81	gold quality
seminal vesicle	UBERON:0000998	95.72	gold quality
eye	UBERON:0000970	95.70	gold quality
epithelial cell of pancreas	CL:0000083	95.43	gold quality
caput epididymis	UBERON:0004358	95.28	gold quality
cauda epididymis	UBERON:0004360	95.22	gold quality
upper arm skin	UBERON:0004263	94.90	gold quality
urethra	UBERON:0000057	94.65	gold quality
superficial temporal artery	UBERON:0001614	94.17	gold quality
corpus epididymis	UBERON:0004359	94.11	gold quality
endothelial cell	CL:0000115	94.05	silver quality
calcaneal tendon	UBERON:0003701	93.97	gold quality
trigeminal ganglion	UBERON:0001675	93.91	gold quality
tibia	UBERON:0000979	93.78	gold quality
pigmented layer of retina	UBERON:0001782	93.67	gold quality
thymus	UBERON:0002370	93.66	gold quality
esophagus squamous epithelium	UBERON:0006920	93.58	gold quality
penis	UBERON:0000989	93.37	gold quality
epithelium of mammary gland	UBERON:0003244	93.32	gold quality
mammary duct	UBERON:0001765	93.30	gold quality
adult organism	UBERON:0007023	93.19	gold quality
mucosa of paranasal sinus	UBERON:0005030	93.07	gold quality
saphenous vein	UBERON:0007318	92.94	gold quality
layer of synovial tissue	UBERON:0007616	92.93	gold quality
buccal mucosa cell	CL:0002336	92.79	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.07

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

203 targeting DENND6A, 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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775

Literature-anchored findings (GeneRIF, showing 1)

• FAM116 and Rab14 therefore define an endocytic recycling pathway needed for ADAM protease trafficking and regulation of cell-cell junctions. (PMID:22595670)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dennd6aa	ENSDARG00000030239
mus_musculus	Dennd6a	ENSMUSG00000040818
rattus_norvegicus	Dennd6a	ENSRNOG00000011636
drosophila_melanogaster	CG3309	FBGN0029756
caenorhabditis_elegans		WBGENE00018777

Paralogs (1): DENND6B (ENSG00000205593)

Protein

Protein identifiers

Protein DENND6A — Q8IWF6 (reviewed: Q8IWF6)

Alternative names: DENN domain-containing protein 6A

All UniProt accessions (3): Q8IWF6, H7C598, H7C5D0

UniProt curated annotations — full annotation on UniProt →

Function. Guanine nucleotide exchange factor (GEF) for RAB14. Component of an endocytic recycling pathway that is required for the control of ADAM10 transport, shedding of N-cadherin/CDH2 by ADAM9 or ADAM10 and regulation of cell-cell junctions. Required for RAB14 recruitment to recycling endosomes.

Subcellular location. Recycling endosome. Cytoplasm.

Similarity. Belongs to the DENND6 family.

RefSeq proteins (1): NP_689891* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR018307	ABL9/DENND6_dom	Domain
IPR024224	DENND6	Family
IPR037516	Tripartite_DENN	Domain

Pfam: PF09794

UniProt features (8 total): domain 3, modified residue 2, chain 1, region of interest 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IWF6-F1	84.94	0.63

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): 127, 510

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: 188 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, ACTACCT_MIR196A_MIR196B, TAATAAT_MIR126, GOBP_REGULATION_OF_CELL_CELL_ADHESION_MEDIATED_BY_CADHERIN, REACTOME_MEMBRANE_TRAFFICKING, ACTGCAG_MIR173P, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION, GOBP_CELL_CELL_ADHESION, GTGCCTT_MIR506, USF_01, LYF1_01, NKX22_01, AACTTT_UNKNOWN, GOBP_POSITIVE_REGULATION_OF_CELL_CELL_ADHESION, CAAGGAT_MIR362

GO Biological Process (1): positive regulation of cell-cell adhesion mediated by cadherin (GO:2000049)

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

GO Cellular Component (4): cytoplasm (GO:0005737), cytosol (GO:0005829), recycling endosome (GO:0055037), endosome (GO:0005768)

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
positive regulation of cell-cell adhesion	1
cell-cell adhesion mediated by cadherin	1
regulation of cell-cell adhesion mediated by cadherin	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
binding	1
intracellular anatomical structure	1
cytoplasm	1
endosome	1
endomembrane system	1
cytoplasmic vesicle	1

Protein interactions and networks

STRING

526 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DENND6A	DENND10	Q8TCE6	935
DENND6A	DENND11	A4D1U4	933
DENND6A	AVL9	Q8NBF6	920
DENND6A	ZNF285	Q96NJ3	545
DENND6A	TTF2	Q9UNY4	427
DENND6A	DNM1L	O00429	424
DENND6A	WDR87	Q6ZQQ6	391
DENND6A	ASAH2B	P0C7U1	385
DENND6A	TSPAN15	O95858	377
DENND6A	TMED4	Q7Z7H5	350
DENND6A	SCAMP1	O15126	349
DENND6A	SART3	Q15020	342
DENND6A	PAQR3	Q6TCH7	328
DENND6A	TMEM150C	B9EJG8	327
DENND6A	NRBP2	Q9NSY0	326

IntAct

47 interactions, top by confidence:

A	B	Type	Score
EFNB3	DENND11	psi-mi:“MI:0914”(association)	0.640
DENND6A	RPS6KC1	psi-mi:“MI:0915”(physical association)	0.560
BTN2A1	POTEF	psi-mi:“MI:0914”(association)	0.530
HAVCR2	TCAF2	psi-mi:“MI:0914”(association)	0.530
VSIG4	TCAF2	psi-mi:“MI:0914”(association)	0.530
EFNB2	FAM171A2	psi-mi:“MI:0914”(association)	0.530
TGFBR2	PIK3R2	psi-mi:“MI:0914”(association)	0.530
SPACA1	GOLIM4	psi-mi:“MI:0914”(association)	0.530
PRKCSH	AURKA	psi-mi:“MI:0914”(association)	0.530
MAS1	POTEF	psi-mi:“MI:0914”(association)	0.530
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
DLK1	TCAF2	psi-mi:“MI:0914”(association)	0.530
PDCD1	RTL8C	psi-mi:“MI:0914”(association)	0.530
TPCN2	AP3B1	psi-mi:“MI:0914”(association)	0.530
RNF19B	PIK3R2	psi-mi:“MI:0914”(association)	0.530
PSME1	POLR3A	psi-mi:“MI:0914”(association)	0.530
ZNRD2	MYO9A	psi-mi:“MI:0914”(association)	0.530
PDCD1	TMEM223	psi-mi:“MI:0914”(association)	0.350
TPCN2	DDX11L8	psi-mi:“MI:0914”(association)	0.350
RNF19B		psi-mi:“MI:0914”(association)	0.350
PMEL	MAN1A2	psi-mi:“MI:0914”(association)	0.350
SPACA1	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (114): DENND6A (Affinity Capture-MS), DENND6A (Affinity Capture-MS), DENND6A (Affinity Capture-MS), DENND6A (Affinity Capture-MS), DENND6A (Affinity Capture-MS), DENND6A (Affinity Capture-MS), DENND6A (Affinity Capture-MS), DENND6A (Affinity Capture-MS), DENND6A (Affinity Capture-MS), DENND6A (Affinity Capture-MS), DENND6A (Affinity Capture-MS), DENND6A (Affinity Capture-MS), DENND6A (Affinity Capture-MS), DENND6A (Affinity Capture-MS), DENND6A (Affinity Capture-MS)

ESM2 similar proteins: A6NMX2, B4G0F3, B8BKI7, C6JS30, E0CSI1, F1MF74, F1QWK4, F4JJJ3, M1BYJ7, O35473, O70566, O88984, O89046, O94851, P14019, P19517, P28492, P31949, P31950, P50543, P58797, Q2HXK9, Q2KIY0, Q2R483, Q3V4B5, Q571F8, Q5F3L4, Q5I0R6, Q5R752, Q68EQ9, Q6INE8, Q6P4W8, Q6PH52, Q7SYN4, Q7TSU0, Q7Z4G1, Q8BH65, Q8IWF6, Q8VDG3, Q924K8

Diamond homologs: Q54VA9, Q5F3L4, Q8BH65, Q8IWF6, Q8NEG7, Q9D9V7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	46
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2649 predictions. Top by Δscore:

Variant	Effect	Δscore
3:57628806:CATA:C	donor_loss	1.0000
3:57628807:ATACC:A	donor_loss	1.0000
3:57628808:TA:T	donor_loss	1.0000
3:57628809:ACC:A	donor_loss	1.0000
3:57628810:CCAG:C	donor_gain	1.0000
3:57628884:TCC:T	acceptor_loss	1.0000
3:57628885:CCTAG:C	acceptor_loss	1.0000
3:57628886:C:CC	acceptor_gain	1.0000
3:57628886:CTAG:C	acceptor_loss	1.0000
3:57628887:T:C	acceptor_loss	1.0000
3:57630711:TAA:T	donor_loss	1.0000
3:57630712:AAC:A	donor_loss	1.0000
3:57630713:A:AC	donor_gain	1.0000
3:57630714:C:CA	donor_gain	1.0000
3:57630820:GGACT:G	acceptor_gain	1.0000
3:57630821:GACT:G	acceptor_gain	1.0000
3:57630823:CT:C	acceptor_gain	1.0000
3:57630824:TC:T	acceptor_loss	1.0000
3:57630825:C:CC	acceptor_gain	1.0000
3:57630826:T:C	acceptor_loss	1.0000
3:57630833:C:CT	acceptor_gain	1.0000
3:57630834:A:T	acceptor_gain	1.0000
3:57630919:TCATA:T	donor_loss	1.0000
3:57630920:CATA:C	donor_loss	1.0000
3:57630921:ATAC:A	donor_loss	1.0000
3:57630922:TACCT:T	donor_loss	1.0000
3:57630974:CTTTC:C	acceptor_gain	1.0000
3:57630975:TTTC:T	acceptor_gain	1.0000
3:57630978:CCTA:C	acceptor_loss	1.0000
3:57630979:C:CC	acceptor_gain	1.0000

AlphaMissense

3957 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:57641692:A:G	W365R	1.000
3:57641692:A:T	W365R	1.000
3:57641720:G:C	N355K	1.000
3:57641720:G:T	N355K	1.000
3:57641730:C:T	G352E	1.000
3:57641731:C:G	G352R	1.000
3:57641731:C:T	G352R	1.000
3:57645704:G:C	H332D	1.000
3:57645706:A:T	I331N	1.000
3:57645721:C:G	R326P	1.000
3:57646367:A:T	V297D	1.000
3:57646401:A:G	W286R	1.000
3:57646401:A:T	W286R	1.000
3:57660819:A:G	W214R	1.000
3:57660819:A:T	W214R	1.000
3:57661551:A:G	S172P	1.000
3:57663639:C:A	Q170H	1.000
3:57663639:C:G	Q170H	1.000
3:57663651:T:A	R166S	1.000
3:57663651:T:G	R166S	1.000
3:57663652:C:G	R166T	1.000
3:57663679:C:G	R157P	1.000
3:57663681:G:C	F156L	1.000
3:57663681:G:T	F156L	1.000
3:57663683:A:G	F156L	1.000
3:57672267:T:A	D103V	1.000
3:57672268:C:G	D103H	1.000
3:57672270:G:T	P102Q	1.000
3:57672273:A:G	F101S	1.000
3:57692795:C:T	G75D	1.000

dbSNP variants (sampled 300 via entrez): RS1000090389 (3:57663028 C>A,T), RS1000121583 (3:57663353 T>C), RS1000206469 (3:57688207 G>A), RS1000238938 (3:57629400 C>T), RS1000291555 (3:57669943 C>A,G), RS1000315046 (3:57682100 T>G), RS1000358219 (3:57648723 G>A), RS1000389483 (3:57649056 G>A,T), RS1000391896 (3:57693680 T>C), RS1000418462 (3:57648381 C>G,T), RS1000420139 (3:57671033 C>G,T), RS1000427286 (3:57669701 C>A,T), RS1000457669 (3:57643138 T>C), RS1000492092 (3:57642776 T>C,G), RS1000561139 (3:57688867 A>G)

Disease associations

OMIM: gene MIM:620561 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): primary amenorrhea (MONDO:1060208)

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
Valproic Acid	affects expression, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Caffeine	decreases phosphorylation	1
Lead	affects expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Cyclosporine	decreases expression	1
Aflatoxin M1	decreases expression	1
Cadmium Chloride	increases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07164248	Not specified	COMPLETED	Evaluation of Bone Mineral Density Indications and Outcomes in Female Adolescents: Implications for Early Detection of Osteopenia/Osteoporosis and Gynecologic Practice