DENND5A

Summary

DENND5A (DENN domain containing 5A, HGNC:19344) is a protein-coding gene on chromosome 11p15.4, encoding DENN domain-containing protein 5A (Q6IQ26). Guanine nucleotide exchange factor (GEF) which may activate RAB6A and RAB39A and/or RAB39B.

This gene encodes a DENN-domain-containing protein that functions as a RAB-activating guanine nucleotide exchange factor (GEF). This protein catalyzes the conversion of GDP to GTP and thereby converts inactive GDP-bound Rab proteins into their active GTP-bound form. The encoded protein is recruited by RAB6 onto Golgi membranes and is therefore referred to as RAB6-interacting protein 1. This protein binds with RAB39 as well. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Mutations in this gene are associated with early infantile epileptic encephalopathy-49.

Source: NCBI Gene 23258 — RefSeq curated summary.

At a glance

• Gene–disease (curated): developmental and epileptic encephalopathy, 49 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 770 total — 18 pathogenic, 16 likely-pathogenic
• Phenotypes (HPO): 42
• MANE Select transcript: NM_015213

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19344
Approved symbol	DENND5A
Name	DENN domain containing 5A
Location	11p15.4
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1091, FLJ22354, FLJ33829, FLJ43455
Ensembl gene	ENSG00000184014
Ensembl biotype	protein_coding
OMIM	617278
Entrez	23258

Gene structure

Transcript identifiers

Ensembl transcripts: 43 — 20 retained_intron, 11 protein_coding, 9 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000328194, ENST00000524446, ENST00000525784, ENST00000526707, ENST00000527700, ENST00000527896, ENST00000528725, ENST00000529977, ENST00000530044, ENST00000530780, ENST00000530867, ENST00000531580, ENST00000531747, ENST00000532696, ENST00000533737, ENST00000679446, ENST00000679458, ENST00000679460, ENST00000679568, ENST00000679745, ENST00000679773, ENST00000679926, ENST00000679999, ENST00000680252, ENST00000680294, ENST00000680358, ENST00000680470, ENST00000680554, ENST00000680576, ENST00000680599, ENST00000680742, ENST00000680791, ENST00000680885, ENST00000681158, ENST00000681173, ENST00000681203, ENST00000681371, ENST00000681425, ENST00000681639, ENST00000681915, ENST00000929629, ENST00000929630, ENST00000965473

RefSeq mRNA: 4 — MANE Select: NM_015213 NM_001243254, NM_001348749, NM_001348750, NM_015213

CCDS: CCDS31423, CCDS58119, CCDS91437

Canonical transcript exons

ENST00000328194 — 23 exons

Exon	Start	End
ENSE00001294463	9178132	9178366
ENSE00001298034	9180767	9181084
ENSE00001302149	9264961	9265350
ENSE00001309969	9178858	9179073
ENSE00001323631	9207561	9207632
ENSE00001328433	9203660	9204317
ENSE00001330140	9193494	9193681
ENSE00002168042	9138825	9139854
ENSE00003502002	9143403	9143485
ENSE00003535664	9144995	9145113
ENSE00003593534	9144097	9144278
ENSE00003612513	9170627	9170777
ENSE00003613232	9206673	9206782
ENSE00003620459	9147030	9147151
ENSE00003654487	9141940	9142108
ENSE00003662588	9150081	9150209
ENSE00003667366	9142722	9142845
ENSE00003755868	9150680	9150764
ENSE00003756330	9145670	9145815
ENSE00003756508	9160713	9160865
ENSE00003756849	9165836	9165967
ENSE00003757633	9169856	9169949
ENSE00003758574	9152358	9152442

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 98.77.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 50.7951 / max 2386.2041, expressed in 1812 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
118560	46.2038	1810
118561	2.3520	1354
118562	0.8030	468
118563	0.6877	421
118558	0.5288	249
118559	0.1543	61
118557	0.0656	21

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus callosum	UBERON:0002336	98.77	gold quality
medial globus pallidus	UBERON:0002477	98.58	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.54	gold quality
spinal cord	UBERON:0002240	98.42	gold quality
ventricular zone	UBERON:0003053	98.32	gold quality
inferior vagus X ganglion	UBERON:0005363	98.31	gold quality
globus pallidus	UBERON:0001875	98.28	gold quality
subthalamic nucleus	UBERON:0001906	98.12	gold quality
inferior olivary complex	UBERON:0002127	98.07	gold quality
medulla oblongata	UBERON:0001896	97.96	gold quality
substantia nigra	UBERON:0002038	97.78	gold quality
superior vestibular nucleus	UBERON:0007227	97.71	gold quality
midbrain	UBERON:0001891	97.70	gold quality
cranial nerve II	UBERON:0000941	97.67	gold quality
blood	UBERON:0000178	97.58	gold quality
hypothalamus	UBERON:0001898	97.54	gold quality
amygdala	UBERON:0001876	97.51	gold quality
dorsal plus ventral thalamus	UBERON:0001897	97.43	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	97.39	gold quality
ganglionic eminence	UBERON:0004023	97.38	gold quality
putamen	UBERON:0001874	97.25	gold quality
stromal cell of endometrium	CL:0002255	97.20	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.18	gold quality
olfactory bulb	UBERON:0002264	97.15	gold quality
middle frontal gyrus	UBERON:0002702	97.14	gold quality
caudate nucleus	UBERON:0001873	97.10	gold quality
prefrontal cortex	UBERON:0000451	97.04	gold quality
paraflocculus	UBERON:0005351	97.02	gold quality
monocyte	CL:0000576	96.99	gold quality
cerebellar hemisphere	UBERON:0002245	96.99	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-9221	yes	18.79
E-MTAB-9467	yes	17.93
E-ANND-3	yes	17.68

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

95 targeting DENND5A, 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-450A-1-3P	100.00	69.33	1837
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349

Literature-anchored findings (GeneRIF, showing 5)

• crystal structure of Rab6a(GTP) in complex with a 378-residue internal fragment of the effector Rab6IP1 was solved at 3.2 angstroms resolution. This Rab6IP1 region encompasses an all alpha-helical RUN domain followed in tandem by a PLAT domain (PMID:19141279)
• A RUN Domain from DENND5/Rab6IP1 binds sorting Nexin 1 and is involved in the trafficking of vesicles at the level of Golgi. (PMID:22558185)
• identification of an epileptic encephalopathy additionally featuring cerebral calcifications and coarse facial features caused by recessive loss-of-function mutations in DENND5A (PMID:27866705)
• Novel loss-of-function variant in DENND5A impedes melanosomal cargo transport and predisposes to familial cutaneous melanoma. (PMID:34906508)
• Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy. (PMID:39174524)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	dennd5a	ENSDARG00000017006
mus_musculus	Dennd5a	ENSMUSG00000035901
rattus_norvegicus	Dennd5a	ENSRNOG00000012206

Paralogs (10): PKD1 (ENSG00000008710), PKD2L2 (ENSG00000078795), PKD2L1 (ENSG00000107593), PKD2 (ENSG00000118762), PKDREJ (ENSG00000130943), PKD1L1 (ENSG00000158683), PKD1L2 (ENSG00000166473), LOXHD1 (ENSG00000167210), DENND5B (ENSG00000170456), PKD1L3 (ENSG00000277481)

Protein

Protein identifiers

DENN domain-containing protein 5A — Q6IQ26 (reviewed: Q6IQ26)

Alternative names: Rab6-interacting protein 1

All UniProt accessions (15): Q6IQ26, A0A7P0T8L1, A0A7P0T8L8, A0A7P0T9H0, A0A7P0T9Z2, A0A7P0TAA7, A0A7P0TAF6, A0A7P0TAH5, A0A7P0Z4N9, B4DFB6, E9PIS3, H0YCW5, H0YDS8, H0YDV6, H0YEA8

UniProt curated annotations — full annotation on UniProt →

Function. Guanine nucleotide exchange factor (GEF) which may activate RAB6A and RAB39A and/or RAB39B. Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab proteins into their active GTP-bound form. Involved in the negative regulation of neurite outgrowth.

Subunit / interactions. Interacts with RAB6A bound to GTP.

Subcellular location. Golgi apparatus membrane.

Disease relevance. Developmental and epileptic encephalopathy 49 (DEE49) [MIM:617281] A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE49 is a severe autosomal recessive form characterized by onset of seizures in the neonatal period, global developmental delay, intellectual disability, and additionally cerebral calcifications and coarse facial features. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the RAB6IP1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6IQ26-1	1	yes
Q6IQ26-2	2

RefSeq proteins (4): NP_001230183, NP_001335678, NP_001335679, NP_056028* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001024	PLAT/LH2_dom	Domain
IPR001194	cDENN_dom	Domain
IPR004012	Run_dom	Domain
IPR005112	dDENN_dom	Domain
IPR005113	uDENN_dom	Domain
IPR036392	PLAT/LH2_dom_sf	Homologous_superfamily
IPR037213	Run_dom_sf	Homologous_superfamily
IPR037516	Tripartite_DENN	Domain
IPR043153	DENN_C	Homologous_superfamily
IPR047277	PLAT_RAB6IP1	Domain
IPR047278	DEN5A/B	Family
IPR047294	RUN1_DENND5A	Domain
IPR047295	RUN2_DENND5A	Domain

Pfam: PF01477, PF02141, PF02759, PF03455, PF03456

UniProt features (20 total): domain 6, modified residue 5, sequence conflict 4, sequence variant 2, chain 1, splice variant 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6IQ26-F1	77.74	0.44

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 (5): 1085, 1087, 1096, 193, 1079

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: 412 (showing top): BORCZUK_MALIGNANT_MESOTHELIOMA_UP, FREAC2_01, TGCGCANK_UNKNOWN, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, GOMF_GTPASE_BINDING, GGGTGGRR_PAX4_03, GOLDRATH_ANTIGEN_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_ERYTHROCYTE_UP, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, MODULE_205, GOCC_TRANS_GOLGI_NETWORK, ONKEN_UVEAL_MELANOMA_UP

GO Biological Process (2): negative regulation of neuron projection development (GO:0010977), retrograde transport, endosome to Golgi (GO:0042147)

GO Molecular Function (3): guanyl-nucleotide exchange factor activity (GO:0005085), small GTPase binding (GO:0031267), protein binding (GO:0005515)

GO Cellular Component (6): Golgi membrane (GO:0000139), trans-Golgi network (GO:0005802), cytosol (GO:0005829), Golgi apparatus (GO:0005794), membrane (GO:0016020), retromer complex (GO:0030904)

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
cytoplasm	2
cellular anatomical structure	2
endomembrane system	2
regulation of neuron projection development	1
neuron projection development	1
negative regulation of cell projection organization	1
intercellular transport	1
endosomal transport	1
cytosolic transport	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
GTPase binding	1
binding	1
Golgi apparatus	1
bounding membrane of organelle	1
Golgi apparatus subcompartment	1
intracellular membrane-bounded organelle	1
membrane protein complex	1

Protein interactions and networks

STRING

893 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DENND5A	RAB6A	P20340	986
DENND5A	RAB11A	P24410	976
DENND5A	SNX1	Q13596	740
DENND5A	AVL9	Q8NBF6	565
DENND5A	GCC2	Q8IWJ2	545
DENND5A	RAB4A	P20338	545
DENND5A	SNX2	P82862	535
DENND5A	RAB5A	P20339	527
DENND5A	RAB13	P51153	458
DENND5A	RAB28	P51157	449
DENND5A	RBSN	Q9H1K0	408
DENND5A	RIC1	Q4ADV7	400
DENND5A	RAB35	Q15286	382
DENND5A	DENND4C	Q5VZ89	382
DENND5A	RAB10	P61026	375

IntAct

118 interactions, top by confidence:

A	B	Type	Score
GOLGA6L9	DENND5A	psi-mi:“MI:0915”(physical association)	0.560
DENND5A	MPP7	psi-mi:“MI:0407”(direct interaction)	0.440
DENND5A	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.440
DENND5A	ARHGAP21	psi-mi:“MI:0407”(direct interaction)	0.440
DENND5A	PARD3B	psi-mi:“MI:0407”(direct interaction)	0.440
DENND5A	ARHGEF12	psi-mi:“MI:0407”(direct interaction)	0.440
DENND5A	HTRA4	psi-mi:“MI:0407”(direct interaction)	0.440
DENND5A	LNX2	psi-mi:“MI:0407”(direct interaction)	0.440
DENND5A	TJP1	psi-mi:“MI:0407”(direct interaction)	0.440
DENND5A	PDZD2	psi-mi:“MI:0407”(direct interaction)	0.440
DENND5A	HTRA3	psi-mi:“MI:0407”(direct interaction)	0.440
APBA3	DENND5A	psi-mi:“MI:0407”(direct interaction)	0.440
MAST1	DENND5A	psi-mi:“MI:0407”(direct interaction)	0.440
DENND5A	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440
DENND5A	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
DENND5A	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
DENND5A	MPP2	psi-mi:“MI:0407”(direct interaction)	0.440
DENND5A	SNX27	psi-mi:“MI:0407”(direct interaction)	0.440
DENND5A	PALS2	psi-mi:“MI:0407”(direct interaction)	0.440
DENND5A	TJP2	psi-mi:“MI:0407”(direct interaction)	0.440
DENND5A	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
DENND5A	PDZK1	psi-mi:“MI:0407”(direct interaction)	0.440
DENND5A	SIPA1L2	psi-mi:“MI:0407”(direct interaction)	0.440
SNTB1	DENND5A	psi-mi:“MI:0407”(direct interaction)	0.440
DENND5A	MAGI1	psi-mi:“MI:0407”(direct interaction)	0.440
DENND5A	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440
DENND5A	PDZRN4	psi-mi:“MI:0407”(direct interaction)	0.440
DENND5A	GRIP1	psi-mi:“MI:0407”(direct interaction)	0.440
PTPN13	DENND5A	psi-mi:“MI:0407”(direct interaction)	0.440
PATJ	DENND5A	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (22): DENND5A (Affinity Capture-RNA), DENND5A (Affinity Capture-RNA), DENND5A (Affinity Capture-RNA), DENND5A (Affinity Capture-MS), DENND5A (Affinity Capture-MS), DENND5A (Affinity Capture-MS), GOLGA6L9 (Two-hybrid), DENND5A (Proximity Label-MS), PCDHGA9 (Affinity Capture-MS), DENND5B (Affinity Capture-MS), DENND5A (Affinity Capture-MS), BIRC6 (Affinity Capture-MS), BEND3 (Affinity Capture-MS), DENND5A (Proximity Label-MS), DENND5A (Affinity Capture-RNA)

ESM2 similar proteins: A0A4X1TB62, A4VCH4, G3V7Q0, O14795, O35841, O43237, O70585, P23116, P48553, Q0P5J8, Q14152, Q15542, Q1JU68, Q3TLI0, Q3UHE1, Q4R5P6, Q5R660, Q5R7S4, Q5R7U7, Q5RE09, Q5RE70, Q5VSL9, Q5XI83, Q658Y4, Q68E01, Q6IQ26, Q6PAL8, Q6PDL0, Q6TEP1, Q6WKZ8, Q7SYD9, Q7TPD0, Q8BIK4, Q8BWQ6, Q8C079, Q8C092, Q8C9H6, Q8CBY8, Q8IWV8, Q8K400

Diamond homologs: A2RSQ0, C8YR32, G3V7Q0, Q5FVJ0, Q6IQ26, Q6NXD8, Q6P3S1, Q6PAL8, Q6ZUT9, Q8BIJ7, Q8C4S8, Q8CFK6, Q8IV53, Q8IVV2, Q8RXA7, Q8WXG6, Q96T51, Q9TXP3, B8UU59, E7FKV8, O08852, O16025, P09917, P12527, P48999, P51399, P98161, Q09624, Q2EG98, Q7TN88, Q7Z442, Q7Z443, Q8R526, Q8TDX9, Q9NTG1, Q9Z0T6, Q3U1T9, Q9ULE3, A7YDW0, O08576

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 85 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ras activation upon Ca2+ influx through NMDA receptor	5	53.9×	1e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	51.3×	1e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	51.3×	1e-06
Assembly and cell surface presentation of NMDA receptors	10	47.9×	7e-13
Dopamine Neurotransmitter Release Cycle	5	46.8×	2e-06
Long-term potentiation	5	44.9×	2e-06
Neurexins and neuroligins	11	40.9×	3e-13
Protein-protein interactions at synapses	7	35.1×	7e-08

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	10	74.5×	2e-14
protein localization to synapse	6	58.9×	1e-07
receptor clustering	7	56.0×	7e-09
regulation of postsynaptic membrane neurotransmitter receptor levels	6	38.1×	9e-07
protein-containing complex assembly	9	13.1×	2e-06
cell-cell adhesion	10	13.0×	5e-07
regulation of small GTPase mediated signal transduction	5	9.2×	4e-03
chemical synaptic transmission	7	6.9×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	16
Uncertain significance	299
Likely benign	388
Benign	16

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1201466	NM_015213.4(DENND5A):c.1274del (p.Asn425fs)	Pathogenic
1216523	NM_015213.4(DENND5A):c.3387+1G>T	Pathogenic
1971069	NM_015213.4(DENND5A):c.238C>T (p.Arg80Ter)	Pathogenic
1982745	NM_015213.4(DENND5A):c.3488del (p.Asn1163fs)	Pathogenic
2001667	NM_015213.4(DENND5A):c.1118dup (p.Leu374fs)	Pathogenic
2059744	NM_015213.4(DENND5A):c.603_604del (p.Tyr202fs)	Pathogenic
2060506	NM_015213.4(DENND5A):c.3001G>T (p.Glu1001Ter)	Pathogenic
2066479	NM_015213.4(DENND5A):c.955C>T (p.Gln319Ter)	Pathogenic
2426098	NC_000011.9:g.(?9091245)(9286616_?)del	Pathogenic
2426099	NC_000011.9:g.(?9286488)(9286616_?)del	Pathogenic
2641593	NM_015213.4(DENND5A):c.612dup (p.Lys205Ter)	Pathogenic
2729718	NM_015213.4(DENND5A):c.842del (p.Leu281fs)	Pathogenic
2863171	NM_015213.4(DENND5A):c.127C>T (p.Gln43Ter)	Pathogenic
3660574	NM_015213.4(DENND5A):c.2161C>T (p.Gln721Ter)	Pathogenic
374925	NM_015213.4(DENND5A):c.517_518del (p.Asp173fs)	Pathogenic
374926	NM_015213.4(DENND5A):c.2547del (p.Lys850fs)	Pathogenic
374928	NM_015213.4(DENND5A):c.3811del (p.Gln1271fs)	Pathogenic
986921	NM_015213.4(DENND5A):c.2180dup (p.Ser728fs)	Pathogenic
1333616	NM_015213.4(DENND5A):c.949+1G>A	Likely pathogenic
1978557	NM_015213.4(DENND5A):c.949+1G>C	Likely pathogenic
2022272	NM_015213.4(DENND5A):c.2857+1G>A	Likely pathogenic
2029890	NM_015213.4(DENND5A):c.2522-1G>C	Likely pathogenic
2426102	NC_000011.9:g.(?9228200)(9229199_?)dup	Likely pathogenic
2576577	NM_015213.4(DENND5A):c.3388C>T (p.Arg1130Ter)	Likely pathogenic
2690581	NM_015213.4(DENND5A):c.2660G>A (p.Trp887Ter)	Likely pathogenic
2794821	NM_015213.4(DENND5A):c.1455+1G>A	Likely pathogenic
3061326	NM_015213.4(DENND5A):c.2614C>T (p.Gln872Ter)	Likely pathogenic
3337020	NM_015213.4(DENND5A):c.949+1G>T	Likely pathogenic
375553	NM_015213.4(DENND5A):c.3629G>A (p.Arg1210Gln)	Likely pathogenic
4714997	NM_015213.4(DENND5A):c.2283+1G>T	Likely pathogenic

SpliceAI

4700 predictions. Top by Δscore:

Variant	Effect	Δscore
11:9139875:C:CT	acceptor_gain	1.0000
11:9139876:A:T	acceptor_gain	1.0000
11:9139884:C:CT	acceptor_gain	1.0000
11:9139885:A:T	acceptor_gain	1.0000
11:9139892:C:CT	acceptor_gain	1.0000
11:9139893:A:T	acceptor_gain	1.0000
11:9141976:T:TA	donor_gain	1.0000
11:9141981:G:A	donor_gain	1.0000
11:9142104:TTTTT:T	acceptor_gain	1.0000
11:9142105:TTTT:T	acceptor_gain	1.0000
11:9142106:TTT:T	acceptor_gain	1.0000
11:9142107:TT:T	acceptor_gain	1.0000
11:9142108:TCTG:T	acceptor_loss	1.0000
11:9142109:C:CC	acceptor_gain	1.0000
11:9142110:T:G	acceptor_loss	1.0000
11:9142844:CG:C	acceptor_gain	1.0000
11:9144095:A:AC	donor_gain	1.0000
11:9144096:C:CA	donor_gain	1.0000
11:9144096:CTGGG:C	donor_gain	1.0000
11:9144277:ACC:A	acceptor_loss	1.0000
11:9144279:CT:C	acceptor_loss	1.0000
11:9144280:T:G	acceptor_loss	1.0000
11:9144993:A:AC	donor_gain	1.0000
11:9144994:C:CA	donor_gain	1.0000
11:9145112:CA:C	acceptor_gain	1.0000
11:9145114:C:CC	acceptor_gain	1.0000
11:9147021:GCTAC:G	donor_loss	1.0000
11:9147022:CTACT:C	donor_loss	1.0000
11:9147023:TAC:T	donor_loss	1.0000
11:9147024:ACT:A	donor_loss	1.0000

AlphaMissense

8516 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:9142734:A:G	W1167R	1.000
11:9142734:A:T	W1167R	1.000
11:9144225:C:G	R1059P	1.000
11:9144262:A:G	W1047R	1.000
11:9144262:A:T	W1047R	1.000
11:9144276:A:G	F1042S	1.000
11:9145047:A:G	W1024R	1.000
11:9145047:A:T	W1024R	1.000
11:9145085:A:T	V1011D	1.000
11:9145731:C:T	G981E	1.000
11:9147083:A:G	L935P	1.000
11:9147086:A:G	L934P	1.000
11:9147095:A:G	L931P	1.000
11:9147122:C:G	R922P	1.000
11:9147127:G:C	F920L	1.000
11:9147127:G:T	F920L	1.000
11:9147128:A:C	F920C	1.000
11:9147128:A:G	F920S	1.000
11:9147129:A:G	F920L	1.000
11:9147131:G:T	A919D	1.000
11:9147144:A:C	Y915D	1.000
11:9150114:A:G	L901P	1.000
11:9150138:T:A	E893V	1.000
11:9150147:A:G	L890P	1.000
11:9150150:C:G	R889P	1.000
11:9150157:A:G	W887R	1.000
11:9150157:A:T	W887R	1.000
11:9150160:C:G	A886P	1.000
11:9150161:T:A	R885S	1.000
11:9150161:T:G	R885S	1.000

dbSNP variants (sampled 300 via entrez): RS1000062108 (11:9253994 C>T), RS1000069326 (11:9218528 C>T), RS1000075715 (11:9260193 A>G), RS1000080078 (11:9262851 C>T), RS1000118269 (11:9154523 T>C), RS1000134110 (11:9195832 C>T), RS1000142066 (11:9187629 A>G), RS1000191859 (11:9190455 G>T), RS1000197175 (11:9154429 T>A), RS1000215785 (11:9151542 A>G), RS1000240706 (11:9227791 C>T), RS1000242819 (11:9190691 A>G), RS1000250763 (11:9240354 C>G), RS1000278013 (11:9209385 G>A), RS1000280311 (11:9140897 A>C)

Disease associations

OMIM: gene MIM:617278 | disease phenotypes: MIM:617281, MIM:606854

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy, 49	Strong	Autosomal recessive
Tourette syndrome	No Known Disease Relationship	Unknown

Mondo (4): developmental and epileptic encephalopathy, 49 (MONDO:0015002), breast ductal adenocarcinoma (MONDO:0005590), bilateral frontoparietal polymicrogyria (MONDO:0011738), Tourette syndrome (MONDO:0007661)

Orphanet (1): Bilateral frontoparietal polymicrogyria (Orphanet:101070)

HPO phenotypes

42 total (30 of 42 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000194	Open mouth
HP:0000215	Thick upper lip vermilion
HP:0000232	Everted lower lip vermilion
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000280	Coarse facial features
HP:0000322	Short philtrum
HP:0000400	Macrotia
HP:0000448	Prominent nose
HP:0000527	Long eyelashes
HP:0000574	Thick eyebrow
HP:0000648	Optic atrophy
HP:0000739	Anxiety
HP:0000752	Hyperactivity
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001305	Dandy-Walker malformation
HP:0001320	Cerebellar vermis hypoplasia
HP:0001336	Myoclonus
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0002007	Frontal bossing
HP:0002069	Bilateral tonic-clonic seizure
HP:0002119	Ventriculomegaly
HP:0002135	Basal ganglia calcification
HP:0002267	Exaggerated startle response
HP:0002353	EEG abnormality
HP:0002510	Spastic tetraplegia
HP:0002514	Cerebral calcification

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST005196_43	Coronary artery disease	6.000000e-06

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390
D005879	Tourette Syndrome	C10.228.140.079.898; C10.228.662.825.800; C10.574.500.850; C16.320.400.820; F03.625.992.850
C564652	Polymicrogyria, Bilateral Frontoparietal (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
cobaltous chloride	increases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Cyclosporine	increases expression	2
Cadmium Chloride	increases abundance, increases expression	2
FR900359	increases phosphorylation	1
ethylbenzene	increases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
2-xylene	increases expression	1
aflatoxin B2	decreases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases 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	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
eprenetapopt	affects expression	1
PCI 5002	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Leflunomide	increases expression	1
Air Pollutants, Occupational	affects expression	1
Arsenic	increases abundance, affects cotreatment, decreases expression	1
Aspirin	increases expression	1
Benzene	increases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1Q0	Abcam HeLa DENND5A KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00152750	PHASE4	UNKNOWN	Study of Clonidine on Sleep Architecture in Children With Tourette’s Syndrome (TS) and Comorbid ADHD
NCT00226824	PHASE4	TERMINATED	Safety Study of Galantamine in Tic Disorders
NCT00241176	PHASE4	COMPLETED	Open Label Trial of Aripiprazole in Children and Adolescents With Tourette’s Disorder
NCT00370838	PHASE4	COMPLETED	Comparison of Keppra and Clonidine in the Treatment of Tics
NCT01018056	PHASE4	COMPLETED	Developing New Treatments for Tourette Syndrome: Therapeutic Trials With Modulators of Glutamatergic Neurotransmission
NCT01547000	PHASE4	COMPLETED	Guanfacine in Children With Tic Disorders
NCT03239210	PHASE4	COMPLETED	Effects of Ondansetron in Obsessive-compulsive and Tic Disorders
NCT00004376	PHASE3	COMPLETED	Phase III Randomized, Double-Blind, Placebo-Controlled Study of Guanfacine for Tourette Syndrome and Attention Deficit Hyperactivity Disorder
NCT00206323	PHASE3	COMPLETED	A Randomized, Placebo-controlled, Tourette Syndrome Study.
NCT00206336	PHASE3	COMPLETED	An Open-label Study to Determine the Efficacy and Safety of Topiramate in the Treatment of Tourette Syndrome.
NCT00478842	PHASE3	COMPLETED	Pallidal Stimulation and Gilles de la Tourette Syndrome
NCT00681863	PHASE3	TERMINATED	Open-label Extension Study of Pramipexole in the Treatment of Children and Adolescents With Tourette Syndrome
NCT01501695	PHASE3	COMPLETED	Phase III Study of 5LGr to Treat Tic Disorder
NCT03087201	PHASE3	COMPLETED	CANNAbinoids in the Treatment of TICS (CANNA-TICS)
NCT03487783	PHASE3	COMPLETED	Aripiprazole Oral Solution in the Treatment of Children and Adolescents With Tourette’s Syndrome
NCT03567291	PHASE3	TERMINATED	Evaluation of Safety and Tolerability of Long-term TEV-50717 (Deutetrabenazine) for Treatment of Tourette Syndrome in Children and Adolescents
NCT03571256	PHASE3	COMPLETED	A Study to Test if TEV-50717 is Effective in Relieving Tics Associated With Tourette Syndrome (TS)
NCT06021522	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate Long-term Safety of Ecopipam Tablets in Children, Adolescents and Adults With Tourette’s Disorder
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT00004393	PHASE2	COMPLETED	Phase II Double Blind Placebo Controlled Trial of Risperidone in Tourette Syndrome
NCT00004652	PHASE2	COMPLETED	Phase II Pilot Controlled Study of Short Vs Longer Term Pimozide (Orap) Therapy in Tourette Syndrome
NCT00231985	PHASE2	COMPLETED	Effectiveness of Behavior Therapy and Psychosocial Therapy for the Treatment of Tourette Syndrome and Chronic Tic Disorder
NCT00311909	PHASE2	COMPLETED	Thalamic Deep Brain Stimulation for Tourette Syndrome
NCT00529308	PHASE2	COMPLETED	Transcranial Magnetic Stimulation (TMS) for Individuals With Tourette’s Syndrome
NCT00558467	PHASE2	COMPLETED	Pramipexole Pilot Phase II Study in Children and Adolescents With Tourette Disorder According to DSM-IV Criteria
NCT01043549	PHASE2	TERMINATED	Repetitive Transcranial Magnetic Stimulation of the Posterior Parietal Cortex in Patients Suffering From Gilles de la Tourette Syndrome
NCT01133353	PHASE2	WITHDRAWN	A Study of the Effectiveness and Safety of Tetrabenazine MR in Pediatric Subjects With Tourette’s Syndrome
NCT01475383	PHASE2	WITHDRAWN	Study Evaluating The Safety And Efficacy Of PF-03654746 In Adult Subjects With Tourette’s Syndrome
NCT01647269	PHASE2	COMPLETED	A Trial of Bilateral Deep Brain Stimulation to the Globus Pallidus Internum in Tourette Syndrome
NCT01904773	PHASE2	COMPLETED	Safety, Tolerability, Pharmacokinetic, and Efficacy Study of AZD5213 in Adolescents With Tourette’s Disorder
NCT02102698	PHASE2	COMPLETED	Ecopipam Treatment of Tourette’s Syndrome in Subjects 7-17 Years
NCT02217007	PHASE2	WITHDRAWN	A Trial Evaluating the Efficacy, Safety, and Pharmacokinetics of SNC-102 in Subjects With Tourette Syndrome
NCT02247206	PHASE2	COMPLETED	VoIP Delivered Behavior Therapy for Tourette Syndrome
NCT02581865	PHASE2	COMPLETED	Safety and Efficacy Study of NBI-98854 in Adults With Tourette Syndrome
NCT02619084	PHASE2	COMPLETED	Subthalamic Stimulation in Tourette’s Syndrome
NCT02679079	PHASE2	COMPLETED	Safety and Efficacy Study of NBI-98854 in Children and Adolescents With Tourette Syndrome
NCT02879578	PHASE2	COMPLETED	Safety and Tolerability Study of NBI-98854 for the Treatment of Subjects With Tourette Syndrome
NCT03066193	PHASE2	COMPLETED	Efficacy of a Therapeutic Combination of Dronabinol and PEA for Tourette Syndrome
NCT03247244	PHASE2	TERMINATED	Safety and Efficacy of Cannabis in Tourette Syndrome
NCT03325010	PHASE2	COMPLETED	Safety, Tolerability, and Efficacy of NBI-98854 for the Treatment of Pediatric Subjects With Tourette Syndrome