GGA3

Summary

GGA3 (golgi associated, gamma adaptin ear containing, ARF binding protein 3, HGNC:17079) is a protein-coding gene on chromosome 17q25.1, encoding ADP-ribosylation factor-binding protein GGA3 (Q9NZ52). Plays a role in protein sorting and trafficking between the trans-Golgi network (TGN) and endosomes.

This gene encodes a member of the Golgi-localized, gamma adaptin ear-containing, ARF-binding (GGA) family. This family includes ubiquitous coat proteins that regulate the trafficking of proteins between the trans-Golgi network and the lysosome. These proteins share an amino-terminal VHS domain which mediates sorting of the mannose 6-phosphate receptors at the trans-Golgi network. They also contain a carboxy-terminal region with homology to the ear domain of gamma-adaptins. Multiple alternatively spliced transcript variants have been identified in this gene.

Source: NCBI Gene 23163 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 187 total — 2 likely-pathogenic
• MANE Select transcript: NM_138619

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17079
Approved symbol	GGA3
Name	golgi associated, gamma adaptin ear containing, ARF binding protein 3
Location	17q25.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0154
Ensembl gene	ENSG00000125447
Ensembl biotype	protein_coding
OMIM	606006
Entrez	23163

Gene structure

Transcript identifiers

Ensembl transcripts: 37 — 21 protein_coding, 9 nonsense_mediated_decay, 7 retained_intron

ENST00000537686, ENST00000538886, ENST00000577435, ENST00000578208, ENST00000578348, ENST00000578773, ENST00000578896, ENST00000579743, ENST00000580646, ENST00000580799, ENST00000582232, ENST00000582376, ENST00000582486, ENST00000582717, ENST00000582821, ENST00000583282, ENST00000583667, ENST00000584243, ENST00000584550, ENST00000613421, ENST00000614198, ENST00000621217, ENST00000621870, ENST00000649398, ENST00000878323, ENST00000924698, ENST00000924699, ENST00000924700, ENST00000924701, ENST00000924702, ENST00000924703, ENST00000924704, ENST00000924705, ENST00000924706, ENST00000924707, ENST00000955609, ENST00000955610

RefSeq mRNA: 6 — MANE Select: NM_138619 NM_001172703, NM_001172704, NM_001291641, NM_001291642, NM_014001, NM_138619

CCDS: CCDS11716, CCDS11717, CCDS54164, CCDS58597

Canonical transcript exons

ENST00000537686 — 17 exons

Exon	Start	End
ENSE00003460104	75240812	75241057
ENSE00003462293	75246509	75246584
ENSE00003466935	75243447	75243570
ENSE00003479931	75239375	75239571
ENSE00003497237	75240342	75240412
ENSE00003520367	75238652	75238762
ENSE00003530142	75239789	75240108
ENSE00003560181	75246712	75246796
ENSE00003567208	75244619	75244717
ENSE00003576769	75243063	75243166
ENSE00003578343	75241615	75241696
ENSE00003622814	75242831	75242911
ENSE00003639366	75241400	75241516
ENSE00003640077	75242336	75242473
ENSE00003642735	75238914	75239083
ENSE00003741321	75261548	75261606
ENSE00003903203	75236599	75238389

Expression profiles

Bgee: expression breadth ubiquitous, 268 present calls, max score 96.11.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.3154 / max 128.5350, expressed in 1796 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
168050	15.2431	1796
168048	0.0399	13
168051	0.0325	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	96.11	gold quality
granulocyte	CL:0000094	95.50	gold quality
pylorus	UBERON:0001166	95.34	gold quality
mucosa of stomach	UBERON:0001199	93.78	gold quality
lower esophagus mucosa	UBERON:0035834	93.74	gold quality
spleen	UBERON:0002106	93.04	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.91	gold quality
monocyte	CL:0000576	92.72	gold quality
nipple	UBERON:0002030	92.60	gold quality
leukocyte	CL:0000738	92.59	gold quality
mononuclear cell	CL:0000842	92.58	gold quality
tibial nerve	UBERON:0001323	92.40	gold quality
lymph node	UBERON:0000029	92.17	gold quality
upper lobe of left lung	UBERON:0008952	92.07	gold quality
esophagus mucosa	UBERON:0002469	92.01	gold quality
fundus of stomach	UBERON:0001160	92.00	gold quality
right hemisphere of cerebellum	UBERON:0014890	91.90	gold quality
transverse colon	UBERON:0001157	91.75	gold quality
secondary oocyte	CL:0000655	91.74	gold quality
body of stomach	UBERON:0001161	91.73	gold quality
minor salivary gland	UBERON:0001830	91.56	gold quality
apex of heart	UBERON:0002098	91.56	gold quality
skin of leg	UBERON:0001511	91.46	gold quality
small intestine	UBERON:0002108	91.35	gold quality
right lobe of thyroid gland	UBERON:0001119	91.31	gold quality
metanephros cortex	UBERON:0010533	91.26	gold quality
esophagus	UBERON:0001043	91.24	gold quality
skin of abdomen	UBERON:0001416	91.21	gold quality
right lung	UBERON:0002167	91.16	gold quality
cerebellar hemisphere	UBERON:0002245	91.15	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.24

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

88 targeting GGA3, 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-4500	99.99	72.72	2367
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-3934-5P	99.67	64.04	846
HSA-MIR-6073	99.60	70.36	793
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-6727-3P	99.49	65.92	1333
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4519	99.48	66.10	859
HSA-MIR-4688	99.48	64.68	828
HSA-MIR-6743-5P	99.48	63.60	721
HSA-MIR-2392	99.43	67.50	708
HSA-MIR-4480	99.42	66.02	735
HSA-MIR-372-5P	99.41	69.11	2299

Literature-anchored findings (GeneRIF, showing 24)

• structures of the VHS domain of human GGA3 complexed with signals from both mannose-6-phosphate receptors (PMID:11859375)
• These results indicate that GGA3-S is predominantly expressed in human tissues except the brain and in cell lines. (PMID:12810073)
• RNAi of GGA3 expression results in accumulation of the cation-independent mannose 6-phosphate receptor and internalized epidermal growth factor (EGF) within enlarged early endosomes. This perturbation impairs the degradation of internalized EGF. (PMID:15039775)
• found that the human GGA3 protein GAT domain contains two ubiquitin binding motifs that bind to the same surface of ubiquitin (PMID:15494413)
• GGA proteins funstion with the phosphorylated ACDL in the memasin 2-recycling pathway from endosomes to trans Golgi on the way back to the cell surface. (PMID:15615712)
• crystal structure of the GAT domain (PMID:15701688)
• GGA3, becomes transiently phosphorylated upon activation of the epidermal growth factor (EGF) receptor. (GGA3) (PMID:16135791)
• CK2-activated phosphorylation cascade controlling PACS-1- and GGA3-mediated CI-MPR sorting, is reported. (PMID:16977309)
• ubiquitin binding and ubiquitylation of GGA3-GAT domain are mutually inseparable through a ubiquitin ligase activity of hVPS18 (PMID:16996030)
• These results show that the dual roles of PI4P can promote specific GGA targeting and cargo recognition at the trans-Golgi network. (PMID:17494868)
• We have elucidated a GGA3-dependent mechanism regulating BACE levels and beta-secretase activity. This mechanism may explain increased cerebral levels of BACE and Abeta following cerebral ischemia and existing in AD. (PMID:17553422)
• GGA overexpression causes various sorting defects as measured by recycling of CD-MPR, internalization of transferrin receptor, and the subcellular localization of proteins like Tsg101, ubiquitin, and Hrs. (PMID:19788741)
• seladin-1 downregulation increases BACE1 levels and activity through enhanced GGA3 depletion during apoptosis (PMID:19815556)
• GGA3 tightly and inversely regulate BACE1 levels via interaction with ubiquitin sorting machinery (PMID:20484053)
• Subcellular fractionation of Alzheimer’s disease cortex with low levels of Golgi-localized GGA proteins shows an alteration of beta-secretase distribution and extensive co-localization with amyloid beta precursor protein APP. (PMID:21440067)
• GGA3 is involved in the cellular processes relevant for Alzheimer’s disease pathogenesis. (PMID:23970038)
• These data indicate that clathrin is required for the function of AP-1- and GGA-coated carriers at the trans-Golgi network but may be dispensable for outward traffic en route to the plasma membrane. (PMID:24407285)
• This work identifies GGA3 as a key player in a novel DXXLL-mediated endosomal sorting machinery that targets TrkA to the plasma membrane, where it prolongs the activation of Akt signaling and survival responses. (PMID:26446845)
• role of GGA3 in the cell surface export of alpha2B-adrenergic receptor (PMID:26811329)
• In the absence of GGA3, integrins are increasingly retained inside the cell, traffic toward the perinuclear lysosomal compartment and their degradation is enhanced. (PMID:26935970)
• SNPs: rs6414624 in EVC and rs78338345 in GGA3 are novel susceptibility loci for type 2 diabetes mellitus in Japanese individuals. (PMID:29273463)
• GGA3 interacts with L-type prostaglandin D synthase and regulates the recycling and signaling of the DP1 receptor for prostaglandin D2 in a Rab4-dependent mechanism. (PMID:32334026)
• Inactivation of the three GGA genes in HeLa cells partially compromises lysosomal enzyme sorting. (PMID:33206455)
• Do PACS1 variants impeding adaptor protein binding predispose to syndromic intellectual disability? (PMID:37141437)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	gga3b	ENSDARG00000098871
danio_rerio	gga3a	ENSDARG00000103667
mus_musculus	Gga3	ENSMUSG00000020740
rattus_norvegicus	Gga3	ENSRNOG00000027057
drosophila_melanogaster	Stam	FBGN0027363
drosophila_melanogaster	Gga	FBGN0030141
drosophila_melanogaster	Wdfy2	FBGN0032246
caenorhabditis_elegans	stam-1	WBGENE00004109
caenorhabditis_elegans		WBGENE00008402

Paralogs (10): WDFY1 (ENSG00000085449), GGA1 (ENSG00000100083), TOM1 (ENSG00000100284), GGA2 (ENSG00000103365), STAM2 (ENSG00000115145), STAM (ENSG00000136738), WDFY2 (ENSG00000139668), TOM1L1 (ENSG00000141198), TOM1L2 (ENSG00000175662), HGS (ENSG00000185359)

Protein

Protein identifiers

ADP-ribosylation factor-binding protein GGA3 — Q9NZ52 (reviewed: Q9NZ52)

Alternative names: Golgi-localized, gamma ear-containing, ARF-binding protein 3

All UniProt accessions (12): Q9NZ52, A0A087WYN2, B7Z1E9, G3V1K5, J3KS27, J3KSG3, J3KSS7, J3KTR5, J3QRK7, J3QRP3, J3QRS8, J3QS87

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in protein sorting and trafficking between the trans-Golgi network (TGN) and endosomes. Mediates the ARF-dependent recruitment of clathrin to the TGN and binds ubiquitinated proteins and membrane cargo molecules with a cytosolic acidic cluster-dileucine (DXXLL) motif. Mediates export of the GPCR receptor ADRA2B to the cell surface. nvolved in BACE1 transport and sorting as well as regulation of BACE1 protein levels. Regulates retrograde transport of BACE1 from endosomes to the trans-Golgi network via interaction through the VHS motif and dependent of BACE1 phosphorylation. Modulates BACE1 protein levels independently of the interaction between VHS domain and DXXLL motif through recognition of ubiquitination. Key player in a novel DXXLL-mediated endosomal sorting machinery to the recycling pathway that targets NTRK1 to the plasma membrane.

Subunit / interactions. Monomer. Interacts with GGA1 and GGA2. Binds to clathrin and activated ARFs, such as ARF1, ARF5 and ARF6. Binds RABEP1 and RABGEF1. Interacts with the membrane proteins M6PR/CD-MPR and IGF2R/CI-MPR and the accessory proteins SYNRG, EPN4, NECAP1, NECAP2 and AFTPH/aftiphilin. Interacts with TSG101 and UBC. Interacts with ADRA2B. Interacts with NTRK1; the interaction is independent of NTRK1 activation and ubiquitination. Interacts (via VHS domain) with BACE1 (via DXXLL motif).

Subcellular location. Golgi apparatus. trans-Golgi network membrane. Endosome membrane. Early endosome membrane. Recycling endosome membrane.

Tissue specificity. Ubiquitously expressed.

Post-translational modifications. Phosphorylated by CK2 and dephosphorylated by PP2A. Phosphorylation of GGA3 allows the internal DXXLL motif to bind the VHS domain and to inhibit the recognition of cargo signals. Ubiquitinated. Proteolytically cleaved during apoptosis by CASP3.

Domain organisation. The VHS domain functions as a recognition module for sorting signals composed of an acidic cluster followed by two leucines (DXXLL motif). The GAT domain is responsible for interaction with ARF-GTP, UBC and RABEP1. Required for recruitment to the TGN it prevents ARF-GTP hydrolysis. The unstructured hinge region contains clathrin-binding and an autoinhibitory (DXXLL) motifs. The GAE domain binds accessory proteins regulating GGAs function.

Similarity. Belongs to the GGA protein family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9NZ52-1	Long	yes
Q9NZ52-2	Short
Q9NZ52-3	3
Q9NZ52-4	4

RefSeq proteins (6): NP_001166174, NP_001166175, NP_001278570, NP_001278571, NP_054720, NP_619525* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002014	VHS_dom	Domain
IPR004152	GAT_dom	Domain
IPR008152	Clathrin_a/b/g-adaptin_app_Ig	Domain
IPR008153	GAE_dom	Domain
IPR008942	ENTH_VHS	Homologous_superfamily
IPR013041	Clathrin_app_Ig-like_sf	Homologous_superfamily
IPR027422	GGA1-3	Family
IPR038425	GAT_sf	Homologous_superfamily
IPR041198	GGA_N-GAT	Domain
IPR044111	GAT_GGA3	Domain
IPR046996	VHS_GGA3	Domain

Pfam: PF00790, PF02883, PF03127, PF18308

UniProt features (68 total): mutagenesis site 18, helix 15, strand 9, splice variant 4, region of interest 4, domain 3, compositionally biased region 3, sequence variant 3, turn 3, modified residue 2, sequence conflict 2, chain 1, short sequence motif 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
1JUQ	X-RAY DIFFRACTION	2.2
1P4U	X-RAY DIFFRACTION	2.2
1LF8	X-RAY DIFFRACTION	2.3
1JPL	X-RAY DIFFRACTION	2.4
1WR6	X-RAY DIFFRACTION	2.6
1YD8	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZ52-F1	71.16	0.49

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): 159, 275

Mutagenesis-validated functional residues (18):

Position	Phenotype
91	no effect on regulation of bace1 degradation.
194	loss of interaction with arf1 and golgi localization.
199	loss of interaction with arf1 and golgi localization.
217	loss of interaction with arf1 and golgi localization.
247	loss of ubc-binding and ubiquitination.
258	no effect. confers an affinity to rabep1 identical to gga1; when associated with n-283.
262	loss of ubc-binding and ubiquitination.
276	loss of ubc-binding and ubiquitination. abolishes binding to ubiquitin. abolishes regulation of bace1 degradation. no ef
276	loss of ubc-binding and ubiquitination.
280	loss of ubc-binding and ubiquitination.
283	can bind rabep1. confers an affinity to rabep1 identical to gga1; when associated with m-258.
284	loss of ubc-binding and ubiquitination.
293	loss of ubc-binding and ubiquitination.
313	acts as a dominant negative. prevents proteolytic cleavage by casp3; when associated with a-328, a-333 and a-428.
328	prevents proteolytic cleavage by casp3; when associated with a-313, a-333 and a-428.
333	prevents proteolytic cleavage by casp3; when associated with a-313, a-328 and a-428.
391–395	increased binding to igf2r.
428	prevents proteolytic cleavage by casp3; when associated with a-313, a-328 and a-333.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-8854214	TBC/RABGAPs
R-HSA-8875656	MET receptor recycling
R-HSA-977225	Amyloid fiber formation

MSigDB gene sets: 209 (showing top): ACTACCT_MIR196A_MIR196B, GOBP_LYSOSOMAL_TRANSPORT, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_PROTEIN_TARGETING, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_VACUOLAR_TRANSPORT, KEGG_LYSOSOME, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOMF_GTPASE_BINDING, GOBP_NEGATIVE_REGULATION_OF_AMIDE_METABOLIC_PROCESS, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY

GO Biological Process (17): protein targeting to lysosome (GO:0006622), intracellular protein transport (GO:0006886), Golgi to plasma membrane transport (GO:0006893), protein catabolic process (GO:0030163), regulation of protein stability (GO:0031647), protein destabilization (GO:0031648), endocytic recycling (GO:0032456), protein localization to cell surface (GO:0034394), Golgi to plasma membrane protein transport (GO:0043001), negative regulation of amyloid-beta formation (GO:1902430), positive regulation of lysosomal protein catabolic process (GO:1905167), protein transport (GO:0015031), vesicle-mediated transport (GO:0016192), positive regulation of protein catabolic process (GO:0045732), protein localization to lysosome (GO:0061462), protein localization to membrane (GO:0072657), protein localization to cell periphery (GO:1990778)

GO Molecular Function (6): small GTPase binding (GO:0031267), phosphatidylinositol binding (GO:0035091), ubiquitin binding (GO:0043130), protein-containing complex binding (GO:0044877), protein transporter activity (GO:0140318), protein binding (GO:0005515)

GO Cellular Component (12): lysosome (GO:0005764), Golgi apparatus (GO:0005794), trans-Golgi network (GO:0005802), endosome membrane (GO:0010008), early endosome membrane (GO:0031901), protein-containing complex (GO:0032991), recycling endosome membrane (GO:0055038), endosome (GO:0005768), early endosome (GO:0005769), membrane (GO:0016020), recycling endosome (GO:0055037), intracellular vesicle (GO:0097708)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Rab regulation of trafficking	1
Signaling by MET	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular protein localization	5
endosome	3
protein transport	2
vesicle-mediated transport to the plasma membrane	2
transport	2
binding	2
endomembrane system	2
intracellular membrane-bounded organelle	2
endosome membrane	2
protein targeting to vacuole	1
lysosomal transport	1
protein localization to lysosome	1
intracellular transport	1
post-Golgi vesicle-mediated transport	1
macromolecule catabolic process	1
protein metabolic process	1
regulation of biological quality	1
regulation of protein stability	1
endosomal transport	1
Golgi to plasma membrane transport	1
establishment of protein localization to plasma membrane	1
protein localization to plasma membrane	1
amyloid-beta formation	1
regulation of amyloid-beta formation	1
negative regulation of amyloid precursor protein catabolic process	1
positive regulation of protein catabolic process in the vacuole	1
lysosomal protein catabolic process	1
regulation of lysosomal protein catabolic process	1
establishment of protein localization	1
cellular process	1
positive regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
positive regulation of protein metabolic process	1
protein localization to vacuole	1
localization within membrane	1
GTPase binding	1
anion binding	1
ubiquitin-like protein binding	1
transporter activity	1

Protein interactions and networks

STRING

1893 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GGA3	ARF6	P26438	848
GGA3	M6PR	P20645	847
GGA3	ARF1	P10947	807
GGA3	IGF2R	P11717	786
GGA3	CSNK2A1	P19138	768
GGA3	CSNK2A2	P19784	764
GGA3	GOLPH3	Q9H4A6	757
GGA3	BACE1	P56817	751
GGA3	AP1M1	Q9BXS5	724
GGA3	SYNRG	Q9UMZ2	704
GGA3	RABEP1	Q15276	688
GGA3	ARF3	P16587	657
GGA3	AP1S1	P61966	616
GGA3	CDKN2A	P42771	611
GGA3	TSG101	Q99816	586

IntAct

97 interactions, top by confidence:

A	B	Type	Score
GGA3	IGF2R	psi-mi:“MI:0407”(direct interaction)	0.760
GGA3	IGF2R	psi-mi:“MI:0915”(physical association)	0.760
IGF2R	GGA3	psi-mi:“MI:0407”(direct interaction)	0.760
GGA3	IGF2R	psi-mi:“MI:0403”(colocalization)	0.760
IGF2R	GGA3	psi-mi:“MI:0915”(physical association)	0.760
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
GGA3	RABEP1	psi-mi:“MI:0407”(direct interaction)	0.700
GGA3	RABEP1	psi-mi:“MI:0915”(physical association)	0.700
RABEP1	GGA3	psi-mi:“MI:0915”(physical association)	0.700
ARF1	GGA3	psi-mi:“MI:0915”(physical association)	0.650
ARF1	GGA3	psi-mi:“MI:0407”(direct interaction)	0.650
GGA3	ARF1	psi-mi:“MI:0915”(physical association)	0.650
GGA3	PTGDR	psi-mi:“MI:0915”(physical association)	0.610
PTGDR	GGA3	psi-mi:“MI:0915”(physical association)	0.610
GGA3	PTGDR	psi-mi:“MI:0403”(colocalization)	0.610
GGA3	ARF6	psi-mi:“MI:0915”(physical association)	0.590
ARF6	GGA3	psi-mi:“MI:0915”(physical association)	0.590

BioGRID (184): RNF11 (Protein-peptide), ITCH (Affinity Capture-Western), ARF1 (Reconstituted Complex), GGA3 (Reconstituted Complex), GGA3 (Affinity Capture-RNA), GGA3 (Affinity Capture-RNA), TOLLIP (Reconstituted Complex), RNF11 (Co-localization), GGA3 (Co-fractionation), ARF6 (Reconstituted Complex), GGA3 (Two-hybrid), GGA3 (Proximity Label-MS), GGA3 (Affinity Capture-Western), GGA3 (Two-hybrid), GGA3 (Proximity Label-MS)

ESM2 similar proteins: A0A0G2JV04, B0V207, D3Z8X7, D3ZFJ3, D3ZND0, F1LM81, G9CGD6, O00499, O08539, O08839, O12940, O60308, O60784, O75674, O88746, P42567, P55194, Q05DH4, Q0GNC1, Q0IHV1, Q27J81, Q3B7M3, Q3UN70, Q4KLN4, Q505K2, Q5FVK6, Q5T0F9, Q5U3K5, Q66HA5, Q68EF0, Q6P1N0, Q6P5E6, Q6P9Q4, Q6P9Q6, Q80V31, Q80V94, Q8BMI3, Q8BRN9, Q8K1A6, Q8R0H9

Diamond homologs: A0A0G2JV04, A3LXQ8, F4KAU9, O01498, O14964, O43747, O60784, O75843, O75886, O88512, O88746, O93436, P22892, P70297, Q0V8S0, Q5R5M2, Q68FJ8, Q6P5E6, Q8BMI3, Q8R0H9, Q92783, Q960X8, Q99LI8, Q9JJ50, Q9NZ52, Q9UJY4, Q9UJY5, A0JNB0, A1A5H8, A1CEK6, A1DFN5, A1Y2K1, A2QW93, A4RF61, A5D8S5, A6H7G2, A6QLK6, A7MBI0, D3ZG83, F1RDG9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
VPS18	“down-regulates activity”	GGA3	monoubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 66 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
TBC/RABGAPs	5	26.5×	2e-04
Golgi Associated Vesicle Biogenesis	5	20.4×	4e-04
Signaling by ALK fusions and activated point mutants	6	18.4×	2e-04
Cargo recognition for clathrin-mediated endocytosis	8	17.1×	5e-06
Clathrin-mediated endocytosis	9	15.7×	3e-06
Constitutive Signaling by Aberrant PI3K in Cancer	6	15.5×	3e-04
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	6	11.8×	9e-04
RAF/MAP kinase cascade	7	8.7×	9e-04

GO biological processes:

GO term	Partners	Fold	FDR
cellular response to retinoic acid	5	20.9×	1e-03
positive regulation of neuron projection development	7	17.1×	1e-04
protein autophosphorylation	5	13.0×	5e-03
positive regulation of MAPK cascade	6	8.6×	6e-03
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	6	8.4×	6e-03
intracellular protein transport	6	6.9×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	2
Uncertain significance	130
Likely benign	11
Benign	14

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
590316	NM_024844.5(NUP85):c.1933C>T (p.Arg645Trp)	Likely pathogenic
590318	NM_024844.5(NUP85):c.1741G>C (p.Ala581Pro)	Likely pathogenic

SpliceAI

2896 predictions. Top by Δscore:

Variant	Effect	Δscore
17:75238760:TGA:T	acceptor_gain	1.0000
17:75238763:C:CC	acceptor_gain	1.0000
17:75238908:TGGTA:T	donor_loss	1.0000
17:75238909:GGTAC:G	donor_loss	1.0000
17:75238910:GTAC:G	donor_loss	1.0000
17:75238911:TAC:T	donor_loss	1.0000
17:75239080:CTGC:C	acceptor_gain	1.0000
17:75239083:CCTG:C	acceptor_loss	1.0000
17:75239373:A:AC	donor_gain	1.0000
17:75239374:C:CC	donor_gain	1.0000
17:75239374:CTAGG:C	donor_gain	1.0000
17:75239788:CA:C	donor_gain	1.0000
17:75241396:TCA:T	donor_loss	1.0000
17:75241398:A:AG	donor_loss	1.0000
17:75241399:CCT:C	donor_loss	1.0000
17:75241402:T:A	donor_gain	1.0000
17:75241512:GTCCC:G	acceptor_gain	1.0000
17:75241513:TCCC:T	acceptor_gain	1.0000
17:75241514:CCC:C	acceptor_gain	1.0000
17:75241514:CCCC:C	acceptor_gain	1.0000
17:75241515:CC:C	acceptor_gain	1.0000
17:75241515:CCC:C	acceptor_gain	1.0000
17:75241516:CC:C	acceptor_gain	1.0000
17:75241517:C:CC	acceptor_gain	1.0000
17:75241518:T:C	acceptor_loss	1.0000
17:75241523:C:CT	acceptor_gain	1.0000
17:75241608:CACT:C	donor_loss	1.0000
17:75241609:ACTC:A	donor_loss	1.0000
17:75241610:CTCA:C	donor_loss	1.0000
17:75241611:T:TA	donor_loss	1.0000

AlphaMissense

4708 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:75244658:G:C	F87L	1.000
17:75244658:G:T	F87L	1.000
17:75244660:A:G	F87L	1.000
17:75241489:A:G	L286P	0.999
17:75241507:A:G	L280P	0.999
17:75242850:A:C	I197S	0.999
17:75242850:A:G	I197T	0.999
17:75242850:A:T	I197N	0.999
17:75242853:A:G	L196P	0.999
17:75243458:A:G	L138P	0.999
17:75243510:A:G	W121R	0.999
17:75243510:A:T	W121R	0.999
17:75244634:T:A	K95N	0.999
17:75244634:T:G	K95N	0.999
17:75244636:T:C	K95E	0.999
17:75244713:A:G	L69P	0.999
17:75246561:A:G	L50P	0.999
17:75246564:A:G	L49P	0.999
17:75246573:G:T	A46D	0.999
17:75246574:C:G	A46P	0.999
17:75246713:C:G	G42R	0.999
17:75246713:C:T	G42R	0.999
17:75246790:G:T	A16D	0.999
17:75261550:A:G	L13P	0.999
17:75261550:A:T	L13H	0.999
17:75238364:A:G	L696P	0.998
17:75242400:A:G	L228P	0.998
17:75242862:G:T	A193D	0.998
17:75242863:C:G	A193P	0.998
17:75242898:A:G	L181P	0.998

dbSNP variants (sampled 300 via entrez): RS1000003367 (17:75260882 A>C,G), RS1000101018 (17:75236315 A>AAAAACAAAC), RS1000105026 (17:75250943 T>C,G), RS1000105412 (17:75255710 T>C), RS1000160793 (17:75240011 G>A,C,T), RS1000184743 (17:75237375 G>A,T), RS1000311939 (17:75245383 T>C), RS1000403465 (17:75235301 A>G), RS1000412026 (17:75245188 C>T), RS1000705016 (17:75240041 G>A), RS1000768457 (17:75230569 G>A,C), RS1000808619 (17:75250916 T>C), RS1000811583 (17:75241130 C>T), RS1000863247 (17:75230919 C>G,T), RS1000973297 (17:75236576 G>A)

Disease associations

OMIM: gene MIM:606006 | disease phenotypes: MIM:618176, MIM:617872

GenCC curated gene-disease

Mondo (2): nephrotic syndrome, type 17 (MONDO:0032580), combined oxidative phosphorylation deficiency 34 (MONDO:0054741)

Orphanet (1): Syndromic sensorineural deafness due to combined oxidative phosphorylation defect (Orphanet:457223)

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

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects acetylation, affects methylation, increases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases expression	2
FR900359	decreases phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
methacrylaldehyde	increases expression, increases abundance, affects cotreatment	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
monomethylarsonous acid	affects acetylation, affects methylation	1
abrine	increases expression	1
Arsenic Trioxide	affects binding, decreases reaction	1
Acetaminophen	increases expression	1
Acrolein	increases abundance, affects cotreatment, increases expression	1
Benzo(a)pyrene	decreases methylation	1
Doxorubicin	decreases expression	1
Ozone	affects cotreatment, increases expression, increases abundance	1
Rotenone	decreases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Cyclosporine	increases expression	1
Cadmium Chloride	decreases expression	1
Particulate Matter	increases abundance, increases expression	1
Volatile Organic Compounds	affects cotreatment, increases expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E0DR	Ubigene HeLa GGA3 KO	Cancer cell line	Female
CVCL_F1B8	HeLa GGA3-/-	Cancer cell line	Female
CVCL_F1B9	HeLa GGA23-/-	Cancer cell line	Female
CVCL_F1BA	HeLa GGA123-/-	Cancer cell line	Female

Clinical trials (associated diseases)

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