RAP1GDS1

Summary

RAP1GDS1 (Rap1 GTPase-GDP dissociation stimulator 1, HGNC:9859) is a protein-coding gene on chromosome 4q23, encoding Rap1 GTPase-GDP dissociation stimulator 1 (P52306). Acts as a GEF (guanine nucleotide exchange factor) for the Rho family of small GTP-binding proteins (G proteins) that stimulates the dissociation of GDP to enable subsequent binding of GTP.

The smg GDP dissociation stimulator (smgGDS) protein is a stimulatory GDP/GTP exchange protein with GTPase activity (Riess et al., 1993 [PubMed 8262526]).

Source: NCBI Gene 5910 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Alfadhel syndrome (Strong, GenCC)
• GWAS associations: 8
• Clinical variants (ClinVar): 109 total — 2 pathogenic
• Phenotypes (HPO): 31
• Cancer driver (intOGen): activating (oncogene-like) across 2 cancer types
• MANE Select transcript: NM_001100427

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9859
Approved symbol	RAP1GDS1
Name	Rap1 GTPase-GDP dissociation stimulator 1
Location	4q23
Locus type	gene with protein product
Status	Approved
Aliases	SmgGDS
Ensembl gene	ENSG00000138698
Ensembl biotype	protein_coding
OMIM	179502
Entrez	5910

Gene structure

Transcript identifiers

Ensembl transcripts: 57 — 48 protein_coding, 3 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined, 3 retained_intron

ENST00000264572, ENST00000339360, ENST00000380158, ENST00000408900, ENST00000408927, ENST00000453712, ENST00000503667, ENST00000503745, ENST00000505378, ENST00000507303, ENST00000508213, ENST00000508490, ENST00000509011, ENST00000509501, ENST00000510870, ENST00000511212, ENST00000511379, ENST00000512857, ENST00000514122, ENST00000514139, ENST00000515187, ENST00000884480, ENST00000884481, ENST00000884482, ENST00000884483, ENST00000884484, ENST00000884485, ENST00000884486, ENST00000884487, ENST00000884488, ENST00000884489, ENST00000884490, ENST00000884491, ENST00000884492, ENST00000884493, ENST00000884494, ENST00000884495, ENST00000884496, ENST00000884497, ENST00000932075, ENST00000932076, ENST00000932077, ENST00000932078, ENST00000932079, ENST00000932080, ENST00000932081, ENST00000945538, ENST00000945539, ENST00000945540, ENST00000945541, ENST00000945542, ENST00000945543, ENST00000945544, ENST00000945546, ENST00000945547, ENST00000945548, ENST00000945549

RefSeq mRNA: 6 — MANE Select: NM_001100427 NM_001100426, NM_001100427, NM_001100428, NM_001100429, NM_001100430, NM_021159

CCDS: CCDS43253, CCDS43254, CCDS47105, CCDS47106, CCDS47107, CCDS47108

Canonical transcript exons

ENST00000408927 — 15 exons

Exon	Start	End
ENSE00001364296	98441990	98443858
ENSE00001577177	98404477	98404602
ENSE00001578183	98436940	98437068
ENSE00001578328	98433936	98434062
ENSE00001582351	98420019	98420144
ENSE00001583800	98421255	98421394
ENSE00001583904	98417367	98417498
ENSE00001584967	98416745	98416888
ENSE00001586509	98418657	98418791
ENSE00003464230	98293408	98293515
ENSE00003695398	98379017	98379163
ENSE00003700333	98352476	98352601
ENSE00003702204	98343139	98343261
ENSE00003788697	98391952	98392080
ENSE00003899387	98261384	98261569

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 98.48.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.3188 / max 243.7578, expressed in 1809 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
48975	13.8900	1797
48976	5.3831	1681
48974	1.0457	627

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	98.48	gold quality
pons	UBERON:0000988	98.14	gold quality
substantia nigra pars compacta	UBERON:0001965	97.83	gold quality
trigeminal ganglion	UBERON:0001675	97.63	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.56	gold quality
middle temporal gyrus	UBERON:0002771	97.51	gold quality
dorsal root ganglion	UBERON:0000044	97.34	gold quality
cortical plate	UBERON:0005343	97.27	gold quality
superior vestibular nucleus	UBERON:0007227	96.86	gold quality
dorsal plus ventral thalamus	UBERON:0001897	96.64	gold quality
sperm	CL:0000019	96.62	gold quality
corpus callosum	UBERON:0002336	96.47	gold quality
medulla oblongata	UBERON:0001896	96.42	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.20	gold quality
postcentral gyrus	UBERON:0002581	96.03	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.98	gold quality
parietal lobe	UBERON:0001872	95.97	gold quality
Brodmann (1909) area 46	UBERON:0006483	95.97	gold quality
prefrontal cortex	UBERON:0000451	95.96	gold quality
inferior olivary complex	UBERON:0002127	95.94	gold quality
ventral tegmental area	UBERON:0002691	95.91	gold quality
inferior vagus X ganglion	UBERON:0005363	95.91	gold quality
subthalamic nucleus	UBERON:0001906	95.86	gold quality
entorhinal cortex	UBERON:0002728	95.82	gold quality
male germ cell	CL:0000015	95.53	gold quality
globus pallidus	UBERON:0001875	95.45	gold quality
medial globus pallidus	UBERON:0002477	95.44	gold quality
spinal cord	UBERON:0002240	95.43	gold quality
lateral globus pallidus	UBERON:0002476	95.39	gold quality
orbitofrontal cortex	UBERON:0004167	95.11	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

113 targeting RAP1GDS1, 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-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-3924	100.00	72.09	2394
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-489-3P	99.80	66.46	839
HSA-MIR-323A-3P	99.79	70.30	1739
HSA-MIR-8076	99.78	68.52	1170
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-3913-3P	99.74	66.53	938
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-548AU-3P	99.70	68.22	1373
HSA-MIR-7161-5P	99.68	68.92	1592

Literature-anchored findings (GeneRIF, showing 26)

• activated by turbulence and is involved in integrin [alpha]IIb[beta]3-mediated cell adhesion in human megakaryocytes (PMID:12690117)
• results demonstrate that B-CLL cells uniquely activate Rap1 in response to PDE4 inhibitors and suggest that physiologic stimuli that activate EPAC may transmit an antiapoptotic signal (PMID:14615375)
• SmgGDS promotes the malignant Non-small cell lung carcinoma (NSCLC)phenotype and is an intriguing therapeutic target in NSCLC. (PMID:17951244)
• Epac activates the small G proteins Rap1 and Rab3A to achieve exocytosis. (PMID:19546222)
• ALK activation of Rap1 via the Rap1-specific GEF C3Gmay contribute to cell proliferation and oncogenesis of neuroblastoma. (PMID:20190816)
• C3G stimulates guanine nucleotide exchange on Drosophila Rap GTPases in vitro (PMID:20209136)
• Results indicate that guanine nucleotide exchange and interactions with SmgGDS splice variants can regulate the entrance and passage of PBR-possessing small GTPases through the prenylation pathway. (PMID:20709748)
• Results indicate that SmgGDS is a bona fide GEF that specifically activates RhoA and RhoC through a unique mechanism not used by other Rho family exchange factors. (PMID:21242305)
• findings provide compelling evidence of a novel role for junctional adhesion molecule-A (JAM-A)in driving breast cancer cell migration via activation of Rap1 GTPase and beta1-integrin (PMID:21429211)
• These results indicate that statins exert their pleiotropic effects through SmgGDS upregulation with a resultant Rac1 degradation and reduced oxidative stress in animals and humans. (PMID:23640485)
• findings identify SmgGDS-558 as an activator of RhoA and NF-kB in breast cancer, and demonstrate a functional role for SmgGDS-558 in the proliferation of breast cancer cells and tumorigenesis. (PMID:24197117)
• TG2 contributes to apoptosis induction in Jurkat T cells by modulating Ca2+ homeostasis via cross-linking RAP1GDS1. (PMID:24349085)
• this study provides evidence that SmgGDS-607 associates with GTPases through recognition of the last amino acid in the CAAX motif. (PMID:24415755)
• SmgGDS promotes cell cycle progression in multiple types of cancer, making SmgGDS a valuable target for cancer therapeutics. (PMID:24552806)
• results indicate that statins selectively up-regulate SmgGDS in endothelial cells, for which the beta1-integrin/Akt1 pathway may be involved, demonstrating the novel aspects of the pleiotropic effects of statins (PMID:26598509)
• DiRas1 expression inhibits malignant features of cancers in part by nonproductively binding to SmgGDS and inhibiting the binding of other small GTPases to SmgGDS (PMID:26814130)
• In addition, a PINK1 mutant, which induced mitochondrial enlargement and had been considered as a Drosophila model of Parkinson’s disease (PD), caused fly muscle defects, and the loss of vimar could rescue these defects. Furthermore, we found that the mammalian homolog of Vimar, RAP1GDS1, played a similar role in regulating mitochondrial morphology, suggesting a functional conservation of this GEF member. (PMID:27716788)
• Unlike Rap1B, phosphorylation in the polybasic region of Rap1A does not detectably inhibit its prenylation or its binding to SmgGDS-607. (PMID:27760305)
• Data suggest that SmgGDS-558 splice variant exhibits a fold containing tandem copies of armadillo-repeat motifs not present in other guanine nucleotide exchange factors (GEFs); SmgGDS harbors distinct positively and negatively charged regions, both of which play critical roles in binding to RhoA and in GEF activity. (SmgGDS = smg p21 stimulatory GDP exchange protein; RhoA = ras homolog gene family, member A) (PMID:28630045)
• a novel nuclear role for SmgGDS in protecting malignant cells from nucleolar stress, thus promoting cell cycle progression and tumorigenesis. (PMID:28806394)
• SmgGDS-607 completely inhibits RhoA prenylation catalyzed by protein geranylgeranyltransferase I (GGTase-I) in an in vitro radiolabel incorporation assay. SmgGDS-607 inhibits prenylation by binding to and blocking access to the C-terminal tail of the small GTPase (substrate sequestration mechanism) rather than via inhibition of the prenyltransferase activity. (PMID:29940100)
• Study reveals a cryptic pocket by which SmgGDS-558 accommodates RhoA prenylation, loosening the structure of Rho when it interacts with SmgGDS, which may enable drug development strategies for targeting SmgGDS and small GTPases. (PMID:30190425)
• The competitive binding affinities of the small GTPase for SmgGDS-607 and FTase dictate the extent of this inhibition. SmgGDS-607 increases the rate of farnesylation of HRas by enhancing product release from FTase. (PMID:31197034)
• Targeting SmgGDS splicing to lower the protein isoform ratio is effective to inhibit the malignant phenotype generated by small GTPases. (PMID:32019878)
• Mutated RAP1GDS1 causes a new syndrome of dysmorphic feature, intellectual disability & speech delay. (PMID:32431071)
• Silencing of SmgGDS, a Novel mTORC1 Inducer That Binds to RHEBs, Inhibits Malignant Mesothelioma Cell Proliferation. (PMID:33574130)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	RAP1GDS1	ENSDARG00000073741
mus_musculus	Rap1gds1	ENSMUSG00000028149
rattus_norvegicus	Rap1gds1	ENSRNOG00000015987
drosophila_melanogaster	vimar	FBGN0022960

Protein

Protein identifiers

Rap1 GTPase-GDP dissociation stimulator 1 — P52306 (reviewed: P52306)

Alternative names: Exchange factor smgGDS, SMG GDS protein, SMG P21 stimulatory GDP/GTP exchange protein

All UniProt accessions (10): P52306, D6RB97, D6RBC6, D6RC12, D6RC85, D6REZ0, D6RHH8, D6RHZ7, H0Y8M2, U3KQJ4

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a GEF (guanine nucleotide exchange factor) for the Rho family of small GTP-binding proteins (G proteins) that stimulates the dissociation of GDP to enable subsequent binding of GTP. Additionally, appears to chaperone the processing and/or trafficking of small GTPases containing a C-terminal polybasic region independently of GEF activity. Targets include RAP1A/RAP1B, RHOA, RHOB, RHOC, RAC1 and KRAS. Regulates mitochondrial dynamics by controlling RHOT function to promote mitochondrial fission during high calcium conditions. Able to promote the Ca(2+) release from the endoplasmic reticulum via both inositol trisphosphate (Ins3P) and ryanodine sensitive receptors leading to a enhanced mitochondrial Ca(2+) uptake. Acts as a GEF (guanine nucleotide exchange factor) for unprenylated RHOA. Chaperones the entry and passage of small GTPases through the prenylation pathway. Recognizes the last amino acid in the GTPase C-terminal CAAX motif with a preference for ‘Leu’ over ‘Met’, indicating involvement in the geranylgeranylation pathway. Acts as a GEF (guanine nucleotide exchange factor) for prenylated RHOA. Acts as a GEF for RHOC. Chaperones the downstream trafficking and/or processing of small newly prenylated GTPases. Escorts RAC1 to the nucleus.

Subunit / interactions. Interacts with RABL3. Interacts with RHOT1. Interacts with unprenylated RHOA; the interaction is direct. Interacts with RAP1A. Interacts with KRAS. Interacts with RAC1. Interacts with RAP1B. Preferentially interacts with unprenylated GTPases that will become geranylgeranylated. May also interact with prenylated GTPases. Interacts with prenylated RHOA; the interaction is direct and in a 1:1 stoichiometry. Interacts with RAP1A. Interacts with KRAS. Interacts with RAC1. Interacts with RAP1B. Preferentially interacts with prenylated GTPases.

Subcellular location. Cytoplasm. Cytosol. Endoplasmic reticulum. Mitochondrion. Nucleus.

Post-translational modifications. Forms covalent cross-links mediated by transglutaminase TGM2, between a glutamine and the epsilon-amino group of a lysine residue, forming homopolymers and heteropolymers.

Disease relevance. Alfadhel syndrome (AFDL) [MIM:620655] An autosomal recessive neurodevelopmental disorder characterized by global developmental delay and regression, intellectual disability, hypotonia, delayed motor development, stereotypy, behavioral abnormalities, and dysmorphic features. The disease is caused by variants affecting the gene represented in this entry. A chromosomal aberration involving RAP1GDS1 has been found in M0 type acute myeloid leukemia. Translocation (t4;11)(q23;p15) with NUP98. A chromosomal aberration involving RAP1GDS1 has been found in T-cell acute lymphocytic leukemia. Translocation t(4;11)(q23;p15) with NUP98.

Isoforms (6)

UniProt ID	Names	Canonical?
P52306-1	1, SmgGDS-607	yes
P52306-2	2, SmgGDS-558
P52306-3	3
P52306-4	4
P52306-5	5
P52306-6	6

RefSeq proteins (6): NP_001093896, NP_001093897, NP_001093898, NP_001093899, NP_001093900, NP_066982 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000225	Armadillo	Repeat
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR040144	RAP1GDS1	Family

Pfam: PF00514

UniProt features (62 total): helix 33, turn 6, repeat 5, splice variant 4, sequence conflict 4, region of interest 3, sequence variant 2, chain 1, site 1, modified residue 1, strand 1, short sequence motif 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
5XGC	X-RAY DIFFRACTION	2.1
5ZHX	X-RAY DIFFRACTION	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P52306-F1	95.51	0.93

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 1–2 (breakpoint for translocation to form the nup98-rap1gds1 fusion protein)

Post-translational modifications (1): 230

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9013419	RHOT2 GTPase cycle
R-HSA-9013425	RHOT1 GTPase cycle

MSigDB gene sets: 323 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_RESPONSE_TO_ANGIOTENSIN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, AP2_Q3, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, SP1_Q2_01, GOBP_MITOCHONDRIAL_CALCIUM_ION_HOMEOSTASIS, YORDY_RECIPROCAL_REGULATION_BY_ETS1_AND_SP100_UP, GOBP_REGULATION_OF_MITOCHONDRION_ORGANIZATION, GOBP_REGULATION_OF_PROTEIN_SECRETION, GOBP_REGULATION_OF_ANATOMICAL_STRUCTURE_SIZE

GO Biological Process (13): cardiac muscle hypertrophy (GO:0003300), regulation of mitochondrion organization (GO:0010821), vascular associated smooth muscle contraction (GO:0014829), myosin filament assembly (GO:0031034), negative regulation of endoplasmic reticulum calcium ion concentration (GO:0032471), protein localization to nucleus (GO:0034504), positive regulation of mitochondrial calcium ion concentration (GO:0051561), regulation of ERK5 cascade (GO:0070376), CAAX-box protein maturation (GO:0080120), angiotensin-activated signaling pathway involved in heart process (GO:0086098), regulation of matrix metallopeptidase secretion (GO:1904464), heart process (GO:0003015), positive regulation of GTPase activity (GO:0043547)

GO Molecular Function (3): guanyl-nucleotide exchange factor activity (GO:0005085), protein binding (GO:0005515), GTPase regulator activity (GO:0030695)

GO Cellular Component (7): nucleus (GO:0005634), mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), extracellular exosome (GO:0070062), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Miro GTPase Cycle	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	3
cytoplasm	3
GTPase activity	2
cellular anatomical structure	2
striated muscle hypertrophy	1
mitochondrion organization	1
regulation of organelle organization	1
smooth muscle contraction	1
vasoconstriction	1
myosin filament organization	1
protein-containing complex assembly	1
endoplasmic reticulum calcium ion homeostasis	1
protein localization to organelle	1
mitochondrial calcium ion homeostasis	1
regulation of MAPK cascade	1
ERK5 cascade	1
protein processing	1
protein prenylation	1
protein maturation	1
heart process	1
angiotensin-activated signaling pathway	1
G protein-coupled receptor signaling pathway involved in heart process	1
regulation of protein secretion	1
matrix metallopeptidase secretion	1
circulatory system process	1
regulation of GTPase activity	1
positive regulation of hydrolase activity	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
binding	1
nucleoside-triphosphatase regulator activity	1
endomembrane system	1
extracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

908 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RAP1GDS1	NUP98	P52948	772
RAP1GDS1	DDX10	Q13206	751
RAP1GDS1	ADD3	Q9UEY8	697
RAP1GDS1	PSIP1	O75475	649
RAP1GDS1	RABIF	P47224	641
RAP1GDS1	HOXC13	P31276	630
RAP1GDS1	NSD1	Q96L73	620
RAP1GDS1	PRRX1	P54821	616
RAP1GDS1	SETBP1	Q9Y6X0	615
RAP1GDS1	NSD3	Q9BZ95	605
RAP1GDS1	RHOA	P06749	577
RAP1GDS1	PHF23	Q9BUL5	576
RAP1GDS1	TTC23	Q5W5X9	533
RAP1GDS1	KRAS	P01116	525
RAP1GDS1	HOXD13	P35453	513
RAP1GDS1	NUP214	P35658	513

IntAct

155 interactions, top by confidence:

A	B	Type	Score
CDKN2A	CDK4	psi-mi:“MI:0914”(association)	0.960
RHOA	ARHGEF11	psi-mi:“MI:0914”(association)	0.900
RAP1GDS1	rep	psi-mi:“MI:0407”(direct interaction)	0.840
RAP1GDS1	rep	psi-mi:“MI:0915”(physical association)	0.840
RAC1	RAP1GDS1	psi-mi:“MI:0914”(association)	0.800
RHOC	RAP1GDS1	psi-mi:“MI:0914”(association)	0.730
RHOA	CTSA	psi-mi:“MI:0914”(association)	0.730
IFT27	IFT56	psi-mi:“MI:0914”(association)	0.690
HRAS	RAP1GDS1	psi-mi:“MI:0915”(physical association)	0.690
RAP1GDS1	HRAS	psi-mi:“MI:0915”(physical association)	0.690
PLEKHB1	RAP1GDS1	psi-mi:“MI:0915”(physical association)	0.670
RAP1GDS1	PLEKHB1	psi-mi:“MI:0915”(physical association)	0.670
ARL4C	RGS12	psi-mi:“MI:0914”(association)	0.640
RAP1GDS1	DIRAS1	psi-mi:“MI:0914”(association)	0.640
RAB15	RAP1GDS1	psi-mi:“MI:0914”(association)	0.640
RAC1	COX6C	psi-mi:“MI:0914”(association)	0.640
IFT22	IFT56	psi-mi:“MI:0914”(association)	0.640
RAB31	CHM	psi-mi:“MI:0914”(association)	0.640
POLR2L	POLR3A	psi-mi:“MI:0914”(association)	0.640
DNAJC7	PLD2	psi-mi:“MI:0914”(association)	0.640

BioGRID (237): MBIP (Two-hybrid), PLEKHB1 (Two-hybrid), RAP1GDS1 (Affinity Capture-RNA), RAP1GDS1 (Two-hybrid), RAP1GDS1 (Affinity Capture-MS), RAP1GDS1 (Affinity Capture-MS), RAP1GDS1 (Affinity Capture-MS), RAP1GDS1 (Affinity Capture-MS), RAP1GDS1 (Affinity Capture-MS), RAP1GDS1 (Affinity Capture-MS), RAP1GDS1 (Affinity Capture-MS), RAP1GDS1 (Affinity Capture-MS), RAP1GDS1 (Affinity Capture-MS), RAP1GDS1 (Affinity Capture-MS), RAP1GDS1 (Affinity Capture-MS)

ESM2 similar proteins: A2AU72, B0F9L4, E9Q912, F1QWA8, O35099, O46563, O75165, O75602, O93614, P0C6R2, P39968, P42345, P42346, P52306, Q04173, Q1RMS6, Q21029, Q5EFZ4, Q5PPZ9, Q5W041, Q5ZL91, Q66L58, Q68FK4, Q6BTZ4, Q6C5Y8, Q6CX49, Q6DD21, Q6FJV1, Q6NUP7, Q6PIY5, Q757R0, Q7YRF1, Q80TR8, Q80W92, Q80WQ2, Q84ZC0, Q8BVE3, Q8BW49, Q8C0Y0, Q8NFP9

Diamond homologs: E9Q912, O93614, P52306, Q04173, Q5PPZ9, A1Z6S7

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
RAP1GDS1	up-regulates	RHOA	binding
RAP1GDS1	up-regulates	RHOC	binding
RAP1GDS1	up-regulates	CDC42	binding
RAP1GDS1	up-regulates	KRAS	binding
RAP1GDS1	up-regulates	RAC1	binding
RAP1GDS1	up-regulates	RAC2	binding
RAP1GDS1	up-regulates	RAP1A	binding
RAP1GDS1	up-regulates	RAP1B	binding
RAP1GDS1	up-regulates	RHOB	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 143 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
RAB geranylgeranylation	9	14.8×	6e-06
GPVI-mediated activation cascade	5	14.7×	1e-03
Signaling by SCF-KIT	5	11.8×	2e-03
Regulation of RAS by GAPs	5	9.2×	4e-03
RAB GEFs exchange GTP for GDP on RABs	7	8.3×	1e-03
Signaling by BRAF and RAF1 fusions	5	8.1×	5e-03
RAC1 GTPase cycle	8	4.7×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
Ras protein signal transduction	10	15.7×	4e-07
small GTPase-mediated signal transduction	9	12.6×	1e-05
regulation of actin cytoskeleton organization	8	9.6×	5e-04
intracellular protein transport	16	7.9×	2e-07

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 2 cancer types — CCRCC, ESCC.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	75
Likely benign	5
Benign	2

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1334172	NM_001100427.2(RAP1GDS1):c.1441-1G>A	Pathogenic
2671875	NM_001100427.2(RAP1GDS1):c.80del (p.Leu27fs)	Pathogenic

SpliceAI

3287 predictions. Top by Δscore:

Variant	Effect	Δscore
4:98261565:CATGG:C	donor_gain	1.0000
4:98261566:ATGG:A	donor_gain	1.0000
4:98261567:TGG:T	donor_gain	1.0000
4:98261567:TGGGT:T	donor_loss	1.0000
4:98261568:GG:G	donor_gain	1.0000
4:98261568:GGG:G	donor_gain	1.0000
4:98261568:GGGTA:G	donor_loss	1.0000
4:98261569:GG:G	donor_gain	1.0000
4:98261569:GGTA:G	donor_loss	1.0000
4:98261570:G:GG	donor_gain	1.0000
4:98261571:T:A	donor_loss	1.0000
4:98267013:G:GT	donor_gain	1.0000
4:98293402:A:AG	acceptor_gain	1.0000
4:98293403:A:G	acceptor_gain	1.0000
4:98293403:AGCAG:A	acceptor_gain	1.0000
4:98293404:GC:G	acceptor_gain	1.0000
4:98293404:GCA:G	acceptor_gain	1.0000
4:98293404:GCAGA:G	acceptor_gain	1.0000
4:98293405:CA:C	acceptor_loss	1.0000
4:98293406:A:AG	acceptor_gain	1.0000
4:98293406:A:AT	acceptor_loss	1.0000
4:98293407:G:GG	acceptor_gain	1.0000
4:98293407:GAT:G	acceptor_gain	1.0000
4:98293407:GATA:G	acceptor_gain	1.0000
4:98293511:AAATA:A	donor_gain	1.0000
4:98293512:AATA:A	donor_gain	1.0000
4:98293512:AATAG:A	donor_loss	1.0000
4:98293513:ATA:A	donor_gain	1.0000
4:98293513:ATAG:A	donor_loss	1.0000
4:98293514:TA:T	donor_gain	1.0000

AlphaMissense

4012 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:98352581:G:A	G114E	1.000
4:98416865:T:C	L295P	1.000
4:98417429:T:A	W324R	1.000
4:98417429:T:C	W324R	1.000
4:98417466:G:A	G336E	1.000
4:98417483:A:G	N342D	1.000
4:98417485:T:A	N342K	1.000
4:98417485:T:G	N342K	1.000
4:98417490:C:A	A344D	1.000
4:98417493:G:C	R345T	1.000
4:98417494:A:C	R345S	1.000
4:98417494:A:T	R345S	1.000
4:98418666:G:A	C350Y	1.000
4:98418667:T:G	C350W	1.000
4:98418752:C:G	H379D	1.000
4:98418756:C:A	A380E	1.000
4:98418762:T:C	L382P	1.000
4:98418764:A:C	S383R	1.000
4:98418766:T:A	S383R	1.000
4:98418766:T:G	S383R	1.000
4:98418768:C:A	A384D	1.000
4:98418774:G:C	R386T	1.000
4:98418774:G:T	R386I	1.000
4:98418775:A:C	R386S	1.000
4:98418775:A:T	R386S	1.000
4:98418776:A:G	N387D	1.000
4:98418778:C:A	N387K	1.000
4:98418778:C:G	N387K	1.000
4:98418780:T:C	L388P	1.000
4:98418783:C:A	A389D	1.000

dbSNP variants (sampled 300 via entrez): RS10000338 (4:98428355 C>T), RS1000040232 (4:98392061 T>A), RS1000086797 (4:98399282 C>G), RS1000087170 (4:98340828 A>C,G), RS1000094019 (4:98384297 T>C), RS1000104002 (4:98275522 C>T), RS10001086 (4:98423217 C>A,G,T), RS1000111180 (4:98360575 T>A), RS1000117691 (4:98383169 T>C), RS1000118228 (4:98341318 A>G), RS1000121879 (4:98441780 T>C), RS1000122272 (4:98300210 T>C), RS10001453 (4:98423633 C>T), RS1000152089 (4:98429733 G>A,C), RS1000152396 (4:98374024 AT>A,ATT)

Disease associations

OMIM: gene MIM:179502 | disease phenotypes: MIM:620655

GenCC curated gene-disease

Disease	Classification	Inheritance
Alfadhel syndrome	Strong	Autosomal recessive

Mondo (1): Alfadhel syndrome (MONDO:0958001)

Orphanet (0):

HPO phenotypes

31 total (30 of 31 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000085	Horseshoe kidney
HP:0000233	Thin vermilion border
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000322	Short philtrum
HP:0000325	Triangular face
HP:0000348	High forehead
HP:0000369	Low-set ears
HP:0000414	Bulbous nose
HP:0000718	Aggressive behavior
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001258	Spastic paraplegia
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001270	Motor delay
HP:0001382	Joint hypermobility
HP:0001762	Talipes equinovarus
HP:0002069	Bilateral tonic-clonic seizure
HP:0002188	Delayed CNS myelination
HP:0002474	Expressive language delay
HP:0002553	Highly arched eyebrow
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0004322	Short stature
HP:0008936	Axial hypotonia
HP:0010863	Receptive language delay

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST000328_11	Biochemical measures	6.000000e-06
GCST003487_18	Response to fenofibrate (total cholesterol levels)	8.000000e-06
GCST012279_3	Suicide attempt severity in mood disorders	4.000000e-07
GCST012279_4	Suicide attempt severity in mood disorders	6.000000e-07
GCST012279_5	Suicide attempt severity in mood disorders	8.000000e-07
GCST012280_1	Suicidality in mood disorders	4.000000e-07
GCST012280_2	Suicidality in mood disorders	6.000000e-07
GCST012280_3	Suicidality in mood disorders	8.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0007806	total cholesterol change measurement
EFO:0006882	suicide behaviour measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, decreases expression, decreases methylation, affects cotreatment	6
bisphenol A	decreases expression, increases expression	3
sodium arsenite	increases expression	2
entinostat	affects cotreatment, decreases expression	2
Arsenic Trioxide	affects binding, decreases reaction, increases expression	2
Air Pollutants	increases oxidation, affects cotreatment, decreases expression, increases abundance	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
glycidyl methacrylate	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
manganese chloride	decreases expression, increases abundance	1
potassium chromate(VI)	decreases expression	1
nickel sulfate	decreases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
methacrylaldehyde	decreases expression, increases oxidation, increases abundance, affects cotreatment	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
candoxin	increases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
bisphenol S	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
bisphenol AF	increases expression	1
Sunitinib	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_6864	Kasumi-5	Cancer cell line	Male
CVCL_B2DE	Abcam HeLa RAP1GDS1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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