RGL2

Summary

RGL2 (ral guanine nucleotide dissociation stimulator like 2, HGNC:9769) is a protein-coding gene on chromosome 6p21.32, encoding Ral guanine nucleotide dissociation stimulator-like 2 (O15211). Probable guanine nucleotide exchange factor.

Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in Ras protein signal transduction. Predicted to act upstream of or within negative regulation of cardiac muscle cell apoptotic process; positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; and regulation of Ral protein signal transduction. Predicted to be located in cytosol.

Source: NCBI Gene 5863 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 149 total
• MANE Select transcript: NM_004761

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9769
Approved symbol	RGL2
Name	ral guanine nucleotide dissociation stimulator like 2
Location	6p21.32
Locus type	gene with protein product
Status	Approved
Aliases	KE1.5, HKE1.5
Ensembl gene	ENSG00000237441
Ensembl biotype	protein_coding
OMIM	602306
Entrez	5863

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 19 protein_coding, 5 retained_intron, 4 protein_coding_CDS_not_defined

ENST00000425946, ENST00000437840, ENST00000460988, ENST00000471319, ENST00000476616, ENST00000478610, ENST00000483151, ENST00000485077, ENST00000491168, ENST00000494550, ENST00000497454, ENST00000908150, ENST00000908151, ENST00000908152, ENST00000908153, ENST00000908154, ENST00000908155, ENST00000908156, ENST00000913501, ENST00000968834, ENST00000968835, ENST00000968836, ENST00000968837, ENST00000968838, ENST00000968839, ENST00000968840, ENST00000968841, ENST00000968842

RefSeq mRNA: 2 — MANE Select: NM_004761 NM_001243738, NM_004761

CCDS: CCDS4774

Canonical transcript exons

ENST00000383204 — 0 exons

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 98.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.2571 / max 803.2397, expressed in 1796 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
73123	8.8094	1659
73117	3.6267	706
73122	1.7780	1134
73119	1.4642	872
73125	1.3709	697
73121	1.3319	925
73126	0.6218	342
73120	0.5533	300
73124	0.3019	140
73116	0.2409	134

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
spleen	UBERON:0002106	98.47	gold quality
right uterine tube	UBERON:0001302	98.43	gold quality
pituitary gland	UBERON:0000007	98.40	gold quality
adenohypophysis	UBERON:0002196	98.00	gold quality
right lobe of thyroid gland	UBERON:0001119	97.96	gold quality
fundus of stomach	UBERON:0001160	97.71	gold quality
left lobe of thyroid gland	UBERON:0001120	97.70	gold quality
thyroid gland	UBERON:0002046	97.57	gold quality
prostate gland	UBERON:0002367	97.38	gold quality
right adrenal gland cortex	UBERON:0035827	97.32	gold quality
saliva-secreting gland	UBERON:0001044	97.19	gold quality
lower esophagus mucosa	UBERON:0035834	97.19	gold quality
right adrenal gland	UBERON:0001233	97.12	gold quality
minor salivary gland	UBERON:0001830	97.11	gold quality
body of stomach	UBERON:0001161	97.09	gold quality
endocervix	UBERON:0000458	96.99	gold quality
granulocyte	CL:0000094	96.93	gold quality
blood	UBERON:0000178	96.93	gold quality
apex of heart	UBERON:0002098	96.84	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.84	gold quality
metanephros cortex	UBERON:0010533	96.79	gold quality
esophagus mucosa	UBERON:0002469	96.76	gold quality
descending thoracic aorta	UBERON:0002345	96.74	gold quality
body of uterus	UBERON:0009853	96.74	gold quality
right coronary artery	UBERON:0001625	96.65	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.65	gold quality
vagina	UBERON:0000996	96.62	gold quality
right ovary	UBERON:0002118	96.59	gold quality
left ovary	UBERON:0002119	96.57	gold quality
left adrenal gland cortex	UBERON:0035825	96.50	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.42

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

45 targeting RGL2, 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-4481	100.00	66.42	1669
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-142-3P	99.62	71.30	974
HSA-MIR-4743-3P	99.62	68.12	2095
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-19A-5P	99.36	66.93	1675
HSA-MIR-19B-1-5P	99.36	67.07	1669
HSA-MIR-19B-2-5P	99.36	67.07	1669
HSA-MIR-6505-3P	99.34	67.39	1071
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-4738-3P	98.98	67.98	1846

Literature-anchored findings (GeneRIF, showing 3)

• RGL2 is phosphorylated by PKA and phosphorylation reduces the ability of RGL2 to bind H-Ras. results of the present study indicate that Ras may distinguish between the different RalGDS family members by their phosphorylation by PKA. (PMID:18540861)
• Rgl2 and RalB both localized to the leading edge, and this localization of RalB was dependent on endogenous Rgl2 expression. (PMID:20801877)
• SAMD9, an IFN-gamma-responsive protein, interacts with RGL2 to diminish the expression of EGR1, a protein of direct relevance to the pathogenesis of ectopic calcification and inflammation. (PMID:21160498)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Rgl2	ENSMUSG00000041354
rattus_norvegicus	Ralgdsl2	ENSRNOG00000000474

Paralogs (24): RASGRF1 (ENSG00000058335), RASGRP2 (ENSG00000068831), RAPGEF3 (ENSG00000079337), RAPGEF4 (ENSG00000091428), SOS2 (ENSG00000100485), RAPGEF1 (ENSG00000107263), RAPGEFL1 (ENSG00000108352), RAPGEF2 (ENSG00000109756), RASGRF2 (ENSG00000113319), SOS1 (ENSG00000115904), RALGPS2 (ENSG00000116191), RAPGEF5 (ENSG00000136237), RALGPS1 (ENSG00000136828), RASGEF1B (ENSG00000138670), RGL1 (ENSG00000143344), RASGEF1C (ENSG00000146090), RASGRP3 (ENSG00000152689), RAPGEF6 (ENSG00000158987), RGL4 (ENSG00000159496), RALGDS (ENSG00000160271), RASGRP4 (ENSG00000171777), RASGRP1 (ENSG00000172575), RASGEF1A (ENSG00000198915), RGL3 (ENSG00000205517)

Protein

Protein identifiers

Ral guanine nucleotide dissociation stimulator-like 2 — O15211 (reviewed: O15211)

Alternative names: RalGDS-like factor, Ras-associated protein RAB2L

All UniProt accessions (3): O15211, A0A024RCS9, A2AB89

UniProt curated annotations — full annotation on UniProt →

Function. Probable guanine nucleotide exchange factor. Putative effector of Ras and/or Rap. Associates with the GTP-bound form of Rap 1A and H-Ras in vitro.

Subunit / interactions. Interacts with SAMD9.

Isoforms (2)

UniProt ID	Names	Canonical?
O15211-1	1	yes
O15211-2	2

RefSeq proteins (2): NP_001230667, NP_004752* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000159	RA_dom	Domain
IPR000651	Ras-like_Gua-exchang_fac_N	Domain
IPR001895	RASGEF_cat_dom	Domain
IPR008937	Ras-like_GEF	Family
IPR019804	Ras_G-nucl-exch_fac_CS	Conserved_site
IPR023578	Ras_GEF_dom_sf	Homologous_superfamily
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR036964	RASGEF_cat_dom_sf	Homologous_superfamily

Pfam: PF00617, PF00618, PF00788

UniProt features (32 total): compositionally biased region 6, strand 6, domain 3, splice variant 3, helix 3, region of interest 3, modified residue 2, sequence variant 2, sequence conflict 2, chain 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8B69	X-RAY DIFFRACTION	3.07
8AU4	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15211-F1	72.89	0.46

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): 13, 409

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5673001	RAF/MAP kinase cascade

MSigDB gene sets: 227 (showing top): ACTACCT_MIR196A_MIR196B, CGGAARNGGCNG_UNKNOWN, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, MORI_IMMATURE_B_LYMPHOCYTE_UP, GOBP_NEGATIVE_REGULATION_OF_MUSCLE_CELL_APOPTOTIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_3_KINASE_PROTEIN_KINASE_B_SIGNAL_TRANSDUCTION, GATA1_01, HSIAO_LIVER_SPECIFIC_GENES, GOBP_RAS_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, NAKAMURA_TUMOR_ZONE_PERIPHERAL_VS_CENTRAL_DN, GOBP_POSITIVE_REGULATION_OF_PHOSPHATIDYLINOSITOL_3_KINASE_PROTEIN_KINASE_B_SIGNAL_TRANSDUCTION, MA_MYELOID_DIFFERENTIATION_UP, CREIGHTON_AKT1_SIGNALING_VIA_MTOR_DN, MODULE_60

GO Biological Process (6): Ras protein signal transduction (GO:0007265), negative regulation of cardiac muscle cell apoptotic process (GO:0010667), regulation of Ral protein signal transduction (GO:0032485), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), signal transduction (GO:0007165), small GTPase-mediated signal transduction (GO:0007264)

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

GO Cellular Component (1): cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
MAPK1/MAPK3 signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
small GTPase-mediated signal transduction	1
cardiac muscle cell apoptotic process	1
negative regulation of striated muscle cell apoptotic process	1
regulation of cardiac muscle cell apoptotic process	1
Ral protein signal transduction	1
regulation of small GTPase mediated signal transduction	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
positive regulation of intracellular signal transduction	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
intracellular signaling cassette	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
binding	1
cytoplasm	1
cellular anatomical structure	1

Protein interactions and networks

STRING

734 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RGL2	PFDN6	O15212	878
RGL2	RPS18	P25232	874
RGL2	KIFC1	Q9BW19	861
RGL2	HSD17B8	Q92506	854
RGL2	SLC39A7	Q92504	811
RGL2	SAMD9	Q5K651	798
RGL2	COL11A2	P13942	786
RGL2	TAPBP	O15533	776
RGL2	RXRB	P28702	770
RGL2	RING1	Q06587	712
RGL2	RALA	P11233	686
RGL2	RALB	P11234	631
RGL2	ARAF	P07557	597
RGL2	RASSF5	Q8WWW0	585
RGL2	RAF1	P04049	582

IntAct

42 interactions, top by confidence:

A	B	Type	Score
HRAS	RGL2	psi-mi:“MI:0914”(association)	0.660
NOTCH2NLA	RGL2	psi-mi:“MI:0915”(physical association)	0.560
RGL2	ADAMTSL4	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	RGL2	psi-mi:“MI:0915”(physical association)	0.560
RGL2	KRTAP10-8	psi-mi:“MI:0915”(physical association)	0.560
RGL2	KPRP	psi-mi:“MI:0915”(physical association)	0.560
RGL2	GORASP2	psi-mi:“MI:0915”(physical association)	0.560
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
NRAS	RGL2	psi-mi:“MI:0914”(association)	0.550
NRAS	RGL2	psi-mi:“MI:0915”(physical association)	0.550
YWHAB	SHTN1	psi-mi:“MI:0914”(association)	0.530
YWHAE	SHTN1	psi-mi:“MI:0914”(association)	0.530
CCND1	RGL2	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
RGL2	Cdk4	psi-mi:“MI:0915”(physical association)	0.400
KPNA2	RGL2	psi-mi:“MI:0915”(physical association)	0.370
KRAS	RGL2	psi-mi:“MI:0915”(physical association)	0.370
RAP1B	RGL2	psi-mi:“MI:0915”(physical association)	0.370
k8	RGL2	psi-mi:“MI:0914”(association)	0.350
YWHAH	SHTN1	psi-mi:“MI:0914”(association)	0.350
YWHAQ	SHTN1	psi-mi:“MI:0914”(association)	0.350
KRAS		psi-mi:“MI:0914”(association)	0.350
RGL2	ADAMTSL4	psi-mi:“MI:0915”(physical association)	0.000
RGL2	CYSRT1	psi-mi:“MI:0915”(physical association)	0.000
RGL2	KPRP	psi-mi:“MI:0915”(physical association)	0.000
RGL2	KRTAP10-8	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (37): NOTCH2NL (Two-hybrid), RAP1B (Two-hybrid), RGL2 (Affinity Capture-MS), RGL2 (Two-hybrid), CCDC90B (Two-hybrid), KAT5 (Two-hybrid), KAT7 (Two-hybrid), UNC119 (Two-hybrid), CRMP1 (Two-hybrid), EEF1G (Two-hybrid), RGL2 (Two-hybrid), RGL2 (Two-hybrid), RGL2 (Two-hybrid), RGL2 (Two-hybrid), RGL2 (Two-hybrid)

ESM2 similar proteins: A7UA95, A8MQ27, O15211, O75808, O76050, O95382, Q08DQ0, Q0MW30, Q0P5E6, Q0QWG9, Q13425, Q14451, Q2MJR0, Q32P44, Q4ACU6, Q5NCX5, Q5TJE5, Q60806, Q61193, Q6P6N5, Q6V7V2, Q6WVG3, Q8BJ66, Q8C6B2, Q8N2R8, Q8TE68, Q8TF61, Q8VC03, Q8VHK1, Q8WXD9, Q8WXE0, Q923S6, Q96CX2, Q96EP0, Q96I82, Q96JN8, Q9BG99, Q9BR09, Q9BST9, Q9BYB0

Diamond homologs: O15211, Q03385, Q03386, Q12967, Q3MIN7, Q3UYI5, Q5TJE5, Q60695, Q61193, Q6P112, Q8IZJ4, Q9NZL6, A2AR50, A2CEA7, P27671, P28818, Q4R7W3, Q55GH9, Q5JS13, Q5ZJK0, Q86X27, Q8IS18, Q9ERD6, P70392, Q54C94, Q99JE4, B0UXH6, Q13972, Q86G47, O14827, P04821, Q02342, Q552M5, Q8IS15, Q8IS20, Q8MVR1, C8ZCV7, G5EDB9, P0CF32, P0CF34

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 26 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
Activation of BAD and translocation to mitochondria	5	181.3×	5e-09
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	5	159.9×	6e-09
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	5	159.9×	6e-09
Activation of BH3-only proteins	5	118.2×	2e-08
RHO GTPases activate PKNs	5	75.5×	1e-07
Signaling by high-kinase activity BRAF mutants	5	75.5×	1e-07
Intrinsic Pathway for Apoptosis	5	69.7×	2e-07
MAP2K and MAPK activation	5	68.0×	2e-07

GO biological processes:

GO term	Partners	Fold	FDR
intracellular protein localization	5	23.8×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	99
Likely benign	17
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

2925 predictions. Top by Δscore:

Variant	Effect	Δscore
6:33292464:CT:C	donor_gain	1.0000
6:33292545:C:CC	acceptor_gain	1.0000
6:33292549:C:CT	acceptor_gain	1.0000
6:33292550:A:T	acceptor_gain	1.0000
6:33292554:C:CT	acceptor_gain	1.0000
6:33292555:A:T	acceptor_gain	1.0000
6:33293523:CC:C	acceptor_gain	1.0000
6:33293524:CC:C	acceptor_gain	1.0000
6:33293602:A:AC	donor_gain	1.0000
6:33293603:C:CC	donor_gain	1.0000
6:33293603:CT:C	donor_gain	1.0000
6:33294759:CACC:C	acceptor_gain	1.0000
6:33294975:ACC:A	donor_gain	1.0000
6:33294976:CCC:C	donor_gain	1.0000
6:33294976:CCCCA:C	donor_gain	1.0000
6:33295122:CTCA:C	donor_loss	1.0000
6:33295123:TCAC:T	donor_loss	1.0000
6:33295124:CA:C	donor_loss	1.0000
6:33295125:AC:A	donor_loss	1.0000
6:33295126:CCT:C	donor_loss	1.0000
6:33295207:TGTCC:T	acceptor_gain	1.0000
6:33295208:GTCC:G	acceptor_gain	1.0000
6:33295209:TCC:T	acceptor_gain	1.0000
6:33295210:CC:C	acceptor_gain	1.0000
6:33295210:CCC:C	acceptor_gain	1.0000
6:33295211:CC:C	acceptor_gain	1.0000
6:33295212:C:CC	acceptor_gain	1.0000
6:33295212:C:T	acceptor_gain	1.0000
6:33295212:CTGGG:C	acceptor_loss	1.0000
6:33295313:CCGCA:C	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000156828 (6:33298156 C>T), RS1000414397 (6:33294906 C>A,T), RS1000566047 (6:33301891 A>G), RS1000726351 (6:33300253 A>G), RS1000999105 (6:33301233 C>G), RS1001539749 (6:33294516 T>C), RS1002103424 (6:33300013 G>A), RS1002171692 (6:33300908 G>A), RS1002811200 (6:33291620 C>G), RS1003331367 (6:33292526 C>A,G,T), RS1003433081 (6:33299584 C>T), RS1003512221 (6:33298787 G>A), RS1004161227 (6:33300970 A>G), RS1004278805 (6:33294712 A>C,G), RS1004593992 (6:33302778 T>C)

Disease associations

OMIM: gene MIM:602306 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST004521_251	Autism spectrum disorder or schizophrenia	6.000000e-12
GCST004521_287	Autism spectrum disorder or schizophrenia	5.000000e-08

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1059288	RGL2, TAPBP	3	3.00	1	aspirin

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	3
Arsenic	affects methylation, decreases expression, increases abundance	2
Valproic Acid	affects expression, increases methylation	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
FR900359	decreases phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
cobaltous chloride	decreases expression	1
nickel sulfate	increases expression	1
jinfukang	increases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	affects expression, increases abundance	1
Benzalkonium Compounds	affects response to substance	1
Cadmium	increases abundance, increases expression	1
Caffeine	decreases phosphorylation	1
Diazinon	increases methylation	1
Doxorubicin	increases expression	1
Estradiol	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Ozone	affects expression, increases abundance	1
Rotenone	decreases expression	1
Smoke	decreases expression	1
Tretinoin	increases expression	1
Vanadates	increases expression	1
Asbestos, Crocidolite	affects expression	1

Clinical trials (associated diseases)

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