RASAL3

Summary

RASAL3 (RAS protein activator like 3, HGNC:26129) is a protein-coding gene on chromosome 19p13.12, encoding RAS protein activator like-3 (Q86YV0). Functions as a Ras GTPase-activating protein.

This gene belongs to the Ras GTPase-activating proteins (RasGAP) family and encodes a protein with pleckstrin homology (PH), C2, and Ras GTPase-activation protein (RasGAP) domains. This protein is localized near or at the plasma membrane when expressed exogenously. Reduced expression of this gene in some cell lines resulted in increased levels of the active form of Ras (Ras-GTP), suggesting that this gene may play a role in negatively regulating the Ras signaling pathway. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 64926 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 181 total
• MANE Select transcript: NM_022904

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26129
Approved symbol	RASAL3
Name	RAS protein activator like 3
Location	19p13.12
Locus type	gene with protein product
Status	Approved
Aliases	FLJ21438
Ensembl gene	ENSG00000105122
Ensembl biotype	protein_coding
OMIM	616561
Entrez	64926

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 9 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000343625, ENST00000595098, ENST00000597025, ENST00000599694, ENST00000602101, ENST00000608577, ENST00000609274, ENST00000909959, ENST00000909960, ENST00000909961, ENST00000909962, ENST00000909963, ENST00000909964, ENST00000909965

RefSeq mRNA: 5 — MANE Select: NM_022904 NM_001400377, NM_001400378, NM_001400379, NM_001400380, NM_022904

CCDS: CCDS46006

Canonical transcript exons

ENST00000343625 — 18 exons

Exon	Start	End
ENSE00000873303	15452045	15452108
ENSE00001254604	15452658	15452815
ENSE00001367140	15458328	15458426
ENSE00001367657	15464505	15464544
ENSE00001379496	15464031	15464377
ENSE00001382839	15457292	15457834
ENSE00003498449	15454361	15454562
ENSE00003522995	15454657	15454893
ENSE00003533958	15458529	15458655
ENSE00003549307	15461218	15461296
ENSE00003553707	15461060	15461121
ENSE00003554782	15456502	15456646
ENSE00003556655	15460203	15460258
ENSE00003565458	15456104	15456248
ENSE00003633464	15461471	15461607
ENSE00003637768	15451624	15451938
ENSE00004282820	15454149	15454267
ENSE00004282821	15453107	15453497

Expression profiles

Bgee: expression breadth ubiquitous, 217 present calls, max score 98.72.

FANTOM5 (CAGE): breadth broad, TPM avg 5.7071 / max 252.8718, expressed in 504 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
179751	4.7289	473
179752	0.8175	265
179748	0.0582	42
179750	0.0581	31
179749	0.0444	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	98.72	gold quality
spleen	UBERON:0002106	95.27	gold quality
lymph node	UBERON:0000029	94.67	gold quality
vermiform appendix	UBERON:0001154	93.74	gold quality
blood	UBERON:0000178	93.19	gold quality
caecum	UBERON:0001153	92.12	gold quality
pancreatic ductal cell	CL:0002079	91.57	silver quality
bone marrow cell	CL:0002092	90.57	gold quality
ileal mucosa	UBERON:0000331	89.85	gold quality
thymus	UBERON:0002370	89.75	gold quality
leukocyte	CL:0000738	89.39	gold quality
monocyte	CL:0000576	88.89	gold quality
small intestine Peyer’s patch	UBERON:0003454	87.03	gold quality
upper lobe of left lung	UBERON:0008952	85.93	gold quality
bone marrow	UBERON:0002371	85.21	gold quality
upper lobe of lung	UBERON:0008948	84.97	gold quality
small intestine	UBERON:0002108	84.56	gold quality
kidney epithelium	UBERON:0004819	84.56	gold quality
right lung	UBERON:0002167	83.89	gold quality
pylorus	UBERON:0001166	83.88	gold quality
vena cava	UBERON:0004087	83.84	silver quality
parotid gland	UBERON:0001831	83.59	gold quality
mucosa of transverse colon	UBERON:0004991	83.54	gold quality
nasal cavity epithelium	UBERON:0005384	83.45	silver quality
superficial temporal artery	UBERON:0001614	83.20	silver quality
cardia of stomach	UBERON:0001162	82.51	gold quality
subthalamic nucleus	UBERON:0001906	81.92	silver quality
upper arm skin	UBERON:0004263	81.66	gold quality
cerebellar vermis	UBERON:0004720	81.37	gold quality
trabecular bone tissue	UBERON:0002483	81.28	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.01

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

3 targeting RASAL3, 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-1827	99.63	68.57	3265
HSA-MIR-520E-5P	99.27	68.90	1513
HSA-MIR-4286	97.20	64.37	1587

Literature-anchored findings (GeneRIF, showing 2)

• identified a novel Ras GTPase-activating proteins protein, RASAL3, which is predominantly expressed in cells of hematopoietic lineages, including NKT, B, and T cells (PMID:25652366)
• CD229 interacts with RASAL3 to activate RAS/ERK pathway in multiple myeloma proliferation. (PMID:36445333)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	rasal3	ENSDARG00000089933
mus_musculus	Rasal3	ENSMUSG00000052142
rattus_norvegicus	Rasal3	ENSRNOG00000006167
drosophila_melanogaster	RasGAP1	FBGN0004390
drosophila_melanogaster	raskol	FBGN0261570
caenorhabditis_elegans		WBGENE00001515
caenorhabditis_elegans		WBGENE00001516

Paralogs (10): RASAL2 (ENSG00000075391), RASA4 (ENSG00000105808), RASAL1 (ENSG00000111344), DAB2IP (ENSG00000136848), RASA1 (ENSG00000145715), RASA2 (ENSG00000155903), RASA4B (ENSG00000170667), RASA3 (ENSG00000185989), NF1 (ENSG00000196712), SYNGAP1 (ENSG00000197283)

Protein

Protein identifiers

RAS protein activator like-3 — Q86YV0 (reviewed: Q86YV0)

All UniProt accessions (2): Q86YV0, M0QX12

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a Ras GTPase-activating protein. Plays an important role in the expansion and functions of natural killer T (NKT) cells in the liver by negatively regulating RAS activity and the down-stream ERK signaling pathway.

Subcellular location. Cytoplasm. Cell cortex.

Tissue specificity. Predominantly expressed in cells of hematopoietic lineages.

Isoforms (2)

UniProt ID	Names	Canonical?
Q86YV0-1	1	yes
Q86YV0-2	2

RefSeq proteins (5): NP_001387306, NP_001387307, NP_001387308, NP_001387309, NP_075055* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR001936	RasGAP_dom	Domain
IPR008936	Rho_GTPase_activation_prot	Homologous_superfamily
IPR023152	RasGAP_CS	Conserved_site
IPR035892	C2_domain_sf	Homologous_superfamily
IPR039360	Ras_GTPase	Family
IPR057606	SynGAP1-like_PH	Domain

Pfam: PF00616, PF25321

UniProt features (37 total): modified residue 13, compositionally biased region 8, region of interest 6, domain 3, sequence variant 3, chain 1, coiled-coil region 1, site 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86YV0-F1	66.34	0.28

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): 500 (arginine finger; crucial for gtp hydrolysis by stabilizing the transition state)

Post-translational modifications (13): 18, 51, 164, 166, 167, 170, 224, 228, 231, 234, 787, 790, 988

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5658442	Regulation of RAS by GAPs

MSigDB gene sets: 133 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_NEGATIVE_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_CELL_CELL_ADHESION, GOBP_LEUKOCYTE_PROLIFERATION, GOBP_POSITIVE_REGULATION_OF_CELL_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_ALPHA_BETA_T_CELL_PROLIFERATION, GOBP_RAS_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_LEUKOCYTE_CELL_CELL_ADHESION

GO Biological Process (4): negative regulation of Ras protein signal transduction (GO:0046580), positive regulation of NK T cell proliferation (GO:0051142), regulation of intracellular signal transduction (GO:1902531), regulation of GTPase activity (GO:0043087)

GO Molecular Function (3): GTPase activator activity (GO:0005096), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (6): cytoplasm (GO:0005737), cytosol (GO:0005829), cell cortex (GO:0005938), membrane (GO:0016020), extracellular exosome (GO:0070062), cytoplasmic side of membrane (GO:0098562)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
RAF/MAP kinase cascade	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
GTPase activity	2
cytoplasm	2
Ras protein signal transduction	1
regulation of Ras protein signal transduction	1
negative regulation of small GTPase mediated signal transduction	1
NK T cell proliferation	1
positive regulation of alpha-beta T cell proliferation	1
positive regulation of NK T cell activation	1
regulation of NK T cell proliferation	1
regulation of signal transduction	1
intracellular signal transduction	1
regulation of hydrolase activity	1
enzyme activator activity	1
GTPase regulator activity	1
protein binding	1
binding	1
intracellular anatomical structure	1
cell periphery	1
extracellular vesicle	1
side of membrane	1

Protein interactions and networks

STRING

1308 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RASAL3	ITIH5	Q86UX2	497
RASAL3	SASH3	O75995	482
RASAL3	GAPVD1	Q14C86	426
RASAL3	EML3	Q32P44	383
RASAL3	ARHGAP5	Q13017	381
RASAL3	HOXD10	P28358	378
RASAL3	IGSF6	O95976	376
RASAL3	REXO1	Q8N1G1	369
RASAL3	IQGAP3	Q86VI3	367
RASAL3	ACY3	Q96HD9	355
RASAL3	SUSD3	Q96L08	355
RASAL3	EEIG2	Q5T8I3	351
RASAL3	GRAP2	O75791	345
RASAL3	SPINK9	Q5DT21	334
RASAL3	RASA3	Q14644	331

IntAct

80 interactions, top by confidence:

A	B	Type	Score
RASAL3	NTAQ1	psi-mi:“MI:0915”(physical association)	0.560
MTUS2	RASAL3	psi-mi:“MI:0915”(physical association)	0.560
RASAL3	RABGEF1	psi-mi:“MI:0915”(physical association)	0.560
HOMER1	RASAL3	psi-mi:“MI:0915”(physical association)	0.560
CCDC102B	RASAL3	psi-mi:“MI:0915”(physical association)	0.560
RASAL3	DEF6	psi-mi:“MI:0915”(physical association)	0.560
RASAL3	HNRNPK	psi-mi:“MI:0915”(physical association)	0.560
RASAL3	PICK1	psi-mi:“MI:0915”(physical association)	0.560
PRKAA2	RASAL3	psi-mi:“MI:0915”(physical association)	0.560
KRT27	RASAL3	psi-mi:“MI:0915”(physical association)	0.560
RASAL3	WASF3	psi-mi:“MI:0915”(physical association)	0.560
	RASAL3	psi-mi:“MI:0915”(physical association)	0.560
CDR2L	RASAL3	psi-mi:“MI:0915”(physical association)	0.560
RASAL3	PPP1R13B	psi-mi:“MI:0915”(physical association)	0.560
RASAL3	RASAL3	psi-mi:“MI:0915”(physical association)	0.560
RASAL3	ZRANB1	psi-mi:“MI:0915”(physical association)	0.560
TP53BP2	RASAL3	psi-mi:“MI:0915”(physical association)	0.560
SNRPA	RASAL3	psi-mi:“MI:0915”(physical association)	0.560
KHDRBS3	RASAL3	psi-mi:“MI:0915”(physical association)	0.560
RASAL3	AMOTL2	psi-mi:“MI:0915”(physical association)	0.560
RASAL3	RASD1	psi-mi:“MI:0915”(physical association)	0.560
RASAL3	BEGAIN	psi-mi:“MI:0915”(physical association)	0.560
MAP1LC3B	RASAL3	psi-mi:“MI:0407”(direct interaction)	0.440
MAP1LC3A	RASAL3	psi-mi:“MI:0407”(direct interaction)	0.440
	EIF3F	psi-mi:“MI:0914”(association)	0.350
	DDX3X	psi-mi:“MI:0914”(association)	0.350
	SUPT5H	psi-mi:“MI:0914”(association)	0.350
	KIF2A	psi-mi:“MI:0914”(association)	0.350
INSR	UBXN8	psi-mi:“MI:0914”(association)	0.350

BioGRID (29): RASAL3 (Two-hybrid), RASAL3 (Two-hybrid), RASAL3 (Two-hybrid), RASAL3 (Two-hybrid), RASAL3 (Two-hybrid), RASAL3 (Two-hybrid), RASD1 (Two-hybrid), CDR2L (Two-hybrid), AMOTL2 (Two-hybrid), CCDC136 (Two-hybrid), KHDRBS3 (Two-hybrid), MTUS2 (Two-hybrid), WASF3 (Two-hybrid), TP53BP2 (Two-hybrid), CCDC102B (Two-hybrid)

ESM2 similar proteins: A2ARS0, A5PJP1, A5PKW4, A6QQ91, C9JTQ0, D3ZG83, F1MUS9, O14512, O14559, O75427, O95996, P0C0T2, P46062, Q02779, Q09019, Q12852, Q18PE0, Q18PE1, Q1LZC5, Q2KI85, Q2TAL5, Q2VPJ9, Q3UMT1, Q53LP3, Q566C8, Q5BJT1, Q5DTT2, Q60700, Q63HR2, Q66L42, Q69YU3, Q6GQX6, Q6NSJ2, Q6NXT1, Q6QNY0, Q7TN12, Q80YF9, Q86YV0, Q8C0J6, Q8C2K5

Diamond homologs: A6QQ91, F6SEU4, P48423, P97526, Q14644, Q15283, Q28013, Q3UHC7, Q54Y08, Q5VWQ8, Q60790, Q6P730, Q86YV0, Q8C2K5, Q8MLZ5, Q8T498, Q96PV0, Q9QUH6, Q9QYJ2, Q9UJF2, Q9Z268, P58069, Q63713, O95294, P09851, P18963, P20936, P50904, P19158, P21359, P41823, P42680, Q04690, Q5M7N9, Q5T7P8, Q62746, Q99N80, C9J798, O00445, O08625

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 35 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
Transcriptional Regulation by TP53	5	11.1×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	158
Likely benign	12
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2776 predictions. Top by Δscore:

Variant	Effect	Δscore
19:15452654:TCA:T	donor_loss	1.0000
19:15452655:CA:C	donor_loss	1.0000
19:15452656:AC:A	donor_gain	1.0000
19:15452657:C:CT	donor_loss	1.0000
19:15452657:CC:C	donor_gain	1.0000
19:15452811:GCCAA:G	acceptor_gain	1.0000
19:15452812:CCAA:C	acceptor_gain	1.0000
19:15452812:CCAAC:C	acceptor_gain	1.0000
19:15452813:CAA:C	acceptor_gain	1.0000
19:15452813:CAAC:C	acceptor_gain	1.0000
19:15452814:AA:A	acceptor_gain	1.0000
19:15452814:AAC:A	acceptor_loss	1.0000
19:15452816:C:CC	acceptor_gain	1.0000
19:15452816:CT:C	acceptor_loss	1.0000
19:15452818:G:C	acceptor_gain	1.0000
19:15452818:G:GC	acceptor_gain	1.0000
19:15453103:TTA:T	donor_loss	1.0000
19:15453105:A:AC	donor_gain	1.0000
19:15453106:C:CC	donor_gain	1.0000
19:15453495:AGG:A	acceptor_gain	1.0000
19:15453496:GG:G	acceptor_gain	1.0000
19:15453498:C:CC	acceptor_gain	1.0000
19:15454655:A:AC	donor_gain	1.0000
19:15454656:C:CC	donor_gain	1.0000
19:15456102:A:AC	donor_gain	1.0000
19:15456103:C:CC	donor_gain	1.0000
19:15456103:CT:C	donor_gain	1.0000
19:15456134:T:TA	donor_gain	1.0000
19:15456522:T:TA	donor_gain	1.0000
19:15456548:A:AC	donor_gain	1.0000

AlphaMissense

6426 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:15454686:C:A	K643N	0.996
19:15454686:C:G	K643N	0.996
19:15456556:C:G	A508P	0.996
19:15454677:C:A	Q646H	0.994
19:15454677:C:G	Q646H	0.994
19:15458533:A:G	F262S	0.994
19:15454559:G:C	F654L	0.993
19:15454559:G:T	F654L	0.993
19:15454561:A:G	F654L	0.993
19:15454672:A:G	L648P	0.992
19:15454773:G:C	C614W	0.992
19:15454788:G:C	F609L	0.992
19:15454788:G:T	F609L	0.992
19:15454790:A:G	F609L	0.992
19:15454856:A:G	W587R	0.992
19:15454856:A:T	W587R	0.992
19:15458398:A:G	F273S	0.992
19:15456557:C:A	K507N	0.991
19:15456557:C:G	K507N	0.991
19:15457346:C:A	K459N	0.991
19:15457346:C:G	K459N	0.991
19:15457409:G:C	F438L	0.991
19:15457409:G:T	F438L	0.991
19:15457411:A:G	F438L	0.991
19:15454669:G:T	A649D	0.990
19:15454690:G:T	A642D	0.990
19:15454775:A:G	C614R	0.990
19:15456582:A:G	F499S	0.990
19:15457659:A:G	F355S	0.990
19:15454532:G:C	F663L	0.989

dbSNP variants (sampled 300 via entrez): RS1000266910 (19:15461365 G>C,T), RS1000599366 (19:15463033 T>C), RS1000651772 (19:15462716 G>A,C), RS1000833888 (19:15459107 T>C), RS1001128259 (19:15455896 T>C), RS1001606025 (19:15464288 CG>C), RS1001939194 (19:15465634 C>G,T), RS1002156484 (19:15453454 G>C,T), RS1002236183 (19:15460014 T>C), RS1002239760 (19:15455755 G>A,T), RS1002252724 (19:15453841 C>T), RS1002397002 (19:15462644 G>A), RS1002447698 (19:15462336 A>G), RS1002489992 (19:15454945 G>A,T), RS1002584925 (19:15455229 C>G,T)

Disease associations

OMIM: gene MIM:616561 | disease phenotypes:

GenCC curated gene-disease

Mondo (2): acute megakaryoblastic leukemia (MONDO:0018872), mediastinal germ cell tumor (MONDO:0021067)

Orphanet (1): Acute megakaryoblastic leukemia (Orphanet:518)

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST90002388_43	Lymphocyte count	3.000000e-09
GCST90002388_44	Lymphocyte count	2.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004587	lymphocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D007947	Leukemia, Megakaryoblastic, Acute	C04.557.337.539.275.450; C15.378.508.539.275.450

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects expression, increases abundance, increases expression	2
sodium arsenite	increases abundance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1
(+)-JQ1 compound	decreases expression	1
Acetaminophen	increases expression	1
Arsenic	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation	1
Diuron	decreases expression	1
Ivermectin	decreases expression	1
Nickel	increases expression	1
Ozone	affects expression, increases abundance	1
Tobacco Smoke Pollution	decreases expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	decreases expression	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04083170	PHASE2	TERMINATED	Cord Blood Transplant With Dilanubicel for the Treatment of HIV Positive Hematologic Cancers
NCT00392353	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Vorinostat and Azacitidine in Treating Patients With Myelodysplastic Syndromes or Acute Myeloid Leukemia
NCT01823198	PHASE1/PHASE2	COMPLETED	Donor Natural Killer Cells and Donor Stem Cell Transplant in Treating Patients With High Risk Myeloid Malignancies
NCT02530619	Not specified	UNKNOWN	Alisertib in Treating Patients With Myelofibrosis or Relapsed or Refractory Acute Megakaryoblastic Leukemia