RASGEF1A

Summary

RASGEF1A (RasGEF domain family member 1A, HGNC:24246) is a protein-coding gene on chromosome 10q11.21, encoding Ras-GEF domain-containing family member 1A (Q8N9B8). Guanine nucleotide exchange factor (GEF) with specificity for RAP2A, KRAS, HRAS, and NRAS (in vitro).

Enables guanyl-nucleotide exchange factor activity. Involved in cell migration and positive regulation of Ras protein signal transduction. Predicted to be located in cytosol. Predicted to be active in plasma membrane.

Source: NCBI Gene 221002 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 54 total
• MANE Select transcript: NM_145313

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24246
Approved symbol	RASGEF1A
Name	RasGEF domain family member 1A
Location	10q11.21
Locus type	gene with protein product
Status	Approved
Aliases	CG4853, FLJ37817
Ensembl gene	ENSG00000198915
Ensembl biotype	protein_coding
OMIM	614531
Entrez	221002

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 9 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000374455, ENST00000374459, ENST00000395809, ENST00000395810, ENST00000472864, ENST00000898231, ENST00000898232, ENST00000898233, ENST00000954344, ENST00000954345

RefSeq mRNA: 2 — MANE Select: NM_145313 NM_001282862, NM_145313

CCDS: CCDS60517, CCDS7202

Canonical transcript exons

ENST00000395810 — 13 exons

Exon	Start	End
ENSE00001095734	43198004	43198195
ENSE00001095737	43196976	43197099
ENSE00001095739	43198933	43199012
ENSE00001095743	43199092	43199194
ENSE00001095749	43199676	43199768
ENSE00001095752	43200182	43200256
ENSE00001164640	43196476	43196548
ENSE00001418099	43266845	43267065
ENSE00001463569	43194535	43196268
ENSE00003495454	43205919	43206122
ENSE00003605087	43201808	43201945
ENSE00003652215	43200667	43200888
ENSE00003689797	43203298	43203420

Expression profiles

Bgee: expression breadth ubiquitous, 209 present calls, max score 98.63.

FANTOM5 (CAGE): breadth broad, TPM avg 2.0808 / max 32.2446, expressed in 573 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
109160	1.2230	378
109162	0.3534	131
109164	0.2525	125
109163	0.2279	99
109161	0.0239	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	98.63	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.54	gold quality
middle temporal gyrus	UBERON:0002771	95.88	gold quality
entorhinal cortex	UBERON:0002728	95.33	gold quality
Brodmann (1909) area 46	UBERON:0006483	94.85	gold quality
postcentral gyrus	UBERON:0002581	94.25	gold quality
parietal lobe	UBERON:0001872	94.24	gold quality
superior frontal gyrus	UBERON:0002661	93.78	gold quality
lateral globus pallidus	UBERON:0002476	93.20	gold quality
cerebellar vermis	UBERON:0004720	92.76	gold quality
substantia nigra pars compacta	UBERON:0001965	91.91	gold quality
occipital lobe	UBERON:0002021	91.83	gold quality
primary visual cortex	UBERON:0002436	91.82	gold quality
superior vestibular nucleus	UBERON:0007227	91.70	gold quality
lateral nuclear group of thalamus	UBERON:0002736	90.62	gold quality
substantia nigra pars reticulata	UBERON:0001966	90.01	gold quality
pons	UBERON:0000988	89.74	gold quality
medulla oblongata	UBERON:0001896	89.18	gold quality
temporal lobe	UBERON:0001871	88.98	gold quality
frontal cortex	UBERON:0001870	88.89	gold quality
cerebral cortex	UBERON:0000956	88.16	gold quality
prefrontal cortex	UBERON:0000451	88.12	gold quality
neocortex	UBERON:0001950	88.01	gold quality
Ammon’s horn	UBERON:0001954	87.92	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	87.92	gold quality
nucleus accumbens	UBERON:0001882	87.64	gold quality
trigeminal ganglion	UBERON:0001675	87.11	gold quality
right frontal lobe	UBERON:0002810	87.03	gold quality
ventral tegmental area	UBERON:0002691	86.75	gold quality
adult organism	UBERON:0007023	86.61	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.06

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

108 targeting RASGEF1A, 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-3646	100.00	73.56	5283
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-98-3P	100.00	74.08	3907
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-300	99.92	71.76	2856

Literature-anchored findings (GeneRIF, showing 2)

• analyzed residues that allow RasGEF1 proteins to discriminate between Rap1 and Rap2, and identified Phe39 in the switch I region of Rap2 as a specificity residue. (PMID:19645719)
• The prognostic value of RASGEF1A RNA expression and DNA methylation in cytogenetically normal acute myeloid leukemia. (PMID:36404533)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Rasgef1a	ENSMUSG00000030134
rattus_norvegicus	Rasgef1a	ENSRNOG00000031671

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), RGL3 (ENSG00000205517), RGL2 (ENSG00000237441)

Protein

Protein identifiers

Ras-GEF domain-containing family member 1A — Q8N9B8 (reviewed: Q8N9B8)

All UniProt accessions (2): Q8N9B8, H7BYA3

UniProt curated annotations — full annotation on UniProt →

Function. Guanine nucleotide exchange factor (GEF) with specificity for RAP2A, KRAS, HRAS, and NRAS (in vitro). Plays a role in cell migration.

Tissue specificity. Detected in brain and spinal cord. Highly expressed in a number of intrahepatic cholangiocarcinoma tissue biopsies.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8N9B8-1	1	yes
Q8N9B8-2	2

RefSeq proteins (2): NP_001269791, NP_660356* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000651	Ras-like_Gua-exchang_fac_N	Domain
IPR001895	RASGEF_cat_dom	Domain
IPR008937	Ras-like_GEF	Family
IPR023578	Ras_GEF_dom_sf	Homologous_superfamily
IPR036964	RASGEF_cat_dom_sf	Homologous_superfamily

Pfam: PF00617, PF00618

UniProt features (5 total): domain 2, chain 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N9B8-F1	85.79	0.70

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 157 (showing top): TGCGCANK_UNKNOWN, GCANCTGNY_MYOD_Q6, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, AP4_Q6, AP2_Q3, CAGCTG_AP4_Q5, GTGCCTT_MIR506, IRF7_01, GGARNTKYCCA_UNKNOWN, GOBP_RAS_PROTEIN_SIGNAL_TRANSDUCTION, CYTAGCAAY_UNKNOWN, RICKMAN_HEAD_AND_NECK_CANCER_A, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, ATF4_Q2, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_UP

GO Biological Process (4): Ras protein signal transduction (GO:0007265), cell migration (GO:0016477), positive regulation of Ras protein signal transduction (GO:0046579), small GTPase-mediated signal transduction (GO:0007264)

GO Molecular Function (1): guanyl-nucleotide exchange factor activity (GO:0005085)

GO Cellular Component (2): cytosol (GO:0005829), plasma membrane (GO:0005886)

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
cell motility	1
Ras protein signal transduction	1
regulation of Ras protein signal transduction	1
positive regulation of small GTPase mediated signal transduction	1
intracellular signaling cassette	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
cytoplasm	1
cellular anatomical structure	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

516 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RASGEF1A	SBNO1	A3KN83	812
RASGEF1A	RIOX1	Q9H6W3	797
RASGEF1A	RIOK1	Q9BRS2	796
RASGEF1A	TGFBRAP1	Q8WUH2	790
RASGEF1A	TRRAP	Q9Y4A5	528
RASGEF1A	NUCLEOLIN	P19338	497
RASGEF1A	ZNF485	Q8NCK3	475
RASGEF1A	RASGRP4	Q8TDF6	429
RASGEF1A	NPM1	P06748	428
RASGEF1A	PLK2	Q9NYY3	405
RASGEF1A	VAV2	P52735	396
RASGEF1A	GDF10	P55107	396
RASGEF1A	H4C7	Q99525	388
RASGEF1A	TIAM1	Q13009	387
RASGEF1A	H4C16	P02304	386

IntAct

3 interactions, top by confidence:

A	B	Type	Score
SLC23A2	RASGEF1A	psi-mi:“MI:0915”(physical association)	0.400
RASGEF1A	MYO9A	psi-mi:“MI:0914”(association)	0.350

BioGRID (6): ATP1A3 (Affinity Capture-MS), MYO9A (Affinity Capture-MS), RASGEF1A (Affinity Capture-MS), GTF3C2 (Affinity Capture-MS), TEX10 (Affinity Capture-MS), RASGEF1A (Biochemical Activity)

ESM2 similar proteins: A0JM95, A1A4S6, A2A2Y4, A4II46, A4IJ06, A6NI28, B2RQE8, B5DFQ4, F1LVW7, O60879, O60890, O70566, O95267, P0C7A6, P0CAX5, Q02384, Q07889, Q07890, Q08DP6, Q0P4Q4, Q28EC1, Q4V7P7, Q566W7, Q5R6F6, Q5R803, Q5U4T3, Q62245, Q69ZK0, Q6DBW1, Q6DHR3, Q6NTL4, Q6PCS4, Q6Y5D8, Q6ZM89, Q7YQL5, Q7YQL6, Q8AVG0, Q8BHD4, Q8IV61, Q8N9B8

Diamond homologs: A0JM95, A4IFE4, F1M386, F1MSG6, F1PBJ0, Q0VAM2, Q28EC1, Q5RC04, Q6DBW1, Q6DHR3, Q8CHG7, Q8IS18, Q8IS19, Q8JZL7, Q8MVR1, Q8N431, Q8N9B8, Q95KH6, Q9D300, Q9Y4G8, O95398, P28818, P83900, Q02342, Q8C0Q9, Q8VCC8, Q8WZA2, Q92565, Q9EQZ6, Q9UHV5, Q9Z1C7, Q9Z1C8, A2AR50, A2CEA7, A7A0P0, B0M0P8, B3LTF3, B5VMS9, C8ZCV7, E9Q9W7

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
RASGEF1A	up-regulates	HRAS	binding
RASGEF1A	up-regulates	KRAS	“guanine nucleotide exchange factor”
RASGEF1A	up-regulates	NRAS	binding
PLPPR1	“up-regulates activity”	RASGEF1A	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	42
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3015 predictions. Top by Δscore:

Variant	Effect	Δscore
10:43196216:T:TA	donor_gain	1.0000
10:43196549:C:CC	acceptor_gain	1.0000
10:43196970:CCTCA:C	donor_loss	1.0000
10:43196971:CTCA:C	donor_loss	1.0000
10:43196972:TCACC:T	donor_loss	1.0000
10:43196973:CA:C	donor_loss	1.0000
10:43196974:A:C	donor_loss	1.0000
10:43196974:ACCTT:A	donor_gain	1.0000
10:43196975:C:CG	donor_loss	1.0000
10:43196975:CCTTC:C	donor_gain	1.0000
10:43196978:T:A	donor_gain	1.0000
10:43197096:ATTT:A	acceptor_gain	1.0000
10:43197097:TTT:T	acceptor_gain	1.0000
10:43197097:TTTC:T	acceptor_loss	1.0000
10:43197098:TT:T	acceptor_gain	1.0000
10:43197099:TCTGA:T	acceptor_loss	1.0000
10:43197100:C:CC	acceptor_gain	1.0000
10:43197101:T:A	acceptor_loss	1.0000
10:43197998:GCTCA:G	donor_loss	1.0000
10:43197999:CTCA:C	donor_loss	1.0000
10:43198000:TCA:T	donor_loss	1.0000
10:43198001:CA:C	donor_loss	1.0000
10:43198003:C:CT	donor_loss	1.0000
10:43198065:T:TA	donor_gain	1.0000
10:43198191:TGATG:T	acceptor_gain	1.0000
10:43198192:GATG:G	acceptor_gain	1.0000
10:43198193:ATG:A	acceptor_gain	1.0000
10:43198194:TG:T	acceptor_gain	1.0000
10:43198194:TGCT:T	acceptor_loss	1.0000
10:43198195:GC:G	acceptor_loss	1.0000

AlphaMissense

3224 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:43198158:C:G	R357P	1.000
10:43198982:A:G	L328P	1.000
10:43198985:C:A	R327M	1.000
10:43198985:C:G	R327T	1.000
10:43199009:C:T	G319D	1.000
10:43199010:C:G	G319R	1.000
10:43199117:G:C	N309K	1.000
10:43199117:G:T	N309K	1.000
10:43199132:G:C	C304W	1.000
10:43199134:A:G	C304R	1.000
10:43199142:G:T	A301D	1.000
10:43199692:G:T	A278D	1.000
10:43200683:A:G	L222P	1.000
10:43196533:G:A	S455F	0.999
10:43196534:A:G	S455P	0.999
10:43196545:A:G	L451P	0.999
10:43198159:G:T	R357S	0.999
10:43198162:A:C	Y356D	0.999
10:43198169:G:C	F353L	0.999
10:43198169:G:T	F353L	0.999
10:43198171:A:G	F353L	0.999
10:43198937:A:G	L343S	0.999
10:43198969:C:A	W332C	0.999
10:43198969:C:G	W332C	0.999
10:43198984:C:A	R327S	0.999
10:43198984:C:G	R327S	0.999
10:43198986:T:C	R327G	0.999
10:43198991:A:T	V325E	0.999
10:43199097:A:T	I316N	0.999
10:43199100:G:T	A315D	0.999

dbSNP variants (sampled 300 via entrez): RS1000073761 (10:43217929 T>C), RS1000076983 (10:43220546 G>A), RS1000088491 (10:43255016 C>T), RS1000170018 (10:43212247 C>T), RS1000172676 (10:43259734 C>A,T), RS1000201507 (10:43197518 T>C), RS1000211931 (10:43236254 C>A,T), RS1000291190 (10:43242558 C>T), RS1000327626 (10:43203712 T>C,G), RS1000383659 (10:43203981 G>A), RS1000438532 (10:43210011 G>A), RS1000448264 (10:43237086 G>C), RS1000476434 (10:43264720 T>C), RS1000493441 (10:43249075 C>T), RS1000501814 (10:43237396 T>A)

Disease associations

OMIM: gene MIM:614531 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000334_2	Hirschsprung disease	4.000000e-18
GCST001762_309	Obesity-related traits	5.000000e-08
GCST001762_8	Obesity-related traits	2.000000e-06
GCST002336_5	Telomere length	7.000000e-06
GCST002658_5	Hirschsprung disease	6.000000e-19
GCST005230_20	Recurrent major depressive disorder	4.000000e-06
GCST005986_13	Blood urea nitrogen levels	2.000000e-10
GCST009597_192	Multiple sclerosis	5.000000e-07
GCST010043_13	Asthma	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004626	IGFBP-3 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, affects cotreatment	5
methylmercuric chloride	decreases expression	3
entinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
fluorene-9-bisphenol	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
bisphenol A	affects methylation, affects cotreatment, increases methylation	1
trichostatin A	increases expression	1
sodium arsenite	affects methylation	1
butyraldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
pentanal	increases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
bisphenol S	decreases methylation	1
jinfukang	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Vorinostat	increases expression	1
Estradiol	increases expression	1
Lead	affects expression	1
Methapyrilene	increases methylation	1
Thimerosal	decreases expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	decreases expression	1

Clinical trials (associated diseases)

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