DIRAS1

Summary

DIRAS1 (DIRAS family GTPase 1, HGNC:19127) is a protein-coding gene on chromosome 19p13.3, encoding GTP-binding protein Di-Ras1 (O95057). Displays low GTPase activity and exists predominantly in the GTP-bound form.

DIRAS1 belongs to a distinct branch of the functionally diverse Ras (see HRAS; MIM 190020) superfamily of monomeric GTPases.

Source: NCBI Gene 148252 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 20 total
• MANE Select transcript: NM_145173

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19127
Approved symbol	DIRAS1
Name	DIRAS family GTPase 1
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	Di-Ras1, GBTS1, RIG
Ensembl gene	ENSG00000176490
Ensembl biotype	protein_coding
OMIM	607862
Entrez	148252

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 14 protein_coding

ENST00000323469, ENST00000585334, ENST00000588128, ENST00000861580, ENST00000861581, ENST00000861582, ENST00000861583, ENST00000861584, ENST00000861585, ENST00000861586, ENST00000861587, ENST00000914891, ENST00000914892, ENST00000914893

RefSeq mRNA: 1 — MANE Select: NM_145173 NM_145173

CCDS: CCDS12092

Canonical transcript exons

ENST00000323469 — 2 exons

Exon	Start	End
ENSE00001245147	2714567	2717875
ENSE00001309728	2721304	2721372

Expression profiles

Bgee: expression breadth ubiquitous, 196 present calls, max score 98.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.2230 / max 195.2116, expressed in 1019 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
178199	5.6593	967
178200	0.3868	194
178201	0.1211	53
178198	0.0558	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ventricle myocardium	UBERON:0006566	98.45	gold quality
apex of heart	UBERON:0002098	97.88	gold quality
right frontal lobe	UBERON:0002810	96.12	gold quality
cortical plate	UBERON:0005343	96.11	gold quality
heart left ventricle	UBERON:0002084	95.92	gold quality
prefrontal cortex	UBERON:0000451	95.86	gold quality
cardiac ventricle	UBERON:0002082	95.79	gold quality
cardiac muscle of right atrium	UBERON:0003379	95.76	gold quality
frontal cortex	UBERON:0001870	95.03	gold quality
right atrium auricular region	UBERON:0006631	95.03	gold quality
cardiac atrium	UBERON:0002081	94.93	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.83	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.72	gold quality
myocardium	UBERON:0002349	94.56	gold quality
neocortex	UBERON:0001950	94.50	gold quality
anterior cingulate cortex	UBERON:0009835	94.45	gold quality
ganglionic eminence	UBERON:0004023	93.13	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.02	gold quality
cerebellar cortex	UBERON:0002129	92.85	gold quality
cerebellar hemisphere	UBERON:0002245	92.80	gold quality
cerebral cortex	UBERON:0000956	92.68	gold quality
heart right ventricle	UBERON:0002080	92.43	gold quality
cerebellum	UBERON:0002037	92.35	gold quality
superior frontal gyrus	UBERON:0002661	92.24	gold quality
lateral nuclear group of thalamus	UBERON:0002736	92.10	gold quality
parietal lobe	UBERON:0001872	91.90	gold quality
postcentral gyrus	UBERON:0002581	91.75	gold quality
cerebellar vermis	UBERON:0004720	90.89	gold quality
heart	UBERON:0000948	90.65	gold quality
brain	UBERON:0000955	89.82	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.25

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

110 targeting DIRAS1, 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-7110-3P	100.00	73.18	2486
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-370-5P	99.78	66.81	706
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-92A-2-5P	99.75	67.01	2164

Literature-anchored findings (GeneRIF, showing 8)

• a novel Ras-related protein and potential neural tumor suppressor (RIG) (PMID:12107278)
• DIRAS1 downregulation is associated with esophageal squamous cell carcinoma metastasis. (PMID:23436800)
• 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)
• This neuronal DIRAS1 gene with a proposed role in cholinergic transmission provides not only a candidate for human myoclonic epilepsy but also insights into the disease etiology, while establishing a spontaneous model for future intervention studies and functional characterization. (PMID:28223533)
• Results show that DIRAS1 is frequently methylated in human colorectal cancer and the expression of DIRAS1 is silenced by promoter region methylation. (PMID:28491151)
• Analysis of the function and mechanism of DIRAS1 in osteosarcoma. (PMID:35413492)
• Entorhinal cortex epigenome-wide association study highlights four novel loci showing differential methylation in Alzheimer’s disease. (PMID:37149695)
• M6A modification regulates tumor suppressor DIRAS1 expression in cervical cancer cells. (PMID:38372700)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	diras1b	ENSDARG00000009372
danio_rerio	diras1a	ENSDARG00000028066
mus_musculus	Diras1	ENSMUSG00000043670
rattus_norvegicus	Diras1	ENSRNOG00000029738

Paralogs (35): RALA (ENSG00000006451), REM1 (ENSG00000088320), RASL10A (ENSG00000100276), RASD2 (ENSG00000100302), RASL12 (ENSG00000103710), RHEB (ENSG00000106615), RASD1 (ENSG00000108551), RERGL (ENSG00000111404), RAP1A (ENSG00000116473), RASL11A (ENSG00000122035), RAP2C (ENSG00000123728), RAP2A (ENSG00000125249), RRAS (ENSG00000126458), RAP1B (ENSG00000127314), RASL11B (ENSG00000128045), KRAS (ENSG00000133703), RRAS2 (ENSG00000133818), RERG (ENSG00000134533), REM2 (ENSG00000139890), RIT1 (ENSG00000143622), RALB (ENSG00000144118), RIT2 (ENSG00000152214), MRAS (ENSG00000158186), DIRAS3 (ENSG00000162595), GEM (ENSG00000164949), DIRAS2 (ENSG00000165023), RRAD (ENSG00000166592), RHEBL1 (ENSG00000167550), NKIRAS2 (ENSG00000168256), HRAS (ENSG00000174775), RAP2B (ENSG00000181467), ERAS (ENSG00000187682), NKIRAS1 (ENSG00000197885), NRAS (ENSG00000213281), RASL10B (ENSG00000270885)

Protein

Protein identifiers

GTP-binding protein Di-Ras1 — O95057 (reviewed: O95057)

Alternative names: Distinct subgroup of the Ras family member 1, Ras-related inhibitor of cell growth, Small GTP-binding tumor suppressor 1

All UniProt accessions (2): O95057, K7EN06

UniProt curated annotations — full annotation on UniProt →

Function. Displays low GTPase activity and exists predominantly in the GTP-bound form.

Subcellular location. Cell membrane.

Tissue specificity. Highly expressed in heart and brain.

Similarity. Belongs to the small GTPase superfamily. Di-Ras family.

RefSeq proteins (1): NP_660156* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001806	Small_GTPase	Family
IPR005225	Small_GTP-bd	Domain
IPR020849	Small_GTPase_Ras-type	Family
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF00071

UniProt features (29 total): helix 8, strand 7, binding site 6, chain 1, propeptide 1, modified residue 1, lipid moiety-binding region 1, region of interest 1, turn 1, short sequence motif 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2GF0	X-RAY DIFFRACTION	1.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95057-F1	87.01	0.71

Functional residue map

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

Ligand- & substrate-binding residues (6): 151; 17–22; 33–39; 61–65; 121–125; 151–152

Post-translational modifications (2): 195, 195

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 130 (showing top): AP1_01, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, TGACCTY_ERR1_Q2, MEF2_02, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY, AP1_Q4_01, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, GOBP_POSITIVE_REGULATION_OF_PHOSPHORUS_METABOLIC_PROCESS, BACH2_01, GOBP_POSITIVE_REGULATION_OF_PROTEIN_SERINE_THREONINE_KINASE_ACTIVITY, TGANTCA_AP1_C, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, OUYANG_PROSTATE_CANCER_PROGRESSION_DN

GO Biological Process (1): signal transduction (GO:0007165)

GO Molecular Function (5): GTPase activity (GO:0003924), GTP binding (GO:0005525), GDP binding (GO:0019003), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
guanyl ribonucleotide binding	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
ribonucleoside triphosphate phosphatase activity	1
purine ribonucleoside triphosphate binding	1
anion binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2889 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DIRAS1	LRCH1	Q9Y2L9	535
DIRAS1	COMMD9	Q9P000	495
DIRAS1	UBL4B	Q8N7F7	481
DIRAS1	PDP2	Q9P2J9	480
DIRAS1	TRMT11	Q7Z4G4	463
DIRAS1	GEMIN5	Q8TEQ6	443
DIRAS1	ZFAND4	Q86XD8	443
DIRAS1	IPO8	O15397	432
DIRAS1	ZFP1	Q6P2D0	427
DIRAS1	RAP1GDS1	P52306	423
DIRAS1	OR51T1	Q8NGJ9	418
DIRAS1	WDR82	Q6UXN9	410
DIRAS1	VSNL1	P28677	400
DIRAS1	PLXDC2	Q6UX71	395
DIRAS1	PCBP3	P57721	377

IntAct

44 interactions, top by confidence:

A	B	Type	Score
ARL4C	RGS12	psi-mi:“MI:0914”(association)	0.640
RAP1GDS1	DIRAS1	psi-mi:“MI:0914”(association)	0.640
DIRAS1	TP53BP2	psi-mi:“MI:0915”(physical association)	0.560
DIRAS1	PPP1R13B	psi-mi:“MI:0915”(physical association)	0.560
DIRAS1	RAP1GDS1	psi-mi:“MI:0915”(physical association)	0.560
MANSC1	KLRG2	psi-mi:“MI:0914”(association)	0.530
IL20RA	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
AKR1D1	AKR1B10	psi-mi:“MI:0914”(association)	0.530
SLC9A5	PRKAB2	psi-mi:“MI:0914”(association)	0.530
AKR1D1	DIRAS1	psi-mi:“MI:0914”(association)	0.530
DIRAS1	UNC13B	psi-mi:“MI:0914”(association)	0.500
DIRAS1	UNC13B	psi-mi:“MI:0915”(physical association)	0.500
NCOA7	DIRAS1	psi-mi:“MI:0915”(physical association)	0.400
ZNF274	DIRAS1	psi-mi:“MI:0915”(physical association)	0.400
SNX20	DIRAS1	psi-mi:“MI:0914”(association)	0.350
RTN4	ESYT2	psi-mi:“MI:0914”(association)	0.350
LINC01587	UBA6	psi-mi:“MI:0914”(association)	0.350
SUCLA2	GTPBP10	psi-mi:“MI:0914”(association)	0.350
RABEP2	HECTD4	psi-mi:“MI:0914”(association)	0.350
GBA3	DIRAS1	psi-mi:“MI:0914”(association)	0.350
TCEAL9	DIRAS1	psi-mi:“MI:0914”(association)	0.350

BioGRID (40): DIRAS1 (Affinity Capture-MS), DIRAS1 (Affinity Capture-MS), DIRAS1 (Affinity Capture-MS), DIRAS1 (Affinity Capture-MS), DIRAS1 (Affinity Capture-MS), DIRAS1 (Affinity Capture-MS), DIRAS1 (Affinity Capture-MS), DIRAS1 (Affinity Capture-MS), DIRAS1 (Two-hybrid), DIRAS1 (Two-hybrid), DIRAS1 (Two-hybrid), DIRAS1 (Affinity Capture-MS), DIRAS1 (Affinity Capture-MS), DIRAS1 (Affinity Capture-MS), DIRAS1 (Affinity Capture-MS)

ESM2 similar proteins: A6QLK6, O14508, O35717, O70277, O75382, O88582, O95057, P09851, P20936, P49138, P50904, P57790, P62993, P62994, P87379, Q05B84, Q07883, Q08012, Q13588, Q14145, Q16644, Q2T9Z7, Q3SYZ2, Q5PR73, Q5R4J7, Q5R6S2, Q5R774, Q5RKN4, Q5ZLD3, Q60631, Q66H84, Q66II3, Q684M4, Q6GPJ9, Q6TDP3, Q6YKA8, Q6ZPT1, Q7YRV6, Q861R0, Q8TC17

Diamond homologs: A5A6J7, A6NIZ1, A8NU18, B4GFJ8, B4JFU8, B4NJ72, D3Z8L7, G4MZY8, O35626, O42277, O42785, O93856, O95057, P01112, P01113, P01114, P01115, P01117, P03967, P05774, P08642, P08644, P08645, P08647, P0CQ42, P0CQ43, P10114, P10301, P10833, P13856, P18613, P20171, P22123, P22126, P22278, P22279, P22280, P23175, P28775, P32252

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	16
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

291 predictions. Top by Δscore:

Variant	Effect	Δscore
19:2719389:T:TA	donor_gain	1.0000
19:2719409:AGCC:A	donor_gain	1.0000
19:2721298:GCCTA:G	donor_loss	1.0000
19:2721299:CCTAC:C	donor_loss	1.0000
19:2721300:CTACC:C	donor_loss	1.0000
19:2721301:TACCT:T	donor_loss	1.0000
19:2721302:ACC:A	donor_loss	1.0000
19:2721303:C:CA	donor_loss	1.0000
19:2717871:CGAGC:C	acceptor_gain	0.9900
19:2717874:GC:G	acceptor_gain	0.9900
19:2717875:CC:C	acceptor_gain	0.9900
19:2717876:C:CA	acceptor_loss	0.9900
19:2717876:C:CC	acceptor_gain	0.9900
19:2717877:T:A	acceptor_loss	0.9900
19:2719390:C:A	donor_gain	0.9900
19:2719420:T:TA	donor_gain	0.9900
19:2721302:A:AC	donor_gain	0.9900
19:2721303:C:CC	donor_gain	0.9900
19:2717872:GAGC:G	acceptor_gain	0.9700
19:2719373:T:TA	donor_gain	0.9700
19:2719409:AGC:A	donor_gain	0.9700
19:2717878:G:C	acceptor_gain	0.9600
19:2719409:AG:A	donor_gain	0.9600
19:2717873:AGC:A	acceptor_gain	0.9500
19:2719347:AGCC:A	donor_gain	0.9500
19:2719354:C:CA	donor_gain	0.9500
19:2717878:G:GC	acceptor_gain	0.9400
19:2717876:C:CG	acceptor_loss	0.9300
19:2719410:G:C	donor_gain	0.9300
19:2721318:C:A	donor_gain	0.9300

AlphaMissense

1311 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:2717603:G:C	F68L	1.000
19:2717603:G:T	F68L	1.000
19:2717605:A:G	F68L	1.000
19:2717711:G:C	F32L	1.000
19:2717711:G:T	F32L	1.000
19:2717713:A:G	F32L	1.000
19:2717441:C:A	K122N	0.999
19:2717441:C:G	K122N	0.999
19:2717444:G:C	N121K	0.999
19:2717444:G:T	N121K	0.999
19:2717624:G:C	D61E	0.999
19:2717624:G:T	D61E	0.999
19:2717625:T:A	D61V	0.999
19:2717625:T:C	D61G	0.999
19:2717625:T:G	D61A	0.999
19:2717626:C:G	D61H	0.999
19:2717637:A:G	L57P	0.999
19:2717748:T:A	K20M	0.999
19:2717749:T:G	K20Q	0.999
19:2717751:C:T	G19D	0.999
19:2717752:C:G	G19R	0.999
19:2717766:C:T	G14E	0.999
19:2717355:G:T	A151D	0.998
19:2717358:G:C	S150W	0.998
19:2717359:A:G	S150P	0.998
19:2717454:A:T	L118H	0.998
19:2717548:A:G	S87P	0.998
19:2717561:G:C	F82L	0.998
19:2717561:G:T	F82L	0.998
19:2717563:A:G	F82L	0.998

dbSNP variants (sampled 300 via entrez): RS1000147654 (19:2718269 C>A,T), RS1000267749 (19:2719150 A>C), RS1000289216 (19:2718697 A>G), RS1000313433 (19:2720335 C>G,T), RS1000722544 (19:2716530 T>C,G), RS1001104595 (19:2714721 C>T), RS1001151519 (19:2716468 G>A), RS1001157861 (19:2719422 C>T), RS1001368534 (19:2721275 G>A,T), RS1001626402 (19:2722900 C>G), RS1001715229 (19:2721403 C>T), RS1001900030 (19:2717022 G>A), RS1002153997 (19:2717802 G>A,C), RS1002773596 (19:2722244 G>A), RS1003372600 (19:2723209 G>A,C)

Disease associations

OMIM: gene MIM:607862 | disease phenotypes: MIM:616540, MIM:608709

GenCC curated gene-disease

Mondo (2): progressive myoclonic epilepsy type 9 (MONDO:0014685), lipodystrophy, partial, acquired, susceptibility to (MONDO:0100476)

Orphanet (1): Progressive myoclonic epilepsy type 9 (Orphanet:457265)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002381_271	Eosinophil count	3.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004842	eosinophil count

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
Benzo(a)pyrene	increases methylation, affects methylation, decreases methylation, increases expression	3
Tobacco Smoke Pollution	increases expression	2
propionaldehyde	increases expression	1
bisphenol A	affects cotreatment, decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	increases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	increases methylation, decreases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
diallyl trisulfide	increases expression	1
pentanal	increases expression	1
abrine	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
Aldehydes	increases expression	1
Catechin	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	increases expression, affects cotreatment	1
Indomethacin	affects cotreatment, decreases expression	1
Lipopolysaccharides	decreases expression, affects cotreatment	1
Mercury	decreases expression	1
Methapyrilene	decreases methylation	1
Triclosan	increases expression	1
Urethane	decreases expression	1
Valproic Acid	increases methylation	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
1-Methyl-4-phenylpyridinium	increases expression	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

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