DIRAS2

Summary

DIRAS2 (DIRAS family GTPase 2, HGNC:19323) is a protein-coding gene on chromosome 9q22.2, encoding GTP-binding protein Di-Ras2 (Q96HU8). Displays low GTPase activity and exists predominantly in the GTP-bound form.

DIRAS2 belongs to a distinct branch of the functionally diverse Ras (see HRAS; MIM 190020) superfamily of monomeric GTPases.

Source: NCBI Gene 54769 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 11 total
• MANE Select transcript: NM_017594

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19323
Approved symbol	DIRAS2
Name	DIRAS family GTPase 2
Location	9q22.2
Locus type	gene with protein product
Status	Approved
Aliases	Di-Ras2, DKFZp761C07121
Ensembl gene	ENSG00000165023
Ensembl biotype	protein_coding
OMIM	607863
Entrez	54769

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000375765, ENST00000636786, ENST00000637905

RefSeq mRNA: 1 — MANE Select: NM_017594 NM_017594

CCDS: CCDS6687

Canonical transcript exons

ENST00000375765 — 2 exons

Exon	Start	End
ENSE00001468329	90609832	90613863
ENSE00003794375	90642752	90642824

Expression profiles

Bgee: expression breadth ubiquitous, 186 present calls, max score 99.49.

FANTOM5 (CAGE): breadth broad, TPM avg 6.7197 / max 459.3157, expressed in 464 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
101342	5.1300	402
101344	0.7181	146
101349	0.1858	67
101343	0.1055	45
101346	0.0902	41
101347	0.0784	39
101351	0.0778	45
101350	0.0772	46
101345	0.0735	42
101352	0.0632	36

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar vermis	UBERON:0004720	99.49	gold quality
endothelial cell	CL:0000115	99.36	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.23	gold quality
orbitofrontal cortex	UBERON:0004167	98.81	gold quality
CA1 field of hippocampus	UBERON:0003881	98.44	gold quality
superior frontal gyrus	UBERON:0002661	98.34	gold quality
cerebellum	UBERON:0002037	98.12	gold quality
parietal lobe	UBERON:0001872	98.05	gold quality
postcentral gyrus	UBERON:0002581	98.04	gold quality
cerebellar cortex	UBERON:0002129	97.98	gold quality
cerebellar hemisphere	UBERON:0002245	97.95	gold quality
primary visual cortex	UBERON:0002436	97.73	gold quality
occipital lobe	UBERON:0002021	97.70	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.56	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.33	gold quality
adult organism	UBERON:0007023	96.98	gold quality
Brodmann (1909) area 46	UBERON:0006483	96.94	gold quality
prefrontal cortex	UBERON:0000451	96.92	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.28	gold quality
frontal cortex	UBERON:0001870	96.14	gold quality
entorhinal cortex	UBERON:0002728	96.04	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	95.88	gold quality
neocortex	UBERON:0001950	94.66	gold quality
cerebral cortex	UBERON:0000956	94.58	gold quality
right frontal lobe	UBERON:0002810	93.45	gold quality
pons	UBERON:0000988	93.13	gold quality
cingulate cortex	UBERON:0003027	92.18	gold quality
anterior cingulate cortex	UBERON:0009835	92.17	gold quality
middle temporal gyrus	UBERON:0002771	92.12	gold quality
Ammon’s horn	UBERON:0001954	91.86	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-9388	yes	6.21
E-ANND-3	yes	3.41

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1

miRNA regulators (miRDB)

161 targeting DIRAS2, 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-3163	100.00	77.23	8605
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029

Literature-anchored findings (GeneRIF, showing 6)

• Four single nucleotide polymorphisms (SNPs) and two haplotype blocks in DIRAS2 show evidence of association with attention deficit/hyperactivity disorder (ADHD) in adults. (PMID:21750579)
• The results from the present study imply that rs1412005 in the DIRAS2 gene is in itself a causal variant, and that it is not only functional on the molecular, but also the inhibition-related brain activation level, the latter specifically in patients suffering from ADHD. (PMID:27364329)
• Our findings support the idea of DIRAS2 as a candidate gene for attention-deficit/hyperactivity disorder (PMID:29488099)
• Di-Ras2 promotes renal cell carcinoma formation by activating the mitogen-activated protein kinase pathway in the absence of von Hippel-Lindau protein. (PMID:32161311)
• ADHD patients with DIRAS2 risk allele need more thalamic activation during emotional face-voice recognition. (PMID:34990989)
• Diverse Ras-related GTPase DIRAS2, downregulated by PSMD2 in a proteasome-mediated way, inhibits colorectal cancer proliferation by blocking NF-kappaB signaling. (PMID:35173535)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Diras2	ENSMUSG00000047842
rattus_norvegicus	Diras2	ENSRNOG00000062731
drosophila_melanogaster	CG8500	FBGN0037754

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), RRAD (ENSG00000166592), RHEBL1 (ENSG00000167550), NKIRAS2 (ENSG00000168256), HRAS (ENSG00000174775), DIRAS1 (ENSG00000176490), RAP2B (ENSG00000181467), ERAS (ENSG00000187682), NKIRAS1 (ENSG00000197885), NRAS (ENSG00000213281), RASL10B (ENSG00000270885)

Protein

Protein identifiers

GTP-binding protein Di-Ras2 — Q96HU8 (reviewed: Q96HU8)

Alternative names: Distinct subgroup of the Ras family member 2

All UniProt accessions (3): A0A1B0GVC3, A0A1B0GWA9, Q96HU8

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 brain.

Post-translational modifications. Ubiquitinated by the ECS(ASB11) complex via ‘Lys-11’-linked ubiquitin chains, leading to its degradation by the proteasome.

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

RefSeq proteins (1): NP_060064* (*=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

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (27 total): helix 8, strand 6, binding site 5, modified residue 3, chain 1, propeptide 1, lipid moiety-binding region 1, short sequence motif 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2ERX	X-RAY DIFFRACTION	1.65
6NAZ	X-RAY DIFFRACTION	3.08

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96HU8-F1	88.69	0.70

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 (5): 14–21; 33–39; 61–65; 121–124; 152–153

Post-translational modifications (4): 196, 196, 35, 126

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 149 (showing top): GOBP_REGULATION_OF_PHOSPHORYLATION, MODULE_255, TTTGTAG_MIR520D, GOZGIT_ESR1_TARGETS_DN, AAGCCAT_MIR135A_MIR135B, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, MODULE_317, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, GOBP_POSITIVE_REGULATION_OF_PHOSPHORUS_METABOLIC_PROCESS, INGRAM_SHH_TARGETS_DN, MODULE_301, GNF2_TM4SF2, GOBP_POSITIVE_REGULATION_OF_PROTEIN_SERINE_THREONINE_KINASE_ACTIVITY

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

GO Molecular Function (6): GTPase activity (GO:0003924), GTP binding (GO:0005525), GDP binding (GO:0019003), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

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
catalytic activity	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2923 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DIRAS2	R3HDM4	Q96D70	399
DIRAS2	RAP1GDS1	P52306	379
DIRAS2	PLEKHG7	Q6ZR37	367
DIRAS2	DZANK1	Q9NVP4	351
DIRAS2	C2CD2L	O14523	346
DIRAS2	TBC1D9	Q6ZT07	332
DIRAS2	OR1F1	O43749	325
DIRAS2	ADGRL3	Q9HAR2	323
DIRAS2	RNFT2	Q96EX2	321
DIRAS2	CLXN	Q9HAE3	316
DIRAS2	ZCCHC18	P0CG32	316
DIRAS2	CPNE9	Q8IYJ1	308
DIRAS2	ANKRD34A	Q69YU3	307
DIRAS2	LRRC40	Q9H9A6	306
DIRAS2	LRRC24	Q50LG9	305

IntAct

27 interactions, top by confidence:

A	B	Type	Score
DIRAS2	UNC45A	psi-mi:“MI:0915”(physical association)	0.560
UNC45A	DIRAS2	psi-mi:“MI:0915”(physical association)	0.560
RAP1GDS1	DIRAS2	psi-mi:“MI:0915”(physical association)	0.560
RIPPLY1	DIRAS2	psi-mi:“MI:0915”(physical association)	0.560
DIRAS2	UNC13B	psi-mi:“MI:0914”(association)	0.530
ZNF581	DMWD	psi-mi:“MI:0914”(association)	0.530
SIRPD	HIKESHI	psi-mi:“MI:0914”(association)	0.530
NFKB1	NFKB1	psi-mi:“MI:0914”(association)	0.350
JUN		psi-mi:“MI:0914”(association)	0.350
MYC		psi-mi:“MI:0914”(association)	0.350
SMIM26	METTL15	psi-mi:“MI:0914”(association)	0.350
FAAP20	FANCG	psi-mi:“MI:0914”(association)	0.350
DIRAS2	DIRAS1	psi-mi:“MI:0914”(association)	0.350
VCP	SHTN1	psi-mi:“MI:0914”(association)	0.350
RAP1GDS1	MRAS	psi-mi:“MI:0914”(association)	0.350
HTT	TPP1	psi-mi:“MI:0914”(association)	0.350
CALM1	Ckap5	psi-mi:“MI:0914”(association)	0.350
RAP1GDS1	DIRAS2	psi-mi:“MI:0915”(physical association)	0.000
RIPPLY1	DIRAS2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (65): UNC13B (Affinity Capture-MS), RAP1GDS1 (Affinity Capture-MS), DIRAS2 (Affinity Capture-MS), DIRAS2 (Affinity Capture-MS), FTO (Affinity Capture-MS), DIRAS2 (Two-hybrid), DIRAS2 (Two-hybrid), DIRAS2 (Two-hybrid), VHL (Affinity Capture-Western), DIRAS2 (Affinity Capture-Western), DIRAS2 (Affinity Capture-MS), DIRAS2 (Affinity Capture-MS), RAP1GDS1 (Affinity Capture-MS), DIRAS2 (Affinity Capture-MS), UNC13B (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, A8XAD0, B3M185, B3NZR4, B4GFJ8, B4HKC7, B4JFU8, B4LY29, B4NJ72, B4PUP5, C4YKT4, D3Z8L7, E9R5S0, G4MZY8, O42277, O42785, O93856, O94363, P01111, P01116, P01119, P01120, P03967, P05774, P08556, P08644, P08645, P08646, P08647, P0CQ42, P0CQ43, P0CY32, P12825, P15064, P18613, P22123, P22126, P22278

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 23 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
Cellular responses to stimuli	5	11.2×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	9
Likely benign	0
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

368 predictions. Top by Δscore:

Variant	Effect	Δscore
9:90613859:CGCAC:C	acceptor_gain	0.9900
9:90613860:GCACC:G	acceptor_loss	0.9800
9:90613862:ACC:A	acceptor_loss	0.9800
9:90613864:C:CA	acceptor_loss	0.9800
9:90613865:T:G	acceptor_loss	0.9800
9:90642746:GGTTA:G	donor_loss	0.9700
9:90642747:GTTAC:G	donor_loss	0.9700
9:90642748:TTACC:T	donor_loss	0.9700
9:90642749:TACCT:T	donor_loss	0.9700
9:90613861:CAC:C	acceptor_gain	0.9600
9:90613868:C:CT	acceptor_gain	0.9600
9:90613877:CAGA:C	acceptor_gain	0.9600
9:90613869:A:T	acceptor_gain	0.9500
9:90624344:TAA:T	donor_gain	0.9500
9:90624345:AAA:A	donor_gain	0.9500
9:90624346:A:C	donor_gain	0.9400
9:90613862:AC:A	acceptor_gain	0.9300
9:90613863:CC:C	acceptor_gain	0.9300
9:90613876:CCAGA:C	acceptor_gain	0.9200
9:90613860:GCAC:G	acceptor_gain	0.9100
9:90613861:CACC:C	acceptor_gain	0.9100
9:90624345:A:AC	donor_gain	0.9100
9:90624350:T:TA	donor_gain	0.9100
9:90613864:C:CC	acceptor_gain	0.8900
9:90613877:C:T	acceptor_gain	0.8900
9:90642770:C:CA	donor_gain	0.8800
9:90626659:AAAC:A	acceptor_gain	0.8700
9:90636323:C:CT	donor_gain	0.8500
9:90636324:T:TT	donor_gain	0.8500
9:90642615:CCAA:C	donor_gain	0.8400

AlphaMissense

1330 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:90613624:G:C	F68L	0.999
9:90613624:G:T	F68L	0.999
9:90613626:A:G	F68L	0.999
9:90613732:G:C	F32L	0.999
9:90613732:G:T	F32L	0.999
9:90613734:A:G	F32L	0.999
9:90613625:A:C	F68C	0.998
9:90613646:T:C	D61G	0.998
9:90613646:T:G	D61A	0.998
9:90613647:C:G	D61H	0.998
9:90613768:C:A	K20N	0.998
9:90613768:C:G	K20N	0.998
9:90613769:T:A	K20M	0.998
9:90613770:T:G	K20Q	0.998
9:90613772:C:T	G19D	0.998
9:90613773:C:G	G19R	0.998
9:90613787:C:T	G14E	0.998
9:90613373:G:T	A152D	0.997
9:90613377:A:G	S151P	0.997
9:90613465:G:C	N121K	0.997
9:90613465:G:T	N121K	0.997
9:90613470:C:A	G120W	0.997
9:90613569:A:G	S87P	0.997
9:90613582:G:C	F82L	0.997
9:90613582:G:T	F82L	0.997
9:90613584:A:G	F82L	0.997
9:90613625:A:G	F68S	0.997
9:90613645:G:C	D61E	0.997
9:90613645:G:T	D61E	0.997
9:90613646:T:A	D61V	0.997

dbSNP variants (sampled 300 via entrez): RS1000020926 (9:90628047 A>T), RS1000059451 (9:90620939 A>G,T), RS1000189181 (9:90631184 T>C), RS1000238786 (9:90627163 T>C,G), RS1000261639 (9:90643112 T>C), RS1000469970 (9:90633104 T>C), RS1000617092 (9:90620125 A>G,T), RS1000646012 (9:90631374 AG>A), RS1000806510 (9:90631554 G>A), RS1000821633 (9:90613921 AAGG>A), RS1000994328 (9:90615281 T>G), RS1001029245 (9:90636112 A>C), RS1001033297 (9:90637815 T>C), RS1001046871 (9:90636271 C>T), RS1001077178 (9:90644120 A>G)

Disease associations

OMIM: gene MIM:607863 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST000098_9	Cognitive test performance	8.000000e-06
GCST000189_1	Protein quantitative trait loci	3.000000e-06
GCST006994_3	Logical memory (immediate recall) in Alzheimer’s disease dementia	9.000000e-07
GCST009597_222	Multiple sclerosis	6.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0003926	neuropsychological test
EFO:0004874	memory performance

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, increases expression	4
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
pirinixic acid	increases activity, increases expression, affects binding	1
bisphenol A	affects cotreatment, decreases methylation	1
terbufos	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases 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, increases expression	1
2,2’,4,4’,5-brominated diphenyl ether	increases expression	1
beta-hydroxy simvastatin acid	decreases expression	1
dorsomorphin	increases expression, affects cotreatment	1
Resveratrol	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Arsenic	increases expression	1
Atrazine	increases expression	1
Fonofos	increases methylation	1
Lipopolysaccharides	affects response to substance, increases expression	1
Parathion	increases methylation	1
Phenylmercuric Acetate	affects cotreatment, increases expression	1
Phthalic Acids	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Dronabinol	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

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