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
• GTEx eGene: eQTL in 12 tissues, sQTL in 1 (q < 0.05)
• Constraint (gnomAD): pLI 0.46 (intermediate), LOEUF 0.78 (unconstrained)
• 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: 4 — 4 protein_coding

MANE Select: ENST00000375765

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 4: 2

ENST00000375765, ENST00000636786, ENST00000637905, ENST00001136488

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.

Highest expression (Bgee): cerebellar vermis, endothelial cell, Brodmann (1909) area 23, orbitofrontal cortex, CA1 field of hippocampus.

Genetic regulation across tissues (GTEx eQTL / sQTL)

DIRAS2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 12 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

13 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Brain Spinal cord cervical c-1	eqtl	5.4e-19	-0.59	9:90494397:G:A
Thyroid	eqtl	7.7e-11	+0.38	9:90483430:G:A
Nerve Tibial	eqtl	3.5e-08	-0.34	9:90414580:G:T
Colon Transverse	eqtl	1.0e-04	-0.23	9:90447641:C:T
Adipose Subcutaneous	eqtl	1.3e-04	+0.23	9:90475747:T:C
Skin Not Sun Exposed Suprapubic	eqtl	1.4e-04	-0.24	9:90665065:A:G
Testis	eqtl	4.2e-04	-0.39	9:90414198:T:C
Small Intestine Terminal Ileum	eqtl	6.5e-03	-0.33	9:90484271:A:G
Brain Putamen basal ganglia	eqtl	8.5e-03	-0.46	9:90587684:T:C
Breast Mammary Tissue	eqtl	1.2e-02	-0.29	9:90826647:G:A
Thyroid	sqtl	2.8e-02	+0.24	9:90679392:A:C
Skin Sun Exposed Lower leg	eqtl	2.9e-02	-0.17	9:90296613:C:T
Brain Hypothalamus	eqtl	4.0e-02	+0.17	9:90650976:G:A

FANTOM5 promoters

showing 10 of 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

showing 100 of 274 tissues 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
telencephalon	UBERON:0001893	90.71	gold quality
substantia nigra pars compacta	UBERON:0001965	90.10	gold quality
superior vestibular nucleus	UBERON:0007227	88.90	gold quality
temporal lobe	UBERON:0001871	88.65	gold quality
brain	UBERON:0000955	88.30	gold quality
dorsal plus ventral thalamus	UBERON:0001897	88.00	gold quality
substantia nigra pars reticulata	UBERON:0001966	87.90	gold quality
forebrain	UBERON:0001890	87.21	gold quality
medulla oblongata	UBERON:0001896	87.13	gold quality
ventral tegmental area	UBERON:0002691	85.77	gold quality
cortical plate	UBERON:0005343	85.65	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	85.23	gold quality
spinal cord	UBERON:0002240	85.20	gold quality
decidua	UBERON:0002450	84.95	gold quality
lateral globus pallidus	UBERON:0002476	83.74	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.71	gold quality
subthalamic nucleus	UBERON:0001906	83.59	gold quality
putamen	UBERON:0001874	83.56	gold quality
amygdala	UBERON:0001876	83.56	gold quality
caudate nucleus	UBERON:0001873	83.24	gold quality
nucleus accumbens	UBERON:0001882	82.83	gold quality
hypothalamus	UBERON:0001898	82.81	gold quality
midbrain	UBERON:0001891	81.59	gold quality
substantia nigra	UBERON:0002038	81.42	gold quality
stromal cell of endometrium	CL:0002255	80.38	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	79.02	gold quality
dorsal root ganglion	UBERON:0000044	78.44	gold quality
secondary oocyte	CL:0000655	77.36	gold quality
corpus callosum	UBERON:0002336	75.78	gold quality
islet of Langerhans	UBERON:0000006	75.49	gold quality
gall bladder	UBERON:0002110	75.44	gold quality
tibia	UBERON:0000979	74.51	gold quality
inferior olivary complex	UBERON:0002127	74.46	gold quality
trigeminal ganglion	UBERON:0001675	72.08	gold quality
inferior vagus X ganglion	UBERON:0005363	71.12	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	70.61	gold quality
jejunal mucosa	UBERON:0000399	69.84	gold quality
ganglionic eminence	UBERON:0004023	68.62	gold quality
duodenum	UBERON:0002114	65.69	gold quality
palpebral conjunctiva	UBERON:0001812	64.73	gold quality
cranial nerve II	UBERON:0000941	64.53	gold quality
choroid plexus epithelium	UBERON:0003911	63.38	gold quality
pancreas	UBERON:0001264	62.71	gold quality
left lobe of thyroid gland	UBERON:0001120	62.55	gold quality
thyroid gland	UBERON:0002046	62.10	gold quality
embryo	UBERON:0000922	61.86	gold quality
tibial nerve	UBERON:0001323	60.84	gold quality
right lobe of thyroid gland	UBERON:0001119	60.54	gold quality
globus pallidus	UBERON:0001875	59.12	gold quality
adenohypophysis	UBERON:0002196	57.84	gold quality
oviduct epithelium	UBERON:0004804	57.32	silver quality
epithelial cell of pancreas	CL:0000083	57.18	silver quality
endometrium	UBERON:0001295	56.80	gold quality
jejunum	UBERON:0002115	56.54	gold quality
periodontal ligament	UBERON:0008266	56.50	gold quality
oocyte	CL:0000023	56.13	silver quality
body of pancreas	UBERON:0001150	56.04	gold quality
endocervix	UBERON:0000458	55.16	gold quality
cortex of kidney	UBERON:0001225	54.12	gold quality
adult mammalian kidney	UBERON:0000082	54.09	gold quality
anatomical system	UBERON:0000467	53.72	gold quality
pituitary gland	UBERON:0000007	53.68	gold quality
multicellular organism	UBERON:0000468	53.52	gold quality
material anatomical entity	UBERON:0000465	53.51	gold quality
medial globus pallidus	UBERON:0002477	53.42	gold quality
kidney	UBERON:0002113	52.65	gold quality
apex of heart	UBERON:0002098	52.46	gold quality
skin of abdomen	UBERON:0001416	52.38	gold quality
smooth muscle tissue	UBERON:0001135	52.20	gold quality
ventricular zone	UBERON:0003053	52.18	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

HPA expression

RNA tissue specificity: Tissue enriched

showing 60 of 73 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Postcentral gyrus	tissue	181.7
Frontal cortex	tissue	149.7
Cerebral cortex	tissue	148.9
Somatosensory cortex	tissue	148.9
Occipital cortex	tissue	148.6
Hippocampal formation	tissue	137.2
Motor cortex	tissue	132.4
Caudate putamen	tissue	130.3
Retrosplenial cortex	tissue	126.7
Retrosplenial and cingulate cortex	tissue	112.4
Prefrontal cortex	tissue	105.0
Cerebellum	tissue	95.7
Hippocampus	tissue	80.9
Putamen	tissue	79.7
Entorhinal cortex	tissue	78.2
Insular cortex	tissue	77.5
Temporal cortex	tissue	73.9
Basal ganglia	tissue	71.1
Ventral forebrain	tissue	48.9
Septum	tissue	42.2
Midbrain	tissue	41.3
Thalamus	tissue	40.5
Retina	tissue	36.6
Nucleus accumbens	tissue	36.1
Superior colliculi	tissue	33.8
Pons	tissue	31.5
Amygdala	tissue	30.4
Locus coeruleus	tissue	28.4
Olfactory bulb	tissue	20.3
Medulla oblongata	tissue	16.7
Corpus callosum	tissue	16.4
Spinal cord	tissue	14.9
Hypothalamus	tissue	13.9
Substantia nigra	tissue	13.6
Periaqueductal gray	tissue	10.4
Cervix	tissue	8.7
Choroid plexus	tissue	7.6
Gallbladder	tissue	4.8
Parathyroid gland	tissue	3.7
Adrenal gland	tissue	2.7
Thyroid gland	tissue	2.5
Small intestine	tissue	2.4
Duodenum	tissue	2.0
Salivary gland	tissue	1.8
Pancreas	tissue	1.3
Stomach 1	tissue	1.2
Skin 1	tissue	0.9
Pituitary gland	tissue	0.8
Breast	tissue	0.8
Kidney	tissue	0.8
Placenta	tissue	0.6
Bone marrow	tissue	0.6
Fallopian tube	tissue	0.5
Seminal vesicle	tissue	0.4
Colon	tissue	0.4
Epididymis	tissue	0.4
Liver	tissue	0.4
Lymph node	tissue	0.3
Smooth muscle	tissue	0.3
Endometrium 1	tissue	0.3

Brain sub-regions (HPA Brain Atlas): detected in 188; highest nTPM — Cerebellar cortex (202.7), Vermis (177.0), Flocculonodular lobe (175.2), Somatomor cortex, precentral gyrus (white matter) (170.6), Somatosensory cortex, postcentral gyrus, ventral (white matter) (170.5).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1

miRNA regulators (miRDB)

Targeting DIRAS2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 161 miRNAs:

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

Functional genomics

gnomAD constraint: pLI 0.464, LOEUF 0.782, missense Z 1.92 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000375765 — one region, missense o/e 0.73.

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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1915453) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 2 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased bone mineral density	1
preweaning lethality, incomplete penetrance	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	Q56JV3	99.5%	Diamond
Pongo abelii	Q5R6S2	99.5%	Diamond
Macaca fascicularis	Q95KD9	99.5%	Diamond
Caenorhabditis briggsae	A8XAD0	79.0%	Diamond
Caenorhabditis elegans	P34443	72.1%	Diamond
Schizosaccharomyces pombe 972h-	O94363	67.4%	Diamond
Danio rerio	Q6DGN0	64.4%	Diamond
Dictyostelium discoideum	Q55BW0	51.2%	Diamond
Saccharomyces cerevisiae S288C	P25378	46.4%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
LINC01501	ncRNA	340515
LINC01508	ncRNA	101927873
SYK	protein-coding	6850

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)

• 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 by resolution:

PDB	Title	Method	Resolution (Å)
2ERX	Crystal Structure of DiRas2 in Complex With GDP and Inorganic Phosphate	X-RAY DIFFRACTION	1.65
6NAZ	Crystal structure of DIRAS 2/3 chimera in complex with GDP	X-RAY DIFFRACTION	3.08

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Predicted intracellular proteins

Protein evidence: Evidence at protein level

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)

Position	Role
14–21	GTP
33–39	GTP
61–65	GTP
121–124	GTP
152–153	GTP

Post-translational modifications (4)

Type	Positions
Cysteine methyl ester	196
S-geranylgeranyl cysteine	196
Phosphoserine	35, 126

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

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 (2): small GTPase-mediated signal transduction (GO:0007264), signal transduction (GO:0007165)

GO Molecular Function (5): GTPase activity (GO:0003924), GTP binding (GO:0005525), 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

17 GO namespaces:

Category	Terms
intracellular signaling cassette	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
ribonucleoside triphosphate phosphatase activity	1
guanyl ribonucleotide binding	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

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 3 of 9 annotations. The rest are phylogenetic / computational / electronic (IEA).

3 experimentally-supported GO terms:

GO term	NS	Evidence
plasma membrane	CC	direct assay
GTP binding	MF	direct assay
GTPase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,268 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DIRAS2	C2CD2L	O14523	400
DIRAS2	MTURN	Q8N3F0	396
DIRAS2	CLDND1	Q9NY35	392
DIRAS2	LCAT	P04180	370
DIRAS2	LRRC17	Q8N6Y2	370
DIRAS2	HEY2	Q9UBP5	370
DIRAS2	VENTX	O95231	370
DIRAS2	LEUTX	A8MZ59	370
DIRAS2	AKR1C3	P42330	370
DIRAS2	AKR1C8	Q5T2L2	370
DIRAS2	ANKRD34A	Q69YU3	370
DIRAS2	CREB3L1	Q96BA8	370
DIRAS2	RARRES2	Q99969	370
DIRAS2	AKR1C4	P17516	363
DIRAS2	DPRX	A6NFQ7	359

IntAct

Human interaction partners of DIRAS2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

5 partners by confidence:

Partner	Interaction type	MIscore	Records
RAP1GDS1	physical association	0.560	3
RIPPLY1	physical association	0.560	3
UNC45A	physical association	0.560	3
UNC13B	association	0.530	2
DIRAS1	association	0.350	1

BioGRID (67 interactions; top human partners by supporting records): ASB11 (Biochemical Activity; 4 records), RAP1GDS1 (Affinity Capture-MS; 3 records), UBE2F (Affinity Capture-MS; 3 records), BRAF (Affinity Capture-Western; 2 records), CUL5 (Affinity Capture-Western; 2 records), FTO (Affinity Capture-MS; 2 records), PSMD2 (Affinity Capture-Western; 2 records), RNF7 (Affinity Capture-Western; 2 records), SIRPD (Affinity Capture-MS; 2 records), UNC13B (Affinity Capture-MS; 2 records), VHL (Affinity Capture-Western; 2 records), ZNF581 (Affinity Capture-MS; 2 records), ACE2 (Affinity Capture-MS), ALYREF (Affinity Capture-MS), ARHGAP24 (Affinity Capture-MS)

Disease & clinical

Genetic variants

Variant evidence for DIRAS2: 11 ClinVar records (0 pathogenic / likely pathogenic); 4 GWAS associations.

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

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 18 predictions of 192):

Position(s)	Effect	Δscore	Sites
9:90642750–90642751	donor_loss	0.9900	5
9:90613864–90613865	acceptor_loss	0.9800	5
9:90642750	donor_loss	0.9800
9:90613864	acceptor_loss	0.9600
9:90613869	acceptor_gain	0.9500
9:90624346	donor_gain	0.9400
9:90621358	donor_gain	0.9100
9:90613877	acceptor_gain	0.8900
9:90642643	donor_gain	0.8500
9:90624426	donor_gain	0.8300

AlphaMissense

646 missense substitutions predicted likely pathogenic (of 1,330 scored), across 146 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M71	9	0.896	0.990
D61	8	0.996	0.998
D124	8	0.976	0.988
D42	8	0.966	0.987
F162	8	0.965	0.995
F68	8	0.962	0.999
F32	8	0.948	0.999
N121	8	0.934	0.997
F82	8	0.931	0.997
F13	8	0.901	0.975
D7	8	0.780	0.872
S21	7	0.986	0.996
K20	7	0.985	0.998
F27	7	0.979	0.994
K122	7	0.934	0.996
R26	7	0.932	0.970
E41	7	0.922	0.970
E149	7	0.916	0.949
W143	7	0.912	0.982
C55	7	0.808	0.929

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Kidney Renal Clear Cell Carcinoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	4.53e-07
Kidney Renal Clear Cell Carcinoma (validation)	favorable	0.000173

Disease associations

OMIM: gene MIM:607863 | disease phenotypes:

GWAS associations

4 associations:

Study	Trait	p-value
GCST009597_280	Multiple sclerosis	6e-7
GCST006994_1	Logical memory (immediate recall) in Alzheimer’s disease dementia	9e-7
GCST000189_1	Protein quantitative trait loci	3e-6
GCST000098_9	Cognitive test performance	8e-6

EFO canonical traits (from GWAS)

2 canonical traits:

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 (CPIC guideline: no)

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	increases methylation, affects methylation, increases expression	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	affects cotreatment, increases expression	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	increases expression, affects response to substance	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)

Via MONDO — disease-level, not drug-specific.