DIRAS3

Summary

DIRAS3 (DIRAS family GTPase 3, HGNC:687) is a protein-coding gene on chromosome 1p31.3, encoding GTP-binding protein Di-Ras3 (O95661).

This gene encodes a member of the ras superfamily. This gene is imprinted gene with monoallelic expression of the paternal allele which is associated with growth suppression. The encoded protein acts as a tumor suppressor whose function is abrogated in many ovarian and breast cancers. This protein may also play a role autophagy in certain cancer cells by regulating the autophagosome initiation complex.

Source: NCBI Gene 9077 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 26 total
• GTEx eGene: eQTL in 21 tissues, sQTL in 10 (q < 0.05)
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• Constraint (gnomAD): pLI 0.34 (intermediate), LOEUF 1.84 (unconstrained)
• MANE Select transcript: NM_004675

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:687
Approved symbol	DIRAS3
Name	DIRAS family GTPase 3
Location	1p31.3
Locus type	gene with protein product
Status	Approved
Aliases	NOEY2
Ensembl gene	ENSG00000162595
Ensembl biotype	protein_coding
OMIM	605193
Entrez	9077

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

MANE Select: ENST00000646789

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

ENST00000646789, ENST00000370981, ENST00000691269, ENST00000693623, ENST00000903449, ENST00001144407

RefSeq mRNA: 1 — MANE Select: NM_004675 NM_004675

CCDS: CCDS641

Canonical transcript exons

ENST00000646789 — 2 exons

Exon	Start	End
ENSE00001454045	68045962	68047362
ENSE00003822354	68050548	68050627

Expression profiles

Bgee: expression breadth ubiquitous, 208 present calls, max score 95.14.

FANTOM5 (CAGE): breadth broad, TPM avg 5.1351 / max 508.2565, expressed in 716 samples.

Highest expression (Bgee): adenohypophysis, pituitary gland, hypothalamus, nucleus accumbens, ovary.

Genetic regulation across tissues (GTEx eQTL / sQTL)

DIRAS3 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 21 tissues and its splicing (sQTL) in 10 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 31 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Esophagus Gastroesophageal Junction	sqtl	2.8e-28	-0.77	1:68125169:A:G
Colon Sigmoid	sqtl	9.1e-25	-0.77	1:68125722:G:A
Thyroid	eqtl	3.0e-21	+0.88	1:68050752:T:C
Stomach	sqtl	4.3e-13	-0.66	1:68125169:A:G
Heart Left Ventricle	eqtl	4.0e-08	-0.47	1:68015682:T:C
Nerve Tibial	eqtl	1.0e-06	-0.22	1:67850816:A:G
Artery Tibial	sqtl	1.3e-06	+0.32	1:68125490:A:G
Heart Atrial Appendage	eqtl	1.5e-05	+0.66	1:67952260:C:G
Colon Sigmoid	eqtl	6.3e-05	+0.55	1:68117603:C:A
Heart Left Ventricle	sqtl	7.6e-05	-0.60	1:68015682:T:C
Brain Caudate basal ganglia	eqtl	8.2e-05	-0.21	1:68018217:G:A
Esophagus Muscularis	eqtl	1.0e-04	-0.18	1:68125169:A:G
Artery Aorta	eqtl	2.5e-04	-0.87	1:67703386:A:G
Spleen	eqtl	3.4e-04	+0.39	1:67899209:G:T
Artery Tibial	eqtl	5.8e-04	+0.39	1:68058939:C:T
Artery Aorta	sqtl	8.6e-04	+0.86	1:68126201:C:T
Muscle Skeletal	sqtl	1.0e-03	-0.32	1:68128877:G:A
Adipose Subcutaneous	eqtl	1.2e-03	-0.19	1:68125490:A:G
Testis	eqtl	2.3e-03	+0.49	1:68044287:C:T
Brain Nucleus accumbens basal ganglia	eqtl	5.8e-03	-1.81	1:67182291:G:A

FANTOM5 promoters

6 alternative TSS:

Promoter ID	TPM avg	Samples expressed
12771	3.7765	563
12769	0.5050	159
12770	0.2738	112
12773	0.2416	105
12772	0.2343	98
12774	0.1039	39

Top tissues by expression

showing 100 of 280 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
adenohypophysis	UBERON:0002196	95.14	gold quality
pituitary gland	UBERON:0000007	95.07	gold quality
hypothalamus	UBERON:0001898	94.34	gold quality
nucleus accumbens	UBERON:0001882	93.60	gold quality
left ovary	UBERON:0002119	93.60	gold quality
right ovary	UBERON:0002118	91.87	gold quality
ovary	UBERON:0000992	91.33	gold quality
oocyte	CL:0000023	88.18	gold quality
apex of heart	UBERON:0002098	88.11	gold quality
body of pancreas	UBERON:0001150	86.74	gold quality
germinal epithelium of ovary	UBERON:0001304	86.31	gold quality
right adrenal gland cortex	UBERON:0035827	85.20	gold quality
left adrenal gland	UBERON:0001234	84.83	gold quality
left adrenal gland cortex	UBERON:0035825	84.58	gold quality
right adrenal gland	UBERON:0001233	84.49	gold quality
secondary oocyte	CL:0000655	84.11	gold quality
pancreas	UBERON:0001264	84.06	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.73	gold quality
calcaneal tendon	UBERON:0003701	83.54	gold quality
adrenal cortex	UBERON:0001235	83.43	gold quality
islet of Langerhans	UBERON:0000006	83.34	gold quality
mucosa of stomach	UBERON:0001199	82.81	gold quality
adrenal gland	UBERON:0002369	82.76	gold quality
amygdala	UBERON:0001876	81.53	gold quality
gall bladder	UBERON:0002110	81.52	gold quality
adrenal tissue	UBERON:0018303	81.31	gold quality
caudate nucleus	UBERON:0001873	80.95	gold quality
heart right ventricle	UBERON:0002080	80.63	gold quality
putamen	UBERON:0001874	80.33	gold quality
heart left ventricle	UBERON:0002084	78.88	gold quality
cardiac ventricle	UBERON:0002082	78.63	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	77.60	gold quality
descending thoracic aorta	UBERON:0002345	76.57	gold quality
corpus epididymis	UBERON:0004359	76.53	gold quality
right atrium auricular region	UBERON:0006631	76.10	gold quality
heart	UBERON:0000948	76.04	gold quality
right lobe of liver	UBERON:0001114	75.83	gold quality
lower esophagus muscularis layer	UBERON:0035833	75.62	gold quality
lower esophagus	UBERON:0013473	75.56	gold quality
cingulate cortex	UBERON:0003027	75.52	gold quality
ectocervix	UBERON:0012249	75.49	gold quality
forebrain	UBERON:0001890	75.30	gold quality
mammalian vulva	UBERON:0000997	75.28	gold quality
anterior cingulate cortex	UBERON:0009835	75.25	gold quality
right coronary artery	UBERON:0001625	75.13	gold quality
cardiac atrium	UBERON:0002081	74.93	gold quality
cortical plate	UBERON:0005343	74.41	gold quality
duodenum	UBERON:0002114	74.32	gold quality
endocervix	UBERON:0000458	74.18	gold quality
superior vestibular nucleus	UBERON:0007227	74.14	gold quality
thoracic aorta	UBERON:0001515	73.78	gold quality
ascending aorta	UBERON:0001496	73.62	gold quality
muscle layer of sigmoid colon	UBERON:0035805	73.62	gold quality
left uterine tube	UBERON:0001303	73.47	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	73.23	gold quality
vagina	UBERON:0000996	73.16	gold quality
prefrontal cortex	UBERON:0000451	72.98	gold quality
telencephalon	UBERON:0001893	72.38	gold quality
Brodmann (1909) area 9	UBERON:0013540	72.31	gold quality
aorta	UBERON:0000947	72.26	gold quality
temporal lobe	UBERON:0001871	72.20	gold quality
body of stomach	UBERON:0001161	72.18	gold quality
urethra	UBERON:0000057	72.09	gold quality
stromal cell of endometrium	CL:0002255	71.81	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	71.65	gold quality
brain	UBERON:0000955	71.47	gold quality
central nervous system	UBERON:0001017	71.44	gold quality
popliteal artery	UBERON:0002250	71.40	gold quality
tibial artery	UBERON:0007610	71.40	gold quality
adult mammalian kidney	UBERON:0000082	71.38	gold quality
caput epididymis	UBERON:0004358	71.28	gold quality
spinal cord	UBERON:0002240	70.98	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	70.85	gold quality
right frontal lobe	UBERON:0002810	70.13	gold quality
esophagus	UBERON:0001043	70.08	gold quality
left coronary artery	UBERON:0001626	69.91	gold quality
upper lobe of left lung	UBERON:0008952	69.53	gold quality
stomach	UBERON:0000945	69.24	gold quality
upper lobe of lung	UBERON:0008948	69.09	gold quality
neocortex	UBERON:0001950	69.07	gold quality
upper leg skin	UBERON:0004262	68.83	gold quality
tibial nerve	UBERON:0001323	68.76	gold quality
coronary artery	UBERON:0001621	68.71	gold quality
cerebral cortex	UBERON:0000956	68.50	gold quality
liver	UBERON:0002107	68.43	gold quality
skin of abdomen	UBERON:0001416	68.35	gold quality
blood vessel layer	UBERON:0004797	68.32	gold quality
minor salivary gland	UBERON:0001830	68.31	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	68.28	gold quality
frontal cortex	UBERON:0001870	68.15	gold quality
sigmoid colon	UBERON:0001159	67.98	gold quality
female reproductive system	UBERON:0000474	67.93	gold quality
metanephros cortex	UBERON:0010533	67.90	gold quality
body of uterus	UBERON:0009853	67.68	gold quality
Ammon’s horn	UBERON:0001954	67.61	gold quality
inferior olivary complex	UBERON:0002127	67.39	gold quality
tendon	UBERON:0000043	67.24	gold quality
substantia nigra	UBERON:0002038	66.99	gold quality
lower esophagus mucosa	UBERON:0035834	66.95	gold quality
cauda epididymis	UBERON:0004360	66.56	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-8559	yes	1608.45
E-MTAB-5061	yes	9.86
E-MTAB-7249	yes	4.57
E-GEOD-81608	yes	4.44
E-HCAD-31	yes	3.69
E-ENAD-27	no	3.90
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Group enriched

showing 60 of 77 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Hypothalamus	tissue	824.2
Septum	tissue	785.0
Substantia nigra	tissue	667.7
Ventral pallidum	tissue	476.8
Pons	tissue	467.0
Periaqueductal gray	tissue	383.8
Basal ganglia	tissue	358.1	low
Thalamus	tissue	356.0
Superior colliculi	tissue	312.9
Medulla oblongata	tissue	277.8
Hippocampal formation	tissue	263.3
Midbrain	tissue	261.8
Putamen	tissue	254.3
Amygdala	tissue	213.3
Prefrontal cortex	tissue	208.1
Cerebral cortex	tissue	208.1	low
Motor cortex	tissue	206.2
Somatosensory cortex	tissue	203.8
Cingulate cortex	tissue	186.9
Occipital cortex	tissue	184.0
Insular cortex	tissue	181.2
Retrosplenial cortex	tissue	172.5
Entorhinal cortex	tissue	169.3
Temporal cortex	tissue	160.3
Spinal cord	tissue	159.8
Olfactory bulb	tissue	137.0
Pituitary gland	tissue	65.9
Corpus callosum	tissue	62.2
Ovary	tissue	49.8	not detected
Nucleus accumbens	tissue	36.6
Cerebellum	tissue	35.8	low
Locus coeruleus	tissue	35.8
Adrenal gland	tissue	19.0	medium
Pancreas	tissue	18.8	low
Heart muscle	tissue	10.8	medium
Epididymis	tissue	10.3	medium
Gallbladder	tissue	9.7	medium
Liver	tissue	9.0	not detected
Vagina	tissue	7.6	medium
Parathyroid gland	tissue	7.1	low
Duodenum	tissue	7.0	low
Kidney	tissue	6.5	medium
Testis	tissue	5.2	medium
Lung	tissue	4.9	medium
Breast	tissue	4.8	medium
Postcentral gyrus	tissue	4.5
Stomach 1	tissue	4.0	medium
Retina	tissue	3.8
Thyroid gland	tissue	3.6	medium
Choroid plexus	tissue	3.3
Cervix	tissue	3.1	medium
Hippocampus	tissue	2.8	low
Seminal vesicle	tissue	2.5	low
Endometrium 1	tissue	2.4	low
Spleen	tissue	2.4	not detected
Prostate	tissue	2.4	low
Urinary bladder	tissue	2.1	medium
Skin 1	tissue	2.0	medium
Fallopian tube	tissue	1.9	medium
Tongue	tissue	1.8

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Arcuate nucleus (303.0), Dorsal hippocampus (263.3), Ventral hippocampus (258.3), Ventromedial nucleus (207.2), Subiculum (181.3).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, E2F2, E2F3, E2F4, E2F5, HDAC9, STAT3

miRNA regulators (miRDB)

Targeting DIRAS3 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 48 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-548M	99.70	68.87	1749
HSA-MIR-379-3P	99.69	69.60	1524
HSA-MIR-411-3P	99.69	69.63	1524
HSA-MIR-10393-5P	99.65	68.01	1368
HSA-MIR-7156-5P	99.64	68.81	1369
HSA-MIR-105-5P	99.54	69.24	2060
HSA-MIR-7853-5P	99.54	69.30	2055
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-4452	99.50	68.45	1493
HSA-MIR-4273	99.45	67.93	1206
HSA-MIR-3606-5P	99.31	69.67	1168
HSA-MIR-888-5P	99.30	70.15	1855
HSA-MIR-548V	99.29	69.47	1157
HSA-MIR-3191-5P	99.24	66.52	1722
HSA-MIR-664A-3P	99.22	71.08	2696

Functional genomics

gnomAD constraint: pLI 0.34, LOEUF 1.84, missense Z 1.4 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000646789 — one region, missense o/e 0.83. ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• A link between NOEY2 loss expression and the spreading mechanism of breast cancer may possibly exist. (PMID:12485503)
• ARHI inhibits cell growth, and loss of its expression in cells may contribute to the development of breast and ovarian cancers (PMID:12771940)
• Hypermethylation of CpG island II in the promoter region of ARHI is associated with the complete loss of ARHI expression in breast cancer cells. (PMID:12874023)
• ARHI may have a role in development and progression of ductal breast carcinoma in situ (PMID:14506155)
• Association between STAT3 and ARHI as well as the functional inhibition of STAT3 transcriptional activity by ARHI suggests a novel mechanism through which a putative tumor suppressor gene can inhibit STAT3 activity in breast and ovarian cancers. (PMID:16061651)
• Down-regulation of ARHI gene is associated with breast cancer (PMID:16158053)
• Down-regulation of ARHI due to loss of heterozygosity and promoter methylation is associated with ovarian cancers (PMID:18286529)
• DIRAS3 is a novel, prognostically relevant candidate gene that is frequently methylated and silenced in oligodendroglial tumors with 1p deletion. (PMID:18302158)
• provide evidences that ARHI downregulated in HCCs could play a role in liver cancer via acting as a tumor suppressor gene, which mainly was triggered by the epigenetic events in HCC specimens (PMID:18612997)
• ARHI can induce autophagic cell death, but can also promote tumor dormancy in the presence of factors that promote survival in the cancer microenvironment. (PMID:19033662)
• Data show that ARHI could compete for Ran-importin binding and induce disruption of importin-binding to cargo proteins, including STAT3. (PMID:19435463)
• The presence of NOEY2 mutations in human breast cancer and early-stage lesions indicates that NOEY2 mutations may be partly associated with breast tumourigenesis. (PMID:19482475)
• ARHI represents a modulator of cancer cell proliferation and may play an important role in the development of pancreatic cancer. (PMID:19639215)
• Loss of heterozygosity at 1p31 (including ARHI) did not correlate with the mitotic activity index nor provide prognostic information. (PMID:19759414)
• These data highlighted an important role for ARHI in controlling hepatocellular carcinoma growth and angiogenesis. (PMID:21093415)
• Data show that ARHI re-expression induces autophagic cell death in breast cancer cells and enhances the inhibitory effects of paclitaxel by promoting autophagy, apoptosis, and G2/M cell cycle arrest. (PMID:21244707)
• ARHI expression is present in the endometrium and up-regulated in ectopic endometrium, whereas in the ectopic endometrium of patients with malignant endometriosis its expression is often negative. (PMID:21602127)
• ARHI has a critical and previously uncharacterized role in the regulation of ovarian cancer cell migration. (PMID:21643014)
• ARHI has pro-apoptotic effects on HCC cells, which is associated with the inactivation of both Akt and NF-kappaB survival pathways. (PMID:21933150)
• The level of ARHI mRNA was significantly lower in aggressive compared with non-aggressive prostate cancer tissue samples (PMID:22117988)
• downregulation of ARHI may play an important role both in the pathogenesis and aggravation of gastric cancer. ARHI gene CpG island methylation is a potential molecular basis of its downregulation. (PMID:22427032)
• ARHI expression is downregulated in human gastric cancer and it may be a novel tumor suppressive target for gastric cancer therapy. (PMID:22497484)
• The consequence of complex formation is a DiRas3-mediated recruitment and anchorage of C-RAF to components of the membrane skeleton, suppression of C-RAF/B-RAF heterodimerization, and inhibition of C-RAF kinase activity. (PMID:22605333)
• DiRas3 interacts with C-RAF and downregulates MEK1 activity to restrict cell migration. (PMID:23157514)
• overexpression of ARHI gene might be associated with the inhibition of lung cancer cell growth, proliferation and invasion, and the promotion of apoptosis. (PMID:23247805)
• ARHI acts as a tumor suppressor by downregulating the NFkappaB signaling pathway, which results in the inhibition of cell proliferation, apoptosis and the cell cycle in the pancreatic tumor PANC-1 cell line (PMID:23447002)
• acetylated STAT3 bound to the ARHI promoter and recruited DNA methyltransferase 1 for genetic modification. (PMID:23604529)
• Expression of JMJD2A in infiltrating duct carcinoma is higher than in fibroadenoma, and is associated with ARHI, p53 and ER (PMID:23678541)
• Results indicate that the aplysia ras homolog member I (ARHI) 3’UTR was a direct target of miR-221 in breast cancer MCF-7 cells. (PMID:23801152)
• Imprinted chromatin around DIRAS3 regulates alternative splicing of GNG12-AS1, a long noncoding RNA. (PMID:23871723)
• Loss of ARHI expression is associated with glioma. (PMID:24458808)
• The silence of ARHI expression in vitro seems to accelerate the malignant transformation of healthy ovarian cells by restraining apoptosis and autophagy. (PMID:24476894)
• ARHI is required for autophagy-meditated cancer cell arrest and ARHI inhibits signaling through PI3K/AKT and Ras/MAP by enhancing internalization and degradation of the epidermal growth factor receptor. (PMID:24769729)
• suggest that DIRAS3 not only regulates the autophagosome initiation complex, but induces autophagy in dormant, nutrient-deprived ovarian cancer cells that remain after conventional chemotherapy, facilitating their survival (PMID:24879154)
• EZH2-‘‘induced H3K27me3 is associated with epigenetic repression of the ARHI tumor-suppressor gene in epithelial ovarian cancer (PMID:25077680)
• JMJD2A-dependent silencing of Sp1 in advanced breast cancer promotes metastasis by downregulation of DIRAS3. (PMID:25193278)
• ARHI competes with RanGTPase and interacts with importin beta via basic-acidic patch interaction, which leads to inhibition of STAT3 translocation. (PMID:25499977)
• Letter: ARHI suppresses pancreatic cancer by regulating ERK 1/2 signaling. (PMID:25675421)
• study reports somatic mutation of ARHI gene in hepatocellular carcinoma (HCC), however, only one ARHI mutation was detected; data indicate that somatic mutation in ARHI may be rare in HCCs and suggest that somatic mutational events in ARHI may not contribute to development of HCCs (PMID:26143066)
• ARHI mRNA and protein expression is markedly decreased in osteosarcoma MG-63 cells lines. Overexpression of ARHI inhibits cell viability and proliferation. (PMID:26165148)

Cross-species orthologs

0 orthologs

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), GEM (ENSG00000164949), DIRAS2 (ENSG00000165023), RRAD (ENSG00000166592), RHEBL1 (ENSG00000167550), NKIRAS2 (ENSG00000168256), HRAS (ENSG00000174775), DIRAS1 (ENSG00000176490), RAP2B (ENSG00000181467), ERAS (ENSG00000187682), NKIRAS1 (ENSG00000197885), NRAS (ENSG00000213281), RASL10B (ENSG00000270885)

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
Pongo abelii	Q5R6S2	99.5%	Diamond
Macaca fascicularis	Q95KD9	99.5%	Diamond
Mus musculus	Q5PR73	99.0%	Diamond
Rattus norvegicus	P55043	93.8%	Diamond
Gallus gallus	Q5ZJW6	93.7%	Diamond
Caenorhabditis elegans	Q09930	65.7%	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
GNG12-AS1	ncRNA	100289178
GNG12	protein-coding	55970
WLS	protein-coding	79971
MIR1262	ncRNA	100302279
GADD45A	protein-coding	1647

Protein

Protein identifiers

GTP-binding protein Di-Ras3 — O95661 (reviewed: O95661)

Alternative names: Distinct subgroup of the Ras family member 3, Rho-related GTP-binding protein RhoI

All UniProt accessions (1): O95661

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Cell membrane.

Tissue specificity. Expressed in normal ovarian and breast epithelial cells but not in ovarian and breast cancers.

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

RefSeq proteins (1): NP_004666* (*=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 (11 total): binding site 5, chain 1, propeptide 1, helix 1, short sequence motif 1, modified residue 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

1 structures by resolution:

PDB	Title	Method	Resolution (Å)
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-O95661-F1	73.19	0.43

Human Protein Atlas

Protein class: Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; nuclear membrane

Antibody reliability (HPA): IH approved · IF approved

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
44–51	GTP
63–69	GTP
91–95	GTP
152–155	GTP
182–183	GTP

Post-translational modifications (2)

Type	Positions
Cysteine methyl ester	226
S-geranylgeranyl cysteine	226

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: 87 (showing top): GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, MODULE_66, GOBP_GENOMIC_IMPRINTING, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, PIEPOLI_LGI1_TARGETS_UP, GOBP_REGULATION_OF_PROTEIN_SERINE_THREONINE_KINASE_ACTIVITY, GOBP_CHROMATIN_REMODELING, GOBP_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN, GOBP_EPIGENETIC_REGULATION_OF_GENE_EXPRESSION, GOBP_REGULATION_OF_PHOSPHORUS_METABOLIC_PROCESS, BLALOCK_ALZHEIMERS_DISEASE_DN, KAN_RESPONSE_TO_ARSENIC_TRIOXIDE

GO Biological Process (4): regulation of cyclin-dependent protein serine/threonine kinase activity (GO:0000079), small GTPase-mediated signal transduction (GO:0007264), genomic imprinting (GO:0071514), signal transduction (GO:0007165)

GO Molecular Function (4): GTPase activity (GO:0003924), GTP binding (GO:0005525), nucleotide binding (GO:0000166), protein binding (GO:0005515)

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

GO top-level categories

20 GO namespaces:

Category	Terms
cyclin-dependent protein serine/threonine kinase activity	1
regulation of protein serine/threonine kinase activity	1
intracellular signaling cassette	1
germ cell development	1
epigenetic programming of gene expression	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
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

showing 15 of 802 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DIRAS3	MEST	Q5EB52	585
DIRAS3	PLAGL1	Q9UM63	515
DIRAS3	PEG3	P78418	497
DIRAS3	FAM50B	Q9Y247	497
DIRAS3	NAP1L5	Q96NT1	477
DIRAS3	TG	P01266	432
DIRAS3	PHLDA2	Q53GA4	413
DIRAS3	PEG10	Q86TG7	408
DIRAS3	SNRPN	P14648	405
DIRAS3	ZNF597	Q96LX8	396
DIRAS3	NNAT	Q16517	396
DIRAS3	SGCE	O43556	390
DIRAS3	GNAS	Q5JWF2	388
DIRAS3	FLT1	P16057	387
DIRAS3	ZDBF2	Q9HCK1	385

IntAct

Human interaction partners of DIRAS3 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

16 partners by confidence:

Partner	Interaction type	MIscore	Records
MEOX2	physical association	0.560	3
MTIF2	association	0.530	2
DCAF10	association	0.530	1
STAT3	physical association	0.460	3
APC	physical association	0.370	1
BAG4	physical association	0.370	1
BRMS1	physical association	0.370	1
CHEK2	physical association	0.370	1
FGFR4	physical association	0.370	1
KRAS	physical association	0.370	1
PALB2	physical association	0.370	1
PPM1D	physical association	0.370	1
PTPN1	physical association	0.370	1
TGFB1	physical association	0.370	1
WT1	physical association	0.370	1
CBX6	association	0.350	1

BioGRID (279 interactions; top human partners by supporting records): RNF19B (Affinity Capture-MS; 4 records), DCAF10 (Affinity Capture-MS; 3 records), MTIF2 (Affinity Capture-MS; 3 records), SLC30A1 (Affinity Capture-MS; 3 records), ATG14 (Affinity Capture-Western; 2 records), BECN1 (Affinity Capture-Western; 2 records), FEZ2 (Affinity Capture-MS; 2 records), KRAS (Synthetic Growth Defect; 2 records), NAP1L1 (Proximity Label-MS; 2 records), PIK3C3 (Affinity Capture-Western; 2 records), RAC1 (Affinity Capture-Western; 2 records), ABCC1 (Proximity Label-MS), ADCY9 (Proximity Label-MS), ADD3 (Proximity Label-MS), AFG3L2 (Proximity Label-MS)

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 16 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.

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of cell population proliferation	6	15.8×	5e-04
positive regulation of gene expression	5	12.1×	4e-03

Disease & clinical

Genetic variants

Variant evidence for DIRAS3: 26 ClinVar records (0 pathogenic / likely pathogenic).

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	21
Likely benign	4
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 16 predictions of 193):

Position(s)	Effect	Δscore	Sites
1:68047363–68047364	acceptor_loss	0.9900	5
1:68050546–68050547	donor_loss	0.9800	3
1:68051468	donor_gain	0.9800
1:68051557	donor_gain	0.9800
1:68047363	acceptor_loss	0.9700
1:68050546	donor_loss	0.9600
1:68049767	donor_gain	0.9300
1:68050547	donor_loss	0.9200
1:68049998	donor_gain	0.9000
1:68051422	donor_gain	0.9000

AlphaMissense

254 missense substitutions predicted likely pathogenic (of 1,507 scored), across 79 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
D155	8	0.787	0.845
D91	8	0.762	0.859
F177	7	0.868	0.974
F112	7	0.857	0.985
F192	7	0.852	0.952
W173	7	0.834	0.942
E179	7	0.777	0.843
K50	6	0.931	0.958
G49	6	0.916	0.949
K153	6	0.878	0.964
G44	6	0.870	0.933
S51	6	0.870	0.936
K138	6	0.840	0.956
N152	6	0.806	0.939
W57	6	0.797	0.882
C175	6	0.750	0.900
Y116	5	0.865	0.941
F62	5	0.832	0.933
P146	5	0.623	0.674
G151	4	0.885	0.938

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Glioblastoma Multiforme, Thyroid Carcinoma)

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

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Papillary Cell Carcinoma (TCGA)	favorable	2.55e-05
Glioblastoma Multiforme (validation)	unfavorable	0.00037

Disease associations

OMIM: gene MIM:605193 | disease phenotypes:

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

38 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	5
sodium arsenite	increases expression, decreases expression	3
bisphenol A	increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	2
Estradiol	increases expression, affects expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Silicon Dioxide	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
methyleugenol	decreases expression	1
terbufos	increases methylation	1
trichostatin A	increases expression	1
arsenite	increases methylation	1
butyraldehyde	decreases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
archazolid B	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	affects methylation, increases abundance	1
Ethanol	increases expression	1
Fonofos	increases methylation	1
Nickel	decreases expression	1
Nitrogen Dioxide	affects methylation, increases abundance	1
Parathion	increases methylation	1

Clinical trials (associated diseases)

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