ECT2

Summary

ECT2 (epithelial cell transforming 2, HGNC:3155) is a protein-coding gene on chromosome 3q26.31, encoding Protein ECT2 (Q9H8V3). Guanine nucleotide exchange factor (GEF) that catalyzes the exchange of GDP for GTP. It is a common-essential gene (DepMap: required in 96.5% of cancer cell lines).

The protein encoded by this gene is a guanine nucleotide exchange factor and transforming protein that is related to Rho-specific exchange factors and yeast cell cycle regulators. The expression of this gene is elevated with the onset of DNA synthesis and remains elevated during G2 and M phases. In situ hybridization analysis showed that expression is at a high level in cells undergoing mitosis in regenerating liver. Thus, this protein is expressed in a cell cycle-dependent manner during liver regeneration, and is thought to have an important role in the regulation of cytokinesis. Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 1894 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 128 total
• GTEx eGene: eQTL in 16 tissues, sQTL in 2 (q < 0.05)
• Cancer dependency (DepMap): dependent in 96.5% of screened cell lines (common-essential)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.66 (unconstrained)
• MANE Select transcript: NM_001258315
• Interaction hub: 2,858 STRING partners (top 3% of genes corpus-wide)
• Notable: 128 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3155
Approved symbol	ECT2
Name	epithelial cell transforming 2
Location	3q26.31
Locus type	gene with protein product
Status	Approved
Aliases	ARHGEF31
Ensembl gene	ENSG00000114346
Ensembl biotype	protein_coding
OMIM	600586
Entrez	1894

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 26 protein_coding, 3 retained_intron, 3 nonsense_mediated_decay

MANE Select: ENST00000392692

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 4, TSL 3: 5, TSL 4: 3, TSL 5: 4

ENST00000392692, ENST00000232458, ENST00000366090, ENST00000366254, ENST00000415665, ENST00000417960, ENST00000426894, ENST00000428567, ENST00000437296, ENST00000438041, ENST00000441497, ENST00000444250, ENST00000460860, ENST00000486027, ENST00000487073, ENST00000540509, ENST00000894233, ENST00000894234, ENST00000894235, ENST00000894236, ENST00000921495, ENST00000921496, ENST00000921497, ENST00000921498, ENST00000921499, ENST00000921500, ENST00000921501, ENST00000921502, ENST00001075203, ENST00001075204, ENST00001075205, ENST00001140093

RefSeq mRNA: 14 — MANE Select: NM_001258315 NM_001258315, NM_001258316, NM_001349094, NM_001349095, NM_001349096, NM_001349097, NM_001349098, NM_001349099, NM_001349100, NM_001349101, NM_001349102, NM_001349103, NM_001349104, NM_018098

CCDS: CCDS3220, CCDS58860, CCDS87168

Canonical transcript exons

ENST00000392692 — 25 exons

Exon	Start	End
ENSE00000780531	172761610	172761683
ENSE00000780534	172762910	172762972
ENSE00000826251	172762691	172762806
ENSE00000826252	172760156	172760263
ENSE00000826253	172758980	172759069
ENSE00000826254	172756983	172757165
ENSE00000826255	172755295	172755374
ENSE00001151860	172807770	172807924
ENSE00001151868	172805731	172805869
ENSE00001151881	172802616	172802694
ENSE00001151885	172786493	172786574
ENSE00001151890	172784707	172784803
ENSE00001151894	172783799	172783909
ENSE00001151898	172782163	172782231
ENSE00001151904	172773903	172774022
ENSE00001151911	172769007	172769143
ENSE00001151919	172764278	172764500
ENSE00001151940	172762416	172762546
ENSE00001203440	172754509	172754660
ENSE00001512806	172755483	172755575
ENSE00001650515	172820148	172821474
ENSE00001777018	172750726	172750857
ENSE00003669960	172816691	172816837
ENSE00003672259	172815604	172815711
ENSE00003686694	172802861	172802980

Expression profiles

Bgee: expression breadth ubiquitous, 248 present calls, max score 98.50.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 28.7465 / max 1085.8300, expressed in 1749 samples.

Highest expression (Bgee): secondary oocyte, oocyte, ventricular zone, ganglionic eminence, primordial germ cell in gonad.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ECT2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 16 tissues and its splicing (sQTL) in 2 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

18 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Nerve Tibial	eqtl	1.2e-08	+0.69	3:172749994:G:A
Thyroid	eqtl	1.9e-05	-0.53	3:172759687:G:A
Cells EBV-transformed lymphocytes	eqtl	3.2e-05	+0.35	3:172742472:T:G
Muscle Skeletal	eqtl	4.5e-05	+0.48	3:172742472:T:G
Esophagus Muscularis	eqtl	7.4e-04	+0.50	3:172858617:C:A
Artery Tibial	eqtl	7.9e-04	+0.29	3:172831022:G:A
Artery Aorta	eqtl	1.5e-03	+0.16	3:172839332:AC:A
Adipose Subcutaneous	eqtl	2.0e-03	+0.32	3:172687032:T:G
Cells Cultured fibroblasts	eqtl	2.1e-03	+0.06	3:172834615:G:A
Spleen	eqtl	2.3e-03	+0.17	3:173456180:G:A
Skin Not Sun Exposed Suprapubic	eqtl	9.9e-03	-0.26	3:173040206:T:C
Brain Frontal Cortex BA9	eqtl	1.1e-02	+0.17	3:172772431:C:T
Cells Cultured fibroblasts	sqtl	1.2e-02	+0.65	3:173080661:G:C
Nerve Tibial	sqtl	1.3e-02	+0.90	3:172309505:G:A
Colon Sigmoid	eqtl	1.5e-02	+0.37	3:172760357:TAAAG:T
Brain Caudate basal ganglia	eqtl	1.7e-02	-0.71	3:172812227:A:T
Esophagus Mucosa	eqtl	2.6e-02	+0.16	3:172687032:T:G
Prostate	eqtl	3.8e-02	+0.23	3:173137988:T:C

FANTOM5 promoters

4 alternative TSS:

Promoter ID	TPM avg	Samples expressed
39846	25.5197	1700
39847	1.8483	1055
39845	1.1990	668
203030	0.1795	60

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	98.50	gold quality
oocyte	CL:0000023	97.97	gold quality
ventricular zone	UBERON:0003053	97.31	gold quality
ganglionic eminence	UBERON:0004023	93.68	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.75	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.62	gold quality
embryo	UBERON:0000922	90.73	gold quality
rectum	UBERON:0001052	87.46	gold quality
colonic epithelium	UBERON:0000397	86.18	gold quality
esophagus squamous epithelium	UBERON:0006920	85.68	gold quality
sperm	CL:0000019	84.36	gold quality
stromal cell of endometrium	CL:0002255	83.85	gold quality
adrenal tissue	UBERON:0018303	83.77	gold quality
mucosa of transverse colon	UBERON:0004991	82.51	gold quality
endometrium	UBERON:0001295	81.80	gold quality
mucosa of sigmoid colon	UBERON:0004993	81.51	gold quality
male germ cell	CL:0000015	81.46	gold quality
epithelium of nasopharynx	UBERON:0001951	81.21	gold quality
esophagus mucosa	UBERON:0002469	80.97	gold quality
bone marrow	UBERON:0002371	80.83	gold quality
islet of Langerhans	UBERON:0000006	80.76	gold quality
epithelium of esophagus	UBERON:0001976	80.64	gold quality
colonic mucosa	UBERON:0000317	80.46	gold quality
endothelial cell	CL:0000115	79.81	gold quality
testis	UBERON:0000473	79.59	gold quality
gingival epithelium	UBERON:0001949	79.47	gold quality
vermiform appendix	UBERON:0001154	79.30	gold quality
oral cavity	UBERON:0000167	79.03	gold quality
visceral pleura	UBERON:0002401	78.89	gold quality
trabecular bone tissue	UBERON:0002483	78.61	gold quality
right testis	UBERON:0004534	78.52	gold quality
tonsil	UBERON:0002372	78.30	gold quality
amniotic fluid	UBERON:0000173	78.17	gold quality
squamous epithelium	UBERON:0006914	77.98	gold quality
palpebral conjunctiva	UBERON:0001812	77.80	gold quality
lower esophagus mucosa	UBERON:0035834	77.78	gold quality
left testis	UBERON:0004533	77.63	gold quality
gingiva	UBERON:0001828	76.82	gold quality
transverse colon	UBERON:0001157	76.81	gold quality
esophagus	UBERON:0001043	76.77	gold quality
calcaneal tendon	UBERON:0003701	76.65	gold quality
caecum	UBERON:0001153	76.54	gold quality
gall bladder	UBERON:0002110	76.41	gold quality
minor salivary gland	UBERON:0001830	76.22	gold quality
parietal pleura	UBERON:0002400	76.19	gold quality
lymph node	UBERON:0000029	76.17	gold quality
pleura	UBERON:0000977	75.98	gold quality
bone marrow cell	CL:0002092	75.90	gold quality
upper lobe of lung	UBERON:0008948	75.80	gold quality
large intestine	UBERON:0000059	75.73	gold quality
upper lobe of left lung	UBERON:0008952	75.73	gold quality
smooth muscle tissue	UBERON:0001135	75.70	gold quality
mouth mucosa	UBERON:0003729	75.70	gold quality
cortical plate	UBERON:0005343	75.43	gold quality
colon	UBERON:0001155	75.42	gold quality
intestine	UBERON:0000160	75.40	gold quality
thymus	UBERON:0002370	75.40	gold quality
germinal epithelium of ovary	UBERON:0001304	75.22	gold quality
metanephros cortex	UBERON:0010533	75.13	gold quality
right adrenal gland cortex	UBERON:0035827	75.00	gold quality
jejunal mucosa	UBERON:0000399	74.97	gold quality
monocyte	CL:0000576	74.90	gold quality
skin of abdomen	UBERON:0001416	74.89	gold quality
right adrenal gland	UBERON:0001233	74.87	gold quality
mononuclear cell	CL:0000842	74.67	gold quality
leukocyte	CL:0000738	74.59	gold quality
body of stomach	UBERON:0001161	74.50	gold quality
placenta	UBERON:0001987	74.42	gold quality
duodenum	UBERON:0002114	74.37	gold quality
prefrontal cortex	UBERON:0000451	74.32	gold quality
stomach	UBERON:0000945	74.28	gold quality
tibia	UBERON:0000979	73.82	gold quality
small intestine Peyer’s patch	UBERON:0003454	73.79	gold quality
epithelial cell of pancreas	CL:0000083	73.78	gold quality
left adrenal gland	UBERON:0001234	73.74	gold quality
skin of leg	UBERON:0001511	73.68	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	73.46	gold quality
uterus	UBERON:0000995	73.43	gold quality
omental fat pad	UBERON:0010414	73.38	gold quality
small intestine	UBERON:0002108	73.30	gold quality
peritoneum	UBERON:0002358	73.29	gold quality
vagina	UBERON:0000996	73.07	gold quality
left adrenal gland cortex	UBERON:0035825	73.01	gold quality
zone of skin	UBERON:0000014	72.98	gold quality
adrenal gland	UBERON:0002369	72.96	gold quality
bronchial epithelial cell	CL:0002328	72.80	gold quality
pancreas	UBERON:0001264	72.76	gold quality
adipose tissue of abdominal region	UBERON:0007808	72.70	gold quality
subcutaneous adipose tissue	UBERON:0002190	72.47	gold quality
lung	UBERON:0002048	72.46	gold quality
saliva-secreting gland	UBERON:0001044	72.39	gold quality
anterior cingulate cortex	UBERON:0009835	72.24	gold quality
cingulate cortex	UBERON:0003027	72.16	gold quality
Brodmann (1909) area 9	UBERON:0013540	72.04	gold quality
spleen	UBERON:0002106	71.93	gold quality
right lung	UBERON:0002167	71.88	gold quality
lower esophagus	UBERON:0013473	71.83	gold quality
lower esophagus muscularis layer	UBERON:0035833	71.79	gold quality
muscle layer of sigmoid colon	UBERON:0035805	71.74	gold quality
nasal cavity mucosa	UBERON:0001826	71.71	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Thymus	tissue	21.7
Bone marrow	tissue	18.6
Postcentral gyrus	tissue	16.8
Testis	tissue	14.9
Rectum	tissue	14.8
Nucleus accumbens	tissue	14.3
Locus coeruleus	tissue	14.2
Choroid plexus	tissue	13.7
Hippocampus	tissue	13.4
Retina	tissue	11.6
Colon	tissue	10.8
Tonsil	tissue	10.7
Lymph node	tissue	9.8
Stomach 1	tissue	8.9
Duodenum	tissue	8.7
Esophagus	tissue	8.2
Placenta	tissue	8.2
Appendix	tissue	7.8
Cervix	tissue	7.6
Small intestine	tissue	7.1
Breast	tissue	7.0
Smooth muscle	tissue	6.9
Skin 1	tissue	6.6
Urinary bladder	tissue	6.4
Cerebellum	tissue	5.8
Olfactory bulb	tissue	5.3
Gallbladder	tissue	4.9
Corpus callosum	tissue	4.6
Cerebral cortex	tissue	4.4
Lung	tissue	4.4
Retrosplenial cortex	tissue	4.4
Insular cortex	tissue	4.4
Amygdala	tissue	4.3
Retrosplenial and cingulate cortex	tissue	4.3
Endometrium 1	tissue	4.2
Basal ganglia	tissue	4.1
Spleen	tissue	4.1
Hippocampal formation	tissue	4.1
Entorhinal cortex	tissue	4.1
Temporal cortex	tissue	4.1
Vagina	tissue	4.0
Kidney	tissue	4.0
Prefrontal cortex	tissue	3.9
Septum	tissue	3.9
Ventral forebrain	tissue	3.8
Occipital cortex	tissue	3.8
Motor cortex	tissue	3.7
Thyroid gland	tissue	3.6
Putamen	tissue	3.5
Periaqueductal gray	tissue	3.5
Spinal cord	tissue	3.4
Somatosensory cortex	tissue	3.4
Adipose tissue	tissue	3.3
Parathyroid gland	tissue	3.3
Salivary gland	tissue	3.2
Midbrain	tissue	3.2
Hypothalamus	tissue	3.2
Substantia nigra	tissue	3.2
Adrenal gland	tissue	3.2
Medulla oblongata	tissue	3.1

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Orbitofrontal gyrus, anterior (18.7), Angular gyrus (white matter) (18.5), Vermis (18.1), Flocculonodular lobe (17.2), Cerebellar cortex (17.0).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CUX1, DMTF1, E2F1, TP53

miRNA regulators (miRDB)

Targeting ECT2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 96 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-373-3P	99.84	70.68	1668
HSA-MIR-520E-3P	99.84	70.55	1698
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-372-3P	99.83	70.58	1691
HSA-MIR-520A-3P	99.83	70.59	1687

Functional genomics

gnomAD constraint: pLI 0.000154, LOEUF 0.664, missense Z 1.9 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000392692 — one region, missense o/e 0.87. DepMap (CRISPR cell-line fitness): dependent in 96.5% of screened cell lines, common-essential.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): PANC-1 (-2.179), LS513 (-2.049), OS-RC-2 (-2.018), CFPAC-1 (-1.993), SNU-1033 (-1.967), S-117 (-1.964), KP-N-YN (-1.951), HCC1187 (-1.937), L-363 (-1.899), COR-L279 (-1.896), Panc 05.04 (-1.852), JH-EsoAd1 (-1.843), HUP-T4 (-1.83), NCO2 (-1.815), IMR-32 (-1.803).

Literature-anchored findings (GeneRIF, showing 40)

• XRCC1, CLB6, and BRCT domains of ECT2 play a critical role in regulating cytokinesis (PMID:14587037)
• ECT2 regulates the polarity complex Par6/Par3/PKCzeta and possibly plays a role in epithelial cell polarity (PMID:15254234)
• BRCT domains negatively regulate Ect2 GEF activity in interphase cells, and they are also required for the proper function of Ect2 during cytokinesis (PMID:15545273)
• Ect2 regulates the activation and function of Cdc42 in mitosis. (PMID:15642749)
• Central spindle localization of ECT2 assists division plane positioning and the CYK-4 subunit of centralspindlin acts upstream of RhoA to promote furrow assembly. (PMID:16103226)
• Cdk1 inactivation is sufficient to activate a signaling pathway leading to cytokinesis, which emanates from mitotic spindles and is regulated by ECT2, MgcRacGAP, and RhoA (PMID:16118207)
• MgcRacGAP controls the initiation of cytokinesis by regulating ECT2, which in turn induces the assembly of the contractile ring and triggers the ingression of the cleavage furrow (PMID:16129829)
• a conformational change of ECT2 upon phosphorylation at T341. Therefore, ECT2 activity might be regulated by the phosphorylation status of T341. (PMID:16170345)
• ECT2 is regulated by Plk1 and CDK1, phosphorylation of ECT2 leads to accumulation of RHOA (PMID:16247472)
• Data show that RhoA accumulates at the equatorial cortex before furrow initiation and continues to concentrate at the cleavage furrow during cytokinesis, and that centralspindlin and ECT2 are required for this localization and furrowing. (PMID:16352658)
• ECT2 knockdown triggers cell cycle arrest in G1. (PMID:16778203)
• In mitotic cells Ect2 localizes to the central spindle and to the cell cortex. (PMID:16803869)
• Aberrant ECT2 expression, observed in various human tumors, could be the direct result of RB/E2F pathway deficiency, thereby contributing to cell division in cancers. (PMID:16862181)
• Late mitotic Plk1 activity promotes recruitment of Ect2 to the central spindle, triggering the initiation of cytokinesis and contributing to cleavage plane specification in human cells. (PMID:17488623)
• This gene was silenced. (PMID:17688947)
• These results suggest that equatorial Ect2 locally suppresses lamellipodia formation via RhoA activation, which indirectly contributes to restricting lamellipodia formation to polar regions during cytokinesis B. (PMID:17942602)
• Study demonstrates that FIP3 and ECT2 form mutually exclusive complexes with Cyk-4 and that dissociation of ECT2 from the mid-body at late telophase may be required for the recruitment of FIP3 and recycling endosomes to the cleavage furrow. (PMID:18511905)
• results suggest that co-regulation of Rho activity by p190RhoGAP and ECT2 in the cleavage furrow determines whether cells properly complete cytokinesis (PMID:18642445)
• Report correlation between ECT2 gene expression and methylation change of ECT2 promoter region in pancreatic cancer. (PMID:18842503)
• Data show that Trio, Ect2, and Vav3 are expressed at higher levels in glioblastoma versus low-grade glioma, and are involved in tumor cell migration and invasion. (PMID:19008376)
• study reports that mitotic complex genes Ect2, RacGAP, and MKLP1 are coordinately induced in S phase in proliferating T lymphocytes as well as in epithelial cells, depending upon activity of the CUX1 and E2F1 transcription factors (PMID:19015243)
• Immunohistochemical staining showed that a high level of ECT2 expression was associated with poor prognosis for patients with NSCLC (P = 0.0004) as well as ESCC (P = 0.0088). (PMID:19118053)
• Data showed how Plk1 promotes the central spindle recruitment of Ect2. Plk1 phosphorylates the noncatalytic N terminus of the RhoGAP HsCyk-4 at the central spindle, creating a phospho-epitope recognized by the BRCA1 C-terminal (BRCT) repeats of Ect2. (PMID:19468300)
• Data found that Plk1 binds and directly phosphorylates the HsCYK-4 at the midzone and this modification creates a major docking site for the tandem BRCT repeats of the Rho GTP exchange factor Ect2. (PMID:19468302)
• Ect2 and PKCiota are genetically and functionally linked in NSCLC, acting to coordinately drive tumor cell proliferation and invasion through formation of an oncogenic PKCiota-Par6alpha-Ect2 complex. (PMID:19617897)
• Results suggest that ECT2 is an indicator of cellular proliferation in OSCCs and that ECT2 might be a potential therapeutic target for the development of new treatments for OSCCs. (PMID:21124766)
• a model in which PKCiota-mediated phosphorylation regulates Ect2 binding to the oncogenic PKCiota-Par6 complex thereby activating Rac1 activity and driving transformed growth and invasion. (PMID:21189248)
• A mechanism involving the nuclear GEFs Ect2 and Net1 for activating RhoB after genotoxic stress, thereby facilitating cell death after treatment with DNA damaging agents. (PMID:21373644)
• Ect2 was a possible regulator of matrix-contact-side localization of invadopodia-related proteins. (PMID:21474972)
• identify Ect2 as a cell cycle-regulated protein and suggest that its ubiquitination-dependent degradation may play an important role in RhoA regulation at the time of mitosis. (PMID:21886810)
• targeting of Ect2 to the equatorial membrane represents a key step in the delivery of the cytokinetic signal to the cortex (PMID:22172673)
• Data supports an analogous function for the anillin-Ect2 complex in human cells and one hypothesis is that this complex has functionally replaced the Drosophila anillin-RacGAP50C complex. (PMID:22514687)
• ECT2 is important for tight junction function and maintenance of cell polarity. Nonfunction of this gene may cause renal tubulointerstitial injury, progressing to glomerular sclerosis. (PMID:22552385)
• RASAL2 was identified as an ECT2-interacting protein that regulates RHO activity in astrocytoma cells. (PMID:22683310)
• find that Ect2 first becomes active in prophase, when it is exported from the nucleus into the cytoplasm, activating RhoA to induce the formation of a mechanically stiff and rounded metaphase cortex (PMID:22898780)
• miR-223 functions as a tumor suppresser in osteosarcoma and miR-223/Ect2/p21 signaling is an important pathway that regulates the osteosarcoma cell cycle progression and proliferaion (PMID:23601845)
• Data suggest that ECT2 may play an oncogenic role in the pancreatic ductal adenocarcinoma (PDAC) neoplastic process. (PMID:23851435)
• Both Pbl and ECT2 repress Wg/Wnt target gene expression in cultured Drosophila and human cells. (PMID:24198276)
• Abnormality of the ECT2 gene occurs at a relatively early stage of lung adenocarcinogenesis and would be applicable as a new biomarker for prognostication of patients with lung adenocarcinoma (PMID:24484057)
• the deregulation of miR-223 and its target gene ECT2 may be associated with the aggressive tumor progression of human osteosarcoma (PMID:24784921)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ect2	ENSDARG00000007278
mus_musculus	Ect2	ENSMUSG00000027699
rattus_norvegicus	Ect2	ENSRNOG00000024365
drosophila_melanogaster	pbl	FBGN0003041
caenorhabditis_elegans		WBGENE00002297

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:95281) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 8 distinct phenotype terms.

Mouse phenotype (MP)	Records
tremors	1
abnormal inner cell mass morphology	1
failure of blastocyst to hatch from the zona pellucida	1
abnormal auditory brainstem response	1
decreased grip strength	1
prenatal lethality, complete penetrance	1
embryonic lethality before implantation, complete penetrance	1
preweaning lethality, complete 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
Xenopus laevis	Q7ZZY3	98.1%	Diamond
Pongo abelii	Q5R5M3	95.4%	Diamond
Bos taurus	Q29RM4	87.5%	Diamond
Dictyostelium discoideum	Q1ZXH8	43.8%	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
NCEH1	protein-coding	57552
SPATA16	protein-coding	83893
LINC02068	ncRNA	105374219

Protein

Protein identifiers

Protein ECT2 — Q9H8V3 (reviewed: Q9H8V3)

Alternative names: Epithelial cell-transforming sequence 2 oncogene

All UniProt accessions (9): Q9H8V3, C9J0L6, C9J1C4, C9JB41, C9JDB4, C9JDV9, C9JTI2, H7C103, H7C3G1

UniProt curated annotations — full annotation on UniProt →

Function. Guanine nucleotide exchange factor (GEF) that catalyzes the exchange of GDP for GTP. Promotes guanine nucleotide exchange on the Rho family members of small GTPases, like RHOA, RHOC, RAC1 and CDC42. Required for signal transduction pathways involved in the regulation of cytokinesis. Component of the centralspindlin complex that serves as a microtubule-dependent and Rho-mediated signaling required for the myosin contractile ring formation during the cell cycle cytokinesis. Regulates the translocation of RHOA from the central spindle to the equatorial region. Plays a role in the control of mitotic spindle assembly; regulates the activation of CDC42 in metaphase for the process of spindle fibers attachment to kinetochores before chromosome congression. Involved in the regulation of epithelial cell polarity; participates in the formation of epithelial tight junctions in a polarity complex PARD3-PARD6-protein kinase PRKCQ-dependent manner. Plays a role in the regulation of neurite outgrowth. Inhibits phenobarbital (PB)-induced NR1I3 nuclear translocation. Stimulates the activity of RAC1 through its association with the oncogenic PARD6A-PRKCI complex in cancer cells, thereby acting to coordinately drive tumor cell proliferation and invasion. Also stimulates genotoxic stress-induced RHOB activity in breast cancer cells leading to their cell death.

Subunit / interactions. Homodimer. Homooligomer. Found in the centralspindlin complex. Interacts with NR1I3. Interacts (Thr-359 phosphorylated form) with PARD6A; the interaction is observed in cancer cells. Interacts (Thr-359 phosphorylated form) with PRKCI; the interaction is observed in cancer cells. Interacts with PKP4; the interaction is observed at the midbody. Interacts with RACGAP1/CYK4; the interaction is direct, occurs in a microtubule-dependent manner, occurs at anaphase and during cytokinesis, is inhibited in metaphase by phosphorylation of ECT2 on Thr-373 and is stimulated in early anaphase by dephosphorylation of ECT2 probably on Thr-373 through CDK1 activity. Interacts with PLK1; the interaction is stimulated upon its phosphorylation on Thr-444. Interacts with RHOA; the interaction results in allosteric activation of ECT2. Interacts with KIF23, PARD3, PARD6B and PRKCQ. Interacts with NEDD9/HEF1.

Subcellular location. Nucleus. Cytoplasm. Cytoskeleton. Spindle. Cleavage furrow. Midbody. Cell junction. Tight junction. Microtubule organizing center. Centrosome.

Tissue specificity. Expressed in lung epithelial cells (at protein level). Expressed in squamous cell carcinoma, primary non-small cell lung cancer tumors and lung adenocarcinoma.

Post-translational modifications. Phosphorylated by PLK1 in vitro. Hyperphosphorylated during the G2 phase of the cell cycle. Phosphorylation at Thr-373 occurs during the G2/M phase, relieves its auto-inhibition status and stimulates its GEF activity. Phosphorylation at Thr-444 in G2/M phase is required for subsequent binding with PLK1 and Rho exchange activation. Dephosphorylated at the time of cytokinesis. Phosphorylation at Thr-359 is required for its transformation activity in cancer cells.

Activity regulation. Autoinhibited by the C-terminal PH domain which folds back and binds to the surface of the DH domain, blocking binding of RHOA to the catalytic center of the DH domain. The 2nd BRCT domain is also involved in inhibition, probably by helping to impede RHOA binding. Allosterically activated by binding of activated GTP-bound RHOA to the PH domain which stimulates the release of PH inhibition and promotes the binding of substrate RHOA to the catalytic center. Binding of phosphorylated RACGAP1 to the N-terminal BRCT domain-containing region also releases autoinhibition.

Domain organisation. The BRCT domains 1 and 2 are required for intramolecular interaction, but not for intermolecular oligomerization. The BRCT domains negatively inhibit its GEF activity in interphase cells. The same BRCT domains may act as a positive regulatory motif for the completion of cytokinesis after the breakdown of nuclear membrane during mitosis.

Induction. Up-regulated by calcium in cells forming cell-cell contact sites. Up-regulated by DNA damaging agents like H(2)O(2) or ionizing radiation (IR).

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9H8V3-1	1	yes
Q9H8V3-2	2
Q9H8V3-3	3
Q9H8V3-4	4

RefSeq proteins (14): NP_001245244, NP_001245245, NP_001336023, NP_001336024, NP_001336025, NP_001336026, NP_001336027, NP_001336028, NP_001336029, NP_001336030, NP_001336031, NP_001336032, NP_001336033, NP_060568 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000219	DH_dom	Domain
IPR001331	GDS_CDC24_CS	Conserved_site
IPR001357	BRCT_dom	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR026817	Ect2	Family
IPR035899	DBL_dom_sf	Homologous_superfamily
IPR036420	BRCT_dom_sf	Homologous_superfamily
IPR049395	ECT2_PH	Domain
IPR049396	ECT2_BRCT0	Domain

Pfam: PF00533, PF00621, PF12738, PF21242, PF21243

UniProt features (111 total): helix 32, mutagenesis site 23, strand 19, modified residue 12, turn 4, domain 4, splice variant 3, sequence conflict 3, compositionally biased region 2, sequence variant 2, region of interest 2, short sequence motif 2, initiator methionine 1, chain 1, cross-link 1

Structure

Experimental structures (PDB)

3 structures by resolution:

PDB	Title	Method	Resolution (Å)
3L46	Crystal structure of the second BRCT domain of epithelial cell transforming 2 (ECT2)	X-RAY DIFFRACTION	1.48
6L30	Crystal structure of the epithelial cell transforming 2 (ECT2)	X-RAY DIFFRACTION	2.8
4N40	Crystal structure of human Epithelial cell-transforming sequence 2 protein	X-RAY DIFFRACTION	3.11

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H8V3-F1	71.17	0.27

Human Protein Atlas

Protein class: Predicted intracellular proteins, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm; cytosol

Antibody reliability (HPA): IF enhanced

Functional residue map

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

Post-translational modifications (13)

Type	Positions
N-acetylalanine	2
Phosphothreonine	359, 373, 444, 846
Phosphoserine	367, 370, 376, 716, 842, 861, 866
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in sumo2)	611

Mutagenesis-validated functional residues (23)

Position	Phenotype
184	inhibits interaction with racgap1. abolishes targeting to the central spindle.
226	inhibits interaction with racgap1. abolishes targeting to the central spindle.
336	inhibits homodimerization. increases binding with rhoa and gef activity.
338	2-fold increase in gef activity.
359	inhibits its phosphorylation and anchorage-independent growth and invasion in cancer cells. does not inhibit its gef activity.
373	does not inhibit its rho exchange activity. increases interaction with racgap1. does not inhibit anchorage-independent growth and invasion …
373	does not inhibit subcellular localization or homodimerization. enhances its rho exchange activity.
379–381	shows both nuclear and cytoplasmic localization and activates its transforming activity.
402–404	shows both nuclear and cytoplasmic localization and activates its transforming activity.
444	diminishes its phosphorylation status. reduces its interaction with plk1 and rho exchange activity. does not change its subcellular …
444	does not reduce its interaction with plk1, change its subcellular localization and rho exchange activity.
488	partially releases inhibition.
570	2-fold increase in gef activity.
573	2-fold increase in gef activity.
586	complete loss of gef activity and failure to support cytokinesis.
596–599	inhibits activation of the transforming activity.
601	complete loss of gef activity and failure to support cytokinesis.
652	no effect on gef activity but severely decreases ect2 activation by rhoa. localizes correctly but fails to rescue the cytokinesis defect …
656	no effect on gef activity but severely decreases ect2 activation by rhoa. fails to rescue the cytokinesis defect caused by knockdown of …
670	marked increase in gef activity and rescues the cytokinesis defect caused by depletion of endogenous ect2. when expressed in a cancer cell …
734	more than 10-fold increase in gef activity. overexpression causes noticeable changes in interphase cell morphology such as cell rounding …
796	more than 10-fold increase in gef activity. overexpression causes noticeable changes in interphase cell morphology such as cell rounding …
846	diminishes its phosphorylation status.

Function

Pathways and Gene Ontology

Reactome pathways

6 curated (TAS) of 15; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

15 pathways:

ID	Pathway	Evidence
R-HSA-9013148	CDC42 GTPase cycle	curated
R-HSA-416482	G alpha (12/13) signalling events	curated
R-HSA-193648	NRAGE signals death through JNK	curated
R-HSA-9013149	RAC1 GTPase cycle	curated
R-HSA-8980692	RHOA GTPase cycle	curated
R-HSA-9013026	RHOB GTPase cycle	curated
R-HSA-204998	Cell death signalling via NRAGE, NRIF and NADE	—
R-HSA-73887	Death Receptor Signaling	—
R-HSA-388396	GPCR downstream signalling	—
R-HSA-9012999	RHO GTPase cycle	—
R-HSA-162582	Signal Transduction	—
R-HSA-372790	Signaling by GPCR	—
R-HSA-194315	Signaling by Rho GTPases	—
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3	—
R-HSA-193704	p75 NTR receptor-mediated signalling	—

MSigDB gene sets: 437 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GOBP_MITOTIC_CYTOKINESIS, RRAGTTGT_UNKNOWN, GOBP_ATTACHMENT_OF_SPINDLE_MICROTUBULES_TO_KINETOCHORE, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_RESPONSE_TO_IONIZING_RADIATION, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, SEMBA_FHIT_TARGETS_DN, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, PAL_PRMT5_TARGETS_UP, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_CHROMOSOME_LOCALIZATION, GOBP_POSITIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_ACTIVATION_OF_GTPASE_ACTIVITY

GO Biological Process (24): mitotic cytokinesis (GO:0000281), nervous system development (GO:0007399), protein transport (GO:0015031), cell differentiation (GO:0030154), activation of protein kinase activity (GO:0032147), positive regulation of cytokinesis (GO:0032467), intracellular signal transduction (GO:0035556), positive regulation of protein import into nucleus (GO:0042307), positive regulation of apoptotic process (GO:0043065), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), positive regulation of GTPase activity (GO:0043547), positive regulation of neuron differentiation (GO:0045666), regulation of protein kinase activity (GO:0045859), regulation of small GTPase mediated signal transduction (GO:0051056), protein homooligomerization (GO:0051260), regulation of attachment of spindle microtubules to kinetochore (GO:0051988), cellular response to hydrogen peroxide (GO:0070301), bicellular tight junction assembly (GO:0070830), cellular response to calcium ion (GO:0071277), cellular response to ionizing radiation (GO:0071479), activation of GTPase activity (GO:0090630), positive regulation of mitotic cytokinetic process (GO:1903438), regulation of cytokinesis, actomyosin contractile ring assembly (GO:2000431), cell division (GO:0051301)

GO Molecular Function (5): guanyl-nucleotide exchange factor activity (GO:0005085), GTPase activator activity (GO:0005096), small GTPase binding (GO:0031267), protein homodimerization activity (GO:0042803), protein binding (GO:0005515)

GO Cellular Component (14): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), cell-cell junction (GO:0005911), bicellular tight junction (GO:0005923), cell cortex (GO:0005938), midbody (GO:0030496), cleavage furrow (GO:0032154), mitotic spindle (GO:0072686), centralspindlin complex (GO:0097149), spindle (GO:0005819), anchoring junction (GO:0070161)

Reactome top-level categories

9 top-level categories:

Category	Pathways
RHO GTPase cycle	4
Signal Transduction	3
Cell death signalling via NRAGE, NRIF and NADE	1
GPCR downstream signalling	1
Death Receptor Signaling	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
p75 NTR receptor-mediated signalling	1
Signaling by GPCR	1
Signaling by Rho GTPases	1

GO top-level categories

showing 60 of 75 GO namespaces:

Category	Terms
cellular anatomical structure	4
intracellular anatomical structure	2
GTPase activity	2
GTPase regulator activity	2
cytoplasm	2
mitotic cell cycle	1
cytoskeleton-dependent cytokinesis	1
mitotic cell cycle process	1
system development	1
animal gross anatomical part developmental process	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
cellular developmental process	1
positive regulation of protein kinase activity	1
cytokinesis	1
regulation of cytokinesis	1
positive regulation of cell division	1
positive regulation of cell cycle process	1
signal transduction	1
protein import into nucleus	1
regulation of protein import into nucleus	1
positive regulation of nucleocytoplasmic transport	1
positive regulation of intracellular protein transport	1
positive regulation of protein localization to nucleus	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
regulation of GTPase activity	1
positive regulation of hydrolase activity	1
neuron differentiation	1
positive regulation of cell differentiation	1
regulation of neuron differentiation	1
regulation of protein phosphorylation	1
protein kinase activity	1
regulation of kinase activity	1
small GTPase-mediated signal transduction	1
regulation of intracellular signal transduction	1
protein complex oligomerization	1
attachment of spindle microtubules to kinetochore	1
regulation of cell cycle process	1
cellular response to reactive oxygen species	1
response to hydrogen peroxide	1
apical junction assembly	1
tight junction assembly	1
response to calcium ion	1
cellular response to metal ion	1
response to ionizing radiation	1
cellular response to radiation	1
GTP binding	1
GDP binding	1
enzyme activator activity	1
GTPase binding	1
identical protein binding	1
protein dimerization activity	1
binding	1
intracellular membrane-bounded organelle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 27 of 43 annotations. The rest are phylogenetic / computational / electronic (IEA).

27 experimentally-supported GO terms:

GO term	NS	Evidence
activation of GTPase activity	BP	direct assay
activation of protein kinase activity	BP	direct assay
bicellular tight junction assembly	BP	mutant phenotype
cellular response to calcium ion	BP	direct assay
cellular response to hydrogen peroxide	BP	direct assay
cellular response to ionizing radiation	BP	direct assay
mitotic cytokinesis	BP	mutant phenotype
positive regulation of GTPase activity	BP	direct assay
positive regulation of apoptotic process	BP	direct assay
positive regulation of cytokinesis	BP	direct assay
positive regulation of mitotic cytokinetic process	BP	mutant phenotype
protein homooligomerization	BP	direct assay
regulation of attachment of spindle microtubules to kinetochore	BP	mutant phenotype
regulation of protein kinase activity	BP	direct assay
bicellular tight junction	CC	direct assay
cell-cell junction	CC	direct assay
centralspindlin complex	CC	direct assay
cleavage furrow	CC	direct assay
cytoplasm	CC	direct assay
cytosol	CC	direct assay
midbody	CC	direct assay
mitotic spindle	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
GTPase activator activity	MF	mutant phenotype
guanyl-nucleotide exchange factor activity	MF	direct assay
protein homodimerization activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 2,858 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ECT2	RACGAP1	Q9H0H5	958
ECT2	ANLN	Q9NQW6	939
ECT2	KIF23	Q02241	887
ECT2	RHOA	P06749	863
ECT2	PLK1	P53350	801
ECT2	RABIF	P47224	787
ECT2	SLC26A8	Q96RN1	668
ECT2	CDK1	P06493	664
ECT2	BORA	Q6PGQ7	636
ECT2	MYL2	P10916	631
ECT2	CCNB1	P14635	620
ECT2	CLSPN	Q9HAW4	607
ECT2	CEP55	Q53EZ4	603
ECT2	AURKB	Q96GD4	592
ECT2	PRKCI	P41743	581

IntAct

Human interaction partners of ECT2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

14 partners by confidence:

Partner	Interaction type	MIscore	Records
RACGAP1	direct interaction	0.880	13
PLK4	physical association	0.600	3
KIF23	association	0.560	2
CDH1	physical association	0.500	2
CTNNA1	physical association	0.500	1
NCK1	physical association	0.400	3
GRB2	physical association	0.400	1
PIK3R1	physical association	0.400	1
PSME3	association	0.350	1
GKAP1	physical association	0.000	1
LAMTOR5	physical association	0.000	1
MYC	physical association	0.000	1
NPHP4	physical association	0.000	1
RPGRIP1L	physical association	0.000	1

BioGRID (984 interactions; top human partners by supporting records in a sample of 600 records): PARD6A (Affinity Capture-Western; 3 records), RACGAP1 (Reconstituted Complex; 3 records), ARIH1 (Affinity Capture-MS; 2 records), CDC5L (Affinity Capture-MS; 2 records), CIT (Affinity Capture-MS; 2 records), RPGRIP1L (Affinity Capture-MS; 2 records), TUBA1A (Affinity Capture-Western; 2 records), AAAS (Affinity Capture-MS), AATF (Affinity Capture-MS), ABCD3 (Affinity Capture-MS), ABCF1 (Affinity Capture-MS), ABCG2 (Affinity Capture-MS), ABLIM1 (Affinity Capture-MS), ACADVL (Affinity Capture-MS), ACLY (Affinity Capture-MS)

SIGNOR signaling

showing 8 of 9 signaling interactions:

A	Effect	B	Mechanism
CDK1	down-regulates	ECT2	phosphorylation
CDK1	up-regulates	ECT2	phosphorylation
PRKCI	up-regulates	ECT2	phosphorylation
CyclinB/CDK1	down-regulates	ECT2	phosphorylation
CyclinB/CDK1	up-regulates	ECT2	phosphorylation
ECT2	“up-regulates activity”	RHOA	“guanine nucleotide exchange factor”
PLK1	“up-regulates activity”	ECT2	phosphorylation
DMTF1	“down-regulates quantity by repression”	ECT2	“transcriptional regulation”

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
ECT2-KIF23-RACGAP1 complex	3	ECT2, KIF23, RACGAP1

Disease & clinical

Genetic variants

Variant evidence for ECT2: 128 ClinVar records (0 pathogenic / likely pathogenic); 2 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	93
Likely benign	4
Benign	1

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 26 predictions of 2,857):

Position(s)	Effect	Δscore	Sites
3:172754500	acceptor_gain	1.0000
3:172754661–172754662	donor_loss	1.0000	4
3:172755286	acceptor_gain	1.0000
3:172755291	acceptor_gain	1.0000
3:172755293–172755294	acceptor_loss	1.0000	3
3:172755375–172755376	donor_loss	1.0000	4
3:172756967	acceptor_gain	1.0000
3:172756971	acceptor_gain	1.0000
3:172757166–172757167	donor_loss	1.0000	5
3:172761608–172761609	acceptor_loss	1.0000	5

AlphaMissense

2,168 missense substitutions predicted likely pathogenic (of 6,045 scored), across 530 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
M202	9	0.936	0.992
M289	9	0.832	0.959
D699	8	0.998	1.000
F652	8	0.994	1.000
H512	8	0.990	0.996
F697	8	0.990	0.999
N639	8	0.986	0.999
H729	8	0.986	0.998
D609	8	0.982	0.996
F571	8	0.980	0.999
S602	8	0.980	0.997
F502	8	0.974	0.995
D620	8	0.972	0.995
H200	8	0.970	0.998
F271	8	0.968	0.996
F574	8	0.967	0.999
F841	8	0.967	0.999
F771	8	0.958	0.999
H310	8	0.957	0.992
H669	8	0.957	0.994

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

5 prognostic cancer types:

Cancer	Prognostic	p-value
Lung Adenocarcinoma (TCGA)	unfavorable	4.55e-07
Liver Hepatocellular Carcinoma (validation)	unfavorable	1.66e-06
Kidney Renal Clear Cell Carcinoma (validation)	unfavorable	1.88e-06
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	2.93e-06
Pancreatic Adenocarcinoma (TCGA)	unfavorable	1.34e-05

Disease associations

OMIM: gene MIM:600586 | disease phenotypes:

GWAS associations

2 associations:

Study	Trait	p-value
GCST90002404_491	Red cell distribution width	6e-11
GCST001762_664	Obesity-related traits	8e-6

EFO canonical traits (from GWAS)

3 canonical traits:

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Tetrachlorodibenzodioxin	affects expression, decreases expression	3
Cyclosporine	decreases expression, increases expression	3
bisphenol A	decreases expression, increases expression	2
trichostatin A	affects cotreatment, decreases expression	2
cobaltous chloride	decreases expression	2
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	2
perfluorooctane sulfonic acid	decreases expression	2
Acetaminophen	decreases expression, increases expression	2
Acrolein	affects cotreatment, increases expression, increases abundance	2
Cisplatin	affects cotreatment, decreases expression, increases reaction	2
Doxorubicin	decreases expression, decreases reaction, increases cleavage	2
Ozone	affects cotreatment, increases expression, increases abundance	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
testosterone enanthate	affects expression	1
methylmercuric chloride	decreases expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
deoxynivalenol	increases expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
perfluorooctanoic acid	decreases expression	1
ochratoxin A	decreases acetylation, decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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

12 trials:

NCT	Phase	Status	Title
NCT03414970	Phase 3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT00461344	Phase 2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	Phase 2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT00637364	Phase 1/2	SUSPENDED	High Intensity Focused Ultrasound Tumor Treatment for Pancreatic Cancer Pain
NCT02779855	Phase 1/2	COMPLETED	Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
NCT01753908	Early Phase 1	COMPLETED	Broccoli Sprout Extract in Treating Patients With Breast Cancer
NCT01796041	Early Phase 1	COMPLETED	Intraoperative Imaging of Breast Cancer With Indocyanine Green
NCT07628634	Early Phase 1	RECRUITING	Feasibility Study on the Effect of a Methionine-Reduced Diet on Serum Levels in Pts w/ Solid Tumors
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