AMOTL2

Summary

AMOTL2 (angiomotin like 2, HGNC:17812) is a protein-coding gene on chromosome 3q22.2, encoding Angiomotin-like protein 2 (Q9Y2J4). Regulates the translocation of phosphorylated SRC to peripheral cell-matrix adhesion sites.

Angiomotin is a protein that binds angiostatin, a circulating inhibitor of the formation of new blood vessels (angiogenesis). Angiomotin mediates angiostatin inhibition of endothelial cell migration and tube formation in vitro. The protein encoded by this gene is related to angiomotin and is a member of the motin protein family. Alternative splicing results in multiple transcript variants of this gene.

Source: NCBI Gene 51421 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 152 total — 1 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_016201

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17812
Approved symbol	AMOTL2
Name	angiomotin like 2
Location	3q22.2
Locus type	gene with protein product
Status	Approved
Aliases	LCCP
Ensembl gene	ENSG00000114019
Ensembl biotype	protein_coding
OMIM	614658
Entrez	51421

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 11 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000249883, ENST00000422605, ENST00000502491, ENST00000504234, ENST00000505596, ENST00000506107, ENST00000506326, ENST00000510560, ENST00000511759, ENST00000512955, ENST00000513145, ENST00000514516, ENST00000515172, ENST00000873115

RefSeq mRNA: 4 — MANE Select: NM_016201 NM_001278683, NM_001278685, NM_001363943, NM_016201

CCDS: CCDS33860, CCDS63783, CCDS63784, CCDS87138

Canonical transcript exons

ENST00000249883 — 10 exons

Exon	Start	End
ENSE00002053865	134374342	134374447
ENSE00002074942	134355347	134357763
ENSE00002214486	134366283	134366427
ENSE00002262519	134367497	134367803
ENSE00003524819	134370700	134371494
ENSE00003556448	134358540	134358719
ENSE00003578938	134359283	134359503
ENSE00003637457	134365817	134365909
ENSE00003651305	134360106	134360413
ENSE00003652022	134361512	134361807

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 97.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 47.6543 / max 317.3493, expressed in 1518 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
44698	29.3239	1447
44700	13.7988	1474
44696	1.4595	747
44697	1.4178	801
44701	0.8279	442
44699	0.4708	275
44702	0.3555	179

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
amniotic fluid	UBERON:0000173	97.17	gold quality
sural nerve	UBERON:0015488	96.84	gold quality
mammary duct	UBERON:0001765	96.80	gold quality
inferior vagus X ganglion	UBERON:0005363	96.68	gold quality
right coronary artery	UBERON:0001625	96.49	gold quality
tongue squamous epithelium	UBERON:0006919	96.47	gold quality
renal medulla	UBERON:0000362	96.41	gold quality
ventricular zone	UBERON:0003053	96.26	gold quality
germinal epithelium of ovary	UBERON:0001304	96.12	gold quality
epithelium of mammary gland	UBERON:0003244	96.01	gold quality
synovial joint	UBERON:0002217	96.00	gold quality
parietal pleura	UBERON:0002400	95.92	gold quality
saphenous vein	UBERON:0007318	95.82	gold quality
adipose tissue	UBERON:0001013	95.78	gold quality
tibial nerve	UBERON:0001323	95.69	gold quality
subcutaneous adipose tissue	UBERON:0002190	95.62	gold quality
lower lobe of lung	UBERON:0008949	95.52	gold quality
mammary gland	UBERON:0001911	95.41	gold quality
connective tissue	UBERON:0002384	95.41	gold quality
thoracic mammary gland	UBERON:0005200	95.37	gold quality
vena cava	UBERON:0004087	95.33	gold quality
inferior olivary complex	UBERON:0002127	95.30	gold quality
adipose tissue of abdominal region	UBERON:0007808	94.96	gold quality
pleura	UBERON:0000977	94.87	gold quality
omental fat pad	UBERON:0010414	94.81	gold quality
peritoneum	UBERON:0002358	94.80	gold quality
pigmented layer of retina	UBERON:0001782	94.72	gold quality
retina	UBERON:0000966	94.69	gold quality
tibia	UBERON:0000979	94.63	gold quality
subthalamic nucleus	UBERON:0001906	94.63	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	13.13

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

95 targeting AMOTL2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
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-1193	100.00	65.93	529
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-944	99.82	70.85	3042

Literature-anchored findings (GeneRIF, showing 17)

• AMOTL2 is as a novel activator of LATS2. (PMID:21832154)
• Amotl2 plays a pivotal role in polarity, migration and proliferation of angiogenic endothelial cells (PMID:21937427)
• These results demonstrate a role for Amotl2 in synaptic maturation and support the involvement of podosomes in this process. (PMID:23525008)
• AMOTL2 interacts with TAZ and modulates transcriptional activity of TAZ. (PMID:23911299)
• Scaffold proteins angiomotin (Amot) and angiomotin-related AmotL1 and AmotL2 were recently identified as negative regulators of YAP and TAZ by preventing their nuclear translocation. (PMID:24003252)
• These results collectively suggest that the Hippo pathway negatively regulates the actin-binding activity of Amot family members through direct phosphorylation. (PMID:24225952)
• AmotL2 expression correlates with loss of tissue architecture in tumors from human breast and colon cancer patients. (PMID:25080976)
• mTORC2-mediated phosphorylation of AMOTL2 blocks its ability to inhibit YAP signaling. (PMID:25998128)
• study reports for the first time that USP9X is a deubiquitinase of Angiomotin-like 2 (AMOTL2) and that AMOTL2 mono-ubiquitination is required for YAP inhibition (PMID:26598551)
• these results provide novel insights into a dual tumor suppressive function of AMOTL2 by targeting both YAP and AKT in liver size control and cancer prevention (PMID:28368415)
• the localization of IQGAP1, AmotL2, and FKBP51 in malignant cells and tumor microenvironment of human GB tumors (PMID:30794467)
• AMOTL2 inhibits JUN Thr239 dephosphorylation by binding PPP2R2A to suppress the proliferation in non-small cell lung cancer cells. (PMID:32950569)
• AMOTL2knockdown promotes the proliferation, migration and invasion of glioma by regulating betacatenin nuclear localization. (PMID:34036399)
• AmotL2, IQGAP1, and FKBP51 Scaffold Proteins in Glioblastoma Stem Cell Niches. (PMID:34165350)
• AMOTL2 mono-ubiquitination by WWP1 promotes contact inhibition by facilitating LATS activation. (PMID:34404733)
• The cellular localization and oncogenic or tumor suppressive effects of angiomiotin-like protein 2 in tumor and normal cells. (PMID:38717123)
• The VE-cadherin/AmotL2 mechanosensory pathway suppresses aortic inflammation and the formation of abdominal aortic aneurysms. (PMID:39195920)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	amotl2a	ENSDARG00000061923
danio_rerio	amotl2b	ENSDARG00000061948
mus_musculus	Amotl2	ENSMUSG00000032531
rattus_norvegicus	Amotl2	ENSRNOG00000008487

Paralogs (2): AMOT (ENSG00000126016), AMOTL1 (ENSG00000166025)

Protein

Protein identifiers

Angiomotin-like protein 2 — Q9Y2J4 (reviewed: Q9Y2J4)

Alternative names: Leman coiled-coil protein

All UniProt accessions (7): Q9Y2J4, D6RBK2, D6RCL7, D6RF61, D6RFG0, D6RIC7, D6RJA4

UniProt curated annotations — full annotation on UniProt →

Function. Regulates the translocation of phosphorylated SRC to peripheral cell-matrix adhesion sites. Required for proper architecture of actin filaments. Plays a role in coupling actin fibers to cell junctions in endothelial cells and is therefore required for correct endothelial cell morphology via facilitating transcellular transmission of mechanical force resulting in endothelial cell elongation. Required for the anchoring of radial actin fibers to CDH1 junction complexes at the cell membrane which facilitates organization of radial actin fiber structure and cellular response to contractile forces. This contributes to maintenance of cell area, size, shape, epithelial sheet organization and trophectoderm cell properties that facilitate blastocyst zona hatching. Inhibits the Wnt/beta-catenin signaling pathway, probably by recruiting CTNNB1 to recycling endosomes and hence preventing its translocation to the nucleus. Participates in angiogenesis. Activates the Hippo signaling pathway in response to cell contact inhibition via interaction with and ubiquitination by Crumbs complex-bound WWP1. Ubiquitinated AMOTL2 then interacts with LATS2 which in turn phosphorylates YAP1, excluding it from the nucleus and localizing it to the cytoplasm and tight junctions, therefore ultimately repressing YAP1-driven transcription of target genes. Acts to inhibit WWTR1/TAZ transcriptional coactivator activity via sequestering WWTR1/TAZ in the cytoplasm and at tight junctions. Regulates the size and protein composition of the podosome cortex and core at myofibril neuromuscular junctions. Selectively promotes FGF-induced MAPK activation through SRC. May play a role in the polarity, proliferation and migration of endothelial cells.

Subunit / interactions. Part of a complex composed of AMOTL2, MAGI1 and CDH5, within the complex AMOTL2 acts as a scaffold protein for the interaction of MAGI1 with CDH5. The complex is required for coupling actin fibers to cell junctions in endothelial cells. Within the complex AMOTL2 (via its N-terminus) interacts with CDH5. Interacts (via N-terminus) with MAGI1. Interacts (via N-terminus) with ACTB; the interaction facilitates binding of cell junction complexes to actin fibers in endothelial cells. Interacts with CDH1; the interaction may facilitate binding of radial actin fibers to cell junction complexes. Interacts with SRC. Interacts with YAP1; the interaction is required for ubiquitination of AMOTL2 and localization of YAP1 to tight junctions. Interacts with WWP1; the interaction facilitates WWP1 interaction with the Crumbs complex and subsequent WWP1 translocation to the plasma membrane. WWP1 interaction with the Crumbs complex promotes WWP1 monoubiquitination of AMOTL2 which subsequently activates the Hippo signaling pathway. When ubiquitinated interacts with LATS2 (via UBA domain); the interaction promotes LATS2 phosphorylation of YAP1. Interacts (via PPXY motif) with WWTR1/TAZ (via WW domain); the interaction promotes WWTR1/TAZ localization to the cytoplasm and thereby inhibition of its transcriptional properties. Interacts with PHLDB2; interaction may facilitate PHLDB2 localization to the myotube podosome cortex that surrounds the core.

Subcellular location. Recycling endosome. Cytoplasm. Cell projection. Podosome. Cell junction.

Post-translational modifications. Monoubiquitinated at Lys-347 and Lys-408 by Crumbs complex-bound WWP1. De-ubiquitinated at Lys-347 and Lys-408 by USP9X; the interaction may be promoted by cell contact inhibition. Deubiquitination of AMOTL2 negatively regulates Hippo signaling activation. Phosphorylation at Tyr-107 is necessary for efficient binding to SRC and synergistically functioning with SRC to activate the downstream MAPK pathway.

Similarity. Belongs to the angiomotin family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9Y2J4-1	1	yes
Q9Y2J4-2	2
Q9Y2J4-3	3
Q9Y2J4-4	4

RefSeq proteins (4): NP_001265612, NP_001265614, NP_001350872, NP_057285* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009114	Angiomotin	Family
IPR024646	Angiomotin_C	Domain
IPR051747	Angiomotin-like	Family

Pfam: PF12240

UniProt features (39 total): compositionally biased region 9, region of interest 6, mutagenesis site 5, sequence variant 4, modified residue 3, splice variant 3, site 2, cross-link 2, sequence conflict 2, chain 1, coiled-coil region 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y2J4-F1	67.35	0.35

Functional residue map

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

Catalytic / active sites (2): 107 (required for interaction with magi1 and actb); 213 (required for interaction with yap1 and ubiquitination at k-347 and k-408)

Post-translational modifications (5): 107, 759, 762, 347, 408

Mutagenesis-validated functional residues (5):

Position	Phenotype
107	abolishes interaction with magi1 and actb. no effect on interaction with cdh1.
213	abolishes interaction with yap1 and ubiquitination at k-347 and k-408. abolishes interaction with wwtr1, but does not af
347	abolishes monoubiquitination by wwp1 and reduces interaction with lats2 and yap1.
408	abolishes monoubiquitination by wwp1 and reduces interaction with lats2 and yap1.
776–779	no effect on interaction with wwtr1.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2028269	Signaling by Hippo
R-HSA-162582	Signal Transduction

MSigDB gene sets: 206 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GOBP_ENDOTHELIAL_CELL_DEVELOPMENT, BERENJENO_ROCK_SIGNALING_NOT_VIA_RHOA_DN, GOBP_EPITHELIUM_DEVELOPMENT, BROWNE_HCMV_INFECTION_6HR_DN, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, MODULE_255, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, MODULE_317, GOBP_HIPPO_SIGNALING, GOBP_AMEBOIDAL_TYPE_CELL_MIGRATION, CAIRO_HEPATOBLASTOMA_CLASSES_DN

GO Biological Process (9): negative regulation of transcription by RNA polymerase II (GO:0000122), angiogenesis (GO:0001525), endothelial cell morphogenesis (GO:0001886), establishment of cell polarity involved in ameboidal cell migration (GO:0003365), Wnt signaling pathway (GO:0016055), actin cytoskeleton organization (GO:0030036), regulation of cell migration (GO:0030334), hippo signaling (GO:0035329), positive regulation of protein localization (GO:1903829)

GO Molecular Function (2): actin filament binding (GO:0051015), protein binding (GO:0005515)

GO Cellular Component (11): podosome (GO:0002102), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), bicellular tight junction (GO:0005923), cell junction (GO:0030054), cytoplasmic vesicle (GO:0031410), recycling endosome (GO:0055037), endosome (GO:0005768), cell projection (GO:0042995), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
endothelial cell development	1
epithelial cell morphogenesis	1
ameboidal-type cell migration	1
establishment of cell polarity	1
cell surface receptor signaling pathway	1
cytoskeleton organization	1
actin filament-based process	1
cell migration	1
regulation of cell motility	1
intracellular signal transduction	1
intracellular protein localization	1
regulation of protein localization	1
positive regulation of biological process	1
actin binding	1
protein-containing complex binding	1
binding	1
actin-based cell projection	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
apical junction complex	1
tight junction	1
intracellular vesicle	1
endosome	1
endomembrane system	1
cytoplasmic vesicle	1
cell junction	1

Protein interactions and networks

STRING

1478 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AMOTL2	YAP1	P46937	727
AMOTL2	WWTR1	Q9GZV5	680
AMOTL2	LATS1	O95835	671
AMOTL2	CCN1	O00622	652
AMOTL2	LATS2	Q9NRM7	651
AMOTL2	CCN2	P29279	607
AMOTL2	ANKRD1	Q15327	605
AMOTL2	TEAD1	P28347	593
AMOTL2	SAV1	Q9H4B6	571
AMOTL2	TNKS2	Q9H2K2	565
AMOTL2	TNKS	O95271	561
AMOTL2	NF2	P35240	559
AMOTL2	PATJ	Q8NI35	523
AMOTL2	PTPN14	Q15678	517
AMOTL2	BAG3	O95817	508

IntAct

271 interactions, top by confidence:

A	B	Type	Score
CCND3	CDK4	psi-mi:“MI:0914”(association)	0.980
RAD51D	AMOTL2	psi-mi:“MI:0915”(physical association)	0.830
AMOTL2	RAD51D	psi-mi:“MI:0915”(physical association)	0.830
AMOTL2	SH3RF2	psi-mi:“MI:0915”(physical association)	0.670
AMOTL2	RNF20	psi-mi:“MI:0915”(physical association)	0.670
AMOTL2	NDC80	psi-mi:“MI:0915”(physical association)	0.670
AMOTL2	GSTM5	psi-mi:“MI:0915”(physical association)	0.670
MAGOHB	AMOTL2	psi-mi:“MI:0915”(physical association)	0.670
PSMC3	AMOTL2	psi-mi:“MI:0915”(physical association)	0.670
SH3RF2	AMOTL2	psi-mi:“MI:0915”(physical association)	0.670
RNF20	AMOTL2	psi-mi:“MI:0915”(physical association)	0.670
GSTM5	AMOTL2	psi-mi:“MI:0915”(physical association)	0.670
NFIL3	AMOTL2	psi-mi:“MI:0915”(physical association)	0.670
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
CDC11	AMOTL2	psi-mi:“MI:0915”(physical association)	0.560
RPT5	AMOTL2	psi-mi:“MI:0915”(physical association)	0.560
AMOTL2	RRD1	psi-mi:“MI:0915”(physical association)	0.560
AMOTL2	MON1	psi-mi:“MI:0915”(physical association)	0.560
AMOTL2	CAF40	psi-mi:“MI:0915”(physical association)	0.560
AMOTL2		psi-mi:“MI:0915”(physical association)	0.560
AMOTL2	ADY3	psi-mi:“MI:0915”(physical association)	0.560
UBA3	AMOTL2	psi-mi:“MI:0915”(physical association)	0.560
RRD1	AMOTL2	psi-mi:“MI:0915”(physical association)	0.560
CAF40	AMOTL2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (237): AMOTL2 (Two-hybrid), AMOTL2 (Two-hybrid), AMOTL2 (Two-hybrid), AMOTL2 (Two-hybrid), AMOTL2 (Two-hybrid), AMOTL2 (Two-hybrid), AMOTL2 (Two-hybrid), AMOTL2 (Two-hybrid), AMOTL2 (Two-hybrid), AMOTL2 (Two-hybrid), AMOTL2 (Two-hybrid), AMOTL2 (Two-hybrid), AMOTL2 (Two-hybrid), AMOTL2 (Two-hybrid), AMOTL2 (Two-hybrid)

ESM2 similar proteins: A0A8I3QA39, A1YB07, A2A6T1, A2A9T0, A2AHG0, A5PKL7, A6NKD9, A7MCY6, B8A5S6, D3ZD05, E1BEQ5, E1U8D0, E9Q6B2, F1MRK3, G3V735, O14529, O60299, O75145, O94964, P60469, Q1LZH7, Q3LUD4, Q3UIL6, Q499E4, Q5JTD0, Q5RCR6, Q5XIA0, Q62036, Q63ZY3, Q6DG50, Q6IQ23, Q6NZT2, Q6PDH0, Q86UU1, Q86X02, Q8BX02, Q8C7U1, Q8IY63, Q8K1Q4, Q8K371

Diamond homologs: A0A8I3QA39, A1YB07, B8A5S6, E1BEQ5, F1MRK3, G3V735, Q4VCS5, Q8IY63, Q8K371, Q8VHG2, Q9D4H4, Q9Y2J4

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
FGFR1	“up-regulates activity”	AMOTL2	phosphorylation
AMOTL2	“up-regulates activity”	SRC	binding
AMOTL2	up-regulates	Angiogenesis
AMOTL2	up-regulates	Cell_migration
WWP1	“up-regulates activity”	AMOTL2	ubiquitination
AMOTL2	“up-regulates activity”	LATS2	relocalization
LATS2	“down-regulates activity”	AMOTL2	phosphorylation
mTORC2	“down-regulates activity”	AMOTL2	phosphorylation
MTOR	“down-regulates activity”	AMOTL2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 81 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
G2/M Checkpoints	6	16.8×	9e-05
Translocation of SLC2A4 (GLUT4) to the plasma membrane	5	16.1×	5e-04
Programmed Cell Death	5	15.2×	5e-04
TP53 Regulates Metabolic Genes	5	13.5×	8e-04
G2/M DNA damage checkpoint	5	12.5×	1e-03
MITF-M-regulated melanocyte development	5	11.9×	1e-03
Cell Cycle Checkpoints	6	11.1×	5e-04
RHO GTPase Effectors	6	8.5×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	139
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
57831	GRCh38/hg38 3q22.1-22.3(chr3:132972567-136894498)x1	Pathogenic
523199	GRCh37/hg19 3q22.1-22.3(chr3:132642704-136360844)x1	Likely pathogenic

SpliceAI

1788 predictions. Top by Δscore:

Variant	Effect	Δscore
3:134358716:TCTG:T	acceptor_loss	1.0000
3:134358717:CTG:C	acceptor_gain	1.0000
3:134358717:CTGC:C	acceptor_loss	1.0000
3:134358718:TGCTG:T	acceptor_loss	1.0000
3:134358719:GC:G	acceptor_loss	1.0000
3:134358720:C:CC	acceptor_gain	1.0000
3:134358720:CT:C	acceptor_loss	1.0000
3:134358721:T:A	acceptor_loss	1.0000
3:134359280:TACC:T	donor_loss	1.0000
3:134359281:A:C	donor_loss	1.0000
3:134359282:C:A	donor_loss	1.0000
3:134360262:T:A	donor_gain	1.0000
3:134360275:T:TA	donor_gain	1.0000
3:134361506:GCTCA:G	donor_loss	1.0000
3:134361507:CTCA:C	donor_loss	1.0000
3:134361508:TCA:T	donor_loss	1.0000
3:134361509:CACC:C	donor_loss	1.0000
3:134361510:A:AC	donor_gain	1.0000
3:134361510:A:C	donor_loss	1.0000
3:134361511:C:CC	donor_gain	1.0000
3:134361511:CCTG:C	donor_gain	1.0000
3:134361525:AGGG:A	donor_gain	1.0000
3:134361803:GTAGC:G	acceptor_gain	1.0000
3:134361804:TAGC:T	acceptor_gain	1.0000
3:134361805:AGC:A	acceptor_gain	1.0000
3:134361806:GC:G	acceptor_gain	1.0000
3:134361807:CC:C	acceptor_gain	1.0000
3:134361808:C:CC	acceptor_gain	1.0000
3:134365811:A:AC	donor_gain	1.0000
3:134365812:C:CC	donor_gain	1.0000

AlphaMissense

5021 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:134371390:A:G	L15P	1.000
3:134359466:C:G	A641P	0.999
3:134360299:C:G	A564P	0.999
3:134361534:A:G	L518P	0.999
3:134361558:A:G	L510P	0.999
3:134361600:A:G	L496P	0.999
3:134361621:A:G	L489P	0.999
3:134366288:A:G	L394P	0.999
3:134371387:A:G	I16T	0.999
3:134371387:A:T	I16N	0.999
3:134371393:C:G	R14P	0.999
3:134359487:C:G	A634P	0.998
3:134359492:A:G	L632P	0.998
3:134360243:A:C	F582L	0.998
3:134360243:A:T	F582L	0.998
3:134360245:A:G	F582L	0.998
3:134360284:A:G	W569R	0.998
3:134360284:A:T	W569R	0.998
3:134360304:A:G	L562P	0.998
3:134361546:A:G	L514P	0.998
3:134361555:C:G	R511P	0.998
3:134361579:C:G	R503P	0.998
3:134366309:A:G	L387P	0.998
3:134366339:C:G	R377P	0.998
3:134371333:A:G	I34T	0.998
3:134371375:A:G	L20P	0.998
3:134371381:T:A	E18V	0.998
3:134371387:A:C	I16S	0.998
3:134371390:A:T	L15H	0.998
3:134371394:G:T	R14S	0.998

dbSNP variants (sampled 300 via entrez): RS1000272126 (3:134376754 A>G), RS1000307264 (3:134358554 C>G,T), RS1000396438 (3:134364386 G>A), RS1000448707 (3:134364023 TG>T), RS1000619075 (3:134360579 C>T), RS1000844344 (3:134369171 C>A), RS1000875566 (3:134354992 C>G), RS1000926521 (3:134372354 G>T), RS1001319118 (3:134376195 G>A), RS1001584932 (3:134357421 T>C), RS1001841841 (3:134369471 G>A), RS1001851686 (3:134359991 G>C), RS1001900715 (3:134372012 T>C,G), RS1002013165 (3:134365553 C>A,T), RS1002064088 (3:134362866 G>A,C)

Disease associations

OMIM: gene MIM:614658 | disease phenotypes: MIM:617635

GenCC curated gene-disease

Mondo (1): intellectual disability, autosomal dominant 47 (MONDO:0030912)

Orphanet (1): STAG1-related intellectual disability-facial dysmorphism-gastroesophageal reflux syndrome (Orphanet:502434)

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002936_17	Cadmium levels	9.000000e-06
GCST006291_82	Spherical equivalent or myopia (age of diagnosis)	1.000000e-09
GCST009723_19	Vertical cup-disc ratio (adjusted for vertical disc diameter)	5.000000e-09
GCST90002385_438	High light scatter reticulocyte count	2.000000e-09
GCST90002386_561	High light scatter reticulocyte percentage of red cells	4.000000e-11
GCST90002406_46	Reticulocyte fraction of red cells	3.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004847	age at onset
EFO:0006939	cup-to-disc ratio measurement
EFO:0007986	reticulocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	increases expression	2
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	2
Acrolein	increases abundance, affects cotreatment, increases expression	2
Air Pollutants	increases expression, decreases expression, affects cotreatment, increases abundance	2
Benzo(a)pyrene	affects methylation	2
Cadmium	increases abundance, increases expression	2
Ozone	increases expression, increases abundance, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Valproic Acid	affects expression, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, decreases methylation	1
alpha-pinene	increases expression, increases abundance, affects cotreatment	1
bisphenol A	affects cotreatment, increases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction	1
methylparaben	increases expression	1
sodium arsenite	decreases expression	1
ochratoxin A	decreases expression	1
benzo(e)pyrene	increases methylation	1
rutecarpine	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
cupric chloride	increases expression	1
coumarin	affects phosphorylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression, affects response to substance, increases expression	1
perfluorooctane sulfonic acid	decreases 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
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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