MCF2L

Summary

MCF2L (MCF.2 cell line derived transforming sequence like, HGNC:14576) is a protein-coding gene on chromosome 13q34, encoding Guanine nucleotide exchange factor DBS (O15068). Guanine nucleotide exchange factor that catalyzes guanine nucleotide exchange on RHOA and CDC42, and thereby contributes to the regulation of RHOA and CDC42 signaling pathways.

This gene encodes a guanine nucleotide exchange factor that interacts specifically with the GTP-bound Rac1 and plays a role in the Rho/Rac signaling pathways. A variant in this gene was associated with osteoarthritis. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 23263 — RefSeq curated summary.

At a glance

• Gene–disease (curated): vascular malformation (Limited, GenCC)
• GWAS associations: 14
• Clinical variants (ClinVar): 219 total
• Druggable target: yes
• MANE Select transcript: NM_001112732

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14576
Approved symbol	MCF2L
Name	MCF.2 cell line derived transforming sequence like
Location	13q34
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0362, DBS, OST, ARHGEF14
Ensembl gene	ENSG00000126217
Ensembl biotype	protein_coding
OMIM	609499
Entrez	23263

Gene structure

Transcript identifiers

Ensembl transcripts: 37 — 25 protein_coding, 6 retained_intron, 4 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000261963, ENST00000375597, ENST00000375604, ENST00000375608, ENST00000397017, ENST00000397021, ENST00000397024, ENST00000397030, ENST00000397036, ENST00000409954, ENST00000413354, ENST00000420013, ENST00000421756, ENST00000423251, ENST00000433807, ENST00000439475, ENST00000441756, ENST00000442625, ENST00000453297, ENST00000464800, ENST00000469415, ENST00000469558, ENST00000473345, ENST00000475524, ENST00000480321, ENST00000486210, ENST00000486806, ENST00000487354, ENST00000488765, ENST00000491028, ENST00000494043, ENST00000535094, ENST00000704386, ENST00000884941, ENST00000884942, ENST00000884943, ENST00000920919

RefSeq mRNA: 8 — MANE Select: NM_001112732 NM_001112732, NM_001320815, NM_001320816, NM_001320817, NM_001366644, NM_001366645, NM_001366646, NM_024979

CCDS: CCDS45070, CCDS81782, CCDS9527

Canonical transcript exons

ENST00000535094 — 30 exons

Exon	Start	End
ENSE00000862510	113088327	113088405
ENSE00000862511	113088562	113088628
ENSE00001305557	113089610	113089728
ENSE00001604164	113064304	113064420
ENSE00001608870	113087235	113087456
ENSE00001612546	113078666	113078739
ENSE00001621985	113081213	113081279
ENSE00001629152	113083998	113084067
ENSE00001636114	113060593	113060712
ENSE00001646616	113074998	113075189
ENSE00001689681	113078363	113078436
ENSE00001705395	112969214	112969458
ENSE00001737461	113087707	113087799
ENSE00001756561	113024644	113024758
ENSE00001775460	113075966	113076157
ENSE00001776385	113084892	113084984
ENSE00001778675	113077052	113077211
ENSE00001779833	113086124	113086249
ENSE00001800400	113082427	113082542
ENSE00002220516	113094514	113094635
ENSE00002586476	113096774	113099742
ENSE00003463897	113074444	113074563
ENSE00003464315	113066046	113066170
ENSE00003485448	113045271	113045361
ENSE00003492260	113096371	113096483
ENSE00003510019	113064936	113065085
ENSE00003527070	113014763	113014846
ENSE00003559403	113096550	113096653
ENSE00003650489	113070059	113070173
ENSE00003655048	113085086	113085178

Expression profiles

Bgee: expression breadth ubiquitous, 253 present calls, max score 99.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.6525 / max 813.9022, expressed in 924 samples.

FANTOM5 promoters (29 alternative TSS)

Promoter ID	TPM avg	Samples expressed
136188	3.7972	222
136161	2.1695	547
136173	2.0706	192
136170	0.7085	161
136167	0.6340	229
136189	0.4508	104
136172	0.3936	142
136169	0.3000	133
136176	0.2785	121
136178	0.2486	146

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	99.61	gold quality
cerebellar hemisphere	UBERON:0002245	99.56	gold quality
cerebellar cortex	UBERON:0002129	99.43	gold quality
cerebellum	UBERON:0002037	99.28	gold quality
right frontal lobe	UBERON:0002810	98.41	gold quality
paraflocculus	UBERON:0005351	97.78	gold quality
pituitary gland	UBERON:0000007	97.67	gold quality
apex of heart	UBERON:0002098	97.47	gold quality
adenohypophysis	UBERON:0002196	97.41	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.29	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.00	gold quality
prefrontal cortex	UBERON:0000451	96.79	gold quality
primary visual cortex	UBERON:0002436	96.57	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.53	gold quality
frontal cortex	UBERON:0001870	96.48	gold quality
frontal lobe	UBERON:0016525	96.47	gold quality
cingulate cortex	UBERON:0003027	96.31	gold quality
anterior cingulate cortex	UBERON:0009835	96.29	gold quality
omental fat pad	UBERON:0010414	96.26	gold quality
neocortex	UBERON:0001950	96.25	gold quality
peritoneum	UBERON:0002358	96.18	gold quality
cortical plate	UBERON:0005343	96.17	gold quality
superficial temporal artery	UBERON:0001614	96.16	gold quality
sural nerve	UBERON:0015488	95.84	gold quality
adipose tissue of abdominal region	UBERON:0007808	95.80	gold quality
spinal cord	UBERON:0002240	95.79	gold quality
cerebral cortex	UBERON:0000956	95.70	gold quality
middle temporal gyrus	UBERON:0002771	95.64	gold quality
brain	UBERON:0000955	95.61	gold quality
central nervous system	UBERON:0001017	95.60	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-11268	yes	1629.33
E-CURD-119	yes	45.00
E-GEOD-135922	yes	25.15
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

94 targeting MCF2L, 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-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-3613-3P	100.00	76.36	7965
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606

Literature-anchored findings (GeneRIF, showing 9)

• Dbs is activated by Rac1 at the pleckstrin homology domain (PMID:14701795)
• the guanine nucleotide exchange factor Ost has a role in negative regulation of receptor endocytosis by the small GTPase Rac1 (PMID:17562712)
• A single nucleotide polymorphism in MCF2L is associated with osteoarthritis. (PMID:21871595)
• In conclusion, we find that GDF5, but not COG5 or MCF2L, influence the extent of radiographic damage in knee osteoarthritis (PMID:22615457)
• A rare variant in MCF2L has been identified using exclusion linkage in a pedigree with premature atherosclerosis. (PMID:25898923)
• MCF2L is subject to a cis-acting eQTL in synovial membrane that correlates with the OA association signal. This signal contains several functional SNPs that could account for the susceptibility and which therefore merit further investigation (PMID:26584642)
• When compared to the gemcitabine-sensitive cells, the gemcitabine-resistant cells had a higher level of MCF2L expression, suggesting that MCF2L plays an important role in gemcitabine resistance (PMID:29039610)
• miR-140-3p exhibits repressive functions on preosteoblast viability and differentiation by downregulating MCF2L in osteoporosis. (PMID:31732956)
• LncRNA MCF2L-AS1 aggravates the malignant development of colorectal cancer via targeting miR-105-5p/RAB22A axis. (PMID:34592939)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000069929
danio_rerio	mcf2la	ENSDARG00000075859
danio_rerio	mcf2lb	ENSDARG00000076480
mus_musculus	Mcf2l	ENSMUSG00000031442
rattus_norvegicus	Mcf2l	ENSRNOG00000028426

Paralogs (22): TRIO (ENSG00000038382), MCF2L2 (ENSG00000053524), PLEKHG2 (ENSG00000090924), MCF2 (ENSG00000101977), ARHGEF7 (ENSG00000102606), PLEKHG1 (ENSG00000120278), ARHGEF6 (ENSG00000129675), ARHGEF9 (ENSG00000131089), VAV3 (ENSG00000134215), VAV1 (ENSG00000141968), TIAM2 (ENSG00000146426), KIAA1755 (ENSG00000149633), PLEKHG4B (ENSG00000153404), TIAM1 (ENSG00000156299), KALRN (ENSG00000160145), VAV2 (ENSG00000160293), ARHGEF40 (ENSG00000165801), SPATA13 (ENSG00000182957), SESTD1 (ENSG00000187231), PLEKHN1 (ENSG00000187583), PLEKHG4 (ENSG00000196155), ARHGEF25 (ENSG00000240771)

Protein

Protein identifiers

Guanine nucleotide exchange factor DBS — O15068 (reviewed: O15068)

Alternative names: DBL’s big sister, MCF2-transforming sequence-like protein

All UniProt accessions (18): O15068, A0A994J4L8, A2A3G7, A2A3H1, A2A639, A2A640, B7ZBR9, F8WBK7, H0Y4M6, H0Y519, H0Y7A3, H3BLT1, H7BYP9, H7C275, H7C2S1, M0R1J7, M0R393, X6RE72

UniProt curated annotations — full annotation on UniProt →

Function. Guanine nucleotide exchange factor that catalyzes guanine nucleotide exchange on RHOA and CDC42, and thereby contributes to the regulation of RHOA and CDC42 signaling pathways. Seems to lack activity with RAC1. Becomes activated and highly tumorigenic by truncation of the N-terminus. Isoform 5 activates CDC42. Does not catalyze guanine nucleotide exchange on CDC42.

Subunit / interactions. Interacts with GTP-bound RAC1. Interacts with CDC42. Interacts with RHOA. Interacts with CCPG1, which results in specific inhibition of its exchange activity toward RHOA, but does not affect its activity on CDC42.

Subcellular location. Cytoplasm. Cell membrane Cytoplasm. Endomembrane system Cytoplasm. Cell membrane.

Domain organisation. The CRAL-TRIO domain mediates interaction with various inositol phospholipids, such as phosphatidylinositol 3-phosphate (PI3P), phosphatidylinositol 4-phosphate (PI4P) and phosphatidylinositol 5-phosphate (PI5P). The DH domain is involved in interaction with CCPG1.

Similarity. Belongs to the MCF2 family.

Isoforms (9)

UniProt ID	Names	Canonical?
O15068-1	1	yes
O15068-2	2
O15068-3	3, Ost-II
O15068-4	4
O15068-5	5, Ost-I
O15068-6	6
O15068-9	7
O15068-8	8
O15068-10	9

RefSeq proteins (8): NP_001106203, NP_001307744, NP_001307745, NP_001307746, NP_001353573, NP_001353574, NP_001353575, NP_079255 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000219	DH_dom	Domain
IPR001251	CRAL-TRIO_dom	Domain
IPR001331	GDS_CDC24_CS	Conserved_site
IPR001452	SH3_domain	Domain
IPR001849	PH_domain	Domain
IPR002017	Spectrin_repeat	Repeat
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR018159	Spectrin/alpha-actinin	Repeat
IPR035532	DBS_SH3	Domain
IPR035534	DBS_PH	Domain
IPR035899	DBL_dom_sf	Homologous_superfamily
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036865	CRAL-TRIO_dom_sf	Homologous_superfamily
IPR051336	RhoGEF_Guanine_NuclExch_SF	Family
IPR055251	SOS1_NGEF_PH	Domain
IPR056466	Spectrin_DBS	Domain

Pfam: PF00435, PF00621, PF07653, PF13716, PF22697, PF23289

UniProt features (36 total): splice variant 10, modified residue 7, sequence conflict 5, domain 4, compositionally biased region 4, region of interest 3, chain 1, repeat 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15068-F1	77.32	0.54

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 (7): 457, 480, 620, 1033, 1034, 1041, 1042

Function

Pathways and Gene Ontology

Reactome pathways

17 pathways

ID	Pathway
R-HSA-193648	NRAGE signals death through JNK
R-HSA-416482	G alpha (12/13) signalling events
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9013026	RHOB GTPase cycle
R-HSA-9013106	RHOC GTPase cycle
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9013408	RHOG GTPase cycle
R-HSA-162582	Signal Transduction
R-HSA-193704	p75 NTR receptor-mediated signalling
R-HSA-194315	Signaling by Rho GTPases
R-HSA-204998	Cell death signalling via NRAGE, NRIF and NADE
R-HSA-372790	Signaling by GPCR
R-HSA-388396	GPCR downstream signalling
R-HSA-73887	Death Receptor Signaling
R-HSA-9012999	RHO GTPase cycle
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 215 (showing top): GOBP_POSITIVE_REGULATION_OF_RHO_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, REACTOME_NRAGE_SIGNALS_DEATH_THROUGH_JNK, GCGCTTT_MIR518B_MIR518C_MIR518D, AGCGCTT_MIR518F_MIR518E_MIR518A, FOSTER_TOLERANT_MACROPHAGE_UP, AMIT_EGF_RESPONSE_120_HELA, chr13q34, TGANTCA_AP1_C, GOBP_REGULATION_OF_RHO_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, LEF1_Q6, GCM_CALM1, MODULE_48, BOQUEST_STEM_CELL_DN

GO Biological Process (3): positive regulation of Rho protein signal transduction (GO:0035025), intracellular signal transduction (GO:0035556), regulation of small GTPase mediated signal transduction (GO:0051056)

GO Molecular Function (4): guanyl-nucleotide exchange factor activity (GO:0005085), phosphatidylinositol binding (GO:0035091), protein binding (GO:0005515), lipid binding (GO:0008289)

GO Cellular Component (7): obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), endomembrane system (GO:0012505), extrinsic component of cytoplasmic side of plasma membrane (GO:0031234), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
RHO GTPase cycle	6
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

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
intracellular anatomical structure	2
binding	2
Rho protein signal transduction	1
regulation of Rho protein signal transduction	1
positive regulation of small GTPase mediated signal transduction	1
signal transduction	1
small GTPase-mediated signal transduction	1
regulation of intracellular signal transduction	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
anion binding	1
cytoplasm	1
membrane	1
cell periphery	1
vacuole	1
plasma membrane	1
cytoplasmic side of plasma membrane	1
extrinsic component of plasma membrane	1

Protein interactions and networks

STRING

772 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MCF2L	CDC42	P21181	578
MCF2L	DUS4L	O95620	553
MCF2L	PLEK	P08567	547
MCF2L	IL1RAPL1	Q9NZN1	543
MCF2L	GLT8D1	Q68CQ7	510
MCF2L	BEX3	Q00994	505
MCF2L	STK32C	Q86UX6	503
MCF2L	GDF5	P43026	488
MCF2L	MAGED1	Q9Y5V3	486
MCF2L	ARHGEF11	O15085	481
MCF2L	LRRC8B	Q6P9F7	445
MCF2L	FILIP1	Q7Z7B0	444
MCF2L	GPR22	Q99680	443
MCF2L	RABIF	P47224	430
MCF2L	ARHGEF12	Q9NZN5	430

IntAct

9 interactions, top by confidence:

A	B	Type	Score
MCF2L	HSPE1	psi-mi:“MI:0915”(physical association)	0.400
MCF2L	HSP90B1	psi-mi:“MI:0915”(physical association)	0.400
MCF2L	YAE1	psi-mi:“MI:0915”(physical association)	0.370
AIMP2	MCF2L	psi-mi:“MI:0915”(physical association)	0.370
MCF2L	RABAC1	psi-mi:“MI:0915”(physical association)	0.370
AGO1	DDX39A	psi-mi:“MI:0914”(association)	0.350
DISC1	MCF2L	psi-mi:“MI:0915”(physical association)	0.000
SMAD2	MCF2L	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (29): MCF2L (Affinity Capture-MS), MCF2L (Affinity Capture-RNA), MCF2L (Affinity Capture-RNA), MCF2L (Proximity Label-MS), RAC1 (Affinity Capture-Western), CDC42 (Affinity Capture-Western), MCF2L (Affinity Capture-RNA), MCF2L (Affinity Capture-MS), MCF2L (Affinity Capture-RNA), CDC42 (Co-crystal Structure), CDC42 (Reconstituted Complex), HSP90B1 (Proximity Label-MS), HSPE1 (Proximity Label-MS), MCF2L (Reconstituted Complex), MCF2L (FRET)

ESM2 similar proteins: A0AVI2, A0FGR9, A2AP18, A3KGK3, A6QQP7, F1LYQ8, F8VPU2, O00329, O08835, O14976, O15068, O35904, O75038, O75923, O94887, P19687, P40749, P50232, P58069, P97610, P97874, Q14644, Q15283, Q28013, Q5DTI8, Q5FWL4, Q5M7N9, Q5RAB8, Q5RJH2, Q60790, Q63406, Q63713, Q64096, Q6DN12, Q6P7F1, Q7L8C5, Q7ZWU7, Q8IV01, Q8VHQ7, Q91VS8

Diamond homologs: A1IGU3, A1IGU4, A1IGU5, A1ZAY1, E7F1U2, O15068, O15085, O77775, P10569, P15498, P19878, P35991, Q08DN7, Q3LAC4, Q5DU57, Q60992, Q63406, Q69ZK0, Q70Z35, Q80VK6, Q8TCU6, Q96N96, Q9NHV9, Q9NXL2, O60229, P40995, Q1LUA6, Q5BKC9, Q5RDX5, Q64096, Q6RFZ7, Q8CHT1, Q8N5V2, Q9ES67, A1X283, A2AAY5, A4FU49, A4RE77, A5D8S5, A6NI72

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
MCF2L	“up-regulates activity”	RHOA	“guanine nucleotide exchange factor”
MCF2L	“up-regulates activity”	CDC42	“guanine nucleotide exchange factor”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	143
Likely benign	35
Benign	10

Top pathogenic / likely-pathogenic (0)

SpliceAI

6889 predictions. Top by Δscore:

Variant	Effect	Δscore
13:113008631:T:G	acceptor_gain	1.0000
13:113014758:T:TA	acceptor_gain	1.0000
13:113014758:TGCA:T	acceptor_loss	1.0000
13:113014759:GCAG:G	acceptor_loss	1.0000
13:113014760:CA:C	acceptor_loss	1.0000
13:113014761:A:AC	acceptor_loss	1.0000
13:113014761:A:AG	acceptor_gain	1.0000
13:113014761:AGAT:A	acceptor_gain	1.0000
13:113014762:G:GT	acceptor_gain	1.0000
13:113014762:GA:G	acceptor_gain	1.0000
13:113014762:GAT:G	acceptor_gain	1.0000
13:113014762:GATG:G	acceptor_gain	1.0000
13:113014762:GATGA:G	acceptor_gain	1.0000
13:113014842:GTCCG:G	donor_gain	1.0000
13:113014843:TCCG:T	donor_gain	1.0000
13:113014844:CCGGT:C	donor_loss	1.0000
13:113014845:CGGT:C	donor_loss	1.0000
13:113014846:GGT:G	donor_loss	1.0000
13:113014847:G:GG	donor_gain	1.0000
13:113014848:T:G	donor_loss	1.0000
13:113014849:GAG:G	donor_loss	1.0000
13:113024638:CCCCA:C	acceptor_loss	1.0000
13:113024640:CCAG:C	acceptor_loss	1.0000
13:113024641:CAGG:C	acceptor_loss	1.0000
13:113024642:AGGT:A	acceptor_gain	1.0000
13:113024642:AGGTG:A	acceptor_gain	1.0000
13:113024643:GGTG:G	acceptor_gain	1.0000
13:113024643:GGTGG:G	acceptor_gain	1.0000
13:113024756:CAGGT:C	donor_loss	1.0000
13:113024757:AGGTA:A	donor_loss	1.0000

AlphaMissense

7403 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:113081230:T:C	L639P	1.000
13:113085132:T:C	L764P	1.000
13:113085135:T:C	L765P	1.000
13:113085141:C:A	P767Q	1.000
13:113085148:G:C	Q769H	1.000
13:113085148:G:T	Q769H	1.000
13:113085150:G:C	R770T	1.000
13:113085150:G:T	R770M	1.000
13:113085151:G:C	R770S	1.000
13:113085151:G:T	R770S	1.000
13:113085158:A:G	K773E	1.000
13:113085160:G:C	K773N	1.000
13:113085160:G:T	K773N	1.000
13:113085168:T:C	L776P	1.000
13:113087284:T:A	V838D	1.000
13:113087359:T:C	F863S	1.000
13:113087362:T:C	L864P	1.000
13:113087433:T:G	Y888D	1.000
13:113087444:G:C	K891N	1.000
13:113087444:G:T	K891N	1.000
13:113087756:T:C	F912S	1.000
13:113088354:T:A	W936R	1.000
13:113088354:T:C	W936R	1.000
13:113014835:C:A	A81D	0.999
13:113024671:T:A	V94D	0.999
13:113045293:T:C	F131L	0.999
13:113045295:C:A	F131L	0.999
13:113045295:C:G	F131L	0.999
13:113045326:T:A	W142R	0.999
13:113045326:T:C	W142R	0.999

dbSNP variants (sampled 300 via entrez): RS1000020208 (13:112980678 A>G), RS1000032608 (13:113088020 C>T), RS1000060691 (13:112943656 G>A), RS1000065835 (13:113097459 T>C), RS1000066324 (13:113010630 T>G), RS1000097250 (13:113010809 C>T), RS1000100421 (13:112919256 A>G), RS1000103718 (13:112907515 C>A), RS1000112193 (13:113064437 C>A), RS1000127375 (13:113012975 C>T), RS1000130083 (13:112985539 G>A), RS1000139894 (13:112974975 A>G), RS1000143937 (13:113079717 G>T), RS1000163425 (13:113076565 C>T), RS1000187022 (13:113018608 T>C)

Disease associations

OMIM: gene MIM:609499 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
vascular malformation	Limited	Autosomal dominant

Mondo (1): vascular malformation (MONDO:0024291)

Orphanet (0):

HPO phenotypes

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

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST000082_1	Factor VII	5.000000e-16
GCST001209_1	Osteoarthritis	2.000000e-08
GCST004279_12	Systolic blood pressure	2.000000e-08
GCST005194_88	Coronary artery disease	5.000000e-07
GCST005195_53	Coronary artery disease	8.000000e-12
GCST005196_4	Coronary artery disease	8.000000e-12
GCST007094_49	Diastolic blood pressure	3.000000e-06
GCST007096_233	Pulse pressure	5.000000e-08
GCST007099_169	Systolic blood pressure	1.000000e-11
GCST007267_137	Systolic blood pressure	1.000000e-11
GCST007269_323	Pulse pressure	1.000000e-11
GCST010304_65	Cutaneous malignant melanoma	6.000000e-12
GCST010866_55	Coronary artery disease	9.000000e-09
GCST90002395_161	Mean platelet volume	1.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004619	factor VII measurement
EFO:0006335	systolic blood pressure
EFO:0006336	diastolic blood pressure
EFO:0005763	pulse pressure measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D054079	Vascular Malformations	C14.240.850; C16.131.240.850

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4524032 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	5
Valproic Acid	affects cotreatment, decreases expression, affects expression	5
bisphenol A	affects cotreatment, decreases methylation, increases expression	4
trichostatin A	decreases expression, affects cotreatment	3
sodium arsenite	affects methylation, decreases methylation, increases expression	3
Methotrexate	affects response to substance, increases expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
Tobacco Smoke Pollution	affects expression, increases methylation	2
Cyclosporine	decreases expression, decreases methylation	2
Aflatoxin B1	decreases expression, decreases methylation	2
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
bisphenol F	affects cotreatment, increases methylation	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
benzo(e)pyrene	increases methylation	1
ferrous chloride	decreases expression	1
aflatoxin B2	increases methylation	1
1-hydroxypyrene	affects cotreatment, decreases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
tebuconazole	decreases expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Irinotecan	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4881446	Binding	CDC42 activation by DBS assay	Data for DCP probe BAY-293

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E0HN	Ubigene HeLa MCF2L KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04999618	PHASE4	COMPLETED	A New Approach in Laser Surgery Using the Regenerative Solution in Children Diagnosed With Vascular Pathology
NCT02384122	PHASE3	COMPLETED	Efficacy of Octreotide on Blood and Iron Requirements in Patients With Anemia Due to Angiodysplasias
NCT02638389	PHASE3	RECRUITING	Efficacy and Safety of Sirolimus in Vascular Anomalies That Are Refractory to Standard Care
NCT03110783	PHASE3	COMPLETED	Bioseal Dural Sealing Study BIOS-14-001
NCT03987152	PHASE3	UNKNOWN	Treatment of Congenital Vascular Malformations Using Sirolimus: Improving Quality of Life
NCT02509468	PHASE2	COMPLETED	suPERficial Slow-flow Vascular malFORMations Treated With sirolimUS
NCT02754960	PHASE2	WITHDRAWN	Efficacy Study of Thalidomide in Gastrointestinal Vascular Malformation Related Bleeding
NCT02883023	PHASE2	UNKNOWN	Electrosclerotherapy for Capillary Malformations
NCT03972592	PHASE2	COMPLETED	Topical Sirolimus in Cutaneous Lymphatic Malformations
NCT05983159	PHASE2	RECRUITING	A Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations
NCT06788314	PHASE2	RECRUITING	A Study of Enalapril in Treatment of Venous Malformations
NCT06789913	PHASE2	RECRUITING	A Phase 2 Study of Mutant-selective PI3Kα Inhibitor, RLY-2608, in Adults and Children With PIK3CA Related Overgrowth Spectrum and Malformations Driven by PIK3CA Mutation
NCT07037238	PHASE2	RECRUITING	An Open-Label, Single-Arm Exploratory Clinical Study of Everolimus for the Treatment of Vascular Malformations
NCT07477548	PHASE2	NOT_YET_RECRUITING	A Study to Evaluate the Efficacy and Safety of Everolimus in Patients With Teratment-refractory Vascular Anomalies
NCT07579962	PHASE2	NOT_YET_RECRUITING	Treatment of Low-flow Vascular Malformations With Bleomycin Electrosclerotherapy (BEST)
NCT00577213	Not specified	COMPLETED	Diagnosis of Hemangiomas and Vascular Malformations
NCT00833599	Not specified	ENROLLING_BY_INVITATION	Imaging Lymphatic Function in Normal Subjects and in Persons With Lymphatic Disorders
NCT01576601	Not specified	COMPLETED	The Management of Postoperative Craniotomy Pain in Pediatric Patients
NCT02250456	Not specified	UNKNOWN	AVAST Anomalies Vasculaires Associées au Syndrome de Turner (Vascular Abnormalities Associated With Turner Syndrome)
NCT02561182	Not specified	COMPLETED	Bone Health in Patients With Overgrowth
NCT02991352	Not specified	COMPLETED	Stereotactic MRI Based Image Guidance for the Treatment of Vascular Malformations - a Pilot Study
NCT03440827	Not specified	UNKNOWN	Development of a Specific Scale of Life’Quality for Children With Low-flow Vascular Malformations
NCT04104464	Not specified	RECRUITING	Patient Reported Outcomes for Vascular Malformations EmbolizatioN (PROVEN)
NCT04189172	Not specified	ACTIVE_NOT_RECRUITING	MiDura-Study (Neuro-Patch in Duraplasty)
NCT04637997	Not specified	COMPLETED	Influence of Flat-knitted Compression Stockings Class I and II on Venous Malformations
NCT04836884	Not specified	COMPLETED	Vascular Anomaly Pathology and Genomics Biopsy Study
NCT05113420	Not specified	UNKNOWN	The Efficacy and Safety of Different Phlebotonic Drugs in Children With Venous Malformations
NCT05418816	Not specified	ACTIVE_NOT_RECRUITING	SelfWrap-Assisted Arteriovenous Fistulas
NCT05494710	Not specified	UNKNOWN	Bleomycin Electrosclerotherapy Treatment of Vascular Malformations: A Feasibility Study
NCT05563831	Not specified	COMPLETED	National Evaluation of Patients With PIK3CA-Related Overgrowth Spectrum (PROS)
NCT06160739	Not specified	UNKNOWN	Role of Sirolimus in Treatment of Microcystic , Mixed Lymphatic and Vascular Malformations
NCT06189092	Not specified	RECRUITING	Treatment of Low-flow Venous Malformations With Electrosclerotherapy. Prospective Observational Study
NCT06259292	Not specified	RECRUITING	Comprehensive HHT Outcomes Registry of the United States (CHORUS)
NCT06399367	Not specified	ENROLLING_BY_INVITATION	Investigation of Lipedema, Lymphedema and Vascular Malformations by Multispectral Optoacoustic Tomography (MSOT)
NCT06986954	Not specified	RECRUITING	Beacon Tip Sizing Catheter and Slip-Cath Beacon Tip Catheter Study
NCT06994260	Not specified	NOT_YET_RECRUITING	Diagnostic Imaging of Vascular Malformations Using MSOT and ULM
NCT07320430	Not specified	COMPLETED	Comparative Study Between Sclerosing Agents Used in Treatment of Vascular Malformation
NCT07404670	Not specified	NOT_YET_RECRUITING	Microwave Ablation for Treatment of Vascular Malformations: Efficacy and Safety