SOX18

Summary

SOX18 (SRY-box transcription factor 18, HGNC:11194) is a protein-coding gene on chromosome 20q13.33, encoding Transcription factor SOX-18 (P35713). Transcriptional activator that binds to the consensus sequence 5’-AACAAAG-3’ in the promoter of target genes and plays an essential role in embryonic cardiovascular development and lymphangiogenesis.

This gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and in the determination of the cell fate. The encoded protein may act as a transcriptional regulator after forming a protein complex with other proteins. This protein plays a role in hair, blood vessel, and lymphatic vessel development. Mutations in this gene have been associated with recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia.

Source: NCBI Gene 54345 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypotrichosis-lymphedema-telangiectasia-renal defect syndrome (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 211 total — 4 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 50
• Druggable target: yes
• MANE Select transcript: NM_018419

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11194
Approved symbol	SOX18
Name	SRY-box transcription factor 18
Location	20q13.33
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000203883
Ensembl biotype	protein_coding
OMIM	601618
Entrez	54345

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000340356

RefSeq mRNA: 1 — MANE Select: NM_018419 NM_018419

CCDS: CCDS13552

Canonical transcript exons

ENST00000340356 — 2 exons

Exon	Start	End
ENSE00001386393	64049159	64049639
ENSE00001423335	64047582	64048962

Expression profiles

Bgee: expression breadth ubiquitous, 165 present calls, max score 94.46.

FANTOM5 (CAGE): breadth broad, TPM avg 19.0719 / max 598.2369, expressed in 758 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
188449	18.9189	756
188448	0.0976	51
188446	0.0389	19
188447	0.0165	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	94.46	gold quality
right lung	UBERON:0002167	93.96	gold quality
left uterine tube	UBERON:0001303	90.99	gold quality
omental fat pad	UBERON:0010414	90.04	gold quality
peritoneum	UBERON:0002358	89.91	gold quality
right atrium auricular region	UBERON:0006631	89.55	gold quality
right lobe of thyroid gland	UBERON:0001119	89.48	gold quality
heart left ventricle	UBERON:0002084	88.08	gold quality
adipose tissue of abdominal region	UBERON:0007808	88.01	gold quality
right coronary artery	UBERON:0001625	87.69	gold quality
mucosa of stomach	UBERON:0001199	86.94	gold quality
body of uterus	UBERON:0009853	86.85	gold quality
cardiac ventricle	UBERON:0002082	86.51	gold quality
cardiac atrium	UBERON:0002081	86.11	gold quality
left coronary artery	UBERON:0001626	86.08	gold quality
upper lobe of left lung	UBERON:0008952	85.75	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.60	gold quality
lower esophagus muscularis layer	UBERON:0035833	85.37	gold quality
lower esophagus	UBERON:0013473	85.28	gold quality
subcutaneous adipose tissue	UBERON:0002190	85.18	gold quality
left lobe of thyroid gland	UBERON:0001120	85.06	gold quality
metanephros cortex	UBERON:0010533	85.05	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	84.81	gold quality
ectocervix	UBERON:0012249	84.30	gold quality
tibial nerve	UBERON:0001323	83.95	gold quality
coronary artery	UBERON:0001621	83.74	gold quality
heart	UBERON:0000948	83.72	gold quality
hindlimb stylopod muscle	UBERON:0004252	83.71	gold quality
upper lobe of lung	UBERON:0008948	83.62	gold quality
endocervix	UBERON:0000458	82.90	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-6308	yes	1467.91
E-GEOD-135922	yes	46.01
E-GEOD-83139	yes	31.57
E-HCAD-9	yes	16.19
E-ANND-3	yes	10.40
E-MTAB-10553	yes	8.35
E-MTAB-10137	no	4.55
E-MTAB-6678	no	2.44

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

6 targets.

Target	Regulation
CLDN5	Activation
DLL4	Activation
MMP7	Activation
OPRM1	Unknown
PROX1	Activation
VCAM1	Activation

JASPAR motifs

Motif	Name	Family
MA1563.1	SOX18	SOX-related factors
MA1563.2	SOX18	SOX-related factors

JASPAR matrix evidence (PMIDs): PMID:7651823

Upstream regulators (CollecTRI, top): EGR1, NFYA, NFYB, NFYC, SP3, ZNF148

miRNA regulators (miRDB)

34 targeting SOX18, 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-6077	99.99	68.04	2299
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488
HSA-MIR-548Y	99.94	71.28	3514
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-3973	99.20	69.19	1990

Literature-anchored findings (GeneRIF, showing 40)

• Mutations in SOX18 underlie recessive and dominat forms of hypertrichosis-lymphedema- telangiectasis/ (PMID:12740761)
• SOX18 is involved in vascular cell growth and this transcription factor may play a role in atherosclerosis (PMID:16179596)
• Overexpression of wild-type SOX18 promoted capillary tube formation of HUVECs in vitro, whereas expression of dominant-negative SOX18 impaired tube formation of HUVECs and the migration of MCF-7 cells via the disruption of the actin cytoskeleton. (PMID:16882943)
• an obligatory role for SOX-18 in the regulation of claudin-5 gene expression in an endothelial-specific and cell density-dependent manner is established (PMID:18065521)
• Transcription factors Sp3, ZBP-89 and NF-Y are capable of binding to the SOX18 promoter region. (PMID:18496767)
• of the 679 gastric cancer cases, 177 (26.1%) were positive for SOX 18 expression in their tumor stroma, and the frequencies of both lymphovascular invasion and lymph node metastases were higher in the SOX 18 positive than in the negative group. (PMID:21796627)
• Heterogeneous methylation in the promoter region of SOX18 was associated with cancer progression in non-small cell lung cancer. (PMID:22018271)
• The identification of MMP7 as a direct SOX18 target gene as well as other potential candidates including guidance molecules provides a molecular basis for the proposed function of this transcription factor in the regulation of vessel formation. (PMID:22292085)
• Data suggest that SOX18 transcription factor expression may serve as a marker for a poor prognosis in invasive ductal breast carcinoma. (PMID:24065215)
• The repression of Sox18 and its target genes may lead to altered formation of vessels in inflamed settings. (PMID:24269235)
• SOX18wt has potent trans-activation proper- ties, while SOX18DN displayed dominant-negative effect. (PMID:24460943)
• A new, autosomal dominant condition combining hypotrichosis-lymphedema-telangiectasia syndrome with renal defects is associated with a novel truncating mutation in the SOX18 gene. (PMID:24697860)
• SOX18 may be involved in the progression of Non small cell lung cancer. (PMID:25310193)
• The genetic finding of a pathogenic SOX18 mutation enabled the diagnosis of the rare hypotrichosis-lymphedema-telangiectasia syndrome in our patient. (PMID:26148450)
• we demonstrated that upregulation of SOX18 was associated with a poor outcome in hepatocellular carcinoma patients (PMID:26151573)
• NKD2 inhibits SOX18 and MMP-2,7,9 expression and suppresses BGC823 cell xenograft growth. NKD2 methylation may serve as a poor prognostic and chemo-sensitive marker in human gastric cancer. NKD2 impedes gastric cancer metastasis by inhibiting SOX18. (PMID:26396173)
• The downregulation of SOX18 was found to significantly inhibit cell adhesion and invasion. (PMID:26573263)
• GLI1 and GLI2, but not GLI3 are involved in the regulation of SOX18 gene expression in cervical carcinoma cell lines. (PMID:26588701)
• the results of this study suggest that knockdown of SOX18 inhibits breast cancer cell growth and invasion, possibly by downregulating downstream oncogenic proteins, providing novel insights into the development of breast cancer therapy through targeting of SOX18. (PMID:27108946)
• Nuclear expression of SOX18 was shown in vascular endothelial cells, basal layer cells of NS epidermis, as well as in AK, BCC and SCC cancer cells (PMID:27127146)
• SOX18 plays a significant role in promoting the growth of pancreatic ductal adenocarcinoma, and might serve as a promising target for PDAC therapy (PMID:27663663)
• miRNAs interact with the mRNA of the SOX18 gene, but the mechanism by which they could be inhibited in cancer cells requires further examination (PMID:27666488)
• Study reports SOX18 as novel risk gene for Neural tube defects (NTDs) but findings also suggest that SOX18 hypomethylation and increased expression must interplay with other environmental and (epi)genetic factors that are causative for NTDs. (PMID:27757173)
• SOX18 was overexpressed in prostate cancer.SOX18 promotes prostate cancer progression via the regulation of TCF1, c-Myc, cyclin D1 and MMP-7. (PMID:27922675)
• Results showed that on the contrary of the mRNA level, the protein levels of SOX18 were higher in lung adenocarcinoma (AC) cases compared to levels noted in the non-malignant lung tissues (NMLTs). The disparity between the mRNA and protein levels of the SOX18 transcription factor was caused by miR-7a and miR-24-3p, although the mechanism through which lung cancer cells downregulate miRNA molecule levels is still unclear. (PMID:29115529)
• NF-kappaB-dependent decreases in the SOX18-CLDN5 axis are involved in the disruption of human endothelial cell barrier integrity associated with LPS-mediated acute lung injury. (PMID:29115856)
• results suggest that SOX18 is overexpressed in Osteosaroma (OS) and plays an important role in proliferation, apoptosis, migration and invasion of OS cells, and may provide a novel and promising thera-peutic strategy for OS. (PMID:29266413)
• A novel mutation in the SOX18 gene identified in a patient with hypotrichosis-lymphedema-telangiectasia syndrome. (PMID:29307792)
• miR-7-5p targeted SOX18 to inhibit gp130/JAK2/STAT3 signaling pathway to exert its suppressing role in Pancreatic ductal adenocarcinoma (PMID:29408481)
• The present data demonstrate that the endothelial-specific and lymph endothelial-specific transcription factors SOX18 and PROX1 contribute to lymph endothelial cells retraction (PMID:29749465)
• dimerization is a specific feature of SOX18 that enables the recruitment of key endothelial transcription factors (PMID:30335167)
• Down-regulation of SOX18 inhibits laryngeal carcinoma cell proliferation, migration, and invasion through JAK2/STAT3 signaling. (PMID:31189744)
• Data demonstrated a cancer-promoting effect of SOX18 in BCa, revealed the potential mechanisms of SOX18 in mediating cellular functions. (PMID:31260682)
• SOX18 downregulation in HCC cells suppressed cell viability and metastasis, induced cell apoptosis and hindered the occurrence and progression of tumor cells by participating in the EMT process and regulating the autophagy signaling pathway AMPK/mTOR. (PMID:31427562)
• Fibroblast Growth Factor 19-Mediated Up-regulation of SYR-Related High-Mobility Group Box 18 Promotes Hepatocellular Carcinoma Metastasis by Transactivating Fibroblast Growth Factor Receptor 4 and Fms-Related Tyrosine Kinase 4. (PMID:31529503)
• A Study of High-Grade Serous Ovarian Cancer Origins Implicates the SOX18 Transcription Factor in Tumor Development. (PMID:31825847)
• SP1-induced lncRNA LINC00689 overexpression contributes to osteosarcoma progression via the miR-655/SOX18 axis. (PMID:32196572)
• Feedback loops integrating RELA, SOX18 and FAK mediate the breakdown of the lymphendothelial barrier that is triggered by 12(S)HETE. (PMID:32319559)
• Augmented angiogenic transcription factor, SOX18, is associated with asthma exacerbation. (PMID:32419535)
• Oncogenic Herpesvirus Engages Endothelial Transcription Factors SOX18 and PROX1 to Increase Viral Genome Copies and Virus Production. (PMID:32518203)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
mus_musculus	Sox18	ENSMUSG00000046470
rattus_norvegicus	Sox18	ENSRNOG00000016248
drosophila_melanogaster	Sox14	FBGN0005612
drosophila_melanogaster	Sox21a	FBGN0036411
drosophila_melanogaster	Sox102F	FBGN0039938
caenorhabditis_elegans		WBGENE00001182
caenorhabditis_elegans		WBGENE00015716

Paralogs (20): SOX8 (ENSG00000005513), SOX30 (ENSG00000039600), SOX10 (ENSG00000100146), SOX6 (ENSG00000110693), SOX4 (ENSG00000124766), SOX21 (ENSG00000125285), SOX9 (ENSG00000125398), SOX15 (ENSG00000129194), SOX5 (ENSG00000134532), SOX3 (ENSG00000134595), SOX13 (ENSG00000143842), SOX17 (ENSG00000164736), SOX14 (ENSG00000168875), SOX7 (ENSG00000171056), SOX11 (ENSG00000176887), SOX12 (ENSG00000177732), CFAP65 (ENSG00000181378), SOX2 (ENSG00000181449), SOX1 (ENSG00000182968), SRY (ENSG00000184895)

Protein

Protein identifiers

Transcription factor SOX-18 — P35713 (reviewed: P35713)

All UniProt accessions (1): P35713

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional activator that binds to the consensus sequence 5’-AACAAAG-3’ in the promoter of target genes and plays an essential role in embryonic cardiovascular development and lymphangiogenesis. Activates transcription of PROX1 and other genes coding for lymphatic endothelial markers. Plays an essential role in triggering the differentiation of lymph vessels, but is not required for the maintenance of differentiated lymphatic endothelial cells. Plays an important role in postnatal angiogenesis, where it is functionally redundant with SOX17. Interaction with MEF2C enhances transcriptional activation. Besides, required for normal hair development.

Subunit / interactions. Interacts (via C-terminus) with MEF2C (via MADS box).

Subcellular location. Nucleus.

Tissue specificity. Detected in heart, lung, placenta, skeletal muscle, liver, kidney, spleen, prostate, ovary, msosmall intestine and colon.

Disease relevance. Hypotrichosis-lymphedema-telangiectasia syndrome (HLTS) [MIM:607823] A syndrome characterized by absent eyebrows and eyelashes, lymphatic edemas of the inferior members or eyelids, and peripheral vein anomalies. The disease is caused by variants affecting the gene represented in this entry. Hypotrichosis-lymphedema-telangiectasia-renal defect syndrome (HLTRS) [MIM:137940] A syndrome characterized by sparse hair, lymphatic edemas, peripheral vein anomalies, and renal disease. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Binds target DNA via the HMG box domain. The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors.

RefSeq proteins (1): NP_060889* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009071	HMG_box_dom	Domain
IPR021934	Sox_C	Domain
IPR033392	Sox7/17/18_central	Domain
IPR036910	HMG_box_dom_sf	Homologous_superfamily
IPR050140	SRY-related_HMG-box_TF-like	Family

Pfam: PF00505, PF12067

UniProt features (20 total): compositionally biased region 6, region of interest 6, sequence variant 2, chain 1, domain 1, modified residue 1, mutagenesis site 1, DNA-binding region 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35713-F1	63.44	0.22

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 (1): 70

Mutagenesis-validated functional residues (1):

Position	Phenotype
330–331	greatly reduced transactivating activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 267 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_ENDOTHELIAL_CELL_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_EPITHELIAL_CELL_DEVELOPMENT, HNF1_Q6, GOBP_ENDOCARDIUM_DEVELOPMENT, GOBP_STEM_CELL_PROLIFERATION, NKX61_01, GOBP_SPECIFICATION_OF_SYMMETRY, GOBP_ANATOMICAL_STRUCTURE_MATURATION, GOBP_BLOOD_VESSEL_ENDOTHELIAL_CELL_MIGRATION, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_EMBRYONIC_HEART_TUBE_DEVELOPMENT, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT

GO Biological Process (28): negative regulation of transcription by RNA polymerase II (GO:0000122), angiogenesis (GO:0001525), vasculogenesis (GO:0001570), in utero embryonic development (GO:0001701), hair follicle development (GO:0001942), vasculature development (GO:0001944), lymphangiogenesis (GO:0001946), heart looping (GO:0001947), outflow tract morphogenesis (GO:0003151), hair cycle process (GO:0022405), embryonic heart tube development (GO:0035050), blood vessel endothelial cell migration (GO:0043534), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), cell maturation (GO:0048469), stem cell fate specification (GO:0048866), endocardium formation (GO:0060214), lymphatic endothelial cell differentiation (GO:0060836), endocardial cell differentiation (GO:0060956), establishment of endothelial barrier (GO:0061028), regulation of stem cell proliferation (GO:0072091), blood vessel development (GO:0001568), lymph vessel development (GO:0001945), regulation of DNA-templated transcription (GO:0006355), heart development (GO:0007507), tissue development (GO:0009888), anatomical structure formation involved in morphogenesis (GO:0048646)

GO Molecular Function (8): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), transcription regulator complex (GO:0005667)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	3
anatomical structure formation involved in morphogenesis	3
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
transcription by RNA polymerase II	2
blood vessel morphogenesis	2
anatomical structure morphogenesis	2
DNA-templated transcription	2
negative regulation of DNA-templated transcription	1
cell differentiation	1
chordate embryonic development	1
hair cycle process	1
anatomical structure development	1
skin epidermis development	1
system development	1
circulatory system development	1
lymph vessel morphogenesis	1
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
heart morphogenesis	1
molting cycle process	1
hair cycle	1
heart development	1
tube development	1
embryonic organ development	1
epithelium development	1
endothelial cell migration	1
negative regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
cell development	1
cellular developmental process	1
anatomical structure maturation	1
cell fate specification	1
stem cell fate commitment	1
endocardium morphogenesis	1
lymph vessel development	1
endothelial cell differentiation	1
endocardium development	1
cardiac endothelial cell differentiation	1

Protein interactions and networks

STRING

1514 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SOX18	PROX1	Q92786	864
SOX18	FOXC2	Q99958	829
SOX18	NR2F2	P24468	789
SOX18	FLT4	P35916	785
SOX18	RBPJ	Q06330	756
SOX18	MMP7	P09237	696
SOX18	CCBE1	Q6UXH8	689
SOX18	VEGFC	P49767	674
SOX18	LYVE1	Q9Y5Y7	596
SOX18	GJC2	Q5T442	591
SOX18	CDH2	P19022	584
SOX18	IL7R	P16871	552
SOX18	POU5F1	P31359	504
SOX18	CCDC85B	Q15834	504
SOX18	GATA2	P23769	502

IntAct

4 interactions, top by confidence:

A	B	Type	Score
SOX18		psi-mi:“MI:0915”(physical association)	0.400
MECP2	SOX18	psi-mi:“MI:0915”(physical association)	0.370
GKAP1	SOX18	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (7): SOX18 (Reconstituted Complex), SOX18 (Reconstituted Complex), MEF2C (Affinity Capture-Western), SOX18 (Negative Genetic), SOX18 (Proximity Label-MS), SOX18 (Two-hybrid), SOX18 (Two-hybrid)

ESM2 similar proteins: A0A8I6AGW3, A2A9A2, A6NMB9, A8MYZ6, E9PZZ1, J3QK54, O02755, O02756, O35392, O35767, O60548, O70220, P05554, P17676, P21272, P28033, P35713, P42582, P49715, P49716, P52952, P53566, P58012, Q12952, Q13461, Q14526, Q60843, Q61345, Q63244, Q63250, Q6BEB4, Q6VFT5, Q6VFT6, Q6ZQN5, Q70KY4, Q8IU81, Q8MIP2, Q8NDY6, Q8R2I0, Q98937

Diamond homologs: A0A0G2JTZ2, A2TED3, A5D8R3, B1H349, B3DLD3, B3DM43, F1M8W4, O42342, O42601, P0C1G9, P35710, P35711, P35712, P35713, P35716, P36389, P36390, P36393, P36394, P36396, P40645, P40646, P40647, P40649, P40650, P40656, P40657, P43680, P47792, P48433, P48435, Q03255, Q03257, Q04891, Q05738, Q06831, Q06945, Q20201, Q23045, Q27949

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
NFYA	“up-regulates quantity by expression”	SOX18	“transcriptional regulation”
NFYB	“up-regulates quantity by expression”	SOX18	“transcriptional regulation”
SP3	“down-regulates quantity by repression”	SOX18	“transcriptional regulation”
ZNF148	“down-regulates quantity by repression”	SOX18	“transcriptional regulation”
NFYC	“up-regulates quantity by expression”	SOX18	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	3
Uncertain significance	145
Likely benign	44
Benign	6

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
433539	NM_018419.3(SOX18):c.712G>T (p.Glu238Ter)	Pathogenic
564637	GRCh37/hg19 20q13.33(chr20:62002369-62915555)x1	Pathogenic
8000	NM_018419.3(SOX18):c.310G>C (p.Ala104Pro)	Pathogenic
8001	NM_018419.3(SOX18):c.283T>A (p.Trp95Arg)	Pathogenic
1184912	NM_018419.3(SOX18):c.483_490del (p.Ala162fs)	Likely pathogenic
3587628	NM_018419.3(SOX18):c.917_947del (p.Leu306fs)	Likely pathogenic
8002	NM_018419.3(SOX18):c.720C>A (p.Cys240Ter)	Likely pathogenic

SpliceAI

229 predictions. Top by Δscore:

Variant	Effect	Δscore
20:64049155:TCACC:T	donor_loss	1.0000
20:64049157:AC:A	donor_gain	1.0000
20:64049157:ACCCA:A	donor_loss	1.0000
20:64049158:C:CT	donor_loss	1.0000
20:64049158:CC:C	donor_gain	1.0000
20:64049157:A:AC	donor_gain	0.9900
20:64049158:C:CC	donor_gain	0.9900
20:64049158:CCCAG:C	donor_gain	0.9900
20:64048961:GCCT:G	acceptor_loss	0.9800
20:64048963:C:CC	acceptor_gain	0.9800
20:64048963:CT:C	acceptor_loss	0.9800
20:64048964:T:G	acceptor_loss	0.9800
20:64048971:C:T	acceptor_gain	0.9800
20:64049171:TGAG:T	donor_gain	0.9800
20:64048971:C:CT	acceptor_gain	0.9600
20:64049157:ACC:A	donor_gain	0.9600
20:64049158:CCC:C	donor_gain	0.9600
20:64048236:T:A	donor_gain	0.9500
20:64049162:G:C	donor_gain	0.9500
20:64048070:CACG:C	donor_gain	0.9400
20:64048958:TTTGC:T	acceptor_gain	0.9400
20:64048070:CA:C	donor_gain	0.9300
20:64048960:TGC:T	acceptor_gain	0.9300
20:64047908:T:TA	donor_gain	0.9200
20:64048168:AG:A	donor_gain	0.9200
20:64048959:TTGC:T	acceptor_gain	0.9200
20:64049169:G:A	donor_gain	0.9200
20:64049173:A:AC	donor_gain	0.9200
20:64048169:G:C	donor_gain	0.9100
20:64048181:CGCG:C	donor_gain	0.9100

AlphaMissense

2422 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:64048849:G:T	R158S	1.000
20:64048860:T:C	Y154C	1.000
20:64048860:T:G	Y154S	1.000
20:64048861:A:C	Y154D	1.000
20:64048861:A:G	Y154H	1.000
20:64048862:C:A	K153N	1.000
20:64048862:C:G	K153N	1.000
20:64048864:T:C	K153E	1.000
20:64048866:T:C	Y152C	1.000
20:64048867:A:C	Y152D	1.000
20:64048867:A:G	Y152H	1.000
20:64048876:G:C	H149D	1.000
20:64048886:G:C	H145Q	1.000
20:64048886:G:T	H145Q	1.000
20:64048887:T:C	H145R	1.000
20:64048888:G:C	H145D	1.000
20:64048888:G:T	H145N	1.000
20:64048897:G:T	R142S	1.000
20:64048899:A:G	L141P	1.000
20:64048902:C:G	R140P	1.000
20:64048908:G:T	A138D	1.000
20:64048909:C:G	A138P	1.000
20:64048919:G:C	F134L	1.000
20:64048919:G:T	F134L	1.000
20:64048920:A:G	F134S	1.000
20:64048921:A:G	F134L	1.000
20:64048928:C:A	K131N	1.000
20:64048928:C:G	K131N	1.000
20:64048944:A:G	L126P	1.000
20:64048952:C:A	W123C	1.000

dbSNP variants (sampled 300 via entrez): RS1001020971 (20:64051206 A>G), RS1001079250 (20:64051024 C>T), RS1001248624 (20:64051486 C>T), RS1001982818 (20:64050359 G>A), RS1002202183 (20:64050624 A>C), RS1003187909 (20:64050019 C>A,T), RS1003654340 (20:64047773 T>G), RS1003706638 (20:64048037 C>A,T), RS1004588492 (20:64051289 G>A,T), RS1004689208 (20:64049880 C>T), RS1004939447 (20:64051453 T>G), RS1005482045 (20:64050317 G>A), RS1006365002 (20:64048718 G>A,C,T), RS1007608680 (20:64048277 T>C), RS1007660959 (20:64049918 C>T)

Disease associations

OMIM: gene MIM:601618 | disease phenotypes: MIM:137940, MIM:607823, MIM:600057

GenCC curated gene-disease

Disease	Classification	Inheritance
hypotrichosis-lymphedema-telangiectasia-renal defect syndrome	Strong	Autosomal dominant
hypotrichosis-lymphedema-telangiectasia syndrome	Strong	Autosomal recessive
hypotrichosis-lymphedema-telangiectasia syndrome (grouping)	Supportive	Autosomal dominant

Mondo (4): hypotrichosis-lymphedema-telangiectasia-renal defect syndrome (MONDO:0019073), hypotrichosis-lymphedema-telangiectasia syndrome (MONDO:0011914), bladder exstrophy-epispadias-cloacal exstrophy complex (MONDO:0700039), hypotrichosis-lymphedema-telangiectasia syndrome (grouping) (MONDO:0007670)

Orphanet (2): Hypotrichosis-lymphedema-telangiectasia-renal defect syndrome (Orphanet:69735), Classic bladder exstrophy (Orphanet:93930)

HPO phenotypes

50 total (30 of 50 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000034	Hydrocele testis
HP:0000083	Renal insufficiency
HP:0000095	Abnormal renal glomerulus morphology
HP:0000164	Abnormality of the dentition
HP:0000286	Epicanthus
HP:0000300	Oval face
HP:0000303	Mandibular prognathia
HP:0000426	Prominent nasal bridge
HP:0000431	Wide nasal bridge
HP:0000561	Absent eyelashes
HP:0000653	Sparse eyelashes
HP:0000793	Membranoproliferative glomerulonephritis
HP:0000962	Hyperkeratosis
HP:0000963	Thin skin
HP:0000965	Cutis marmorata
HP:0000971	Abnormal sweat gland morphology
HP:0001004	Lymphedema
HP:0001263	Global developmental delay
HP:0001480	Freckling
HP:0001541	Ascites
HP:0001596	Alopecia
HP:0001597	Abnormal nail morphology
HP:0001789	Hydrops fetalis
HP:0001790	Nonimmune hydrops fetalis
HP:0002202	Pleural effusion
HP:0002209	Sparse scalp hair
HP:0002223	Absent eyebrow
HP:0002231	Sparse body hair

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST007001_16	Cerebrospinal AB1-42 levels in normal cognition	3.000000e-07
GCST010002_71	Refractive error	1.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004670	beta-amyloid 1-42 measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C536825	Glomerulonephritis sparse hair telangiectases (supp.)
C564327	Hypotrichosis-Lymphedema-Telangiectasia Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523220 (SINGLE PROTEIN)

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

ChEMBL bioactivities

1 potent at pChembl≥5 of 4 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.48	IC50	3300	nM	CHEMBL2334661

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
aminomethylphosphonic acid (AMPA)	decreases expression	1
dicrotophos	increases expression	1
bisphenol A	decreases methylation	1
nickel chloride	decreases expression	1
periodate-oxidized adenosine	affects expression	1
ferrous chloride	decreases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	affects cotreatment, decreases expression	1
MT19c compound	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Temozolomide	increases expression	1
Decitabine	affects expression	1
Arsenic Trioxide	decreases expression	1
Arsenic	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	increases expression	1
Catechin	affects cotreatment, decreases expression	1
Cisplatin	affects expression	1
Estradiol	decreases expression	1
Fluorouracil	affects response to substance	1
Hydrogen Peroxide	decreases expression	1
Indomethacin	increases expression	1
Mercury	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Tetrachlorodibenzodioxin	decreases expression, affects cotreatment	1
Tretinoin	decreases expression	1
Triclosan	decreases expression	1

ChEMBL screening assays

11 unique, capped per target: 11 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4421261	Binding	Inhibition of SOX18 in HUVEC assessed as reduction of SOX18-DDX17 interactions incubated for 45 mins by Alpha-screen assay	Inhibitors of sox18 protein activity for treating angiogenesis- and/or lymphangiogenesis-related diseases

Clinical trials (associated diseases)

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