VANGL2

Summary

VANGL2 (VANGL planar cell polarity protein 2, HGNC:15511) is a protein-coding gene on chromosome 1q23.2, encoding Vang-like protein 2 (Q9ULK5). Involved in the control of early morphogenesis and patterning of both axial midline structures and the development of neural plate.

The protein encoded by this gene is a membrane protein involved in the regulation of planar cell polarity, especially in the stereociliary bundles of the cochlea. The encoded protein transmits directional signals to individual cells or groups of cells in epithelial sheets. This protein is also involved in the development of the neural plate.

Source: NCBI Gene 57216 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neural tube defects, susceptibility to (Moderate, GenCC)
• GWAS associations: 12
• Clinical variants (ClinVar): 79 total
• Phenotypes (HPO): 33
• MANE Select transcript: NM_020335

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15511
Approved symbol	VANGL2
Name	VANGL planar cell polarity protein 2
Location	1q23.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1215, LTAP, LPP1, STBM, STB1, STBM1, MGC119403, MGC119404
Ensembl gene	ENSG00000162738
Ensembl biotype	protein_coding
OMIM	600533
Entrez	57216

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000368061, ENST00000483408, ENST00000696602

RefSeq mRNA: 1 — MANE Select: NM_020335 NM_020335

CCDS: CCDS30915

Canonical transcript exons

ENST00000368061 — 8 exons

Exon	Start	End
ENSE00001068142	160420411	160420547
ENSE00001068143	160424052	160424283
ENSE00001068145	160416062	160416182
ENSE00001068146	160419002	160419609
ENSE00001446224	160425118	160428670
ENSE00001446225	160415648	160415908
ENSE00001446226	160400564	160400869
ENSE00003640582	160421052	160421187

Expression profiles

Bgee: expression breadth ubiquitous, 210 present calls, max score 96.52.

FANTOM5 (CAGE): breadth broad, TPM avg 7.7993 / max 130.7738, expressed in 847 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
6125	7.5479	846
6126	0.2030	114
6124	0.0484	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	96.52	gold quality
buccal mucosa cell	CL:0002336	95.68	gold quality
ventricular zone	UBERON:0003053	95.62	gold quality
cortical plate	UBERON:0005343	94.93	gold quality
upper arm skin	UBERON:0004263	93.89	gold quality
oviduct epithelium	UBERON:0004804	90.08	gold quality
skin of abdomen	UBERON:0001416	87.46	gold quality
skin of leg	UBERON:0001511	86.21	gold quality
lower esophagus mucosa	UBERON:0035834	85.59	gold quality
zone of skin	UBERON:0000014	85.57	gold quality
upper leg skin	UBERON:0004262	85.02	gold quality
vagina	UBERON:0000996	83.04	gold quality
minor salivary gland	UBERON:0001830	81.58	gold quality
cerebellar hemisphere	UBERON:0002245	81.58	gold quality
cerebellar cortex	UBERON:0002129	81.49	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.33	gold quality
right hemisphere of cerebellum	UBERON:0014890	81.26	gold quality
esophagus mucosa	UBERON:0002469	81.03	gold quality
cerebellum	UBERON:0002037	80.51	gold quality
mouth mucosa	UBERON:0003729	80.20	gold quality
prostate gland	UBERON:0002367	79.59	gold quality
ileal mucosa	UBERON:0000331	79.54	gold quality
endocervix	UBERON:0000458	79.53	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	79.16	gold quality
ectocervix	UBERON:0012249	79.16	gold quality
fallopian tube	UBERON:0003889	78.79	gold quality
uterine cervix	UBERON:0000002	78.46	gold quality
pancreatic ductal cell	CL:0002079	77.86	silver quality
right uterine tube	UBERON:0001302	77.71	gold quality
palpebral conjunctiva	UBERON:0001812	77.67	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.55

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

192 targeting VANGL2, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-12133	99.92	71.82	2006

Literature-anchored findings (GeneRIF, showing 22)

• Results suggest that there is no specific mutation responsible for the Tetralogy of Fallot phenotype in the Vangl2 gene [Vangl2]. (PMID:18034999)
• Van Gogh-Like 2 regulates tumor cell migration and matrix metalloproteinase-dependent invasion. (PMID:19577357)
• The planar cell polarity genes Celsr1 and Vangl2 are required for normal lung branching morphogenesis. (PMID:20223754)
• identified 3 novel missense mutations in fetuses with neural-tube defects (PMID:20558380)
• these findings strongly implicate VANGL2 in the genetic causation of spinal NTDs in a subset of patients and provide additional evidence for a pathogenic role of PCP signaling in these malformations. (PMID:20738329)
• Loss of membrane targeting of Vangl1 and Vangl2 proteins causes neural tube defects. (PMID:21142127)
• Propose that Arfrp1 exposes a binding site on AP-1 that recognizes the Vangl2 sorting motif for capture into a transport vesicle destined for the proximal surface of a polarized epithelial cell. (PMID:23326640)
• Van-Gogh-like 2 is frequently methylated in MSI-CRCs with BRAF mutation and may act as a tumour suppressor gene, counteracting WNT/beta-catenin signaling. (PMID:23579212)
• These results strongly suggest that R181 and R274 play critical roles in Vangl protein function and that their mutations cause neural tube defects in humans. (PMID:25068569)
• The aberrant VANGL2 promoter methylation and the decreased gene expression is associated with Tetralogy of Fallot. (PMID:25200836)
• Asymmetry of VANGL2 in migrating lymphocytes as a tool to monitor activity of the mammalian WNT/planar cell polarity pathway. (PMID:25627785)
• VANGL2 is overexpressed in basal breast cancers. It is involved in the proliferative signal cascade of the VANGL2-SQSTM1-JNK pathway. (PMID:26754771)
• Our experimental data demonstrate that high expression of Prickle1 and Vangl2 reduce the growth of neuroblastoma cells and indicate different roles of PCP proteins in tumorigenic cells compared to normal cells. (PMID:27036398)
• VANGL2 interacts with Integrin alphaVbeta3 to regulate matrix metalloproteinase activity and cell adhesion to the extracellular matrix. (PMID:29097183)
• Expression of constitutively active and dominant-negative isoforms of RHOA revealed that it acts downstream of VANGL2. (PMID:29499154)
• Vangl2 modulates glomerular injury, at least in part by acting as a brake on MMP9, a potentially harmful endogenous enzyme. (PMID:30125361)
• integrin alphav regulates VANGL2 protein levels (PMID:30472097)
• Vangl2 promotes the formation of long cytonemes to enable distant Wnt/beta-catenin signaling. (PMID:33824332)
• Functional analysis of germline VANGL2 variants using rescue assays of vangl2 knockout zebrafish. (PMID:37815931)
• Core planar cell polarity genes VANGL1 and VANGL2 in predisposition to congenital vertebral malformations. (PMID:38669183)
• Expression Profiles of ITGA8 and VANGL2 Are Altered in Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). (PMID:39064873)
• Vangl2 suppresses NF-kappaB signaling and ameliorates sepsis by targeting p65 for NDP52-mediated autophagic degradation. (PMID:39269442)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	vangl2	ENSDARG00000027397
mus_musculus	Vangl2	ENSMUSG00000026556
rattus_norvegicus	Vangl2	ENSRNOG00000004889
drosophila_melanogaster	Vang	FBGN0015838
caenorhabditis_elegans		WBGENE00015171

Paralogs (1): VANGL1 (ENSG00000173218)

Protein

Protein identifiers

Vang-like protein 2 — Q9ULK5 (reviewed: Q9ULK5)

Alternative names: Loop-tail protein 1 homolog, Strabismus 1, Van Gogh-like protein 2

All UniProt accessions (2): A0A8Q3SIN7, Q9ULK5

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the control of early morphogenesis and patterning of both axial midline structures and the development of neural plate. Plays a role in the regulation of planar cell polarity, particularly in the orientation of stereociliary bundles in the cochlea. Required for polarization and movement of myocardializing cells in the outflow tract and seems to act via RHOA signaling to regulate this process. Required for cell surface localization of FZD3 and FZD6 in the inner ear.

Subunit / interactions. Homodimer and heterodimer with VANGL1. Interacts through its C-terminal region with the N-terminal half of DVL1, DVL2 and DVL3. The PDZ domain of DVL1, DVL2 and DVL3 is required for the interaction. Also interacts with the PDZ domains of MAGI3, SCRIB/SCRB1 and FZD3. Interacts with PRICKLE3.

Subcellular location. Cell membrane.

Disease relevance. Neural tube defects (NTD) [MIM:182940] Congenital malformations of the central nervous system and adjacent structures related to defective neural tube closure during the first trimester of pregnancy. Failure of neural tube closure can occur at any level of the embryonic axis. Common NTD forms include anencephaly, myelomeningocele and spina bifida, which result from the failure of fusion in the cranial and spinal region of the neural tube. NTDs have a multifactorial etiology encompassing both genetic and environmental components. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the Vang family.

RefSeq proteins (1): NP_065068* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009539	VANGL	Family

Pfam: PF06638

UniProt features (47 total): helix 14, strand 10, turn 6, topological domain 5, transmembrane region 4, compositionally biased region 3, sequence variant 3, chain 1, region of interest 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
6XA6	X-RAY DIFFRACTION	1.95
6XA8	X-RAY DIFFRACTION	2.2
7R2M	X-RAY DIFFRACTION	2.4
6XA7	X-RAY DIFFRACTION	2.5
7R2T	X-RAY DIFFRACTION	2.5
9JKA	ELECTRON MICROSCOPY	2.5
9JK7	ELECTRON MICROSCOPY	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9ULK5-F1	73.58	0.26

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-4086400	PCP/CE pathway
R-HSA-4608870	Asymmetric localization of PCP proteins
R-HSA-9696264	RND3 GTPase cycle
R-HSA-9696270	RND2 GTPase cycle
R-HSA-9696273	RND1 GTPase cycle

MSigDB gene sets: 372 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_APICAL_PROTEIN_LOCALIZATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_SOMATIC_STEM_CELL_POPULATION_MAINTENANCE, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, GOBP_VENTRICULAR_SEPTUM_MORPHOGENESIS, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS, GOBP_EPITHELIAL_TUBE_BRANCHING_INVOLVED_IN_LUNG_MORPHOGENESIS, GOBP_NON_CANONICAL_WNT_SIGNALING_PATHWAY, ATACCTC_MIR202, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN

GO Biological Process (41): establishment of planar polarity (GO:0001736), neural tube closure (GO:0001843), hair follicle development (GO:0001942), heart looping (GO:0001947), membranous septum morphogenesis (GO:0003149), muscular septum morphogenesis (GO:0003150), Rho protein signal transduction (GO:0007266), anterior/posterior pattern specification (GO:0009952), heparan sulfate proteoglycan biosynthetic process (GO:0015012), convergent extension involved in neural plate elongation (GO:0022007), regulation of Wnt signaling pathway (GO:0030111), glomerulus development (GO:0032835), regulation of actin cytoskeleton organization (GO:0032956), somatic stem cell population maintenance (GO:0035019), cell migration involved in kidney development (GO:0035787), post-anal tail morphogenesis (GO:0036342), dopaminergic neuron axon guidance (GO:0036514), serotonergic neuron axon guidance (GO:0036515), wound healing (GO:0042060), apical protein localization (GO:0045176), establishment or maintenance of epithelial cell apical/basal polarity (GO:0045197), somatic stem cell division (GO:0048103), establishment of body hair planar orientation (GO:0048105), digestive tract morphogenesis (GO:0048546), convergent extension involved in axis elongation (GO:0060028), Wnt signaling pathway, planar cell polarity pathway (GO:0060071), inner ear receptor cell stereocilium organization (GO:0060122), orthogonal dichotomous subdivision of terminal units involved in lung branching morphogenesis (GO:0060488), planar dichotomous subdivision of terminal units involved in lung branching morphogenesis (GO:0060489), lateral sprouting involved in lung morphogenesis (GO:0060490), kidney morphogenesis (GO:0060993), cochlea morphogenesis (GO:0090103), regulation of establishment of planar polarity (GO:0090175), establishment of planar polarity involved in neural tube closure (GO:0090177), non-motile cilium assembly (GO:1905515), regulation of synapse pruning (GO:1905806), multicellular organism development (GO:0007275), non-canonical Wnt signaling pathway (GO:0035567), convergent extension involved in organogenesis (GO:0060029), inner ear receptor cell development (GO:0060119)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (13): stress fiber (GO:0001725), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), lateral plasma membrane (GO:0016328), COPII-coated ER to Golgi transport vesicle (GO:0030134), cell pole (GO:0060187), apical cytoplasm (GO:0090651), postsynaptic density membrane (GO:0098839), glutamatergic synapse (GO:0098978), membrane (GO:0016020), cell periphery (GO:0071944)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
RHO GTPase cycle	3
Beta-catenin independent WNT signaling	1
PCP/CE pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
anatomical structure development	2
anatomical structure morphogenesis	2
ventricular septum morphogenesis	2
axon guidance	2
plasma membrane region	2
apical part of cell	2
morphogenesis of a polarized epithelium	1
establishment of tissue polarity	1
primary neural tube formation	1
tube closure	1
hair cycle process	1
skin epidermis development	1
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
muscle tissue morphogenesis	1
small GTPase-mediated signal transduction	1
regionalization	1
proteoglycan biosynthetic process	1
heparan sulfate proteoglycan metabolic process	1
protein O-linked glycosylation via xylose	1
neural plate elongation	1
convergent extension involved in gastrulation	1
convergent extension involved in organogenesis	1
regulation of signal transduction	1
Wnt signaling pathway	1
nephron development	1
actin cytoskeleton organization	1
regulation of actin filament-based process	1
regulation of cytoskeleton organization	1
stem cell population maintenance	1
kidney development	1
cell migration	1
response to wounding	1
tissue regeneration	1
intracellular protein localization	1
binding	1
actomyosin	1
contractile actin filament bundle	1
membrane	1

Protein interactions and networks

STRING

1334 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VANGL2	PRICKLE1	Q96MT3	980
VANGL2	DVL1	O14640	976
VANGL2	CELSR1	Q9NYQ6	972
VANGL2	PRICKLE2	Q7Z3G6	971
VANGL2	FZD6	O60353	966
VANGL2	PRICKLE3	O43900	966
VANGL2	SCRIB	Q14160	963
VANGL2	PRICKLE4	Q2TBC4	960
VANGL2	DVL2	O14641	901
VANGL2	FZD3	Q9NPG1	892
VANGL2	PTK7	Q13308	887
VANGL2	DVL3	Q92997	871
VANGL2	WNT5A	P41221	867
VANGL2	DACT1	Q9NYF0	866
VANGL2	FAT4	Q6V0I7	864

IntAct

128 interactions, top by confidence:

A	B	Type	Score
PTPN3	MCC	psi-mi:“MI:0914”(association)	0.660
GPR156	PLD2	psi-mi:“MI:0914”(association)	0.640
PNN	CASC3	psi-mi:“MI:0914”(association)	0.640
TMEM9B	DNAJC13	psi-mi:“MI:0914”(association)	0.640
SDC2	PDPK1	psi-mi:“MI:0914”(association)	0.640
VANGL2	HSPA8	psi-mi:“MI:0915”(physical association)	0.560
VANGL2	HSPA8	psi-mi:“MI:0914”(association)	0.560
KCNA5	TMEM223	psi-mi:“MI:0914”(association)	0.530
MANSC1	KLRG2	psi-mi:“MI:0914”(association)	0.530
SPINT2	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
ZNRF4	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
KCNS3	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
DVL3	DVL2	psi-mi:“MI:0914”(association)	0.530
NT5E	SCAMP1	psi-mi:“MI:0914”(association)	0.530
SV2C	EXTL3	psi-mi:“MI:0914”(association)	0.530
KBTBD7	PLD2	psi-mi:“MI:0914”(association)	0.530
JPH4	ZSWIM8	psi-mi:“MI:0914”(association)	0.530
IL20RA	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
EPB41L1	AP3B1	psi-mi:“MI:0914”(association)	0.530
EPB41L3	AP3B1	psi-mi:“MI:0914”(association)	0.530
DVL2	WWP2	psi-mi:“MI:0914”(association)	0.530

BioGRID (301): VANGL2 (Affinity Capture-MS), VANGL2 (Affinity Capture-MS), VANGL2 (Affinity Capture-MS), VANGL2 (Affinity Capture-MS), VANGL2 (Affinity Capture-MS), VANGL2 (Affinity Capture-MS), VANGL2 (Affinity Capture-MS), VANGL2 (Affinity Capture-MS), VANGL2 (Proximity Label-MS), VANGL2 (Proximity Label-MS), VANGL1 (Affinity Capture-MS), SQSTM1 (Affinity Capture-MS), SQSTM1 (Affinity Capture-Western), VANGL2 (Reconstituted Complex), MAPK8 (Affinity Capture-Western)

ESM2 similar proteins: A0A1B0GQX3, A0A1B0GRQ0, A0A1B0GVT2, A0A590UK83, A4QNL6, A5D7B5, A6H770, B3DHH5, E1BAR0, O75324, P0DKX4, P35803, P56695, P58511, P61807, P61808, P84889, Q12016, Q15053, Q17Q87, Q28793, Q2TZ20, Q3MHM8, Q4V786, Q4V921, Q4VBG5, Q56JY4, Q5RBD8, Q5U2S1, Q68FV2, Q6DGP4, Q6GLN5, Q758B5, Q80Z96, Q80ZU4, Q876Z1, Q8BH07, Q8BT42, Q8GUM4, Q8R0W6

Diamond homologs: P84889, Q4VBG5, Q80Z96, Q8TAA9, Q8UVJ6, Q90X64, Q90Z05, Q91ZD4, Q9ULK5

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CHKA	“down-regulates activity”	VANGL2	phosphorylation
ROR2	“down-regulates activity”	VANGL2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 152 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
SHC-mediated cascade:FGFR4	5	27.8×	3e-04
FRS-mediated FGFR4 signaling	5	25.3×	3e-04
RAF/MAP kinase cascade	8	5.0×	5e-03
SARS-CoV Infections	8	4.5×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	55
Likely benign	5
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

1280 predictions. Top by Δscore:

Variant	Effect	Δscore
1:160400865:GGCGG:G	donor_gain	1.0000
1:160400866:GCGG:G	donor_gain	1.0000
1:160400866:GCGGG:G	donor_gain	1.0000
1:160400867:CGGG:C	donor_loss	1.0000
1:160400868:GG:G	donor_gain	1.0000
1:160400869:GG:G	donor_gain	1.0000
1:160400870:G:GG	donor_gain	1.0000
1:160400870:GTGA:G	donor_loss	1.0000
1:160400871:T:A	donor_loss	1.0000
1:160415647:GGAGC:G	acceptor_gain	1.0000
1:160415905:ACAG:A	donor_loss	1.0000
1:160415906:CAG:C	donor_loss	1.0000
1:160415908:GGTG:G	donor_loss	1.0000
1:160416046:T:A	acceptor_gain	1.0000
1:160416047:G:A	acceptor_gain	1.0000
1:160416179:GCGG:G	donor_gain	1.0000
1:160418972:A:AG	acceptor_gain	1.0000
1:160418972:ATTGT:A	acceptor_gain	1.0000
1:160418976:T:TA	acceptor_gain	1.0000
1:160418978:T:TA	acceptor_gain	1.0000
1:160418982:T:TA	acceptor_gain	1.0000
1:160418999:TAG:T	acceptor_loss	1.0000
1:160419000:AG:A	acceptor_gain	1.0000
1:160419001:G:GT	acceptor_gain	1.0000
1:160419001:GG:G	acceptor_gain	1.0000
1:160419001:GGAT:G	acceptor_gain	1.0000
1:160419609:GGTA:G	donor_loss	1.0000
1:160419610:GT:G	donor_loss	1.0000
1:160420408:C:G	acceptor_gain	1.0000
1:160420409:A:AG	acceptor_gain	1.0000

AlphaMissense

3372 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:160419011:T:A	W68R	1.000
1:160419011:T:C	W68R	1.000
1:160419013:G:C	W68C	1.000
1:160419013:G:T	W68C	1.000
1:160419027:C:T	T73I	1.000
1:160419563:C:A	R252S	1.000
1:160419576:G:A	G256D	1.000
1:160419576:G:T	G256V	1.000
1:160420458:T:C	F283S	1.000
1:160421150:G:C	A346P	1.000
1:160421174:A:G	K354E	1.000
1:160421175:A:T	K354M	1.000
1:160421176:G:C	K354N	1.000
1:160421176:G:T	K354N	1.000
1:160421178:G:C	R355T	1.000
1:160421178:G:T	R355M	1.000
1:160421179:G:C	R355S	1.000
1:160421179:G:T	R355S	1.000
1:160421184:C:A	A357D	1.000
1:160421187:G:C	R358T	1.000
1:160421187:G:T	R358M	1.000
1:160424052:G:C	R358S	1.000
1:160424052:G:T	R358S	1.000
1:160424054:T:A	L359H	1.000
1:160424054:T:C	L359P	1.000
1:160424062:G:C	A362P	1.000
1:160424074:G:C	A366P	1.000
1:160424075:C:A	A366D	1.000
1:160424077:T:C	F367L	1.000
1:160424078:T:C	F367S	1.000

dbSNP variants (sampled 300 via entrez): RS1000083348 (1:160425919 A>G,T), RS1000087397 (1:160398760 C>G), RS1000338332 (1:160405307 G>A), RS1000343913 (1:160422877 G>T), RS1000816445 (1:160402000 C>T), RS1000951180 (1:160411921 G>T), RS1000955851 (1:160419639 G>GA), RS1001067083 (1:160411418 C>T), RS1001133861 (1:160400430 G>A), RS1001193620 (1:160427909 A>G), RS1001245243 (1:160418370 T>C), RS1001344546 (1:160421531 G>A), RS1001417911 (1:160403496 G>A), RS1001459139 (1:160421100 C>A,T), RS1001535717 (1:160409604 C>G,T)

Disease associations

OMIM: gene MIM:600533 | disease phenotypes: MIM:182940

GenCC curated gene-disease

Disease	Classification	Inheritance
neural tube defects, susceptibility to	Moderate	Autosomal dominant

Mondo (2): neural tube defect (MONDO:0018075), neural tube defects, susceptibility to (MONDO:0020705)

Orphanet (2): Neural tube defect (Orphanet:3388), Spina bifida and other spinal dysraphisms (Orphanet:823)

HPO phenotypes

33 total (30 of 33 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000020	Urinary incontinence
HP:0000238	Hydrocephalus
HP:0000369	Low-set ears
HP:0000520	Proptosis
HP:0000776	Congenital diaphragmatic hernia
HP:0000835	Adrenal hypoplasia
HP:0000929	Abnormal skull morphology
HP:0000960	Sacral dimple
HP:0001012	Multiple lipomas
HP:0001274	Agenesis of corpus callosum
HP:0001360	Holoprosencephaly
HP:0001511	Intrauterine growth retardation
HP:0001539	Omphalocele
HP:0001561	Polyhydramnios
HP:0002323	Anencephaly
HP:0002475	Myelomeningocele
HP:0002683	Abnormal calvaria morphology
HP:0003298	Spina bifida occulta
HP:0005280	Depressed nasal bridge
HP:0005466	Hypoplasia of the frontal bone
HP:0007360	Aplasia/Hypoplasia of the cerebellum
HP:0008482	Asymmetry of spinal facet joints
HP:0009800	Maternal diabetes
HP:0010305	Absence of the sacrum
HP:0010516	Thymus hyperplasia
HP:0010627	Anterior pituitary hypoplasia
HP:0011756	Posterior pituitary agenesis
HP:0011821	Abnormal facial skeleton morphology
HP:0012032	Lipoma

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST000477_15	Cognitive performance	2.000000e-06
GCST005531_85	Multiple sclerosis	5.000000e-06
GCST005752_174	Systemic lupus erythematosus	4.000000e-06
GCST009597_103	Multiple sclerosis	4.000000e-14
GCST010697_45	Cortical surface area (min-P)	3.000000e-15
GCST010698_9	Subcortical volume (min-P)	3.000000e-09
GCST010699_50	Brain morphology (min-P)	3.000000e-08
GCST010700_20	Cortical thickness (MOSTest)	6.000000e-11
GCST010701_15	Cortical surface area (MOSTest)	4.000000e-08
GCST010702_125	Subcortical volume (MOSTest)	3.000000e-09
GCST010703_15	Brain morphology (MOSTest)	1.000000e-09
GCST90013421_1	Left-handedness	5.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0003926	neuropsychological test
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0009902	handedness

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009436	Neural Tube Defects	C10.500.680; C16.131.666.680

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases methylation	4
Tobacco Smoke Pollution	decreases expression	3
Benzo(a)pyrene	affects methylation	2
propionaldehyde	increases expression	1
sodium arsenite	increases expression, affects cotreatment, increases abundance	1
tobacco tar	decreases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
aflatoxin B2	increases methylation	1
nickel sulfate	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
LDN 193189	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	decreases expression	1
Aerosols	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	increases expression, affects cotreatment, increases abundance	1
Cadmium	decreases expression	1
Camptothecin	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Endosulfan	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Fluorouracil	affects reaction, decreases expression	1
Formaldehyde	increases expression	1
Lead	affects expression	1
Manganese	increases abundance, increases expression, affects cotreatment	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00301587	PHASE3	WITHDRAWN	A Study to Evaluate Folate Levels in Women Taking Oral Contraceptives
NCT00468481	PHASE3	COMPLETED	Efficacy and Safety Study for an Oral Contraceptive Containing Folate
NCT01392989	PHASE2	COMPLETED	Post T-plant Infusion of Allogeneic Cytokine Induced Killer (CIK) Cells as Consolidative Therapy in Myelodysplastic Syndromes/Myeloproliferative Disorders
NCT00452829	PHASE1	COMPLETED	Prevention of Neural Tube Defects by Inositol in Conjunction With Folic Acid (PONTI Study)
NCT03794011	PHASE1	ACTIVE_NOT_RECRUITING	Patch vs. No Patch Fetoscopic Meningomyelocele Repair Study
NCT02230072	PHASE1	COMPLETED	Fetoscopic Meningomyelocele Repair Study
NCT00341068	Not specified	TERMINATED	Genetic Analysis of Neural Tube and Orofacial Cleft Defects in the Irish Population
NCT00394862	Not specified	COMPLETED	Efficacy of Weekly Versus Daily Folic Acid Supplementation
NCT01244399	Not specified	COMPLETED	Influence of Espresso on Adsorption of Myo-inositol
NCT01253746	Not specified	UNKNOWN	Genetics of Neural Tube Defects
NCT01743196	Not specified	COMPLETED	Folate Metabolism in Normal Weight and Obese Women of Child-bearing Age
NCT03090633	Not specified	ACTIVE_NOT_RECRUITING	Fetoscopic Repair of Isolated Fetal Spina Bifida
NCT03315637	Not specified	UNKNOWN	Fetal Endoscopic Surgery for Spina Bifida
NCT03856034	Not specified	RECRUITING	Laparotomy Versus Percutaneous Endoscopic Correction of Myelomeningocele
NCT03936322	Not specified	COMPLETED	Minimally Invasive Fetoscopic Regenerative Repair of Spina Bifida - A Pilot Study
NCT04135274	Not specified	COMPLETED	Is Neutrophil to Lymphocyte Ratio a Prognostic Factor of Sepsis in Newborns With Operated Neural Tube Defects?
NCT04140669	Not specified	TERMINATED	Automated Myocardial Performance Index Using Samsung HERA W10
NCT04362592	Not specified	ACTIVE_NOT_RECRUITING	In-Utero Endoscopic Correction of Spina Bifida
NCT04523233	Not specified	UNKNOWN	Metals/Vitamins Levels in NTD
NCT04760509	Not specified	UNKNOWN	Short- Term Follow up Of Neonates Born With Neural Tube Defect
NCT04770805	Not specified	ACTIVE_NOT_RECRUITING	In Utero Fetoscopic Repair Program for Sacral Myelomeningoceles and Mye-LDM
NCT05454085	Not specified	COMPLETED	Could Bisphenol-A Have a Role in the Etiology of Neural Tube Defects
NCT05672849	Not specified	RECRUITING	Safety and Efficacy of Devices Used in Fetoscopic Neural Tube Defect Repair Cases
NCT05883761	Not specified	COMPLETED	Birth Outcomes In Eswatini After Transition To Dolutegravir-Based Treatment
NCT05935631	Not specified	COMPLETED	Feasibility, Acceptability and Directional Signal Effect on Blood Folate Levels of Iodized Salt Fortified With Folic Acid: Clinical Study
NCT06135883	Not specified	COMPLETED	Assessing Folic Acid in High-Risk Pregnancy for Neural Tube Defects
NCT06174883	Not specified	COMPLETED	Salt-FA to Increase Folate Levels
NCT06734611	Not specified	NOT_YET_RECRUITING	Folic Acid Salt Study (FISFA Zambia)
NCT06904612	Not specified	COMPLETED	Using Iodized Salt to Improve Serum Folate, B12 and Iron Levels
NCT06946563	Not specified	RECRUITING	Fetoscopic Neural Tube Defect Repair
NCT00060606	Not specified	COMPLETED	Management of Myelomeningocele Study (MOMS)
NCT00966927	Not specified	ACTIVE_NOT_RECRUITING	Assessment of Functional Independence and Quality of Life in Adolescents With Spina Bifid
NCT00975338	Not specified	COMPLETED	The LETS Study: A Longitudinal Evaluation of Transition Services
NCT02592291	Not specified	RECRUITING	Mobile Health Self-Management and Support System for Chronic and Complex Health Conditions
NCT03044821	Not specified	TERMINATED	Open Myelomeningocele Repair With High Maternal BMI
NCT03544970	Not specified	COMPLETED	An Audit of the Posterior Fossa Characterization in Open Spina Bifida Based on Tertiary Center Experience
NCT04763382	Not specified	UNKNOWN	The Effect of Nursing Interventions for Clean Intermittent Catheterization Caregivers and Child
NCT05718440	Not specified	RECRUITING	Uronephrological Complications Risk Factors in Spinal Dysraphism
NCT05962086	Not specified	UNKNOWN	Determining Developmental and Clinical Markers Affecting Urinary Function of Children With Spinal Dysraphism
NCT06907732	Not specified	NOT_YET_RECRUITING	Fetoscopic Robotic Open Spina Bifida Treatment