PLXND1

Summary

PLXND1 (plexin D1, HGNC:9107) is a protein-coding gene on chromosome 3q22.1, encoding Plexin-D1 (Q9Y4D7). Cell surface receptor for SEMA4A and for class 3 semaphorins, such as SEMA3A, SEMA3C and SEMA3E.

Enables protein domain specific binding activity. Predicted to be involved in several processes, including positive regulation of axonogenesis; semaphorin-plexin signaling pathway; and synapse assembly. Predicted to act upstream of or within circulatory system development; dichotomous subdivision of terminal units involved in salivary gland branching; and kidney development. Located in lamellipodium.

Source: NCBI Gene 23129 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital heart defects, multiple types, 9 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 102
• Clinical variants (ClinVar): 464 total — 4 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 95
• MANE Select transcript: NM_015103

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9107
Approved symbol	PLXND1
Name	plexin D1
Location	3q22.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0620
Ensembl gene	ENSG00000004399
Ensembl biotype	protein_coding
OMIM	604282
Entrez	23129

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 11 retained_intron, 5 protein_coding, 2 nonsense_mediated_decay

ENST00000324093, ENST00000501038, ENST00000503166, ENST00000504524, ENST00000504689, ENST00000504767, ENST00000504979, ENST00000505237, ENST00000505505, ENST00000505665, ENST00000506979, ENST00000508630, ENST00000511018, ENST00000512744, ENST00000512807, ENST00000514990, ENST00000515191, ENST00000891948

RefSeq mRNA: 1 — MANE Select: NM_015103 NM_015103

CCDS: CCDS33854

Canonical transcript exons

ENST00000324093 — 36 exons

Exon	Start	End
ENSE00000379072	129589351	129589527
ENSE00000379080	129573594	129573745
ENSE00000777765	129586588	129586719
ENSE00000777766	129586172	129586272
ENSE00000777768	129585952	129586081
ENSE00000777770	129584385	129584562
ENSE00000777774	129583567	129583669
ENSE00000777804	129569843	129569957
ENSE00000777833	129566527	129566631
ENSE00000885766	129572609	129572748
ENSE00001079611	129565887	129566017
ENSE00001152030	129560689	129560723
ENSE00001152038	129561646	129561709
ENSE00001152044	129561800	129561903
ENSE00001152051	129562787	129562943
ENSE00001293726	129605329	129606676
ENSE00001295656	129572842	129572941
ENSE00001299110	129567698	129567805
ENSE00001317925	129578329	129578433
ENSE00001322762	129567492	129567604
ENSE00003462504	129565340	129565538
ENSE00003468056	129575469	129575562
ENSE00003516656	129571040	129571303
ENSE00003562524	129571677	129571844
ENSE00003582576	129559620	129559783
ENSE00003583733	129574336	129574490
ENSE00003613154	129560330	129560434
ENSE00003620966	129555214	129556428
ENSE00003635892	129557083	129557223
ENSE00003644289	129570786	129570935
ENSE00003648132	129584125	129584233
ENSE00003661334	129563094	129563240
ENSE00003674388	129575766	129575855
ENSE00003678630	129571509	129571599
ENSE00003686861	129558428	129558575
ENSE00003790172	129556617	129556691

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 98.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 42.2699 / max 429.7904, expressed in 1733 samples.

FANTOM5 promoters (15 alternative TSS)

Promoter ID	TPM avg	Samples expressed
44542	33.9785	1697
44541	1.3258	585
44543	1.3091	697
44532	0.9036	427
44530	0.8172	226
44533	0.7759	389
44535	0.6843	345
44545	0.5434	322
44536	0.4877	75
44544	0.3807	209

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper lobe of left lung	UBERON:0008952	98.60	gold quality
right coronary artery	UBERON:0001625	98.55	gold quality
right lung	UBERON:0002167	98.51	gold quality
tibial nerve	UBERON:0001323	98.44	gold quality
omental fat pad	UBERON:0010414	98.39	gold quality
endocervix	UBERON:0000458	98.35	gold quality
peritoneum	UBERON:0002358	98.33	gold quality
apex of heart	UBERON:0002098	98.29	gold quality
upper lobe of lung	UBERON:0008948	98.26	gold quality
adipose tissue of abdominal region	UBERON:0007808	98.08	gold quality
body of uterus	UBERON:0009853	98.02	gold quality
left uterine tube	UBERON:0001303	97.98	gold quality
gall bladder	UBERON:0002110	97.95	gold quality
left coronary artery	UBERON:0001626	97.86	gold quality
metanephros cortex	UBERON:0010533	97.84	gold quality
right lobe of thyroid gland	UBERON:0001119	97.68	gold quality
coronary artery	UBERON:0001621	97.68	gold quality
sural nerve	UBERON:0015488	97.50	gold quality
granulocyte	CL:0000094	97.43	gold quality
descending thoracic aorta	UBERON:0002345	97.37	gold quality
subcutaneous adipose tissue	UBERON:0002190	97.30	gold quality
stromal cell of endometrium	CL:0002255	97.19	gold quality
ascending aorta	UBERON:0001496	97.09	gold quality
thoracic aorta	UBERON:0001515	97.09	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.08	gold quality
left lobe of thyroid gland	UBERON:0001120	97.06	gold quality
ectocervix	UBERON:0012249	97.02	gold quality
right atrium auricular region	UBERON:0006631	96.96	gold quality
spleen	UBERON:0002106	96.85	gold quality
aorta	UBERON:0000947	96.81	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-135922	yes	23.75
E-MTAB-8271	yes	16.01
E-ANND-3	yes	13.62
E-MTAB-7381	no	511.69
E-CURD-112	no	3.32

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

66 targeting PLXND1, 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-340-5P	100.00	72.50	4437
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-186-5P	99.99	70.83	3707
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
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-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-4728-5P	99.85	69.39	4718

Literature-anchored findings (GeneRIF, showing 30)

• Results of extensive mutational analysis leads to the exclusion of the PLEXIN-D1 gene as the causative gene in Mobius syndrome 2, and in isolated Mobius syndrome. (PMID:15301830)
• These results show that PLXND1 expression during tumor development is strongly correlated with both invasive behavior and metastasis, but exclude Sema3E as an activating ligand. (PMID:18974298)
• Plexin D1 is abundantly expressed on tumor vasculature and malignant cells in the primary and metastatic tumors. (PMID:19703316)
• Sema3E acts on plexin D1 to initiate a two-pronged mechanism involving R-Ras inactivation and Arf6 stimulation, which affect the status of activation of integrins and their intracellular trafficking, respectively. (PMID:20385769)
• Semaphorin 3E-Plexin D1 signaling in cancer cells is crucially implicated in their metastatic behavior and may therefore be a promising target for strategies aimed at blocking tumor metastasis. (PMID:20664171)
• Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice (PMID:21505259)
• analysis of Sema3E/plexin-D1 mediated epithelial-to-mesenchymal transition in ovarian endometrioid cancer (PMID:21559368)
• a novel phospholipid-regulated antiangiogenic signaling pathway whereby Sema3E activates Arf6 through Plexin-D1 and consequently controls integrin-mediated endothelial cell attachment to the extracellular matrix and migration. (PMID:21795701)
• Strong expression of plexD1 was detected in endothelial cells of cervical cancer samples, yet no expression was seen in endothelial cells of normal cervical tissues, which suggests a potential role of PlexD1 in cervical cancer-associated angiogenesis (PMID:22738647)
• A critical role of Sema3E/Plexin D1 interaction in tumor resistance to apoptosis. (PMID:24139859)
• It is therefore suggested that SEMA3C signaling, propagated through the heterodimer receptor plexin-D1/neuropilin, is important for truncus arteriosus septation (PMID:24254849)
• The identification and characterization of SH3BP1 as a novel downstream effector of Sema3E-PlexinD1 provides an explanation for how extracellular signals are translated into cytoskeletal changes and unique cell behavior. (PMID:24841563)
• Plxnd1 is a novel regulator of VAT growth, body fat distribution, and insulin sensitivity in both zebrafish and humans (PMID:25831505)
• The data indicate that Plexin-D1 operates in a cell context-specific fashion, mediating different synaptogenic outcomes depending upon neuron type. (PMID:25976775)
• finding that PLXND1 and REV3L mutations are responsible for a proportion of MBS patients suggests that de novo mutations in other genes might account for other MBS patients (PMID:26068067)
• Findings suggest that Plexin-D1/class III semaphorin (Sema3E) axis is triggered in systemic sclerosis (SSc) endothelium. (PMID:26292963)
• Plexin D1 plays a role in collagen contraction in human lung fibroblasts. (PMID:26648031)
• Measuring electrical impedance allows real-time monitoring of changes in endothelial cell morphology and adhesion induced by SEMA3E via plexin D1 (PMID:27787852)
• the receptor Plexin-D1 contains a sorting motif that interacts with the adaptor protein GIPC1 to facilitate transport to recycling endosomes. (PMID:28224988)
• SNPs associated with type 2 diabetes and obesity may also increase the risk of developing gestational diabetes mellitus (GDM) in the Chinese population. Among these SNPs, we report for the first time that rs945508 in ARHGEF11, rs10804591 in PLXND1 and rs10245353 in NFE2L3 were associated with GDM. (PMID:28554271)
• Authors found that the PlexinD1 cleavage product binds to actin rods, pathological aggregate-like structures which had so far been described for age-related neurodegenerative diseases. Data suggest a novel disease mechanism for SMA involving formation of actin rods as a molecular sink for a cleaved PlexinD1 fragment leading to dysregulation of receptor signaling. (PMID:29016853)
• In the absence of neuropilins, plexin-A4 formed complexes with plexin-D1, and was required in addition to plexin-D1 to enable Sema3C-induced signal transduction. (PMID:29661844)
• Anti-plexin D1 antibodies are a novel biomarker for immunotherapy-responsive neuropathic pain. (PMID:30014510)
• The role of Plexin D1 in tumor development and progression is thereby garnering research interest for its potential as a biomarker and as a therapeutic target. (PMID:31152824)
• Semaphorin4A-Plexin D1 Axis Induces Th2 and Th17 While Represses Th1 Skewing in an Autocrine Manner. (PMID:32971928)
• Identification of plexin D1 on circulating extracellular vesicles as a potential biomarker of polymyositis and dermatomyositis. (PMID:34297034)
• Association of PLXND1 with a novel subtype of anomalous pulmonary venous return. (PMID:34791216)
• Biallelic alterations in PLXND1 cause common arterial trunk and other cardiac malformations in humans. (PMID:35396997)
• PLXND1/SEMA3E Promotes Epithelial-Mesenchymal Transition Partly via the PI3K/AKT-Signaling Pathway and Induces Heterogenity in Colorectal Cancer. (PMID:35917012)
• Downregulation of circ_PLXND1 inhibits tumorigenesis of non-small cell lung carcinoma via miR-1287-5p/ERBB3 axis. (PMID:37073425)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
mus_musculus	Plxnd1	ENSMUSG00000030123
rattus_norvegicus	Plxnd1	ENSRNOG00000025209
drosophila_melanogaster	PlexB	FBGN0025740
drosophila_melanogaster	PlexA	FBGN0025741
caenorhabditis_elegans		WBGENE00004047
caenorhabditis_elegans		WBGENE00004048

Paralogs (8): PLXNA2 (ENSG00000076356), PLXNA1 (ENSG00000114554), PLXNA3 (ENSG00000130827), PLXNC1 (ENSG00000136040), PLXNB1 (ENSG00000164050), PLXNB2 (ENSG00000196576), PLXNB3 (ENSG00000198753), PLXNA4 (ENSG00000221866)

Protein

Protein identifiers

Plexin-D1 — Q9Y4D7 (reviewed: Q9Y4D7)

All UniProt accessions (6): Q9Y4D7, D6RH25, H0Y9D1, H0YA64, H0YAB2, H0YAM9

UniProt curated annotations — full annotation on UniProt →

Function. Cell surface receptor for SEMA4A and for class 3 semaphorins, such as SEMA3A, SEMA3C and SEMA3E. Plays an important role in cell-cell signaling, and in regulating the migration of a wide spectrum of cell types. Regulates the migration of thymocytes in the medulla. Regulates endothelial cell migration. Plays an important role in ensuring the specificity of synapse formation. Required for normal development of the heart and vasculature. Mediates anti-angiogenic signaling in response to SEMA3E.

Subunit / interactions. Interacts with NRP1 and SEMA4A. Interacts with SH3BP1; they dissociate upon SEMA3E binding to PLXND1 allowing SH3BP1 to transduce downstream signal through RAC1 inactivation.

Subcellular location. Cell membrane. Cell projection. Lamellipodium membrane.

Tissue specificity. Detected at low levels in heart, placenta, lung, skeletal muscle, kidney, thymus and liver. Detected at very low levels in brain, colon, spleen, small intestine and peripheral blood leukocytes.

Disease relevance. Congenital heart defects, multiple types, 9 (CHTD9) [MIM:620294] An autosomal recessive disorder characterized by congenital developmental abnormalities involving structures of the heart. CHTD9 features include common arterial trunk, tetralogy of Fallot, interrupted aortic arch, right aortic arch, ventricular hypoplasia, and hypoplastic left heart, as well as other vascular and valvular anomalies. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the plexin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y4D7-1	1	yes
Q9Y4D7-2	2

RefSeq proteins (1): NP_055918* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001627	Semap_dom	Domain
IPR002165	Plexin_repeat	Repeat
IPR002909	IPT_dom	Domain
IPR008936	Rho_GTPase_activation_prot	Homologous_superfamily
IPR013548	Plexin_cytoplasmic_RasGAP_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR014756	Ig_E-set	Homologous_superfamily
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR016201	PSI	Domain
IPR031148	Plexin	Family
IPR036352	Semap_dom_sf	Homologous_superfamily
IPR041019	TIG1_plexin	Domain
IPR042719	Plexin-D1_Sema	Domain
IPR046800	Plexin_RBD	Domain

Pfam: PF01403, PF01437, PF01833, PF08337, PF17960, PF20170

UniProt features (60 total): glycosylation site 18, disulfide bond 9, sequence variant 9, strand 7, domain 4, helix 3, topological domain 2, signal peptide 1, chain 1, compositionally biased region 1, transmembrane region 1, splice variant 1, sequence conflict 1, turn 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3H6N	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y4D7-F1	80.28	0.25

Functional residue map

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

Disulfide bonds (9): 104–114, 140–148, 322–445, 345–389, 549–566, 555–600, 558–575, 569–581, 637–661

Glycosylation sites (18): 86, 155, 188, 224, 481, 500, 583, 696, 736, 802, 965, 1017, 1060, 1099, 1118, 1132, 1237, 1257

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-416700	Other semaphorin interactions
R-HSA-9013508	NOTCH3 Intracellular Domain Regulates Transcription
R-HSA-9696270	RND2 GTPase cycle

MSigDB gene sets: 590 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, VERHAAK_AML_WITH_NPM1_MUTATED_DN, REACTOME_SIGNALING_BY_NOTCH, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEURON_RECOGNITION, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, GOBP_GLAND_MORPHOGENESIS, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_CORONARY_VASCULATURE_DEVELOPMENT, GOBP_SYNAPSE_ASSEMBLY, GOBP_SALIVARY_GLAND_DEVELOPMENT, REACTOME_OTHER_SEMAPHORIN_INTERACTIONS, GOBP_NEUROGENESIS

GO Biological Process (18): angiogenesis (GO:0001525), branching involved in blood vessel morphogenesis (GO:0001569), kidney development (GO:0001822), outflow tract morphogenesis (GO:0003151), cardiac septum development (GO:0003279), negative regulation of cell adhesion (GO:0007162), synapse assembly (GO:0007416), synaptic target recognition (GO:0008039), regulation of cell shape (GO:0008360), regulation of cell migration (GO:0030334), aorta development (GO:0035904), negative regulation of neuron apoptotic process (GO:0043524), endothelial cell migration (GO:0043542), regulation of angiogenesis (GO:0045765), positive regulation of axonogenesis (GO:0050772), dichotomous subdivision of terminal units involved in salivary gland branching (GO:0060666), coronary vasculature development (GO:0060976), semaphorin-plexin signaling pathway (GO:0071526)

GO Molecular Function (3): semaphorin receptor activity (GO:0017154), protein domain specific binding (GO:0019904), protein binding (GO:0005515)

GO Cellular Component (10): semaphorin receptor complex (GO:0002116), plasma membrane (GO:0005886), lamellipodium (GO:0030027), axon (GO:0030424), lamellipodium membrane (GO:0031258), cell body (GO:0044297), glutamatergic synapse (GO:0098978), membrane (GO:0016020), cell projection (GO:0042995), plasma membrane bounded cell projection (GO:0120025)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Semaphorin interactions	1
Signaling by NOTCH3	1
RHO GTPase cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
blood vessel morphogenesis	2
angiogenesis	2
cell migration	2
anatomical structure formation involved in morphogenesis	1
branching morphogenesis of an epithelial tube	1
animal organ development	1
renal system development	1
heart morphogenesis	1
anatomical structure morphogenesis	1
cardiac chamber development	1
anatomical structure development	1
cell adhesion	1
regulation of cell adhesion	1
negative regulation of cellular process	1
nervous system development	1
cell junction assembly	1
synapse organization	1
neuron recognition	1
regulation of cell morphogenesis	1
regulation of biological quality	1
regulation of cell motility	1
artery development	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
regulation of anatomical structure morphogenesis	1
regulation of vasculature development	1
axonogenesis	1
positive regulation of cell projection organization	1
positive regulation of neurogenesis	1
regulation of axonogenesis	1
branching involved in salivary gland morphogenesis	1
dichotomous subdivision of an epithelial terminal unit	1
blood vessel development	1
heart development	1
cell surface receptor signaling pathway	1
transmembrane signaling receptor activity	1
semaphorin-plexin signaling pathway	1
protein binding	1

Protein interactions and networks

STRING

1382 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLXND1	SEMA3E	O15041	999
PLXND1	SEMA3C	Q99985	987
PLXND1	NRP1	O14786	949
PLXND1	SEMA4A	Q9H3S1	937
PLXND1	SEMA3A	Q14563	936
PLXND1	KDR	P35968	914
PLXND1	NRP2	O60462	880
PLXND1	TMCC1	O94876	845
PLXND1	CFAP100	Q494V2	831
PLXND1	PODXL2	Q9NZ53	828
PLXND1	SEMA6A	Q9H2E6	771
PLXND1	SEMA3D	O95025	769
PLXND1	KLF15	Q9UIH9	767
PLXND1	SEMA4D	Q92854	745
PLXND1	NR4A1	P22736	695

IntAct

38 interactions, top by confidence:

A	B	Type	Score
SEMA4A	PLXND1	psi-mi:“MI:0407”(direct interaction)	0.680
PLXND1	SEMA4A	psi-mi:“MI:0407”(direct interaction)	0.680
GYPA	TCAF2	psi-mi:“MI:0914”(association)	0.640
STX12	SNAP23	psi-mi:“MI:0914”(association)	0.640
HOXB5	PLXND1	psi-mi:“MI:0915”(physical association)	0.560
SEMA3E	PLXND1	psi-mi:“MI:0407”(direct interaction)	0.560
PLXND1	SEMA3E	psi-mi:“MI:0407”(direct interaction)	0.560
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
STX3	NBAS	psi-mi:“MI:0914”(association)	0.530
PLXND1	Sema3e	psi-mi:“MI:0915”(physical association)	0.520
PLXND1	NR4A1	psi-mi:“MI:0915”(physical association)	0.510
PLXND1	H1-4	psi-mi:“MI:0915”(physical association)	0.400
PLXND1	MACF1	psi-mi:“MI:0915”(physical association)	0.370
NS3	C15orf61	psi-mi:“MI:0914”(association)	0.350
	NBAS	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
	TMEM223	psi-mi:“MI:0914”(association)	0.350
C1orf54	AGRN	psi-mi:“MI:0914”(association)	0.350
SFTPC	TMEM131L	psi-mi:“MI:0914”(association)	0.350
PTCH1	TMEM131L	psi-mi:“MI:0914”(association)	0.350
DNASE1L1	QSOX1	psi-mi:“MI:0914”(association)	0.350
ADCY9	TAPBP	psi-mi:“MI:0914”(association)	0.350
CLGN	TMEM131L	psi-mi:“MI:0914”(association)	0.350
EFNB2	TCAF2	psi-mi:“MI:0914”(association)	0.350

BioGRID (34): PLXND1 (Affinity Capture-RNA), PLXND1 (Affinity Capture-MS), PLXND1 (Affinity Capture-RNA), HOXB5 (Two-hybrid), PLXND1 (Affinity Capture-MS), PLXND1 (Affinity Capture-MS), KDR (Affinity Capture-Western), Map6 (Affinity Capture-Western), NRP1 (Affinity Capture-Western), PLXND1 (Affinity Capture-Western), PLXND1 (Proximity Label-MS), PLXND1 (Affinity Capture-MS), PLXND1 (Affinity Capture-MS), PLXND1 (Affinity Capture-MS), PLXND1 (Affinity Capture-MS)

ESM2 similar proteins: A6NE02, A8MY62, C9JR72, D3Z7H8, D3ZU57, O09017, O15197, O19179, O95382, P0C0K6, P10588, P43136, P55203, Q02846, Q08DG4, Q15628, Q2KHV9, Q3U0S6, Q3UH93, Q5BK61, Q5U651, Q5W7P8, Q5ZMM1, Q6ZNJ1, Q6ZQA0, Q6ZVZ8, Q80ZD5, Q86WK7, Q8BH02, Q8BH83, Q8C828, Q8CIG9, Q8IUL8, Q8IYS2, Q8JGM4, Q8K2J9, Q8N239, Q8VHA6, Q91X21, Q96CD0

Diamond homologs: B0S5N4, B2RXS4, D3ZLH5, D3ZPX4, O15031, O43157, O60486, O75051, P51805, P70206, P70207, P70208, Q3UH93, Q6BEA0, Q80UG2, Q8CJH3, Q9HCM2, Q9NTN9, Q9QY40, Q9QZC2, Q9UIW2, Q9ULL4, Q9V4A7, Q9WUH7, Q9Y4D7, Q09YN5, Q80ZA4, Q60519, Q9P283, O42236, Q13591, Q9C0C4, Q62190, Q626H5, Q9H2E6, O95754, Q64151, Q9Z123, Q9Z143, Q90665

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	1
Uncertain significance	283
Likely benign	81
Benign	43

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
2445603	NM_015103.3(PLXND1):c.3895C>T (p.Arg1299Cys)	Pathogenic
2445605	NM_015103.3(PLXND1):c.652A>T (p.Ser218Cys)	Pathogenic
2445606	NM_015103.3(PLXND1):c.2733C>G (p.Ile911Met)	Pathogenic
2445607	NM_015103.3(PLXND1):c.880_881del (p.Gln294fs)	Pathogenic
1206015	NM_015103.3(PLXND1):c.2695_2696del (p.Leu899fs)	Likely pathogenic

SpliceAI

5833 predictions. Top by Δscore:

Variant	Effect	Δscore
3:129556687:TATTT:T	acceptor_gain	1.0000
3:129556688:ATTT:A	acceptor_gain	1.0000
3:129556689:TTT:T	acceptor_gain	1.0000
3:129556690:TT:T	acceptor_gain	1.0000
3:129556691:TC:T	acceptor_loss	1.0000
3:129556692:C:A	acceptor_loss	1.0000
3:129556692:C:CC	acceptor_gain	1.0000
3:129556693:T:C	acceptor_loss	1.0000
3:129556694:A:C	acceptor_gain	1.0000
3:129557077:CCGCA:C	donor_loss	1.0000
3:129557078:CGCA:C	donor_loss	1.0000
3:129557079:GCACC:G	donor_loss	1.0000
3:129557080:CACC:C	donor_loss	1.0000
3:129557081:AC:A	donor_gain	1.0000
3:129557082:C:CA	donor_gain	1.0000
3:129557090:T:TA	donor_gain	1.0000
3:129557091:C:CA	donor_gain	1.0000
3:129557112:T:C	donor_gain	1.0000
3:129557118:G:A	donor_gain	1.0000
3:129557138:T:TA	donor_gain	1.0000
3:129557219:GAATC:G	acceptor_gain	1.0000
3:129557220:AATC:A	acceptor_gain	1.0000
3:129557221:ATC:A	acceptor_gain	1.0000
3:129557222:TC:T	acceptor_gain	1.0000
3:129557223:CC:C	acceptor_gain	1.0000
3:129557223:CCTG:C	acceptor_loss	1.0000
3:129557224:C:CC	acceptor_gain	1.0000
3:129557224:C:T	acceptor_gain	1.0000
3:129557229:C:CT	acceptor_gain	1.0000
3:129557230:A:T	acceptor_gain	1.0000

AlphaMissense

12579 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:129557099:A:G	L1857P	1.000
3:129558546:A:G	L1776P	1.000
3:129558559:A:G	W1772R	1.000
3:129558559:A:T	W1772R	1.000
3:129559633:A:G	W1762R	1.000
3:129559633:A:T	W1762R	1.000
3:129559686:A:G	L1744P	1.000
3:129559766:A:C	F1717L	1.000
3:129559766:A:T	F1717L	1.000
3:129559768:A:G	F1717L	1.000
3:129560340:A:G	L1708P	1.000
3:129560343:A:G	L1707P	1.000
3:129560352:A:G	L1704P	1.000
3:129562789:A:G	L1608P	1.000
3:129565372:A:G	W1497R	1.000
3:129565372:A:T	W1497R	1.000
3:129565380:A:G	L1494P	1.000
3:129565413:A:G	L1483P	1.000
3:129567592:A:G	L1329P	1.000
3:129567600:G:C	F1326L	1.000
3:129567600:G:T	F1326L	1.000
3:129567602:A:G	F1326L	1.000
3:129606197:C:G	C148S	1.000
3:129606197:C:T	C148Y	1.000
3:129606198:A:T	C148S	1.000
3:129606221:C:T	C140Y	1.000
3:129556660:G:T	A1873D	0.999
3:129557195:G:T	A1825D	0.999
3:129557204:A:G	L1822P	0.999
3:129558455:G:C	C1806W	0.999

dbSNP variants (sampled 300 via entrez): RS1000034245 (3:129570496 T>C), RS1000078489 (3:129575866 C>T), RS1000095867 (3:129581131 G>A), RS1000142314 (3:129607773 A>G), RS1000183964 (3:129595320 G>A,T), RS1000300682 (3:129571372 G>A,C), RS1000346225 (3:129601351 G>A), RS1000402923 (3:129565337 C>T), RS1000445183 (3:129607956 T>C), RS1000454136 (3:129600674 C>T), RS1000508576 (3:129596392 G>A), RS1000531301 (3:129580821 G>A), RS1000580839 (3:129591385 A>G), RS1000654034 (3:129590123 C>T), RS1000724870 (3:129566681 G>A)

Disease associations

OMIM: gene MIM:604282 | disease phenotypes: MIM:157900, MIM:148840, MIM:620294

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital heart defects, multiple types, 9	Strong	Autosomal recessive
Mobius syndrome	Strong	Autosomal dominant
persistent truncus arteriosus	Supportive	Autosomal recessive

Mondo (4): Mobius syndrome (MONDO:0008006), Kleine-Levin syndrome (MONDO:0007863), congenital heart defects, multiple types, 9 (MONDO:0859532), persistent truncus arteriosus (MONDO:0018072)

Orphanet (2): Moebius syndrome (Orphanet:570), Kleine-Levin syndrome (Orphanet:33543)

HPO phenotypes

95 total (30 of 95 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000044	Hypogonadotropic hypogonadism
HP:0000175	Cleft palate
HP:0000194	Open mouth
HP:0000218	High palate
HP:0000232	Everted lower lip vermilion
HP:0000286	Epicanthus
HP:0000298	Mask-like facies
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000476	Cystic hygroma
HP:0000486	Strabismus
HP:0000498	Blepharitis
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000602	Ophthalmoplegia
HP:0000691	Microdontia
HP:0000717	Autism
HP:0000767	Pectus excavatum
HP:0000778	Hypoplasia of the thymus
HP:0000849	Adrenocortical abnormality
HP:0000961	Cyanosis
HP:0001156	Brachydactyly
HP:0001252	Hypotonia
HP:0001270	Motor delay
HP:0001511	Intrauterine growth retardation
HP:0001522	Death in infancy
HP:0001608	Abnormality of the voice
HP:0001627	Abnormal heart morphology

GWAS associations

102 associations (top):

Study	Trait	p-value
GCST002782_49	Waist-to-hip ratio adjusted for body mass index	6.000000e-13
GCST002782_50	Waist-to-hip ratio adjusted for body mass index	7.000000e-09
GCST002782_51	Waist-to-hip ratio adjusted for body mass index	5.000000e-11
GCST002782_52	Waist-to-hip ratio adjusted for body mass index	4.000000e-08
GCST004064_30	Waist-hip ratio	2.000000e-07
GCST004064_7	Waist-hip ratio	1.000000e-10
GCST004066_141	Hip circumference	8.000000e-06
GCST004066_77	Hip circumference	2.000000e-08
GCST004067_123	Hip circumference adjusted for BMI	6.000000e-07
GCST004067_205	Hip circumference adjusted for BMI	6.000000e-15
GCST004067_9	Hip circumference adjusted for BMI	7.000000e-18
GCST004505_93	Waist-to-hip ratio adjusted for BMI (adjusted for smoking behaviour)	3.000000e-08
GCST004567_1	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	3.000000e-13
GCST004567_141	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	3.000000e-09
GCST004567_65	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	3.000000e-13
GCST004567_74	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	3.000000e-09
GCST004576_117	Waist-to-hip ratio adjusted for body mass index	6.000000e-10
GCST004576_136	Waist-to-hip ratio adjusted for body mass index	5.000000e-08
GCST004576_137	Waist-to-hip ratio adjusted for body mass index	7.000000e-14
GCST004576_144	Waist-to-hip ratio adjusted for body mass index	1.000000e-15
GCST004578_109	Waist-to-hip ratio adjusted for BMI in active individuals	2.000000e-10
GCST004578_118	Waist-to-hip ratio adjusted for BMI in active individuals	3.000000e-06
GCST004578_20	Waist-to-hip ratio adjusted for BMI in active individuals	2.000000e-10
GCST004578_26	Waist-to-hip ratio adjusted for BMI in active individuals	3.000000e-06
GCST004578_92	Waist-to-hip ratio adjusted for BMI in active individuals	2.000000e-10
GCST005956_82	Waist-to-hip ratio adjusted for BMI	2.000000e-07
GCST005958_5	Waist-to-hip ratio adjusted for BMI (age >50)	4.000000e-10
GCST005959_21	Waist-to-hip ratio adjusted for BMI x sex interaction	3.000000e-08
GCST005962_16	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	2.000000e-11
GCST007483_32	Waist-to-hip ratio adjusted for BMI (additive genetic model)	4.000000e-07

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004343	waist-hip ratio
EFO:0008039	BMI-adjusted hip circumference
EFO:0004318	smoking behavior
EFO:0008002	physical activity measurement
EFO:0008343	sex interaction measurement
EFO:0008007	age at assessment
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D017593	Kleine-Levin Syndrome	C10.886.425.800.200.500; F03.870.400.800.200.500
D020331	Mobius Syndrome	C07.465.299.825; C10.292.319.825; C10.292.562.700.375.750; C11.590.436.400.750; C16.131.077.578; C16.614.595
D014339	Truncus Arteriosus, Persistent	C14.240.400.560.098.500; C14.280.400.560.098.500; C16.131.240.400.560.098.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — Neuropilins and Plexins

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases methylation, affects cotreatment, increases expression	8
sodium arsenite	affects splicing, decreases expression, affects cotreatment, increases abundance, increases expression	3
Benzo(a)pyrene	affects methylation, increases methylation, increases mutagenesis	3
bisphenol A	decreases methylation, increases expression	2
perfluorooctanoic acid	decreases expression	2
perfluorooctane sulfonic acid	decreases expression	2
Dexamethasone	increases expression	2
Smoke	decreases expression, increases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Tretinoin	decreases expression	2
dicrotophos	increases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction	1
cobaltous chloride	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
3-nitrobenzanthrone	decreases expression	1
pinostrobin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
perfluorohexanesulfonic acid	decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	decreases methylation	1
(+)-JQ1 compound	decreases expression	1
excavatolide B	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04452188	Not specified	COMPLETED	Targeting Normoxia in Neonates With Cyanotic Congenital Heart Disease in the Intra-operative and Immediate Post-operative Period
NCT04788082	Not specified	WITHDRAWN	Clinical Impact of Rapid Prototyping 3D Models for Surgical Management
NCT05452720	Not specified	RECRUITING	MASA Valve Early Feasibility Study
NCT05809310	Not specified	RECRUITING	Effects Branch PA Stenting d-TGA, ToF and TA
NCT06768008	Not specified	RECRUITING	An Integrated Prenatal and Postnatal Treatment Model for the Treatment of Newborns With Critical Congenital Heart Disease
NCT06771687	Not specified	RECRUITING	High Intensity Interval Training in Patients With a Right Ventricle to Pulmonary Artery Conduit
NCT03059420	Not specified	RECRUITING	Genetic Studies of Strabismus, Congenital Cranial Dysinnervation Disorders (CCDDs), and Their Associated Anomalies
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02337023	Not specified	COMPLETED	Brain Scintigraphy in Normal Versus Kleine-Levin Syndrome Subjects
NCT03754348	Not specified	COMPLETED	Microglial Activation in Narcolepsy Type 1 and Kleine-Levin Syndrome: Positron Emission Tomography (PET) Study in [18F] DPA-714