PLXNA1

Summary

PLXNA1 (plexin A1, HGNC:9099) is a protein-coding gene on chromosome 3q21.3, encoding Plexin-A1 (Q9UIW2). Coreceptor for SEMA3A, SEMA3C, SEMA3F and SEMA6D.

Predicted to enable semaphorin receptor activity. Predicted to be involved in several processes, including T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell; nervous system development; and semaphorin-plexin signaling pathway. Predicted to act upstream of or within dichotomous subdivision of terminal units involved in salivary gland branching; neuron projection extension; and regulation of smooth muscle cell migration. Located in cytosol and nucleoplasm.

Source: NCBI Gene 5361 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Dworschak-Punetha neurodevelopmental syndrome (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 8
• Clinical variants (ClinVar): 1,024 total — 5 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 26
• MANE Select transcript: NM_032242

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9099
Approved symbol	PLXNA1
Name	plexin A1
Location	3q21.3
Locus type	gene with protein product
Status	Approved
Aliases	NOV
Ensembl gene	ENSG00000114554
Ensembl biotype	protein_coding
OMIM	601055
Entrez	5361

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 2 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000393409, ENST00000503234, ENST00000503363, ENST00000505278, ENST00000684469

RefSeq mRNA: 1 — MANE Select: NM_032242 NM_032242

CCDS: CCDS33847

Canonical transcript exons

ENST00000393409 — 32 exons

Exon	Start	End
ENSE00000777132	127005090	127005243
ENSE00000858357	127007799	127007913
ENSE00000858358	127011958	127012158
ENSE00000858359	127014020	127014116
ENSE00000858360	127014182	127014375
ENSE00000858363	127015184	127015320
ENSE00000858364	127016517	127016684
ENSE00000858365	127016944	127017037
ENSE00000858367	127017749	127017892
ENSE00000858370	127022085	127022341
ENSE00001274814	127018294	127018528
ENSE00001274831	127017425	127017664
ENSE00001274860	127014711	127014831
ENSE00001274867	127014478	127014629
ENSE00001274901	127006079	127006178
ENSE00001274912	127004885	127005008
ENSE00001274920	127004611	127004711
ENSE00001274927	127003330	127003470
ENSE00001274936	126991384	126991566
ENSE00002081003	127033922	127037389
ENSE00002344143	127022752	127022818
ENSE00002357561	127027940	127028086
ENSE00002383180	127020202	127020344
ENSE00003495457	127029874	127030064
ENSE00003545831	127029440	127029536
ENSE00003563174	127028993	127029096
ENSE00003577133	127032686	127032836
ENSE00003652529	126988521	126989787
ENSE00003658841	127028181	127028340
ENSE00003659014	127032387	127032599
ENSE00003680377	127030243	127030412
ENSE00003920153	126983115	126983287

Expression profiles

Bgee: expression breadth ubiquitous, 279 present calls, max score 97.46.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0608 / max 6.6168, expressed in 13 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
38373	0.0608	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	97.46	gold quality
cortical plate	UBERON:0005343	96.03	gold quality
stromal cell of endometrium	CL:0002255	95.47	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.88	gold quality
cervix squamous epithelium	UBERON:0006922	94.40	silver quality
endothelial cell	CL:0000115	93.79	gold quality
sural nerve	UBERON:0015488	93.36	gold quality
gingival epithelium	UBERON:0001949	93.15	gold quality
Brodmann (1909) area 46	UBERON:0006483	93.15	gold quality
superior frontal gyrus	UBERON:0002661	92.65	gold quality
CA1 field of hippocampus	UBERON:0003881	92.41	gold quality
orbitofrontal cortex	UBERON:0004167	92.30	gold quality
entorhinal cortex	UBERON:0002728	91.90	gold quality
postcentral gyrus	UBERON:0002581	91.88	gold quality
parietal lobe	UBERON:0001872	91.84	gold quality
pancreatic ductal cell	CL:0002079	91.59	silver quality
tibia	UBERON:0000979	91.49	gold quality
visceral pleura	UBERON:0002401	91.34	gold quality
ventricular zone	UBERON:0003053	91.34	gold quality
gingiva	UBERON:0001828	90.22	gold quality
ganglionic eminence	UBERON:0004023	89.96	gold quality
ascending aorta	UBERON:0001496	89.88	gold quality
gluteal muscle	UBERON:0002000	89.83	gold quality
triceps brachii	UBERON:0001509	89.81	silver quality
thoracic aorta	UBERON:0001515	89.78	gold quality
embryo	UBERON:0000922	89.63	gold quality
frontal cortex	UBERON:0001870	89.63	gold quality
skin of hip	UBERON:0001554	89.28	gold quality
parotid gland	UBERON:0001831	89.15	gold quality
right frontal lobe	UBERON:0002810	89.12	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.87

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CIITA

miRNA regulators (miRDB)

181 targeting PLXNA1, 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-7110-3P	100.00	73.18	2486
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4673	100.00	66.64	1490
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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-106A-5P	99.90	73.94	2683

Literature-anchored findings (GeneRIF, showing 20)

• Breast carcinoma cells support an autocrine pathway involving SEMA3A, plexin-A1, and NP1 that impedes their ability to chemotax. (PMID:14500350)
• Expression of Plexin A1 in gastric carcinoma was significantly higher than that in normal gastric mucosa. (PMID:17520388)
• PlexinA1 may play an important role in the occurrence and development of gastric carcinoma, and be related to tumor angiogenesis and proliferation. (PMID:18161927)
• In malignant pleural mesothelioma cells, plexin-A1 and VEGF-receptor 2 (VEGF-R2) are associated in a complex which are involved in survival pathways. (PMID:19176370)
• Data show that the expression of Sema3A receptors (neuropilin-1 (NRP-1), NRP-2, plexin A1, plexin A2, and plexin A3) significantly increased during M-CSF-mediated differentiation of monocytes into macrophages. (PMID:19480842)
• neuropilin 1 and plexin A1 transmembrane domains interaction (PMID:24858828)
• Data indicate that plexin A1-4 (PLXNA1-4) mediation of neuroanatomical traits can be detected using in vivo neuroimaging techniques. (PMID:25518740)
• Semaphorin-3a, neuropilin-1 and plexin-A1 are axonal guidance molecules that have been recently implicated in regulating bone metabolism. (PMID:26602825)
• a novel mutation in the PLXNA1 receptor (c.2587G>A) in newly established pancreatic cell line, is reported. (PMID:26962861)
• PLEXA1 has a developmental and tumor-associated pro-angiogenic role in brain neoplasms (PMID:27506939)
• We thus screened 250 patients for the presence of mutations in PLXNA1, and identified different nonsynonymous mutations (p.V349L, p.V437L, p.R528W, p.H684Y, p.G720E, p.R740H, p.R813H, p.R840Q, p.A854T, p.R897H, p.L1464V, p.K1618T, p.C1744F), all at heterozygous state, in 15 patients. (PMID:28334861)
• Data suggest that Fyn tyrosine kinase (Fyn)-dependent phosphorylation at two critical tyrosines is a key feature of vertebrate plexin A1 (PlxnA1) and plexin A2 (PlxnA2) signal transduction. (PMID:29091353)
• Our findings indicate that PLXNA1 variants cause not only anosmic but also normosmic IHH with a relatively high prevalence (3.9%). Heterozygous missense PLXNA1 variants appear to be involved together with other IHH gene variants in bringing about the IHH disease phenotype. (PMID:30467832)
• Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies. (PMID:34054129)
• Analysis of PLXNA1, NRP1, and NRP2 variants in a cohort of patients with isolated hypogonadotropic hypogonadism. (PMID:34636164)
• Rare variant screening and burden analysis of PLXNA1 in Parkinson’s disease. (PMID:35852441)
• [PLXNA1 is highly expressed in hepatocellular carcinoma and affects patients’ survival and immune microenvironment]. (PMID:38081609)
• Chronic stress promotes gastric cancer progression via the adrenoceptor beta 2/PlexinA1 pathway. (PMID:38331165)
• PlexinA1 promotes gastric cancer migration through preventing MICAL1 protein ubiquitin/proteasome-mediated degradation in a Rac1-dependent manner. (PMID:38508474)
• PLXNA1 confers enzalutamide resistance in prostate cancer via AKT signaling pathway. (PMID:39226661)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	plxna1a	ENSDARG00000105452
danio_rerio	plxna1b	ENSDARG00000114823
mus_musculus	Plxna1	ENSMUSG00000030084
rattus_norvegicus	Plxna1	ENSRNOG00000017003

Paralogs (8): PLXND1 (ENSG00000004399), PLXNA2 (ENSG00000076356), PLXNA3 (ENSG00000130827), PLXNC1 (ENSG00000136040), PLXNB1 (ENSG00000164050), PLXNB2 (ENSG00000196576), PLXNB3 (ENSG00000198753), PLXNA4 (ENSG00000221866)

Protein

Protein identifiers

Plexin-A1 — Q9UIW2 (reviewed: Q9UIW2)

Alternative names: Semaphorin receptor NOV

All UniProt accessions (2): Q9UIW2, A0A804HKL4

UniProt curated annotations — full annotation on UniProt →

Function. Coreceptor for SEMA3A, SEMA3C, SEMA3F and SEMA6D. Necessary for signaling by class 3 semaphorins and subsequent remodeling of the cytoskeleton. Plays a role in axon guidance, invasive growth and cell migration. Class 3 semaphorins bind to a complex composed of a neuropilin and a plexin. The plexin modulates the affinity of the complex for specific semaphorins, and its cytoplasmic domain is required for the activation of down-stream signaling events in the cytoplasm. Acts as coreceptor of TREM2 for SEMA6D in dendritic cells and is involved in the generation of immune responses and skeletal homeostasis.

Subunit / interactions. Interacts directly with NRP1 and NRP2. Interacts with PLXN1B. Interacts with FARP2, RND1 and KDR/VEGFR2. Binding of SEMA3A leads to dissociation of FARP2. Interacts with CRMP1, DPYSL2/CRMP2, DPYSL3/CRMP3 and DPYSL4/CRMP4. Interacts (via TIG domains) with TREM2; the interaction mediates SEMA6D binding and signaling through TYROBP.

Subcellular location. Cell membrane.

Tissue specificity. Detected in fetal brain, lung, liver and kidney.

Disease relevance. Dworschak-Punetha neurodevelopmental syndrome (DWOPNED) [MIM:619955] An autosomal recessive disorder characterized by global developmental delay, mildly impaired intellectual development, speech delay, and behavioral abnormalities including autism spectrum disorder and hyperactivity. Additional variable additional features include optic disk hypoplasia, ptosis, hypo- or hyperpigmented skin lesions, non-specific facial dysmorphism, and abnormalities of the ventricles or corpus callosum seen on brain imaging. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the plexin family.

RefSeq proteins (1): NP_115618* (*=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
IPR041362	TIG2_plexin	Domain
IPR042744	Plexin-A1_Sema	Domain
IPR046800	Plexin_RBD	Domain

Pfam: PF01403, PF01437, PF01833, PF08337, PF17960, PF18020, PF20170, PF24479

UniProt features (118 total): strand 46, helix 16, turn 15, disulfide bond 10, sequence variant 8, glycosylation site 7, sequence conflict 5, domain 5, topological domain 2, signal peptide 1, chain 1, coiled-coil region 1, transmembrane region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9J4C	ELECTRON MICROSCOPY	3.33
7Y4P	X-RAY DIFFRACTION	3.5
7Y4Q	X-RAY DIFFRACTION	4.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UIW2-F1	85.23	0.51

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 (10): 95–104, 130–138, 286–407, 302–358, 376–395, 515–532, 521–563, 524–541, 535–547, 598–617

Glycosylation sites (7): 77, 660, 672, 701, 1043, 1187, 1212

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-399954	Sema3A PAK dependent Axon repulsion
R-HSA-399955	SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion
R-HSA-399956	CRMPs in Sema3A signaling
R-HSA-416700	Other semaphorin interactions
R-HSA-9013405	RHOD GTPase cycle
R-HSA-9696273	RND1 GTPase cycle

MSigDB gene sets: 303 (showing top): GOBP_FOREBRAIN_NEURON_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_GLAND_MORPHOGENESIS, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_SYNAPSE_ASSEMBLY, GOBP_SALIVARY_GLAND_DEVELOPMENT, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, REACTOME_OTHER_SEMAPHORIN_INTERACTIONS, GOBP_GROWTH, GOBP_NEUROGENESIS, GOBP_CRANIAL_NERVE_MORPHOGENESIS, GOBP_CRANIAL_NERVE_DEVELOPMENT, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_FOREBRAIN_GENERATION_OF_NEURONS

GO Biological Process (10): T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell (GO:0002291), synapse assembly (GO:0007416), regulation of smooth muscle cell migration (GO:0014910), olfactory nerve formation (GO:0021628), gonadotrophin-releasing hormone neuronal migration to the hypothalamus (GO:0021828), regulation of cell migration (GO:0030334), dichotomous subdivision of terminal units involved in salivary gland branching (GO:0060666), semaphorin-plexin signaling pathway (GO:0071526), neuron projection guidance (GO:0097485), neuron projection extension (GO:1990138)

GO Molecular Function (2): semaphorin receptor activity (GO:0017154), protein binding (GO:0005515)

GO Cellular Component (8): semaphorin receptor complex (GO:0002116), nucleoplasm (GO:0005654), cytosol (GO:0005829), plasma membrane (GO:0005886), extracellular exosome (GO:0070062), glutamatergic synapse (GO:0098978), membrane (GO:0016020), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Semaphorin interactions	4
RHO GTPase cycle	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
neuron projection morphogenesis	2
T cell activation involved in immune response	1
nervous system development	1
cell junction assembly	1
synapse organization	1
smooth muscle cell migration	1
regulation of cell migration	1
cranial nerve formation	1
olfactory nerve morphogenesis	1
neuron migration	1
hypothalamic tangential migration using cell-axon interactions	1
hypothalamus gonadotrophin-releasing hormone neuron development	1
cell migration	1
regulation of cell motility	1
branching involved in salivary gland morphogenesis	1
dichotomous subdivision of an epithelial terminal unit	1
cell surface receptor signaling pathway	1
neuron projection development	1
developmental cell growth	1
developmental growth involved in morphogenesis	1
transmembrane signaling receptor activity	1
semaphorin-plexin signaling pathway	1
binding	1
signaling receptor complex	1
nuclear lumen	1
cytoplasm	1
membrane	1
cell periphery	1
extracellular vesicle	1
synapse	1
cell junction	1

Protein interactions and networks

STRING

1290 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLXNA1	SEMA3A	Q14563	999
PLXNA1	NRP1	O14786	998
PLXNA1	NRP2	O60462	992
PLXNA1	SEMA3F	Q13275	990
PLXNA1	SEMA6D	Q8NFY4	989
PLXNA1	SEMA3C	Q99985	958
PLXNA1	SEMA6C	Q9H3T2	918
PLXNA1	PLXNA4	Q9HCM2	904
PLXNA1	RND1	Q92730	885
PLXNA1	MICAL1	Q8TDZ2	870
PLXNA1	SEMA6A	Q9H2E6	869
PLXNA1	KDR	P35968	860
PLXNA1	SEMA5A	Q13591	828
PLXNA1	SEMA3B	Q13214	807
PLXNA1	TYROBP	O43914	802

IntAct

123 interactions, top by confidence:

A	B	Type	Score
C1QTNF9	C1QTNF9B	psi-mi:“MI:0914”(association)	0.780
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CRIPTO	AIP	psi-mi:“MI:0914”(association)	0.640
FBXO6	MAN2B1	psi-mi:“MI:0914”(association)	0.640
SCGB1D1	MANBA	psi-mi:“MI:0914”(association)	0.640
MGAT4C	GXYLT2	psi-mi:“MI:0914”(association)	0.530
SCGB1D1	FAM234B	psi-mi:“MI:0914”(association)	0.530
DEFA5	NUDT19	psi-mi:“MI:0914”(association)	0.530
DEFA1	MANBA	psi-mi:“MI:0914”(association)	0.530
OS9	AGRN	psi-mi:“MI:0914”(association)	0.530
TAFA4	NRP1	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
C1orf54	EXTL3	psi-mi:“MI:0914”(association)	0.530
ANTXR1	WFS1	psi-mi:“MI:0914”(association)	0.530
GPIHBP1	ADAM10	psi-mi:“MI:0914”(association)	0.530
CLEC4M	GRN	psi-mi:“MI:0914”(association)	0.500
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
PDIA3	PLXNA1	psi-mi:“MI:0408”(disulfide bond)	0.440

BioGRID (161): PLXNA1 (Affinity Capture-MS), PLXNA1 (Affinity Capture-MS), PLXNA1 (Affinity Capture-MS), PLXNA1 (Affinity Capture-MS), PLXNA1 (Affinity Capture-MS), PLXNA1 (Affinity Capture-MS), PLXNA1 (Affinity Capture-MS), PLXNA1 (Affinity Capture-MS), NRP1 (Affinity Capture-Western), PLXNA1 (Affinity Capture-MS), PLXNA1 (Affinity Capture-MS), PLXNA1 (Affinity Capture-MS), PLXNA1 (Affinity Capture-MS), PLXNA1 (Affinity Capture-MS), PLXNA1 (Affinity Capture-MS)

ESM2 similar proteins: A7MB70, B0S5N4, B2RXS4, D3ZPX4, F1MMS9, O08665, O15031, O42236, O42237, O75326, O88632, O95025, P17852, P18564, P26006, P51805, P61622, P70206, P70207, P70208, P70275, Q13275, Q14563, Q4LFA9, Q5RE75, Q61738, Q62177, Q62179, Q62181, Q62470, Q63258, Q63548, Q64151, Q6AYF4, Q6BEA0, Q80UG2, Q863C4, Q8BH34, Q8SQB8, Q90607

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

1 interactions.

A	Effect	B	Mechanism
SEMA3A	“up-regulates activity”	PLXNA1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 134 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
NCAM signaling for neurite out-growth	7	20.5×	2e-05
Post-translational modification: synthesis of GPI-anchored proteins	5	9.0×	3e-03
Neutrophil degranulation	12	3.0×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of natural killer cell mediated cytotoxicity	5	37.3×	2e-04
ERAD pathway	7	10.7×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1024 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	9
Uncertain significance	505
Likely benign	406
Benign	49

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
1393762	NM_032242.4(PLXNA1):c.2486del (p.Gly829fs)	Pathogenic
2108224	NM_032242.4(PLXNA1):c.2674C>T (p.Arg892Ter)	Pathogenic
4056814	NM_032242.4(PLXNA1):c.4870+1G>A	Pathogenic
4531875	NM_032242.4(PLXNA1):c.1517del (p.Gln506fs)	Pathogenic
4761009	NM_032242.4(PLXNA1):c.1394C>G (p.Ser465Ter)	Pathogenic
1098571	NM_032242.4(PLXNA1):c.356T>C (p.Leu119Pro)	Likely pathogenic
2031519	NM_032242.4(PLXNA1):c.4509+1G>T	Likely pathogenic
2502183	NM_032242.4(PLXNA1):c.2095del (p.Arg699fs)	Likely pathogenic
3068005	NM_032242.4(PLXNA1):c.2111A>G (p.Glu704Gly)	Likely pathogenic
3377073	NM_032242.4(PLXNA1):c.4852A>T (p.Lys1618Ter)	Likely pathogenic
3768094	NM_032242.4(PLXNA1):c.2757-1G>A	Likely pathogenic
3906929	NM_032242.4(PLXNA1):c.2766_2767del (p.Cys922_Glu923delinsTer)	Likely pathogenic
4818997	NM_032242.4(PLXNA1):c.1997+1G>A	Likely pathogenic
867241	NM_032242.4(PLXNA1):c.5242C>T (p.Arg1748Cys)	Likely pathogenic

SpliceAI

5210 predictions. Top by Δscore:

Variant	Effect	Δscore
3:126989786:CGGT:C	donor_loss	1.0000
3:126989788:G:GA	donor_loss	1.0000
3:126989788:G:GG	donor_gain	1.0000
3:126989789:T:A	donor_loss	1.0000
3:126991382:A:AG	acceptor_gain	1.0000
3:126991383:G:GT	acceptor_gain	1.0000
3:126991383:GC:G	acceptor_gain	1.0000
3:126991383:GCC:G	acceptor_gain	1.0000
3:126991383:GCCC:G	acceptor_gain	1.0000
3:126991383:GCCCC:G	acceptor_gain	1.0000
3:127003326:GCAGA:G	acceptor_loss	1.0000
3:127003327:CAGA:C	acceptor_loss	1.0000
3:127003328:A:AG	acceptor_gain	1.0000
3:127003328:AGATC:A	acceptor_loss	1.0000
3:127003329:G:GG	acceptor_gain	1.0000
3:127003467:GCAG:G	donor_gain	1.0000
3:127003468:CAG:C	donor_loss	1.0000
3:127003470:GG:G	donor_loss	1.0000
3:127003471:G:C	donor_loss	1.0000
3:127005004:TCCCA:T	donor_gain	1.0000
3:127005005:CCCAG:C	donor_loss	1.0000
3:127005008:AG:A	donor_loss	1.0000
3:127005009:G:GG	donor_gain	1.0000
3:127005009:GTAA:G	donor_loss	1.0000
3:127005010:TAAG:T	donor_loss	1.0000
3:127005088:A:AG	acceptor_gain	1.0000
3:127005088:AGCTT:A	acceptor_gain	1.0000
3:127005089:G:GA	acceptor_gain	1.0000
3:127005089:GC:G	acceptor_gain	1.0000
3:127005089:GCT:G	acceptor_gain	1.0000

AlphaMissense

12324 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:126988876:T:A	C95S	1.000
3:126988876:T:C	C95R	1.000
3:126988877:G:C	C95S	1.000
3:126988973:T:C	L127P	1.000
3:126988981:T:C	C130R	1.000
3:126988982:G:A	C130Y	1.000
3:126988999:G:T	G136C	1.000
3:126989005:T:A	C138S	1.000
3:126989005:T:C	C138R	1.000
3:126989006:G:A	C138Y	1.000
3:126989006:G:C	C138S	1.000
3:126989007:C:G	C138W	1.000
3:126989203:C:A	R204S	1.000
3:126989264:T:G	F224C	1.000
3:126989432:C:A	S280Y	1.000
3:126989432:C:T	S280F	1.000
3:126989449:T:C	C286R	1.000
3:126989450:G:A	C286Y	1.000
3:126989719:T:A	C376S	1.000
3:126989719:T:C	C376R	1.000
3:126989720:G:A	C376Y	1.000
3:126989720:G:C	C376S	1.000
3:126989721:C:G	C376W	1.000
3:126989752:T:A	W387R	1.000
3:126989752:T:C	W387R	1.000
3:126989754:G:C	W387C	1.000
3:126989754:G:T	W387C	1.000
3:126989776:T:A	C395S	1.000
3:126989776:T:C	C395R	1.000
3:126989777:G:A	C395Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000019178 (3:126994972 G>T), RS1000021615 (3:127025253 C>G,T), RS1000088831 (3:126996822 G>A), RS1000099156 (3:127014838 C>T), RS1000120171 (3:126996991 C>T), RS1000121034 (3:126986689 G>A), RS1000189451 (3:127024634 G>A,T), RS1000195239 (3:126986934 G>T), RS1000241198 (3:127025526 G>A,C), RS1000302066 (3:126992383 G>T), RS1000373593 (3:127015670 G>T), RS1000380338 (3:127004279 C>T), RS1000544956 (3:127034190 G>A), RS1000624889 (3:126993768 G>GCAAGGCA), RS1000640610 (3:127005529 T>C)

Disease associations

OMIM: gene MIM:601055 | disease phenotypes: MIM:619955, MIM:168600

GenCC curated gene-disease

Disease	Classification	Inheritance
Dworschak-Punetha neurodevelopmental syndrome	Strong	Autosomal recessive
complex neurodevelopmental disorder	Limited	Autosomal dominant

Mondo (6): neurodevelopmental disorder (MONDO:0700092), Dworschak-Punetha neurodevelopmental syndrome (MONDO:0859260), Parkinson disease (MONDO:0005180), parkinsonian disorder (MONDO:0021095), vascular parkinsonism (MONDO:0956980), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (1): NON RARE IN EUROPE: Parkinson disease (Orphanet:319705)

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000076	Vesicoureteral reflux
HP:0000252	Microcephaly
HP:0000378	Cupped ear
HP:0000470	Short neck
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000639	Nystagmus
HP:0000691	Microdontia
HP:0000729	Autistic behavior
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001274	Agenesis of corpus callosum
HP:0002395	Lower limb hyperreflexia
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003477	Peripheral axonal neuropathy
HP:0003623	Neonatal onset
HP:0005280	Depressed nasal bridge
HP:0005338	Sparse lateral eyebrow
HP:0006989	Dysplastic corpus callosum
HP:0007766	Optic disc hypoplasia
HP:0009748	Large earlobe
HP:0011463	Childhood onset
HP:0012520	Dilation of Virchow-Robin spaces
HP:0012583	Unilateral renal hypoplasia
HP:0030048	Colpocephaly

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST000891_1	Whole-brain volume	4.000000e-06
GCST004860_115	Alcoholic chronic pancreatitis	4.000000e-06
GCST004860_138	Alcoholic chronic pancreatitis	2.000000e-06
GCST006585_1857	Blood protein levels	1.000000e-11
GCST008152_152	Weight	6.000000e-06
GCST008749_4	Systolic blood pressure	1.000000e-06
GCST010002_438	Refractive error	9.000000e-21
GCST90002402_324	Platelet count	2.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0005089	whole-brain volume
EFO:0004338	body weight
EFO:0006335	systolic blood pressure
EFO:0004309	platelet count

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625
D010300	Parkinson Disease	C10.228.140.079.862.500; C10.228.662.600.400; C10.574.928.750
D020734	Parkinsonian Disorders	C10.228.140.079.862; C10.228.662.600

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
Benzo(a)pyrene	increases expression, decreases methylation	2
Tobacco Smoke Pollution	decreases expression	2
Valproic Acid	increases expression, increases methylation	2
bisphenol F	affects cotreatment, decreases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
perfluorooctanoic acid	increases expression	1
aflatoxin B2	increases methylation	1
muconaldehyde	decreases expression	1
tamibarotene	increases expression	1
monomethylarsonous acid	decreases expression	1
ICG 001	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Atrazine	increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Smoke	decreases expression	1
Tretinoin	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
Asbestos, Crocidolite	decreases expression	1
Sodium Selenite	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_VJ93	SB.06	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00030979	PHASE4	COMPLETED	Donepezil to Treat Dementia in Parkinson’s Disease
NCT00043849	PHASE4	COMPLETED	Treatment of Agitation/Psychosis in Dementia/Parkinsonism (TAP/DAP)
NCT00095810	PHASE4	COMPLETED	Aripiprazole in Patients With Psychosis Associated With Parkinson’s Disease
NCT00125567	PHASE4	COMPLETED	Stalevo in Early Wearing-Off Patients
NCT00143026	PHASE4	COMPLETED	Study to Compare the Effect of Treatment With Carbidopa/Levodopa/Entacapone on the Quality of Life of Patients With Parkinson’s Disease. This Study is Not Recruiting in the United States
NCT00144300	PHASE4	COMPLETED	Ophthalmologic Safety Study of Pramipexole Immediate Release (IR) Versus Ropinirole in Early Parkinson’s Disease (PD) Patients
NCT00153972	PHASE4	COMPLETED	Dopamine Turnover Rate as Surrogate Parameter for Diagnosis of Early Parkinson’s Disease
NCT00174239	PHASE4	TERMINATED	Study Of Cabaser and Sinemet CR For The Treatment Of Nighttime Symptoms Associated With Parkinson’s Disease.
NCT00215904	PHASE4	COMPLETED	D-serine Adjuvant Treatment for Parkinson’s Disease
NCT00247247	PHASE4	COMPLETED	Comtess® Versus Cabaseril® as Add-on to Levodopa in the Treatment of Parkinsonian Patients Suffering From Wearing- Off.
NCT00272688	PHASE4	COMPLETED	Continuous Delivery of Levodopa in Patients With Advanced Idiopathic Parkinsons Disease - Cost-benefit
NCT00297778	PHASE4	COMPLETED	Pramipexole Versus Placebo in Parkinson’s Disease (PD) Patients With Depressive Symptoms
NCT00304161	PHASE4	COMPLETED	Effectiveness of Antidepressant Treatment for Depression in People With Parkinson’s Disease
NCT00307450	PHASE4	COMPLETED	Efficacy and Safety of Levetiracetam Versus Placebo on Levodopa-induced Dyskinesias in Advanced Parkinson’s Disease
NCT00321854	PHASE4	COMPLETED	Study of (Mirapex) Pramipexole for the Early Treatment of Parkinsons Disease (PD)
NCT00354133	PHASE4	UNKNOWN	Controlled Trial With Deep Brain Stimulation in Patients With Early Parkinson’s Disease
NCT00373087	PHASE4	COMPLETED	COMT Polymorphism and Entacapone Efficacy
NCT00391898	PHASE4	COMPLETED	Efficacy of Levodopa/Carbidopa/Entacapone vs Levodopa/Carbidopa in Parkinson’s Disease Patients With Early Wearing-off
NCT00399477	PHASE4	COMPLETED	A Non-Blinded Study Demonstrating the Effectiveness and Safety of Azilect Alone or in Combination Therapy in Parkinson’s Disease
NCT00402233	PHASE4	COMPLETED	A Randomized, Double-blind, Active (Pramipexole 0.5 mg Tid) and Placebo Controlled, Study of Pramipexole Given 0.5 mg and 0.75 mg Bid Over 12-week Treatment in Early Parkinson’s Disease (PD) Patients
NCT00437125	PHASE4	COMPLETED	Study on the Tolerability of Duloxetine in Depressed Patients With Parkinson’s Disease
NCT00443872	PHASE4	COMPLETED	Efficacy of Orally Disintegrating Selegiline in Parkinson’s Patients Experiencing Adverse Effects With Dopamine Agonists
NCT00455143	PHASE4	TERMINATED	Cognitive Protection - Dexmedetomidine and Cognitive Reserve
NCT00462007	PHASE4	COMPLETED	Study to Evaluate Initiation of Stalevo in Early Wearing-off
NCT00462254	PHASE4	TERMINATED	Ramelteon (ROZEREM) in the Treatment of Sleep Disturbances Associated With Parkinson’s Disease
NCT00477802	PHASE4	TERMINATED	Botulinum Toxin Type A (Botox) in the Management of Levodopa-Induced Peak-Dose Dyskinesias in Parkinson’s Disease
NCT00485069	PHASE4	COMPLETED	REQUIP (Ropinirole Hydrochloride) IR Long-Term Phase 4 Study
NCT00489255	PHASE4	COMPLETED	Safety/Efficacy of Tigan® to Control Nausea/Vomiting Experienced During Apokyn® Initiation and Treatment
NCT00526630	PHASE4	COMPLETED	Methylphenidate for the Treatment of Gait Impairment in Parkinson’s Disease
NCT00561678	PHASE4	COMPLETED	Perioperative Cognitive Function - Dexmedetomidine and Cognitive Reserve
NCT00571285	PHASE4	TERMINATED	Clinical Effects of Vitamin D Repletion in Patients With Parkinson’s Disease
NCT00584025	PHASE4	WITHDRAWN	Keppra IV for the Treatment of Motor Fluctuations in Parkinson’s Disease
NCT00584090	PHASE4	WITHDRAWN	Solifenacin Succinate (VESIcare) for the Treatment of Urinary Incontinence in Parkinson’s Disease
NCT00590122	PHASE4	COMPLETED	Parcopa Versus Carbidopa-levodopa in a Single Dose Cross-over Comparison Study
NCT00594464	PHASE4	COMPLETED	A Trial of Neupro® (Rotigotine Transdermal Patch) in Patients With Parkinson’s Disease Undergoing Surgery
NCT00601978	PHASE4	WITHDRAWN	Carbidopa/Levodopa Versus Carbidopa/Levodopa/Entacapone on Markers of Event Related Potentials (ERPs) in Patients With Idiopathic Parkinson’s Disease (PD) and End-of-dose Wearing Off
NCT00632762	PHASE4	COMPLETED	Long-Term Effects of Amantadine in Parkinsonian (AMANDYSK)
NCT00640159	PHASE4	COMPLETED	Selegiline to Zelapar Switch Study in Parkinson Disease Patients