PTPN23

Summary

PTPN23 (protein tyrosine phosphatase non-receptor type 23, HGNC:14406) is a protein-coding gene on chromosome 3p21.31, encoding Tyrosine-protein phosphatase non-receptor type 23 (Q9H3S7). Plays a role in sorting of endocytic ubiquitinated cargos into multivesicular bodies (MVBs) via its interaction with the ESCRT-I complex (endosomal sorting complex required for transport I), and possibly also other ESCRT complexes. It is a common-essential gene (DepMap: required in 95.0% of cancer cell lines).

This gene encodes a member of the non-receptor type protein-tyrosine phosphatase family. The encoded protein may be involved in the regulation of small nuclear ribonucleo protein assembly and pre-mRNA splicing by modifying the survival motor neuron (SMN) complex. The encoded protein additionally plays a role in ciliogenesis and is part of endosomal sorting complex required for transport (ESCRT) pathways. This gene may serve a tumor suppressor function.

Source: NCBI Gene 25930 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity (Strong, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 1,607 total — 34 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 20
• Cancer dependency (DepMap): dependent in 95.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_015466

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14406
Approved symbol	PTPN23
Name	protein tyrosine phosphatase non-receptor type 23
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	DKFZP564F0923, KIAA1471, HD-PTP
Ensembl gene	ENSG00000076201
Ensembl biotype	protein_coding
OMIM	606584
Entrez	25930

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 8 protein_coding, 5 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000265562, ENST00000456221, ENST00000462998, ENST00000477276, ENST00000495653, ENST00000602307, ENST00000683323, ENST00000683566, ENST00000683708, ENST00000889692, ENST00000889693, ENST00000889694, ENST00000889695, ENST00000889696, ENST00000918778

RefSeq mRNA: 2 — MANE Select: NM_015466 NM_001304482, NM_015466

CCDS: CCDS2754

Canonical transcript exons

ENST00000265562 — 25 exons

Exon	Start	End
ENSE00001054636	47404652	47404779
ENSE00001253311	47412706	47413435
ENSE00001854823	47381021	47381180
ENSE00003458649	47407890	47407955
ENSE00003474173	47407130	47407186
ENSE00003480834	47412094	47412198
ENSE00003497285	47408345	47408490
ENSE00003501275	47405749	47405798
ENSE00003525613	47412514	47412627
ENSE00003537534	47409163	47409317
ENSE00003548306	47396143	47396217
ENSE00003552892	47409928	47411686
ENSE00003564809	47405915	47406046
ENSE00003568901	47407505	47407584
ENSE00003588233	47411783	47411967
ENSE00003589825	47412283	47412421
ENSE00003597045	47408776	47409087
ENSE00003598551	47405005	47405081
ENSE00003617753	47406481	47406612
ENSE00003628525	47406703	47406750
ENSE00003628696	47407309	47407367
ENSE00003636541	47407697	47407811
ENSE00003641608	47406325	47406405
ENSE00003657417	47409655	47409834
ENSE00003677154	47409417	47409568

Expression profiles

Bgee: expression breadth ubiquitous, 228 present calls, max score 93.41.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 40.5774 / max 325.6449, expressed in 1821 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
36541	38.4391	1817
36539	0.9102	497
36542	0.7436	405
36540	0.4846	240

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	93.41	gold quality
pituitary gland	UBERON:0000007	91.57	gold quality
upper arm skin	UBERON:0004263	91.55	silver quality
adenohypophysis	UBERON:0002196	91.27	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.63	gold quality
right lobe of thyroid gland	UBERON:0001119	90.41	gold quality
stromal cell of endometrium	CL:0002255	90.33	gold quality
left lobe of thyroid gland	UBERON:0001120	90.25	gold quality
gastrocnemius	UBERON:0001388	90.20	gold quality
endocervix	UBERON:0000458	89.72	gold quality
skin of leg	UBERON:0001511	89.63	gold quality
cerebellar hemisphere	UBERON:0002245	89.62	gold quality
left adrenal gland cortex	UBERON:0035825	89.62	gold quality
cerebellar cortex	UBERON:0002129	89.54	gold quality
muscle of leg	UBERON:0001383	89.52	gold quality
left adrenal gland	UBERON:0001234	89.49	gold quality
metanephros cortex	UBERON:0010533	89.42	gold quality
right ovary	UBERON:0002118	89.33	gold quality
thyroid gland	UBERON:0002046	89.29	gold quality
ectocervix	UBERON:0012249	89.28	gold quality
body of uterus	UBERON:0009853	89.27	gold quality
right adrenal gland	UBERON:0001233	89.18	gold quality
skin of abdomen	UBERON:0001416	89.12	gold quality
lower esophagus mucosa	UBERON:0035834	89.07	gold quality
tibial nerve	UBERON:0001323	88.90	gold quality
left ovary	UBERON:0002119	88.86	gold quality
apex of heart	UBERON:0002098	88.77	gold quality
right frontal lobe	UBERON:0002810	88.73	gold quality
right adrenal gland cortex	UBERON:0035827	88.73	gold quality
right uterine tube	UBERON:0001302	88.72	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.98

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

23 targeting PTPN23, 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-4795-3P	100.00	74.62	4024
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-142-3P	99.62	71.30	974
HSA-MIR-6073	99.60	70.36	793
HSA-MIR-3682-3P	99.58	67.63	865
HSA-MIR-143-3P	99.49	69.05	1457
HSA-MIR-4770	99.49	69.09	1451
HSA-MIR-1272	99.34	68.79	878
HSA-MIR-6088	99.29	68.45	1284
HSA-MIR-3160-3P	99.07	64.78	955
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-6871-5P	98.90	66.67	671
HSA-MIR-3945	98.68	64.21	553
HSA-MIR-4483	98.09	64.12	1642
HSA-MIR-4708-5P	97.77	67.82	831
HSA-MIR-4253	97.48	65.11	692
HSA-MIR-6862-5P	97.48	64.84	713
HSA-MIR-4296	96.35	63.55	1233
HSA-MIR-1293	96.16	64.69	916
HSA-MIR-541-3P	96.07	66.11	1271
HSA-MIR-654-5P	96.07	66.18	1280
HSA-MIR-6816-3P	95.05	66.08	459

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 95.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 24)

• These results suggest that HD-PTP amounts might be regulated both at the transcriptional and post-transcriptional levels. (PMID:16408268)
• data suggest that HD-PTP might participate in modulating endothelial response to angiogenic factors and play a role in regulating the complex events leading to the formation of new vessels (PMID:16720300)
• We suggest that HD-PTP contributes to the regulation of endothelial motility by modulating the tyrosine phosphorylation of FAK. (PMID:17959146)
• contributes to the regulation of endothelial migration; may play a role in angiogenesis (PMID:18762272)
• in Epidermal Growth Factor (EGF) stimulated cells, Src binds to and phosphorylates HD-PTP on tyrosine residues (PMID:18835089)
• demonstrate that HD-PTP is a catalytically inactive protein tyrosine phosphatase. As such, we identify one residue involved in its inactivation and show that colony growth reduction activity is independent of its PTP activity status in cancer cell lines (PMID:19340315)
• Histidine domain-protein tyrosine phosphatase interacts with Grb2 and GrpL (PMID:21179510)
• loss of PTPN23 may increase the activity of SRC and the phosphorylation status of the E-cadherin/beta-catenin signaling complex to promote tumor growth and invasive behavior in breast cancer (PMID:21724833)
• HD-PTP degradation by calpains might result in the acquisition of a more aggressive phenotype in neoplastic cells. (PMID:22510412)
• our findings suggest an evolutionarily conserved function of HDPTP-Rab4 in the regulation of endocytic trafficking, cell adhesion and migration (PMID:22825871)
• The ESCRT accessory protein HD-PTP/PTPN23 associates with epidermal growth factor receptor (EGFR) and combines with the deubiquitinating enzyme UBPY/USP8 to transfer EGFR from ESCRT-0 to ESCRT-III and drive EGFR sorting to intralumenal vesicles. (PMID:23477725)
• PTPN23 is a tumor suppressor and that repression of PTPN23 expression by miR-142-3p plays an important role in the pathogenesis of testicular germ cell tumors. (PMID:23843459)
• Data indicate a regulatory function of non-receptor-type tyrosine phosphatase PTPN23 in maintaining a highly phosphorylated state of survival motor neuron complex protein SMN. (PMID:25392300)
• HD-PTP acts as an alternative to ESCRT-II and VPS20/CHMP6 as a link between the ESCRT-I and those ESCRT-III protein(s) necessary for ILV formation. (PMID:26221024)
• HD-PTP/PTPN23 as a prominent haploinsufficient tumor suppressor gene preventing tumor progression through control of integrin trafficking. (PMID:27210750)
• Results present crystal structures of the coiled-coil domain of the HD-PTP phosphatase and its complex with UBAP1. The coiled-coil domain adopts an unexpected open and rigid conformation. The HD-PTP:UBAP1 structure identifies the molecular determinants of the interaction and provides a molecular basis for the specific functional cooperation between HD-PTP and UBAP1. (PMID:27839950)
• The role of HD-PTP/PTPN23 in cancer and tumorigenesis is reviewed. (PMID:28620046)
• the underlying mechanism of PTPN23 function in breast tumorigenesis as that of a key phosphatase that normally suppresses the activity of FYN (PMID:29066500)
• Mutations in PTPN23 gene is associated with developmental and epileptic encephalopathy. (PMID:29090338)
• Our report provides the first description of the clinical phenotype of recessive PTPN23 variants with pathogenicity substantiated by a functional study (PMID:29899372)
• Phenotype and mutation expansion of the PTPN23 associated disorder characterized by neurodevelopmental delay and structural brain abnormalities. (PMID:31395947)
• Interactions of ubiquitin and CHMP5 with the V domain of HD-PTP reveals role for regulation of Vps4 ATPase. (PMID:34586919)
• PTPN23 ubiquitination by WDR4 suppresses EGFR and c-MET degradation to define a lung cancer therapeutic target. (PMID:37821451)
• PTPN23[Thr] variant reduces susceptibility and tumorigenesis in esophageal squamous cell carcinoma through dephosphorylation of EGFR. (PMID:38704135)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ptpn23a	ENSDARG00000070124
danio_rerio	ptpn23b	ENSDARG00000098689
mus_musculus	Ptpn23	ENSMUSG00000036057
rattus_norvegicus	Ptpn23	ENSRNOG00000020862

Paralogs (35): PTPRN (ENSG00000054356), PTPRU (ENSG00000060656), PTPN3 (ENSG00000070159), PTPN21 (ENSG00000070778), PTPN18 (ENSG00000072135), PTPRH (ENSG00000080031), PTPRC (ENSG00000081237), PTPN4 (ENSG00000088179), PTPRS (ENSG00000105426), PTPRZ1 (ENSG00000106278), PTPN5 (ENSG00000110786), PTPN6 (ENSG00000111679), PTPRB (ENSG00000127329), PTPN12 (ENSG00000127947), PTPRE (ENSG00000132334), PTPRA (ENSG00000132670), PTPN22 (ENSG00000134242), PTPRF (ENSG00000142949), PTPN7 (ENSG00000143851), PTPRG (ENSG00000144724), PTPRJ (ENSG00000149177), PTPRO (ENSG00000151490), PTPN14 (ENSG00000152104), PTPRK (ENSG00000152894), PTPRR (ENSG00000153233), PTPRD (ENSG00000153707), PTPRN2 (ENSG00000155093), PTPN13 (ENSG00000163629), PTPN9 (ENSG00000169410), PTPRM (ENSG00000173482), PTPN2 (ENSG00000175354), PTPN11 (ENSG00000179295), PTPRT (ENSG00000196090), PTPN1 (ENSG00000196396), PTPN20 (ENSG00000204179)

Protein

Protein identifiers

Tyrosine-protein phosphatase non-receptor type 23 — Q9H3S7 (reviewed: Q9H3S7)

Alternative names: His domain-containing protein tyrosine phosphatase, Protein tyrosine phosphatase TD14

All UniProt accessions (3): Q9H3S7, C9JD91, R4GMM7

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in sorting of endocytic ubiquitinated cargos into multivesicular bodies (MVBs) via its interaction with the ESCRT-I complex (endosomal sorting complex required for transport I), and possibly also other ESCRT complexes. May act as a negative regulator of Ras-mediated mitogenic activity. Plays a role in ciliogenesis.

Subunit / interactions. Interacts with GRAP2 and GRB2. Interacts with UBAP1. Interacts with CHMP4B.

Subcellular location. Nucleus. Cytoplasm. Cytoplasmic vesicle. Endosome. Cytoskeleton. Cilium basal body. Early endosome.

Disease relevance. Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity (NEDBASS) [MIM:618890] An autosomal recessive disorder characterized by global developmental delay, brain abnormalities, mainly ventriculomegaly and/or brain atrophy, intellectual disability, absent speech, peripheral spasticity, and microcephaly. Additional variable features include early-onset seizures, optic atrophy, and dysmorphic facial features. Early death may occur. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the protein-tyrosine phosphatase family. Non-receptor class subfamily.

RefSeq proteins (2): NP_001291411, NP_056281* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000242	PTP_cat	Domain
IPR000387	Tyr_Pase_dom	Domain
IPR003595	Tyr_Pase_cat	Domain
IPR004328	BRO1_dom	Domain
IPR016130	Tyr_Pase_AS	Active_site
IPR025304	ALIX_V_dom	Domain
IPR029021	Prot-tyrosine_phosphatase-like	Homologous_superfamily
IPR038499	BRO1_sf	Homologous_superfamily

Pfam: PF00102, PF03097, PF13949

Enzyme classification (BRENDA):

• EC 3.1.3.48 — protein-tyrosine-phosphatase (BRENDA: 59 organisms, 501 substrates, 1326 inhibitors, 270 Km, 165 kcat entries)

Substrate kinetics (BRENDA)

70 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
4-NITROPHENYL PHOSPHATE	0.0008–148	84
6,8-DIFLUORO-4-METHYLUMBELLIFERYL PHOSPHATE	0.0039–0.862	27
P-NITROPHENYL PHOSPHATE	0.0024–10	20
DADEPYLIPQQG	0.0003–0.1	12
PHOSPHOTYROSINE	0.012–30	11
LYSOZYME	0.0003–0.012	5
MYELIN BASIC PROTEIN	0.0001–0.022	5
ACETYL-DADEPY-NH2	0.0228–0.219	4
ACETYL-DADEPYL-NH2	1.1–97.5	4
4,6,8-TRIMETHYL-2-OXO-2H-CHROMEN-7-YL DIHYDROGEN	0.02–0.156	3
SASASPYSASA	0.53–2.3	3
1-NAPHTHYL PHOSPHATE	1.19–1.88	2
3,6-FLUORESCEIN DIPHOSPHATE	15–19	2
4-METHYLUMBELLIFERYL PHOSPHATE	0.953–2.41	2
BOVINE SERUM ALBUMIN	0.0001–0.0003	2

Catalyzed reactions (Rhea), 1 shown:

• O-phospho-L-tyrosyl-[protein] + H2O = L-tyrosyl-[protein] + phosphate (RHEA:10684)

UniProt features (93 total): helix 27, sequence variant 18, compositionally biased region 10, repeat 8, modified residue 6, turn 6, region of interest 5, mutagenesis site 3, strand 3, domain 2, sequence conflict 2, chain 1, coiled-coil region 1, active site 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
5MK2	X-RAY DIFFRACTION	1.7
5MK0	X-RAY DIFFRACTION	1.76
5MJZ	X-RAY DIFFRACTION	1.87
3RAU	X-RAY DIFFRACTION	1.95
5MK3	X-RAY DIFFRACTION	2
5CRV	X-RAY DIFFRACTION	2
5MJY	X-RAY DIFFRACTION	2.25
5CRU	X-RAY DIFFRACTION	2.4
5MK1	X-RAY DIFFRACTION	2.5
5LM2	X-RAY DIFFRACTION	2.54
5LM1	X-RAY DIFFRACTION	2.55

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H3S7-F1	70.89	0.43

Functional residue map

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

Catalytic / active sites (1): 1392 (phosphocysteine intermediate)

Post-translational modifications (6): 733, 950, 1122, 1123, 1131, 1615

Mutagenesis-validated functional residues (3):

Position	Phenotype
202	nearly abolishes interaction with chmp4b. abolishes interaction with chmp4b; when associated with d-206.
206	abolishes interaction with chmp4b; when associated with d-202.
678	abolishes interaction with ubap1.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9008059	Interleukin-37 signaling

MSigDB gene sets: 227 (showing top): MODULE_451, PAX4_01, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_REGULATION_OF_EPITHELIAL_CELL_MIGRATION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_VACUOLAR_TRANSPORT, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_AMEBOIDAL_TYPE_CELL_MIGRATION, GOBP_CELL_CELL_SIGNALING, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION

GO Biological Process (14): negative regulation of epithelial cell migration (GO:0010633), endocytic recycling (GO:0032456), ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway (GO:0043162), protein transport to vacuole involved in ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway (GO:0043328), early endosome to late endosome transport (GO:0045022), cilium assembly (GO:0060271), positive regulation of Wnt protein secretion (GO:0061357), positive regulation of homophilic cell adhesion (GO:1903387), positive regulation of adherens junction organization (GO:1903393), positive regulation of early endosome to late endosome transport (GO:2000643), protein dephosphorylation (GO:0006470), protein transport (GO:0015031), dephosphorylation (GO:0016311), cell projection organization (GO:0030030)

GO Molecular Function (5): protein tyrosine phosphatase activity (GO:0004725), protein kinase binding (GO:0019901), phosphoprotein phosphatase activity (GO:0004721), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (16): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), endosome (GO:0005768), early endosome (GO:0005769), cytosol (GO:0005829), nuclear body (GO:0016604), centriolar satellite (GO:0034451), ciliary basal body (GO:0036064), extracellular exosome (GO:0070062), sperm midpiece (GO:0097225), sperm glycocalyx (GO:0120238), cytoskeleton (GO:0005856), cilium (GO:0005929), cytoplasmic vesicle (GO:0031410), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Interleukin-1 family signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
cytoplasm	3
intracellular membraneless organelle	2
epithelial cell migration	1
regulation of epithelial cell migration	1
negative regulation of cell migration	1
negative regulation of multicellular organismal process	1
endosomal transport	1
vesicle-mediated transport to the plasma membrane	1
ubiquitin-dependent protein catabolic process	1
protein catabolic process in the vacuole	1
multivesicular body sorting pathway	1
intracellular protein transport	1
late endosome to vacuole transport via multivesicular body sorting pathway	1
ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	1
protein localization to vacuole	1
establishment of protein localization to vacuole	1
vesicle-mediated transport between endosomal compartments	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
protein localization to cilium	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
positive regulation of cell communication	1
positive regulation of signaling	1
positive regulation of protein secretion	1
Wnt protein secretion	1
regulation of Wnt protein secretion	1
homophilic cell-cell adhesion	1
positive regulation of cell-cell adhesion	1
regulation of homophilic cell adhesion	1
adherens junction organization	1
positive regulation of cellular component organization	1
regulation of adherens junction organization	1
positive regulation of intracellular transport	1
early endosome to late endosome transport	1
regulation of early endosome to late endosome transport	1

Protein interactions and networks

STRING

2496 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PTPN23	UBAP1	Q9NZ09	843
PTPN23	PTS	Q03393	833
PTPN23	TSG101	Q99816	823
PTPN23	CHMP4A	Q9BY43	806
PTPN23	STAM2	O75886	764
PTPN23	CHMP4B	Q9H444	730
PTPN23	VPS28	Q9UK41	578
PTPN23	CHMP6	Q96FZ7	561
PTPN23	IST1	P53990	560
PTPN23	CHMP3	Q9Y3E7	531
PTPN23	HGS	O14964	531
PTPN23	VPS36	Q86VN1	529
PTPN23	MVB12A	Q96EY5	528
PTPN23	VPS37A	Q8NEZ2	521
PTPN23	A0A140T963	A0A140T963	519

IntAct

111 interactions, top by confidence:

A	B	Type	Score
GRB2	PTPN23	psi-mi:“MI:0915”(physical association)	0.870
GRB2	PTPN23	psi-mi:“MI:0403”(colocalization)	0.870
GRAP2	STAMBP	psi-mi:“MI:0914”(association)	0.810
GRAP2	PTPN23	psi-mi:“MI:0915”(physical association)	0.790
PTPN23	GRAP2	psi-mi:“MI:0915”(physical association)	0.790
GRAP2	PTPN23	psi-mi:“MI:0403”(colocalization)	0.790
GRB2	WIPF3	psi-mi:“MI:0914”(association)	0.730
PTPN23	NOTCH2NLA	psi-mi:“MI:0915”(physical association)	0.670
NOTCH2NLA	PTPN23	psi-mi:“MI:0915”(physical association)	0.670
CHMP4B	PTPN23	psi-mi:“MI:0407”(direct interaction)	0.660
CHMP4B	PTPN23	psi-mi:“MI:0915”(physical association)	0.660
PTPN23	CHMP4B	psi-mi:“MI:0915”(physical association)	0.660
PTPN23	PTK2	psi-mi:“MI:0217”(phosphorylation reaction)	0.640
PTPN23	PTK2	psi-mi:“MI:0407”(direct interaction)	0.640
PTPN23	PTK2	psi-mi:“MI:0915”(physical association)	0.640
PTPN23	PTK2	psi-mi:“MI:0403”(colocalization)	0.640
Grap2	PTPN23	psi-mi:“MI:0407”(direct interaction)	0.600
CEP55	PTPN23	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (245): PTPN23 (Two-hybrid), PTPN23 (Two-hybrid), CEP55 (Two-hybrid), NOTCH2NL (Two-hybrid), PTPN23 (Affinity Capture-MS), PTPN23 (Affinity Capture-MS), PTPN23 (Affinity Capture-MS), PTPN23 (Co-fractionation), UBAP1 (Two-hybrid), PTPN23 (Affinity Capture-MS), PTPN23 (Affinity Capture-MS), PTPN23 (Affinity Capture-MS), PTPN23 (Affinity Capture-MS), HGS (Affinity Capture-Western), STAM (Affinity Capture-Western)

ESM2 similar proteins: A1A4I4, A2SXS5, A6QQ47, B2DCZ9, O00255, O08908, O55166, O75146, O88559, P70268, Q0P5I0, Q0VCR8, Q155U0, Q16512, Q29RB1, Q2KJ58, Q3MHG0, Q3MII6, Q3SZI7, Q3UVL4, Q4V9Y0, Q505L3, Q5R7R6, Q5TJF0, Q5ZJ25, Q63433, Q63788, Q68FF6, Q68FP9, Q69Z89, Q6PB44, Q6ZT62, Q865S3, Q8BI71, Q8BZQ7, Q8C190, Q8C754, Q8N1B4, Q8R1U1, Q8R3I3

Diamond homologs: A4FUC9, A8MT19, C8V212, F4HXZ1, P0CM44, P0CM45, Q4IBS9, Q4PHA8, Q4X0Z5, Q61085, Q63ZR5, Q6BRL3, Q6CGJ5, Q6DJJ6, Q6PB44, Q6TNR1, Q7SAN9, Q8BWR8, Q8HXG3, Q8IUC4, Q8T7K0, Q8TCX5, Q9H3S7, Q9QZA2, Q5KU05, A0A6I8TCE0, A1L1L3, A2A8L5, A2ALK8, A4IFW2, A7MBJ4, B0V2N1, B0X4T2, B2GV87, B2RU80, B9EKR1, E9Q0N2, E9Q612, F1NWE3, G5EC24

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 90 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
Signaling by CSF1 (M-CSF) in myeloid cells	5	30.9×	8e-05
Lysosome Vesicle Biogenesis	5	29.1×	8e-05
RHOU GTPase cycle	5	24.9×	2e-04
Signaling by SCF-KIT	5	22.2×	2e-04
Recycling pathway of L1	5	20.0×	3e-04
Golgi Associated Vesicle Biogenesis	5	17.9×	4e-04
FCGR3A-mediated phagocytosis	5	16.7×	6e-04
Cargo recognition for clathrin-mediated endocytosis	8	15.0×	2e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

1607 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	34
Likely pathogenic	14
Uncertain significance	737
Likely benign	704
Benign	42

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1448291	NM_015466.4(PTPN23):c.2249_2250del (p.Pro750fs)	Pathogenic
1481074	NM_015466.4(PTPN23):c.2226del (p.Glu743fs)	Pathogenic
1488121	NM_015466.4(PTPN23):c.3334C>T (p.Arg1112Ter)	Pathogenic
1489003	NM_015466.4(PTPN23):c.4039_4040del (p.Leu1347fs)	Pathogenic
1512677	NM_015466.4(PTPN23):c.2425_2432del (p.Gly809fs)	Pathogenic
1907485	NM_015466.4(PTPN23):c.2425_2432dup (p.His811fs)	Pathogenic
2006638	NM_015466.4(PTPN23):c.2411_2418del (p.Gln804fs)	Pathogenic
2039070	NM_015466.4(PTPN23):c.4022del (p.Gln1341fs)	Pathogenic
2107496	NM_015466.4(PTPN23):c.3208C>T (p.Arg1070Ter)	Pathogenic
2114008	NM_015466.4(PTPN23):c.2935C>T (p.Gln979Ter)	Pathogenic
2134575	NM_015466.4(PTPN23):c.3773dup (p.Leu1259fs)	Pathogenic
2699193	NM_015466.4(PTPN23):c.3164del (p.Pro1055fs)	Pathogenic
2735374	NM_015466.4(PTPN23):c.1493G>A (p.Trp498Ter)	Pathogenic
2739549	NM_015466.4(PTPN23):c.1486C>T (p.Arg496Ter)	Pathogenic
2821804	NM_015466.4(PTPN23):c.178C>T (p.Arg60Ter)	Pathogenic
2833707	NM_015466.4(PTPN23):c.2059_2062dup (p.Ala688fs)	Pathogenic
2843796	NM_015466.4(PTPN23):c.1906C>T (p.Gln636Ter)	Pathogenic
2852671	NM_015466.4(PTPN23):c.2981_2997dup (p.Tyr1000fs)	Pathogenic
2995673	NM_015466.4(PTPN23):c.3407dup (p.Gly1137fs)	Pathogenic
3004371	NM_015466.4(PTPN23):c.2225dup (p.Pro742_Glu743insTer)	Pathogenic
3247015	NC_000003.11:g.(?47422587)(47454675_?)del	Pathogenic
3642420	NM_015466.4(PTPN23):c.745dup (p.Ala249fs)	Pathogenic
3645743	NM_015466.4(PTPN23):c.1002del (p.Gly335fs)	Pathogenic
3646494	NM_015466.4(PTPN23):c.2980_2981insACAATCCCCCTACCCC (p.Pro994fs)	Pathogenic
3653317	NM_015466.4(PTPN23):c.3113_3137dup (p.His1046fs)	Pathogenic
3728676	NM_015466.4(PTPN23):c.3582_3583del (p.Trp1195fs)	Pathogenic
3729564	NM_015466.4(PTPN23):c.4121del (p.Val1374fs)	Pathogenic
4712309	NM_015466.4(PTPN23):c.2199_2200del (p.Ser733fs)	Pathogenic
4716235	NM_015466.4(PTPN23):c.947dup (p.Asn316fs)	Pathogenic
4736034	NM_015466.4(PTPN23):c.1837A>T (p.Lys613Ter)	Pathogenic

SpliceAI

3962 predictions. Top by Δscore:

Variant	Effect	Δscore
3:47381177:GAAG:G	donor_gain	1.0000
3:47381178:AAGG:A	donor_loss	1.0000
3:47381179:AGGT:A	donor_loss	1.0000
3:47381181:G:GG	donor_gain	1.0000
3:47381181:GT:G	donor_loss	1.0000
3:47381182:T:G	donor_loss	1.0000
3:47396138:T:TA	acceptor_gain	1.0000
3:47396139:GTA:G	acceptor_loss	1.0000
3:47396140:TAGTT:T	acceptor_loss	1.0000
3:47396141:A:AG	acceptor_gain	1.0000
3:47396141:AGTTT:A	acceptor_gain	1.0000
3:47396142:G:GA	acceptor_gain	1.0000
3:47396142:GT:G	acceptor_gain	1.0000
3:47396142:GTT:G	acceptor_gain	1.0000
3:47396142:GTTT:G	acceptor_gain	1.0000
3:47396142:GTTTG:G	acceptor_gain	1.0000
3:47396213:GACAG:G	donor_gain	1.0000
3:47396214:ACAGG:A	donor_loss	1.0000
3:47396215:CAGG:C	donor_loss	1.0000
3:47396216:AGGTA:A	donor_loss	1.0000
3:47396217:GGT:G	donor_loss	1.0000
3:47396218:GTAG:G	donor_loss	1.0000
3:47396219:T:G	donor_loss	1.0000
3:47402004:GC:G	donor_gain	1.0000
3:47402005:C:G	donor_gain	1.0000
3:47404650:A:AG	acceptor_gain	1.0000
3:47404651:G:GG	acceptor_gain	1.0000
3:47404651:GA:G	acceptor_gain	1.0000
3:47405748:GGA:G	acceptor_gain	1.0000
3:47405940:TCCA:T	acceptor_loss	1.0000

AlphaMissense

10566 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:47381141:G:C	K15N	1.000
3:47381141:G:T	K15N	1.000
3:47404682:G:C	G64R	1.000
3:47404710:G:A	G73D	1.000
3:47404716:T:C	L75P	1.000
3:47404725:T:C	L78P	1.000
3:47404737:T:A	V82D	1.000
3:47404778:T:A	W96R	1.000
3:47404778:T:C	W96R	1.000
3:47405079:T:C	L121P	1.000
3:47405081:G:A	G122R	1.000
3:47405081:G:C	G122R	1.000
3:47405749:G:A	G122E	1.000
3:47405755:T:C	L124P	1.000
3:47405760:T:C	S126P	1.000
3:47405769:G:A	G129R	1.000
3:47405769:G:C	G129R	1.000
3:47405769:G:T	G129W	1.000
3:47405770:G:A	G129E	1.000
3:47405923:G:C	K141N	1.000
3:47405923:G:T	K141N	1.000
3:47405939:T:C	F147L	1.000
3:47405940:T:C	F147S	1.000
3:47405941:C:A	F147L	1.000
3:47405941:C:G	F147L	1.000
3:47405944:G:C	Q148H	1.000
3:47405944:G:T	Q148H	1.000
3:47405951:G:C	A151P	1.000
3:47405952:C:A	A151D	1.000
3:47405955:G:A	G152D	1.000

dbSNP variants (sampled 300 via entrez): RS1000085608 (3:47411951 C>A), RS1000266616 (3:47384474 A>T), RS1000333053 (3:47392318 G>A), RS1000544545 (3:47405488 G>A), RS1000632131 (3:47386195 C>T), RS1000707855 (3:47401942 C>A,T), RS1000807894 (3:47393851 C>T), RS1001009849 (3:47383616 G>A), RS1001099588 (3:47394320 G>A), RS1001440554 (3:47380582 T>C), RS1001523753 (3:47392124 G>A), RS1001582095 (3:47401233 C>G), RS1001756379 (3:47413168 A>T), RS1001804689 (3:47402925 C>T), RS1001943590 (3:47402658 G>A)

Disease associations

OMIM: gene MIM:606584 | disease phenotypes: MIM:303350, MIM:618890

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity	Strong	Autosomal recessive

Mondo (3): hereditary spastic paraplegia (MONDO:0019064), neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity (MONDO:0030046), neurodevelopmental disorder (MONDO:0700092)

Orphanet (1): Hereditary spastic paraplegia (Orphanet:685)

HPO phenotypes

20 total (20 of 20 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000609	Optic nerve hypoplasia
HP:0001257	Spasticity
HP:0001276	Hypertonia
HP:0001298	Encephalopathy
HP:0001623	Breech presentation
HP:0002033	Poor suck
HP:0002079	Hypoplasia of the corpus callosum
HP:0002521	Hypsarrhythmia
HP:0006956	Lateral ventricle dilatation
HP:0007281	Developmental stagnation
HP:0008936	Axial hypotonia
HP:0011153	Focal motor seizure
HP:0011471	Gastrostomy tube feeding in infancy
HP:0012469	Infantile spasms
HP:0012736	Profound global developmental delay
HP:0025404	Abnormal visual fixation
HP:0032792	Tonic seizure
HP:0032794	Myoclonic seizure

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST007516_4	Type 2 diabetes (adjusted for BMI)	5.000000e-08
GCST007518_10	Type 2 diabetes (adjusted for BMI)	2.000000e-07
GCST007615_15	C-reactive protein levels	1.000000e-08
GCST010002_422	Refractive error	4.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004458	C-reactive protein measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression, affects binding, increases reaction	5
bisphenol A	affects cotreatment, increases methylation, decreases expression	2
6,7-dimethoxy-2-(pyrrolidin-1-yl)-N-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine	decreases expression	1
bisphenol F	increases expression	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	decreases expression	1
lead acetate	increases expression	1
titanium dioxide	decreases methylation	1
decabromobiphenyl ether	decreases expression	1
cobaltous chloride	increases expression	1
tetrabromobisphenol A	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	decreases ADP-ribosylation	1
perfluoro-n-nonanoic acid	decreases expression	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	increases abundance, increases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	decreases phosphorylation	1
Cisplatin	decreases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ivermectin	decreases expression	1
Lead	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
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,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT02604186	PHASE2/PHASE3	COMPLETED	Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT06948019	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)
NCT06478238	EARLY_PHASE1	RECRUITING	Calcium Folinate Treatment of Spastic Paraplegia 56
NCT00023075	Not specified	COMPLETED	Nuclear Magnetic Spectroscopy Imaging to Evaluate Primary Lateral Sclerosis, Hereditary Spastic Paraplegia and Amyotrophic Lateral Sclerosis
NCT00136630	Not specified	COMPLETED	Natural History, Genetic Bases and Phenotype-genotype Correlations in Autosomal Dominant Spinocerebellar Degenerations
NCT00140829	Not specified	COMPLETED	SPATAX: Clinical and Genetic Analysis of Cerebellar Ataxias and Spastic Paraplegias
NCT00677768	Not specified	COMPLETED	Validation of Biomarkers in Amyotrophic Lateral Sclerosis (ALS)
NCT01568658	Not specified	ACTIVE_NOT_RECRUITING	Genetic and Physical Study of Childhood Nerve and Muscle Disorders
NCT02327845	Not specified	ENROLLING_BY_INVITATION	Phenotype, Genotype & Biomarkers in ALS and Related Disorders
NCT02852278	Not specified	COMPLETED	A Patient Centric Motor Neuron Disease Activities of Daily Living Scale
NCT02859428	Not specified	TERMINATED	Disease Natural History and Biomarkers of SPG3A, SPG4A, and SPG31
NCT03104088	Not specified	COMPLETED	Studying Cognition in SPG4
NCT03206190	Not specified	RECRUITING	The preSPG4 Study - Studying the Prodromal and Early Phase of SPG4
NCT03627416	Not specified	COMPLETED	Repetitive Transcranial Magnetic Stimulation as Therapy in Hereditary Spastic Paraplegia and Adrenomyeloneuropathy
NCT03981276	Not specified	RECRUITING	Phenotypes, Biomarkers and Pathophysiology in Hereditary Spastic Paraplegias and Related Disorders
NCT04006418	Not specified	RECRUITING	A Registered Cohort Study on Spastic Paraplegia
NCT04180098	Not specified	COMPLETED	Improving Gait Adaptability in Hereditary Spastic Paraplegia
NCT04256681	Not specified	COMPLETED	SNAP: Measurement of the Subjective Perception of the Symptom in Hereditary Spastic Paraparesis (HSP)
NCT04712812	Not specified	RECRUITING	Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia
NCT04875416	Not specified	ACTIVE_NOT_RECRUITING	Phenotype, Genotype and Biomarkers 2
NCT04912609	Not specified	COMPLETED	Trehalose Administration in Subjects With Spastic Paraplegia 11 (3AL-SPG11)
NCT05354622	Not specified	RECRUITING	Hereditary Spastic Paraplegia Genomic Sequencing Initiative (HSPseq)
NCT05373082	Not specified	COMPLETED	Identification of Modifying Factors in Hereditary Spastic Paraplegia