PTPN4

Summary

PTPN4 (protein tyrosine phosphatase non-receptor type 4, HGNC:9656) is a protein-coding gene on chromosome 2q14.2, encoding Tyrosine-protein phosphatase non-receptor type 4 (P29074). Phosphatase that plays a role in immunity, learning, synaptic plasticity or cell homeostasis.

The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This protein contains a C-terminal PTP domain and an N-terminal domain homologous to the band 4.1 superfamily of cytoskeletal-associated proteins. This PTP has been shown to interact with glutamate receptor delta 2 and epsilon subunits, and is thought to play a role in signalling downstream of the glutamate receptors through tyrosine dephosphorylation.

Source: NCBI Gene 5775 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 184 total — 3 pathogenic, 9 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_002830

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9656
Approved symbol	PTPN4
Name	protein tyrosine phosphatase non-receptor type 4
Location	2q14.2
Locus type	gene with protein product
Status	Approved
Aliases	PTPMEG
Ensembl gene	ENSG00000088179
Ensembl biotype	protein_coding
OMIM	176878
Entrez	5775

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 18 protein_coding, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000263708, ENST00000420482, ENST00000430976, ENST00000431283, ENST00000433888, ENST00000441089, ENST00000460162, ENST00000460289, ENST00000469511, ENST00000485247, ENST00000488279, ENST00000488896, ENST00000856003, ENST00000856004, ENST00000856005, ENST00000856006, ENST00000856007, ENST00000856008, ENST00000856009, ENST00000856010, ENST00000856011, ENST00000916485, ENST00000916486, ENST00000916487, ENST00000958273

RefSeq mRNA: 1 — MANE Select: NM_002830 NM_002830

CCDS: CCDS2129

Canonical transcript exons

ENST00000263708 — 27 exons

Exon	Start	End
ENSE00001071376	119882503	119882623
ENSE00001071380	119881786	119881830
ENSE00001071384	119885795	119885882
ENSE00001071395	119882097	119882149
ENSE00001202414	119759922	119760384
ENSE00001703057	119976984	119984899
ENSE00003461656	119962616	119962744
ENSE00003471734	119946341	119946424
ENSE00003478519	119809837	119809991
ENSE00003479783	119951973	119952129
ENSE00003492510	119877464	119877542
ENSE00003502838	119945081	119945240
ENSE00003505874	119956844	119956934
ENSE00003519345	119946518	119946574
ENSE00003523050	119926598	119926666
ENSE00003532927	119957016	119957077
ENSE00003535588	119965497	119965645
ENSE00003561453	119862536	119862643
ENSE00003562325	119960807	119960953
ENSE00003565455	119900718	119900806
ENSE00003580134	119877323	119877365
ENSE00003585220	119967837	119967972
ENSE00003592060	119932424	119932549
ENSE00003609803	119920069	119920241
ENSE00003659408	119955157	119955323
ENSE00003686181	119934800	119934958
ENSE00003687329	119915179	119915242

Expression profiles

Bgee: expression breadth ubiquitous, 273 present calls, max score 97.01.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.4997 / max 379.0192, expressed in 1778 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
22286	9.1985	1644
22287	3.5751	1119
22288	3.0046	1174
22285	1.7346	559
22291	1.6434	96
22292	1.5009	89
22284	0.4304	173
22283	0.3242	159
22290	0.0881	38

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	97.01	gold quality
granulocyte	CL:0000094	92.64	gold quality
cerebellar vermis	UBERON:0004720	92.10	gold quality
calcaneal tendon	UBERON:0003701	91.99	gold quality
renal medulla	UBERON:0000362	90.65	gold quality
adrenal tissue	UBERON:0018303	90.45	gold quality
paraflocculus	UBERON:0005351	89.88	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	89.73	gold quality
corpus callosum	UBERON:0002336	89.70	gold quality
parietal lobe	UBERON:0001872	89.47	gold quality
pons	UBERON:0000988	89.37	gold quality
postcentral gyrus	UBERON:0002581	89.30	gold quality
blood	UBERON:0000178	88.62	gold quality
frontal pole	UBERON:0002795	87.89	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.59	gold quality
dorsal plus ventral thalamus	UBERON:0001897	87.57	gold quality
colonic epithelium	UBERON:0000397	87.34	gold quality
ganglionic eminence	UBERON:0004023	87.27	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.01	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	87.00	gold quality
mammary duct	UBERON:0001765	86.93	gold quality
bone marrow cell	CL:0002092	86.57	gold quality
endothelial cell	CL:0000115	86.34	gold quality
cerebellum	UBERON:0002037	85.93	gold quality
middle temporal gyrus	UBERON:0002771	85.28	gold quality
cerebellar cortex	UBERON:0002129	85.27	gold quality
epithelium of mammary gland	UBERON:0003244	85.17	gold quality
cerebellar hemisphere	UBERON:0002245	85.05	gold quality
body of tongue	UBERON:0011876	85.01	gold quality
secondary oocyte	CL:0000655	84.96	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	13.41
E-GEOD-137537	yes	5.01
E-MTAB-7606	no	400.50

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

503 targeting PTPN4, 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-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-7110-3P	100.00	73.18	2486
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-340-5P	100.00	72.50	4437
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-526A-5P	100.00	67.51	979
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-29A-3P	100.00	73.11	1835

Literature-anchored findings (GeneRIF, showing 13)

• PTPN4 is dispensable for T cell development and/or T cell effector functions. (PMID:18614237)
• These findings suggest that PTPN4 negatively regulates cell proliferation and motility through dephosphorylation of CrkI. (PMID:23666597)
• The physiologically active PTPN4 two-domain (the PDZ and the phosphatase domains) adopts a predominant compact conformation in solution. PDZ ligand binding restores the catalytic competence of PTPN4 disrupting the transient interdomain communication. (PMID:25158884)
• Deletion of PTPN4 has been reported in monozygotic twins with a Rett syndrome-like phenotype. (PMID:25424712)
• the p38gamma.PTPN4 interaction promotes cellular signaling, preventing cell death induction. (PMID:27246854)
• Binding assays confirmed that three (Cyto8-mtxd-1, Cyto8-mtxk-4 and Cyto8-mtxd-1k-4) out of the five designed peptides exhibit moderately or considerably increased affinity as compared to the native peptide Cyto8-RETEV (PMID:27923202)
• Data show that mutations affect the regulation of the protein tyrosine phosphatase non-receptor type 4 (PTPN4) bidomain and indicate that the PDZ-PDZ ligand regulation of PTPN4 is a linker-mediated mechanism. (PMID:28801650)
• Study identified a nonsense mutation of PTPN4 with mutation ratio of 90.90% from 1 case of rectal cancer. Overexpression of PTPN4 suppressed the growth of colorectal cancer cells. PTPN4 dephosphorylates pSTAT3 at the Tyr705 residue with a direct interaction and depresses the transcriptional activity of STAT3. (PMID:31025789)
• Structural and biochemical analysis of the PTPN4 PDZ domain bound to the C-terminal tail of the human papillomavirus E6 oncoprotein. (PMID:35089587)
• MicroRNA-375 is a therapeutic target for castration-resistant prostate cancer through the PTPN4/STAT3 axis. (PMID:36042375)
• E3 Ubiquitin Ligase MARCH8 Promotes Pancreatic Cancer Growth and Metastasis by Activating STAT3 via Degradation of PTPN4. (PMID:37747937)
• circRNA-PTPN4 mediated regulation of FOXO3 and ZO-1 expression: implications for blood-brain barrier integrity and cognitive function in uremic encephalopathy. (PMID:38630149)
• LncRNA SH3BP5-AS1 promotes hepatocellular carcinoma progression by sponging miR-6838-5p and activation of PTPN4. (PMID:38761175)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ptpn4b	ENSDARG00000000183
danio_rerio	ptpn4a	ENSDARG00000000631
mus_musculus	Ptpn4	ENSMUSG00000026384
rattus_norvegicus	Ptpn4	ENSRNOG00000002625

Paralogs (35): PTPRN (ENSG00000054356), PTPRU (ENSG00000060656), PTPN3 (ENSG00000070159), PTPN21 (ENSG00000070778), PTPN18 (ENSG00000072135), PTPN23 (ENSG00000076201), PTPRH (ENSG00000080031), PTPRC (ENSG00000081237), 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 4 — P29074 (reviewed: P29074)

Alternative names: Protein-tyrosine phosphatase MEG1

All UniProt accessions (7): P29074, F5H020, J3KQD3, J3KQP5, J3QT41, J3QT59, J3QT89

UniProt curated annotations — full annotation on UniProt →

Function. Phosphatase that plays a role in immunity, learning, synaptic plasticity or cell homeostasis. Regulates neuronal cell homeostasis by protecting neurons against apoptosis. Negatively regulates TLR4-induced interferon beta production by dephosphorylating adapter TICAM2 and inhibiting subsequent TRAM-TRIF interaction. Also dephosphorylates the immunoreceptor tyrosine-based activation motifs/ITAMs of the TCR zeta subunit and thereby negatively regulates TCR-mediated signaling pathway. May act at junctions between the membrane and the cytoskeleton.

Subunit / interactions. Interacts with MAPK12 (via C-terminus); this interaction abolishes PTPN4 catalytic autoinhibition and thus activates the phosphatase activity. (Microbial infection) Interacts with attenuated rabies virus protein G; this interaction is required for virally-induced apoptosis.

Subcellular location. Cell membrane. Cytoplasm. Cytoskeleton.

Post-translational modifications. Highly phosphorylated on serine and threonine residues but not on tyrosines. Cleaved and activated by calpain I/CAPN1.

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

RefSeq proteins (1): NP_002821* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000242	PTP_cat	Domain
IPR000299	FERM_domain	Domain
IPR000387	Tyr_Pase_dom	Domain
IPR001478	PDZ	Domain
IPR003595	Tyr_Pase_cat	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR012151	Tyr_Pase_non-rcpt_typ-3/4	Family
IPR014352	FERM/acyl-CoA-bd_prot_sf	Homologous_superfamily
IPR014847	FA	Domain
IPR016130	Tyr_Pase_AS	Active_site
IPR018979	FERM_N	Domain
IPR018980	FERM_PH-like_C	Domain
IPR019747	FERM_CS	Conserved_site
IPR019748	FERM_central	Domain
IPR019749	Band_41_domain	Domain
IPR029021	Prot-tyrosine_phosphatase-like	Homologous_superfamily
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR035963	FERM_2	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily
IPR041783	PTPN3/4_FERM_C	Domain

Pfam: PF00102, PF00373, PF00595, PF08736, PF09379, PF09380

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 (55 total): strand 21, helix 15, domain 3, binding site 3, sequence conflict 3, turn 2, region of interest 2, compositionally biased region 2, chain 1, modified residue 1, sequence variant 1, active site 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
3NFK	X-RAY DIFFRACTION	1.43
2VPH	X-RAY DIFFRACTION	1.9
3NFL	X-RAY DIFFRACTION	1.91
5EYZ	X-RAY DIFFRACTION	2.09
5EZ0	X-RAY DIFFRACTION	2.35
2I75	X-RAY DIFFRACTION	2.45
7VZE	X-RAY DIFFRACTION	2.88
2CS5	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P29074-F1	77.48	0.56

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): 852 (phosphocysteine intermediate)

Ligand- & substrate-binding residues (3): 852–858; 896; 820

Post-translational modifications (1): 474

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-166016	Toll Like Receptor 4 (TLR4) Cascade
R-HSA-9008059	Interleukin-37 signaling
R-HSA-9022699	MECP2 regulates neuronal receptors and channels

MSigDB gene sets: 344 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, MULLIGHAN_NPM1_SIGNATURE_3_UP, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, TGCACTT_MIR519C_MIR519B_MIR519A, GNF2_ZAP70, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, GNF2_IL2RB, FONTAINE_PAPILLARY_THYROID_CARCINOMA_DN, LYF1_01, GOBP_DEPHOSPHORYLATION, GOBP_PROTEIN_DEPHOSPHORYLATION, ACTTTAT_MIR1425P, GOMF_SIGNALING_RECEPTOR_BINDING, chr2q14

GO Biological Process (2): protein dephosphorylation (GO:0006470), dephosphorylation (GO:0016311)

GO Molecular Function (7): protein tyrosine phosphatase activity (GO:0004725), non-membrane spanning protein tyrosine phosphatase activity (GO:0004726), cytoskeletal protein binding (GO:0008092), glutamate receptor binding (GO:0035254), phosphoprotein phosphatase activity (GO:0004721), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (7): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), cytoskeleton (GO:0005856), cytoplasmic side of plasma membrane (GO:0009898), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Toll-like Receptor Cascades	1
Interleukin-1 family signaling	1
Transcriptional Regulation by MECP2	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
dephosphorylation	1
protein modification process	1
phosphate-containing compound metabolic process	1
phosphoprotein phosphatase activity	1
protein tyrosine phosphatase activity	1
protein binding	1
signaling receptor binding	1
phosphatase activity	1
catalytic activity, acting on a protein	1
binding	1
catalytic activity	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
intracellular membraneless organelle	1
plasma membrane	1
cytoplasmic side of membrane	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

950 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PTPN4	PTS	Q03393	844
PTPN4	TAAR1	Q96RJ0	761
PTPN4	GRID2	O43424	616
PTPN4	GRIN2A	Q12879	491
PTPN4	MAST2	Q6P0Q8	457
PTPN4	MTMR4	Q9NYA4	440
PTPN4	TMEM185B	Q9H7F4	430
PTPN4	CRB3	Q9BUF7	429
PTPN4	NXN	Q6DKJ4	420
PTPN4	ABHD15	Q6UXT9	411
PTPN4	RBFOX2	O43251	393
PTPN4	GRID2IP	A4D2P6	359
PTPN4	NBEAL1	Q6ZS30	358
PTPN4	CRB2	Q5IJ48	352
PTPN4	ZBTB44	Q8NCP5	350

IntAct

77 interactions, top by confidence:

A	B	Type	Score
PTPN4		psi-mi:“MI:0407”(direct interaction)	0.560
PTPN4	CASP6	psi-mi:“MI:0915”(physical association)	0.560
PTPN4	CCK	psi-mi:“MI:0915”(physical association)	0.560
PTPN4	LAMP2	psi-mi:“MI:0915”(physical association)	0.560
PRPF40A	PTPN4	psi-mi:“MI:0915”(physical association)	0.560
CRK	PTPN4	psi-mi:“MI:0915”(physical association)	0.540
PTPN4	CRK	psi-mi:“MI:0915”(physical association)	0.540
CRK	PTPN4	psi-mi:“MI:0403”(colocalization)	0.540
KCTD17	CBX4	psi-mi:“MI:0914”(association)	0.530
PTPN4	KAT5	psi-mi:“MI:0915”(physical association)	0.510
PTPN4		psi-mi:“MI:0407”(direct interaction)	0.440
E6	PTPN4	psi-mi:“MI:0407”(direct interaction)	0.440
FRMPD4	PTPN4	psi-mi:“MI:0407”(direct interaction)	0.440
ABCC4	PTPN4	psi-mi:“MI:0407”(direct interaction)	0.440
SLCO1C1	PTPN4	psi-mi:“MI:0407”(direct interaction)	0.440
PTPN4	ATP2B4	psi-mi:“MI:0407”(direct interaction)	0.440
SLC15A5	PTPN4	psi-mi:“MI:0407”(direct interaction)	0.440
DGKZ	PTPN4	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (92): PTPN4 (Affinity Capture-MS), ADH5 (Affinity Capture-MS), CADM1 (Affinity Capture-MS), GOLIM4 (Affinity Capture-MS), LTBP1 (Affinity Capture-MS), MPP7 (Affinity Capture-MS), PAK4 (Affinity Capture-MS), PEX19 (Affinity Capture-MS), SHKBP1 (Affinity Capture-MS), SNRPD1 (Affinity Capture-MS), YWHAG (Affinity Capture-MS), YWHAH (Affinity Capture-MS), YWHAQ (Affinity Capture-MS), YWHAZ (Affinity Capture-MS), PTPN4 (Affinity Capture-MS)

ESM2 similar proteins: A0A6I8TCE0, B0X4T2, F1NY98, O00533, O35158, O55005, O60469, O89026, O97394, P12960, P14781, P16092, P17790, P18460, P18461, P21802, P21803, P28685, P29074, P35331, P35832, P57097, P70232, P97686, Q12860, Q12866, Q28106, Q32MD9, Q3UH53, Q4KMG0, Q60805, Q61851, Q63198, Q7Z5N4, Q7ZXX1, Q810U4, Q8AV58, Q8AXZ4, Q8JG38, Q8VHZ8

Diamond homologs: A0A6I8TCE0, A1L1L3, A2ALK8, A4IFW2, B0V2N1, B0X4T2, B1AUH1, B2GV87, B2RU80, B3DK56, B9EKR1, E9Q0N2, E9Q612, F1NWE3, G5EC24, G5EGJ9, H2KZM6, O02695, O08617, O13016, O35239, O55082, P06800, P16620, P17706, P18031, P18052, P18433, P20417, P23467, P23468, P23469, P23470, P23471, P26045, P28191, P29074, P29350, P29351, P29352

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PTPN4	“down-regulates activity”	STAT3	dephosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 54 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
FCGR3A-mediated phagocytosis	5	23.4×	5e-04
VEGFA-VEGFR2 Pathway	5	17.4×	8e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	9
Uncertain significance	113
Likely benign	19
Benign	3

Top pathogenic / likely-pathogenic (12)

Variant ID	HGVS	Classification
1699459	NM_002830.4(PTPN4):c.2338C>T (p.Gln780Ter)	Pathogenic
2210441	NM_002830.4(PTPN4):c.745C>T (p.Arg249Ter)	Pathogenic
4628612	NM_002830.4(PTPN4):c.191T>A (p.Leu64Ter)	Pathogenic
2202475	NM_002830.4(PTPN4):c.138+2T>C	Likely pathogenic
2413540	NM_002830.4(PTPN4):c.1355+1G>A	Likely pathogenic
2817448	NM_002830.4(PTPN4):c.246+1G>T	Likely pathogenic
3254664	NM_002830.4(PTPN4):c.149del (p.Gln50fs)	Likely pathogenic
3602584	NM_002830.4(PTPN4):c.538C>T (p.Gln180Ter)	Likely pathogenic
3775489	NM_002830.4(PTPN4):c.629del (p.Thr210fs)	Likely pathogenic
3940588	NM_002830.4(PTPN4):c.64C>T (p.Arg22Ter)	Likely pathogenic
4628610	NM_002830.4(PTPN4):c.16C>T (p.Arg6Ter)	Likely pathogenic
998079	NM_002830.4(PTPN4):c.1738G>T (p.Asp580Tyr)	Likely pathogenic

SpliceAI

5219 predictions. Top by Δscore:

Variant	Effect	Δscore
2:119809835:A:AG	acceptor_gain	1.0000
2:119809836:G:GA	acceptor_loss	1.0000
2:119809836:G:GG	acceptor_gain	1.0000
2:119809836:GACTT:G	acceptor_gain	1.0000
2:119809987:TCAAT:T	donor_gain	1.0000
2:119809988:CAAT:C	donor_gain	1.0000
2:119809989:AAT:A	donor_gain	1.0000
2:119809989:AATG:A	donor_loss	1.0000
2:119809990:AT:A	donor_gain	1.0000
2:119809990:ATG:A	donor_loss	1.0000
2:119809991:TGT:T	donor_loss	1.0000
2:119809992:G:GG	donor_gain	1.0000
2:119809993:TAAG:T	donor_loss	1.0000
2:119862532:A:AG	acceptor_gain	1.0000
2:119862532:ACAG:A	acceptor_loss	1.0000
2:119862533:C:G	acceptor_gain	1.0000
2:119862533:CA:C	acceptor_loss	1.0000
2:119862534:A:AG	acceptor_gain	1.0000
2:119862534:AGAAA:A	acceptor_loss	1.0000
2:119862535:G:A	acceptor_loss	1.0000
2:119862535:G:GA	acceptor_gain	1.0000
2:119862535:GA:G	acceptor_gain	1.0000
2:119862535:GAA:G	acceptor_gain	1.0000
2:119862535:GAAA:G	acceptor_gain	1.0000
2:119862535:GAAAC:G	acceptor_gain	1.0000
2:119862639:ACCCA:A	donor_gain	1.0000
2:119862640:CCCA:C	donor_gain	1.0000
2:119862641:CCA:C	donor_gain	1.0000
2:119862642:CA:C	donor_gain	1.0000
2:119862644:G:GG	donor_gain	1.0000

AlphaMissense

6101 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:119946411:G:A	G529E	1.000
2:119946414:T:C	F530S	1.000
2:119946518:G:A	G534R	1.000
2:119946518:G:C	G534R	1.000
2:119946549:T:A	V544E	1.000
2:119952013:T:A	V566D	1.000
2:119952112:T:C	L599P	1.000
2:119952118:T:A	V601D	1.000
2:119956912:T:A	N683K	1.000
2:119956912:T:G	N683K	1.000
2:119956913:A:G	R684G	1.000
2:119956914:G:C	R684T	1.000
2:119956914:G:T	R684I	1.000
2:119956915:A:C	R684S	1.000
2:119956915:A:T	R684S	1.000
2:119956916:T:C	Y685H	1.000
2:119956932:C:A	P690H	1.000
2:119957062:T:A	N706K	1.000
2:119957062:T:G	N706K	1.000
2:119960847:C:A	A725D	1.000
2:119960854:A:C	Q727H	1.000
2:119960854:A:T	Q727H	1.000
2:119960855:G:A	G728R	1.000
2:119960855:G:C	G728R	1.000
2:119960855:G:T	G728W	1.000
2:119960856:G:A	G728E	1.000
2:119960885:T:A	W738R	1.000
2:119960885:T:C	W738R	1.000
2:119960928:T:G	L752W	1.000
2:119962619:A:G	K762E	1.000

dbSNP variants (sampled 300 via entrez): RS1000022895 (2:119983105 C>G), RS1000034113 (2:119937168 A>G), RS1000036303 (2:119914339 A>C), RS1000050201 (2:119868907 G>A,C), RS1000058841 (2:119795278 C>T), RS1000072336 (2:119937465 G>A), RS1000083663 (2:119781492 T>A), RS1000096323 (2:119938979 G>T), RS1000096405 (2:119978742 A>G), RS1000097255 (2:119921494 C>G), RS1000133843 (2:119924247 T>G), RS1000143460 (2:119893597 T>A), RS1000168493 (2:119893211 T>A), RS1000174392 (2:119759806 G>A,C), RS1000180870 (2:119944228 G>A,T)

Disease associations

OMIM: gene MIM:176878 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Strong	Autosomal dominant

Mondo (2): neurodevelopmental disorder (MONDO:0700092), intellectual disability (MONDO:0001071)

Orphanet (1): NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002388_292	Lymphocyte count	3.000000e-16

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004587	lymphocyte count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3165 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 3 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.75	IC50	180	nM	CHEMBL4569405
5.27	IC50	5400	nM	CHEMBL4540813

PubChem BioAssay actives

7 with measured affinity, of 15 total; 7 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
phenyl-[[25,26,27,28-tetrahydroxy-11,17,23-tris[[hydroxy(phenyl)phosphoryl]methyl]-2,2,8,8,14,14,20,20-octaoxo-2lambda6,8lambda6,14lambda6,20lambda6-tetrathiapentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(24),3,5,7(28),9,11,13(27),15(26),16,18,21(25),22-dodecaen-5-yl]methyl]phosphinic acid	1624390: Inhibition of recombinant human N-terminal GST-tagged MEG1 catalytic domain (637 to 926 residues) expressed in Escherichia coli using p-nitrophenol as substrate preincubated with substrate for 5 mins followed by enzyme addition	ic50	0.1800	uM
2-[(2-hydroxy-5-nitrophenyl)methylideneamino]benzoic acid;oxo(dioxonio)vanadium	1800517: PTP inhibition assay from Article 10.1039/c2dt30198a: “Synthesis and evaluation of oxovanadium(IV) complexes of Schiff-base condensates from 5-substituted-2-hydroxybenzaldehyde and 2-substituted-benzenamine as selective inhibitors of protein tyrosine phosphatase 1B.”	ic50	0.6000	uM
2-[(5-bromo-2-hydroxyphenyl)methylideneamino]benzoic acid;oxo(dioxonio)vanadium	1800517: PTP inhibition assay from Article 10.1039/c2dt30198a: “Synthesis and evaluation of oxovanadium(IV) complexes of Schiff-base condensates from 5-substituted-2-hydroxybenzaldehyde and 2-substituted-benzenamine as selective inhibitors of protein tyrosine phosphatase 1B.”	ic50	0.9700	uM
bis(4-bromo-2-(phenyliminomethyl)phenol);oxovanadium	1800517: PTP inhibition assay from Article 10.1039/c2dt30198a: “Synthesis and evaluation of oxovanadium(IV) complexes of Schiff-base condensates from 5-substituted-2-hydroxybenzaldehyde and 2-substituted-benzenamine as selective inhibitors of protein tyrosine phosphatase 1B.”	ic50	2.9000	uM
bis(4-nitro-2-(phenyliminomethyl)phenol);oxovanadium	1800517: PTP inhibition assay from Article 10.1039/c2dt30198a: “Synthesis and evaluation of oxovanadium(IV) complexes of Schiff-base condensates from 5-substituted-2-hydroxybenzaldehyde and 2-substituted-benzenamine as selective inhibitors of protein tyrosine phosphatase 1B.”	ic50	3.2000	uM
bis(4-chloro-2-(phenyliminomethyl)phenol);oxovanadium	1800517: PTP inhibition assay from Article 10.1039/c2dt30198a: “Synthesis and evaluation of oxovanadium(IV) complexes of Schiff-base condensates from 5-substituted-2-hydroxybenzaldehyde and 2-substituted-benzenamine as selective inhibitors of protein tyrosine phosphatase 1B.”	ic50	3.6000	uM
phenyl-[[25,26,27,28-tetrahydroxy-11,17,23-tris[[hydroxy(phenyl)phosphoryl]methyl]-2,8,14,20-tetrathiapentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(24),3,5,7(28),9,11,13(27),15(26),16,18,21(25),22-dodecaen-5-yl]methyl]phosphinic acid	1624390: Inhibition of recombinant human N-terminal GST-tagged MEG1 catalytic domain (637 to 926 residues) expressed in Escherichia coli using p-nitrophenol as substrate preincubated with substrate for 5 mins followed by enzyme addition	ic50	5.4000	uM

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
testosterone enanthate	affects expression	1
methylmercuric chloride	decreases expression	1
oxybenzone	increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	increases activity, increases expression, affects binding	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
crocin	increases expression, decreases reaction, affects reaction, increases activity	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
Vorinostat	increases expression	1
Acetaminophen	increases expression	1
Benzo(a)pyrene	decreases expression	1
Cadmium	increases expression, increases abundance	1
Doxorubicin	decreases expression	1
Maneb	affects activity	1
Silicon Dioxide	decreases expression	1
Tamoxifen	affects expression	1
Thimerosal	increases expression	1
Thiram	decreases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	increases abundance, increases expression	1
Raloxifene Hydrochloride	affects expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3888466	Binding	Enzyme Kinetic Assay: PTP activity was assayed using p-nitrophenyl phosphate (pNPP) as a substrate in 3,3-dimethylglutarate buffer (50 mM 3,3-dimethylglutarate, pH 7.0, 1 mM EDTA, 150 mM NaCl, 2 mM DTT, 0.1 mg/mL BSA) at 25° C. The assays w	Inhibitors of protein tyrosine phosphatases

Clinical trials (associated diseases)

202 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,
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
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
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
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice