PKP4

Summary

PKP4 (plakophilin 4, HGNC:9026) is a protein-coding gene on chromosome 2q24.1, encoding Plakophilin-4 (Q99569). Plays a role as a regulator of Rho activity during cytokinesis.

Armadillo-like proteins are characterized by a series of armadillo repeats, first defined in the Drosophila ‘armadillo’ gene product, that are typically 42 to 45 amino acids in length. These proteins can be divided into subfamilies based on their number of repeats, their overall sequence similarity, and the dispersion of the repeats throughout their sequences. Members of the p120(ctn)/plakophilin subfamily of Armadillo-like proteins, including CTNND1, CTNND2, PKP1, PKP2, PKP4, and ARVCF. PKP4 may be a component of desmosomal plaque and other adhesion plaques and is thought to be involved in regulating junctional plaque organization and cadherin function. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 8502 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 729 total
• Druggable target: yes
• MANE Select transcript: NM_003628

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9026
Approved symbol	PKP4
Name	plakophilin 4
Location	2q24.1
Locus type	gene with protein product
Status	Approved
Aliases	p0071
Ensembl gene	ENSG00000144283
Ensembl biotype	protein_coding
OMIM	604276
Entrez	8502

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 18 protein_coding, 6 nonsense_mediated_decay, 4 protein_coding_CDS_not_defined, 4 retained_intron

ENST00000389757, ENST00000389759, ENST00000411900, ENST00000421462, ENST00000426248, ENST00000452162, ENST00000457109, ENST00000462335, ENST00000479398, ENST00000480171, ENST00000481115, ENST00000483881, ENST00000486254, ENST00000492496, ENST00000494945, ENST00000495123, ENST00000866374, ENST00000866375, ENST00000866376, ENST00000866377, ENST00000866378, ENST00000866379, ENST00000866380, ENST00000866381, ENST00000866382, ENST00000866383, ENST00000866384, ENST00000866385, ENST00000930824, ENST00000930825, ENST00000962540, ENST00000962541

RefSeq mRNA: 14 — MANE Select: NM_003628 NM_001005476, NM_001304969, NM_001304970, NM_001304971, NM_001377218, NM_001377219, NM_001377220, NM_001377221, NM_001377222, NM_001377223, NM_001377224, NM_001377225, NM_001377226, NM_003628

CCDS: CCDS33305, CCDS33306

Canonical transcript exons

ENST00000389759 — 22 exons

Exon	Start	End
ENSE00001782645	158680429	158681429
ENSE00001909391	158456952	158457218
ENSE00002730111	158533180	158533316
ENSE00003462421	158642486	158642699
ENSE00003463996	158577271	158577383
ENSE00003521040	158669720	158669915
ENSE00003521315	158678581	158678654
ENSE00003545804	158621231	158621421
ENSE00003558359	158640627	158640759
ENSE00003590716	158631753	158631941
ENSE00003595039	158666413	158666563
ENSE00003596451	158676739	158676867
ENSE00003603488	158673883	158674000
ENSE00003617470	158658131	158658314
ENSE00003621744	158662897	158663088
ENSE00003625025	158620990	158621121
ENSE00003626163	158663272	158663445
ENSE00003653833	158624878	158625427
ENSE00003661532	158634070	158634289
ENSE00003671308	158661333	158661450
ENSE00003677616	158603070	158603104
ENSE00003681078	158673677	158673761

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 99.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.0884 / max 342.1206, expressed in 1642 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
23211	6.8426	1406
23209	2.9179	1245
23213	0.7749	231
23210	0.6045	330
23212	0.5423	254
23221	0.4123	162
23218	0.3405	122
23214	0.3180	191
202454	0.1846	85
23215	0.1508	73

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	99.47	gold quality
spinal cord	UBERON:0002240	99.04	gold quality
inferior vagus X ganglion	UBERON:0005363	98.70	gold quality
medial globus pallidus	UBERON:0002477	98.54	gold quality
corpus callosum	UBERON:0002336	98.30	gold quality
globus pallidus	UBERON:0001875	98.17	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.97	gold quality
subthalamic nucleus	UBERON:0001906	97.89	gold quality
caput epididymis	UBERON:0004358	97.77	gold quality
amygdala	UBERON:0001876	97.66	gold quality
putamen	UBERON:0001874	97.59	gold quality
middle frontal gyrus	UBERON:0002702	97.52	gold quality
metanephros cortex	UBERON:0010533	97.10	gold quality
hypothalamus	UBERON:0001898	97.09	gold quality
caudate nucleus	UBERON:0001873	97.08	gold quality
cranial nerve II	UBERON:0000941	97.03	gold quality
substantia nigra	UBERON:0002038	96.93	gold quality
nucleus accumbens	UBERON:0001882	96.85	gold quality
substantia nigra pars compacta	UBERON:0001965	96.85	gold quality
Ammon’s horn	UBERON:0001954	96.81	gold quality
midbrain	UBERON:0001891	96.77	gold quality
right frontal lobe	UBERON:0002810	96.77	gold quality
prefrontal cortex	UBERON:0000451	96.72	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.55	gold quality
cingulate cortex	UBERON:0003027	96.49	gold quality
cerebellar hemisphere	UBERON:0002245	96.48	gold quality
anterior cingulate cortex	UBERON:0009835	96.48	gold quality
cerebellar cortex	UBERON:0002129	96.37	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.19	gold quality
lateral globus pallidus	UBERON:0002476	96.18	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	51.97
E-MTAB-10287	yes	45.82
E-GEOD-135922	yes	34.53
E-ANND-3	yes	14.95
E-CURD-135	no	649.04

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

90 targeting PKP4, 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-3613-3P	100.00	76.36	7965
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-545-3P	99.95	70.74	2783
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-489-3P	99.80	66.46	839
HSA-MIR-4713-5P	99.78	67.80	1794

Literature-anchored findings (GeneRIF, showing 16)

• ERBIN interacts in vivo with p0071 and that it may be involved in the organization of adherens junctions and the desmosomes of epithelia (PMID:12047349)
• In addition to plakoglobin, p0071 is the second armadillo protein present in both types of adhesive junctions and may play a role in regulating crosstalk between adherens junctions and desmosomes. (PMID:12615965)
• p0071 bound to the first 160 amino-terminal residues of desmoplakin and also interacted directly with plakoglobin, suggesting that p0071 may regulate desmosome assembly by controlling plakoglobin availability (PMID:15304078)
• These findings support an essential role for p0071 in spatially regulating restricted Rho signalling during cytokinesis. (PMID:17115030)
• In this review p0071 catenin, a close relative of p120 catenin, associates and regulates RhoA-GTPase at the cleavage furrow during cytokinesis. (PMID:17264675)
• Protein p0071 has been localized as a plaque protein in adhaerens junctions of diverse epithelia and certain vascular endothelia. (PMID:19005682)
• Using shotgun mass spectrometry, we found this protein differentially expressed in the dorsolateral prefrontal cortex from patients with schizophrenia. (PMID:19165527)
• Data indicate that p0071 and Ect2 are transported via distinct motors and identify a novel pathway implicating KIF3 in the regulation of actin organization during cytokinesis. (PMID:19339549)
• The structural and functional roles of p0071 are suggested by its preferential occurrence in distinct tubule segments, and its potential use as a cytodiagnostic cell type marker in renal pathology is discussed. (PMID:19830446)
• Findings suggest that aspects of folliculin tumour suppressor function are linked to interaction with p0071 and the regulation of RhoA signalling. (PMID:22965878)
• These data support a model in which dysregulation of the FLCN-p0071 interaction leads to alterations in cell adhesion, cell polarity, and RhoA signaling. (PMID:23139756)
• This review article focuses on the functions of the p0071 protein and its closest relatives in regulating cell adhesion and cytoskeletal organization, which are critically involved in the control of cell polarity. [review] (PMID:23640939)
• p0071 has a key role in regulating recycling through the Rab11a-dependent perinuclear recycling compartment. (PMID:24163434)
• p0071 is required for directional vesicle movement and secretion of different KIF3-transported carriers, thereby regulating the transport of intracellular membrane vesicles along microtubules. (PMID:28808088)
• Data show that patients with both abnormal expression of p0071 and E-cadherin had a statistically significant shorter survival than the patients without both abnormal expression. (PMID:28898462)
• Kir2.1 Interactome Mapping Uncovers PKP4 as a Modulator of the Kir2.1-Regulated Inward Rectifier Potassium Currents. (PMID:32541000)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	pkp4	ENSDARG00000045331
mus_musculus	Pkp4	ENSMUSG00000026991
rattus_norvegicus	Pkp4	ENSRNOG00000005504

Paralogs (6): PKP2 (ENSG00000057294), PKP1 (ENSG00000081277), ARVCF (ENSG00000099889), CTNND2 (ENSG00000169862), PKP3 (ENSG00000184363), CTNND1 (ENSG00000198561)

Protein

Protein identifiers

Plakophilin-4 — Q99569 (reviewed: Q99569)

Alternative names: p0071

All UniProt accessions (6): Q99569, E7EMY7, E7EP40, E7EST6, E9PHJ1, H0YFB1

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role as a regulator of Rho activity during cytokinesis. May play a role in junctional plaques.

Subunit / interactions. Interacts with PDZD2. Interacts (via the C-terminus) with FRMPD2 (via the PDZ 2 domain). Interacts with RHOA; the interaction is detected at the midbody. Interacts with ECT2; the interaction is detected at the midbody. Interacts with CCDC85B.

Subcellular location. Cell junction. Desmosome. Cytoplasm. Cytoskeleton. Spindle. Midbody. Cell membrane.

Tissue specificity. Expressed in salivary glands (at protein level). Expressed in arrector pili muscle (at protein level).

Similarity. Belongs to the beta-catenin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q99569-1	1, Long	yes
Q99569-2	2, Short

RefSeq proteins (14): NP_001005476, NP_001291898, NP_001291899, NP_001291900, NP_001364147, NP_001364148, NP_001364149, NP_001364150, NP_001364151, NP_001364152, NP_001364153, NP_001364154, NP_001364155, NP_003619* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000225	Armadillo	Repeat
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR028435	Plakophilin/d_Catenin	Family

Pfam: PF00514

UniProt features (75 total): modified residue 36, sequence conflict 13, repeat 9, compositionally biased region 8, region of interest 6, chain 1, coiled-coil region 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99569-F1	57.96	0.31

Functional residue map

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

Post-translational modifications (36): 75, 84, 106, 132, 136, 139, 221, 231, 236, 254, 270, 273, 281, 314, 327, 337, 372, 392, 403, 406 …

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-6805567	Keratinization
R-HSA-6809371	Formation of the cornified envelope
R-HSA-9696264	RND3 GTPase cycle
R-HSA-9696270	RND2 GTPase cycle
R-HSA-9696273	RND1 GTPase cycle

MSigDB gene sets: 366 (showing top): ATF_B, RNGTGGGC_UNKNOWN, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GCM_PTPRD, PAL_PRMT5_TARGETS_UP, GCANCTGNY_MYOD_Q6, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, TTGGGAG_MIR150, GOBP_CELL_CELL_SIGNALING, SHEDDEN_LUNG_CANCER_GOOD_SURVIVAL_A5, CREB_Q4, GOBP_CELL_CELL_ADHESION, DAWSON_METHYLATED_IN_LYMPHOMA_TCL1, OSWALD_HEMATOPOIETIC_STEM_CELL_IN_COLLAGEN_GEL_UP

GO Biological Process (7): cell-cell junction assembly (GO:0007043), cell-cell signaling (GO:0007267), regulation of cell adhesion (GO:0030155), positive regulation of cytokinesis (GO:0032467), regulation of Rho protein signal transduction (GO:0035023), cell-cell adhesion (GO:0098609), cell adhesion (GO:0007155)

GO Molecular Function (2): cadherin binding (GO:0045296), protein binding (GO:0005515)

GO Cellular Component (21): spindle pole (GO:0000922), cornified envelope (GO:0001533), nucleus (GO:0005634), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), adherens junction (GO:0005912), cytoplasmic side of plasma membrane (GO:0009898), postsynaptic density (GO:0014069), cell junction (GO:0030054), desmosome (GO:0030057), midbody (GO:0030496), perinuclear region of cytoplasm (GO:0048471), spindle midzone (GO:0051233), mitotic spindle (GO:0072686), spindle (GO:0005819), membrane (GO:0016020), organelle (GO:0043226), cell-cell contact zone (GO:0044291), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
RHO GTPase cycle	3
Developmental Biology	1
Keratinization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	8
spindle	3
cell-cell junction	3
cell adhesion	2
plasma membrane	2
intracellular membraneless organelle	2
cell junction assembly	1
cell-cell junction organization	1
cell communication	1
signaling	1
regulation of cellular process	1
cytokinesis	1
regulation of cytokinesis	1
positive regulation of cell division	1
positive regulation of cell cycle process	1
Rho protein signal transduction	1
regulation of small GTPase mediated signal transduction	1
cellular process	1
cell adhesion molecule binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
anchoring junction	1
cytoplasmic side of membrane	1
asymmetric synapse	1
postsynaptic specialization	1
cytoplasm	1
microtubule cytoskeleton	1

Protein interactions and networks

STRING

1290 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PKP4	PDZD2	O15018	915
PKP4	DSP	P15924	837
PKP4	ECT2	Q9H8V3	830
PKP4	FRMPD2	Q68DX3	804
PKP4	ERBIN	Q96RT1	740
PKP4	CDH17	Q12864	727
PKP4	KIF3B	O15066	724
PKP4	CTNNB1	P35222	689
PKP4	LRRC7	Q96NW7	680
PKP4	FLCN	Q8NFG4	636
PKP4	ZBTB33	Q86T24	589
PKP4	CDH1	P12830	581
PKP4	DSC2	Q02487	561
PKP4	CDH5	P33151	544
PKP4	DSC3	Q14574	525

IntAct

240 interactions, top by confidence:

A	B	Type	Score
SCRIB	PKP4	psi-mi:“MI:0915”(physical association)	0.770
SCRIB	PKP4	psi-mi:“MI:0403”(colocalization)	0.770
SCRIB	PKP4	psi-mi:“MI:0407”(direct interaction)	0.770
ERBIN	PKP4	psi-mi:“MI:0915”(physical association)	0.730
CDH1	CTNND1	psi-mi:“MI:0914”(association)	0.730
PKP4	ERBIN	psi-mi:“MI:0407”(direct interaction)	0.730
PKP4	DLG1	psi-mi:“MI:0915”(physical association)	0.720
DLG1	PKP4	psi-mi:“MI:0407”(direct interaction)	0.720
PKP4	DLG1	psi-mi:“MI:0407”(direct interaction)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
TAX1BP3	ARVCF	psi-mi:“MI:0914”(association)	0.690
PKP4	TAX1BP3	psi-mi:“MI:0407”(direct interaction)	0.690
ATPAF2	PKP4	psi-mi:“MI:0915”(physical association)	0.670
PKP4	ATPAF2	psi-mi:“MI:0915”(physical association)	0.670
INAVA	CYTH3	psi-mi:“MI:0914”(association)	0.640
ERBIN	PKP4	psi-mi:“MI:0915”(physical association)	0.630
DLG4	PKP4	psi-mi:“MI:0407”(direct interaction)	0.620
PATJ	PKP4	psi-mi:“MI:0407”(direct interaction)	0.620

BioGRID (224): PKP4 (Two-hybrid), PKP4 (Two-hybrid), LZTS2 (Two-hybrid), ATPAF2 (Two-hybrid), PKP4 (Affinity Capture-RNA), PKP4 (Affinity Capture-RNA), PKP4 (Affinity Capture-MS), PKP4 (Affinity Capture-MS), PKP4 (Proximity Label-MS), PKP4 (Two-hybrid), PKP4 (Affinity Capture-MS), PKP4 (Affinity Capture-MS), PKP4 (Affinity Capture-MS), PKP4 (Affinity Capture-MS), PKP4 (Affinity Capture-MS)

ESM2 similar proteins: A1L1C7, O08873, O42611, O60716, O94776, O94967, P83094, Q01826, Q0P5J8, Q15542, Q3UHE1, Q3UVG3, Q4R8N2, Q58A45, Q5EY87, Q5JSJ4, Q5M7R9, Q5R7S4, Q5RAR8, Q5TKA1, Q60611, Q640Q5, Q658Y4, Q68FH0, Q6ISB3, Q6NT76, Q6TEP1, Q80U28, Q8BIE6, Q8BJA3, Q8C092, Q8C0V0, Q8C735, Q8C8N2, Q8CGF6, Q8K5C0, Q8N9R8, Q8VI24, Q8WXG6, Q90ZY6

Diamond homologs: B0BF33, F1M7L9, O35116, O35927, P97350, Q08DQ0, Q13835, Q28161, Q68FH0, Q99569, Q99959, Q9CQ73, Q9QY23, Q9UQB3, Q9Y446, B4F7F3, O00192, O60716, P30999, P98203, Q8AXM9, Q9U308, Q9C9A6, A2AAJ9, H2KZ60, O01761, O80742, Q8N9C0

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 181 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
Ras activation upon Ca2+ influx through NMDA receptor	9	44.3×	8e-11
Unblocking of NMDA receptors, glutamate binding and activation	6	28.1×	6e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	6	28.1×	6e-06
Long-term potentiation	6	24.6×	1e-05
Assembly and cell surface presentation of NMDA receptors	9	19.7×	2e-07
Neurexins and neuroligins	9	15.3×	1e-06
Protein-protein interactions at synapses	6	13.7×	2e-04
Adherens junctions interactions	6	12.8×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	8	28.5×	3e-07
protein localization to synapse	6	28.2×	1e-05
receptor clustering	7	26.8×	2e-06
regulation of postsynaptic membrane neurotransmitter receptor levels	8	24.3×	4e-07
cell-cell adhesion mediated by cadherin	7	17.6×	3e-05
adherens junction organization	5	15.7×	2e-03
cell-cell adhesion	14	8.7×	4e-07
MAPK cascade	8	7.5×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	407
Likely benign	247
Benign	33

Top pathogenic / likely-pathogenic (0)

SpliceAI

5633 predictions. Top by Δscore:

Variant	Effect	Δscore
2:158457216:A:T	donor_gain	1.0000
2:158457219:G:GG	donor_gain	1.0000
2:158533179:GGA:G	acceptor_gain	1.0000
2:158600443:T:G	donor_gain	1.0000
2:158603068:A:AG	acceptor_gain	1.0000
2:158603069:G:GG	acceptor_gain	1.0000
2:158620983:GTTAC:G	acceptor_loss	1.0000
2:158620984:TTACA:T	acceptor_loss	1.0000
2:158620985:TACAG:T	acceptor_loss	1.0000
2:158620986:ACAG:A	acceptor_loss	1.0000
2:158620987:CA:C	acceptor_loss	1.0000
2:158620988:A:AG	acceptor_gain	1.0000
2:158620988:A:T	acceptor_loss	1.0000
2:158620988:AGAC:A	acceptor_gain	1.0000
2:158620989:G:A	acceptor_loss	1.0000
2:158620989:G:GA	acceptor_gain	1.0000
2:158620989:GA:G	acceptor_gain	1.0000
2:158620989:GAC:G	acceptor_gain	1.0000
2:158620989:GACG:G	acceptor_gain	1.0000
2:158620989:GACGT:G	acceptor_gain	1.0000
2:158621112:GAAA:G	donor_gain	1.0000
2:158621114:AA:A	donor_gain	1.0000
2:158621116:G:GG	donor_gain	1.0000
2:158621120:GG:G	donor_gain	1.0000
2:158621121:GG:G	donor_gain	1.0000
2:158621139:T:TG	donor_gain	1.0000
2:158621221:A:AG	acceptor_gain	1.0000
2:158621222:T:G	acceptor_gain	1.0000
2:158621225:TTACA:T	acceptor_loss	1.0000
2:158621226:TACA:T	acceptor_loss	1.0000

AlphaMissense

7662 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:158577280:T:C	F48L	1.000
2:158577281:T:C	F48S	1.000
2:158577281:T:G	F48C	1.000
2:158577282:T:A	F48L	1.000
2:158577282:T:G	F48L	1.000
2:158577290:T:C	L51P	1.000
2:158577302:T:C	L55P	1.000
2:158640637:T:A	W525R	1.000
2:158640637:T:C	W525R	1.000
2:158640639:G:C	W525C	1.000
2:158640639:G:T	W525C	1.000
2:158640647:C:A	P528H	1.000
2:158640674:T:A	L537H	1.000
2:158640674:T:C	L537P	1.000
2:158640695:T:A	V544D	1.000
2:158640715:T:G	Y551D	1.000
2:158640719:T:C	L552P	1.000
2:158640732:C:G	C556W	1.000
2:158642571:T:C	L594P	1.000
2:158642574:G:C	R595P	1.000
2:158642580:T:C	L597P	1.000
2:158658139:T:A	W640R	1.000
2:158658139:T:C	W640R	1.000
2:158658141:G:C	W640C	1.000
2:158658141:G:T	W640C	1.000
2:158658304:G:C	G695R	1.000
2:158658305:G:A	G695D	1.000
2:158658314:G:C	R698T	1.000
2:158658314:G:T	R698M	1.000
2:158661333:G:C	R698S	1.000

dbSNP variants (sampled 300 via entrez): RS1000020642 (2:158530664 A>G), RS1000028169 (2:158664716 T>G), RS1000029744 (2:158484134 G>A), RS1000053153 (2:158530454 G>A,C,T), RS1000059697 (2:158497735 A>T), RS1000069068 (2:158630530 GCA>G), RS1000080278 (2:158463568 C>T), RS1000086495 (2:158562151 T>C), RS1000094588 (2:158651373 T>C), RS1000096530 (2:158630887 T>A), RS1000097160 (2:158545942 T>C), RS1000110948 (2:158482842 A>AG,AGGG), RS1000112044 (2:158621894 T>A), RS1000120281 (2:158587935 T>TA), RS1000123843 (2:158504685 AC>A,ACC)

Disease associations

OMIM: gene MIM:604276 | disease phenotypes:

GenCC curated gene-disease

Mondo (2): autism spectrum disorder (MONDO:0005258), syndromic intellectual disability (MONDO:0000508)

Orphanet (2): Rare genetic syndromic intellectual disability (Orphanet:183763), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001762_944	Obesity-related traits	1.000000e-06
GCST004641_14	Borderline personality disorder	2.000000e-06
GCST005042_5	Restless legs syndrome	3.000000e-25

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5483009 (PROTEIN-PROTEIN INTERACTION)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	increases expression, affects cotreatment	3
Benzo(a)pyrene	decreases methylation, decreases expression	3
methacrylaldehyde	increases abundance, affects cotreatment, increases expression	2
entinostat	decreases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment, decreases expression	2
Acrolein	affects cotreatment, increases expression, increases abundance	2
Air Pollutants	affects cotreatment, increases abundance, increases expression, decreases expression	2
Cadmium	decreases expression, increases abundance	2
Ozone	affects cotreatment, increases expression, increases abundance	2
Quercetin	decreases expression, decreases phosphorylation	2
Tetrachlorodibenzodioxin	decreases expression	2
Tretinoin	decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Aflatoxin B1	affects expression, decreases methylation	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
ginger extract	affects cotreatment, affects expression, increases abundance	1
alpha-pinene	increases expression, increases abundance, affects cotreatment	1
bisphenol A	affects cotreatment, affects expression, increases abundance	1
testosterone undecanoate	affects cotreatment, decreases expression	1
beta-lapachone	increases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
coumarin	increases phosphorylation	1
beta-methylcholine	affects expression	1
tamibarotene	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	increases reaction, affects binding	1
2-palmitoylglycerol	increases expression	1
monomethylarsonous acid	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5383470	Binding	Inhibition of N-terminal GST-tagged Erbin (unknown origin) expressed in Escherichia coli BL21 (DE3) cells/P0071 (unknown origin) complex incubated for 16 hrs by HTRF assay	Discovery of a PDZ Domain Inhibitor Targeting the Syndecan/Syntenin Protein-Protein Interaction: A Semi-Automated “Hit Identification-to-Optimization” Approach. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	PHASE3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD
NCT06229210	PHASE3	RECRUITING	Safety and Tolerability Trial of Lumateperone in Pediatric Patients With Schizophrenia, Bipolar Disorder or Autism Spectrum Disorder