WASHC4

Summary

WASHC4 (WASH complex subunit 4, HGNC:29174) is a protein-coding gene on chromosome 12q23.3, encoding WASH complex subunit 4 (Q2M389). Acts as a component of the WASH core complex that functions as a nucleation-promoting factor (NPF) at the surface of endosomes, where it recruits and activates the Arp2/3 complex to induce actin polymerization, playing a key role in the fission of tubules that serve as transport….

This gene encodes a component of the WASH complex, which functions in the intracellular transport of endosomes. Mutations in this gene have been detected in individuals with autosomal recessive cognitive disability. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 23325 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual disability, autosomal recessive 43 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 252 total — 3 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 22
• Druggable target: yes
• MANE Select transcript: NM_015275

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29174
Approved symbol	WASHC4
Name	WASH complex subunit 4
Location	12q23.3
Locus type	gene with protein product
Status	Approved
Aliases	SWIP
Ensembl gene	ENSG00000136051
Ensembl biotype	protein_coding
OMIM	615748
Entrez	23325

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 10 protein_coding, 5 retained_intron, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000311317, ENST00000332180, ENST00000547171, ENST00000547404, ENST00000548195, ENST00000548534, ENST00000550036, ENST00000550053, ENST00000550613, ENST00000550786, ENST00000551224, ENST00000551290, ENST00000552203, ENST00000620430, ENST00000890187, ENST00000890188, ENST00000934675, ENST00000934676, ENST00000934677

RefSeq mRNA: 2 — MANE Select: NM_015275 NM_001293640, NM_015275

CCDS: CCDS41826, CCDS73514

Canonical transcript exons

ENST00000332180 — 33 exons

Exon	Start	End
ENSE00002420193	105166864	105169130
ENSE00003463168	105137886	105138011
ENSE00003465049	105114362	105114427
ENSE00003497168	105115661	105115728
ENSE00003501456	105149615	105149749
ENSE00003505457	105121101	105121204
ENSE00003515883	105144287	105144455
ENSE00003517625	105147042	105147146
ENSE00003520523	105111125	105111264
ENSE00003520826	105122118	105122238
ENSE00003524165	105152343	105152451
ENSE00003524990	105143127	105143243
ENSE00003528267	105162749	105162845
ENSE00003565174	105140294	105140401
ENSE00003569356	105164641	105164740
ENSE00003572719	105141167	105141246
ENSE00003584446	105146452	105146526
ENSE00003585805	105127129	105127289
ENSE00003586624	105140899	105141045
ENSE00003587330	105142453	105142558
ENSE00003592900	105107731	105107861
ENSE00003602553	105114216	105114269
ENSE00003603609	105126004	105126127
ENSE00003617155	105164111	105164307
ENSE00003624357	105120555	105120597
ENSE00003626403	105160001	105160148
ENSE00003647894	105126235	105126362
ENSE00003652619	105144718	105144872
ENSE00003658041	105156726	105156792
ENSE00003666334	105118446	105118528
ENSE00003671472	105115184	105115229
ENSE00003693727	105133770	105133896
ENSE00003788443	105157236	105157322

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 97.57.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.6568 / max 426.3680, expressed in 1818 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
127787	34.6568	1818

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	97.57	gold quality
calcaneal tendon	UBERON:0003701	97.50	gold quality
mammary duct	UBERON:0001765	97.00	gold quality
adrenal tissue	UBERON:0018303	96.34	gold quality
tendon	UBERON:0000043	96.18	gold quality
cauda epididymis	UBERON:0004360	96.16	gold quality
superficial temporal artery	UBERON:0001614	95.92	gold quality
monocyte	CL:0000576	95.83	gold quality
mononuclear cell	CL:0000842	95.79	gold quality
epithelium of mammary gland	UBERON:0003244	95.72	gold quality
caput epididymis	UBERON:0004358	95.60	gold quality
cranial nerve II	UBERON:0000941	95.59	gold quality
oocyte	CL:0000023	95.47	gold quality
lower lobe of lung	UBERON:0008949	95.47	gold quality
leukocyte	CL:0000738	95.39	gold quality
corpus epididymis	UBERON:0004359	95.34	gold quality
corpus callosum	UBERON:0002336	95.10	gold quality
bone marrow cell	CL:0002092	94.64	gold quality
decidua	UBERON:0002450	94.47	gold quality
bone marrow	UBERON:0002371	94.31	gold quality
lymph node	UBERON:0000029	94.23	gold quality
inferior vagus X ganglion	UBERON:0005363	94.11	gold quality
colonic epithelium	UBERON:0000397	93.92	gold quality
trabecular bone tissue	UBERON:0002483	93.90	gold quality
renal medulla	UBERON:0000362	93.84	gold quality
lateral globus pallidus	UBERON:0002476	93.82	gold quality
visceral pleura	UBERON:0002401	93.79	gold quality
vermiform appendix	UBERON:0001154	93.77	gold quality
medial globus pallidus	UBERON:0002477	93.74	gold quality
globus pallidus	UBERON:0001875	93.67	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-124858	no	314.20
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

152 targeting WASHC4, 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-3163	100.00	77.23	8605
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4673	100.00	66.64	1490
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-4668-3P	100.00	68.74	2635
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-552-5P	99.93	68.56	1583

Literature-anchored findings (GeneRIF, showing 6)

• WAFL may play an important role in endocytosis and subsequent membrane trafficking by interacting with AP2 through KIAA0196 and KIAA1033 (PMID:20376207)
• SWIP is a novel gene for non-syndromic autosomal recessive intellectual disability (PMID:21498477)
• Ten KIAA1033 SNPs were also significantly associated with AD in a group of African Americans. (PMID:22673115)
• Novel KIAA1033/WASHC4 mutations in three patients with syndromic intellectual disability and a review of the literature. (PMID:31953988)
• Genetic disruption of WASHC4 drives endo-lysosomal dysfunction and cognitive-movement impairments in mice and humans. (PMID:33749590)
• SWIP mediates retromer-independent membrane recruitment of the WASH complex. (PMID:36995008)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	washc4	ENSDARG00000061719
mus_musculus	Washc4	ENSMUSG00000034560
rattus_norvegicus	Washc4	ENSRNOG00000008331
drosophila_melanogaster	SWIP	FBGN0030739
caenorhabditis_elegans		WBGENE00013167

Protein

Protein identifiers

WASH complex subunit 4 — Q2M389 (reviewed: Q2M389)

Alternative names: Strumpellin and WASH-interacting protein, WASH complex subunit SWIP

All UniProt accessions (7): A0A087X256, F8VNZ5, F8VQX3, F8VYH7, F8W1W1, Q2M389, R4GMM5

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a component of the WASH core complex that functions as a nucleation-promoting factor (NPF) at the surface of endosomes, where it recruits and activates the Arp2/3 complex to induce actin polymerization, playing a key role in the fission of tubules that serve as transport intermediates during endosome sorting.

Subunit / interactions. Component of the WASH core complex also described as WASH regulatory complex (SHRC) composed of WASH (WASHC1, WASH2P or WASH3P), WASHC2 (WASHC2A or WASHC2C), WASHC3, WASHC4 and WASHC5. The WASH core complex associates via WASHC2 with the F-actin-capping protein dimer (formed by CAPZA1, CAPZA2 or CAPZA3 and CAPZB) in a transient or substoichiometric manner which was initially described as WASH complex.

Subcellular location. Early endosome.

Disease relevance. Intellectual developmental disorder, autosomal recessive 43 (MRT43) [MIM:615817] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the SWIP family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q2M389-1	1	yes
Q2M389-2	2

RefSeq proteins (2): NP_001280569, NP_056090* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR027307	WASH7	Family
IPR028191	WASH-4_N	Domain
IPR028282	WASH-7_central	Domain
IPR028283	WASH-7_C	Domain

Pfam: PF14744, PF14745, PF14746

UniProt features (19 total): sequence variant 4, sequence conflict 3, modified residue 3, splice variant 2, region of interest 2, compositionally biased region 2, initiator methionine 1, chain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q2M389-F1	83.82	0.36

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 (3): 2, 7, 1154

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 319 (showing top): RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_COGNITION, GOBP_ENDOSOME_ORGANIZATION, GOBP_REGULATION_OF_ACTIN_NUCLEATION, GOBP_VESICLE_ORGANIZATION, AAGCCAT_MIR135A_MIR135B, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_VESICLE_MEDIATED_TRANSPORT, GNF2_LYN, GOBP_REGULATION_OF_ACTIN_FILAMENT_BASED_PROCESS, GOBP_NUCLEAR_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, IRF7_01, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM

GO Biological Process (9): endosome organization (GO:0007032), protein transport (GO:0015031), endosomal transport (GO:0016197), regulation of Arp2/3 complex-mediated actin nucleation (GO:0034315), cognition (GO:0050890), neuromuscular process (GO:0050905), regulation of protein complex stability (GO:0061635), nuclear envelope budding (GO:0140591), endolysosomal toll-like receptor signaling pathway (GO:0140894)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (6): nucleoplasm (GO:0005654), endosome (GO:0005768), early endosome membrane (GO:0031901), WASH complex (GO:0071203), early endosome (GO:0005769), BLOC-1 complex (GO:0031083)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nervous system process	2
endomembrane system organization	1
vesicle organization	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
vesicle-mediated transport	1
intracellular transport	1
Arp2/3 complex-mediated actin nucleation	1
regulation of actin nucleation	1
regulation of biological quality	1
nuclear export	1
cytoplasmic pattern recognition receptor signaling pathway	1
binding	1
nuclear lumen	1
cellular anatomical structure	1
endomembrane system	1
cytoplasmic vesicle	1
early endosome	1
endosome membrane	1
cytoplasm	1
protein-containing complex	1
endosome	1
BLOC complex	1

Protein interactions and networks

STRING

1196 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WASHC4	WASHC3	Q9Y3C0	998
WASHC4	WASHC5	Q12768	998
WASHC4	WASHC1	A8K0Z3	996
WASHC4	WASHC2C	Q9Y4E1	969
WASHC4	WASHC2A	Q641Q2	812
WASHC4	WAS	P42768	750
WASHC4	FKBP15	Q5T1M5	739
WASHC4	VPS29	Q9UBQ0	649
WASHC4	VPS35	Q96QK1	635
WASHC4	VPS26A	O75436	632
WASHC4	SNX27	Q96L92	601
WASHC4	SNX1	Q13596	593
WASHC4	CAPZA1	P52907	571
WASHC4	SNX2	P82862	530
WASHC4	CCDC93	Q567U6	513

IntAct

71 interactions, top by confidence:

A	B	Type	Score
VPS29	VPS26C	psi-mi:“MI:0914”(association)	0.760
WASHC4	rep	psi-mi:“MI:0915”(physical association)	0.660
CCDC93	VPS26C	psi-mi:“MI:0914”(association)	0.640
CAPZB	CNOT1	psi-mi:“MI:0914”(association)	0.640
CAPZA2	CNOT1	psi-mi:“MI:0914”(association)	0.640
WASHC3	WASH3P	psi-mi:“MI:0914”(association)	0.530
rep	SLC27A2	psi-mi:“MI:0914”(association)	0.530
CAPZA1	CNOT1	psi-mi:“MI:0914”(association)	0.530
LDLRAD4	WWP2	psi-mi:“MI:0914”(association)	0.530
TCEANC2	HTATSF1	psi-mi:“MI:0914”(association)	0.530
	AP3D1	psi-mi:“MI:0914”(association)	0.460
Capza1		psi-mi:“MI:0915”(physical association)	0.400
WASHC4	SMAD2	psi-mi:“MI:0915”(physical association)	0.370
Washc1	COX7A2	psi-mi:“MI:0914”(association)	0.350
VPS26A	LCMT2	psi-mi:“MI:0914”(association)	0.350
VPS26B	KIF1B	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
WASHC5	WASHC1	psi-mi:“MI:0914”(association)	0.350
WASHC5	SNX2	psi-mi:“MI:0914”(association)	0.350
SEC22B	NBAS	psi-mi:“MI:0914”(association)	0.350
CAPZA2	CNOT1	psi-mi:“MI:0914”(association)	0.350
LDLRAD4	WWP2	psi-mi:“MI:0914”(association)	0.350

BioGRID (167): KIAA1033 (Affinity Capture-MS), KIAA1033 (Co-fractionation), KIAA1033 (Co-fractionation), KIAA1033 (Affinity Capture-MS), KIAA1033 (Proximity Label-MS), KIAA1033 (Affinity Capture-MS), KIAA1033 (Affinity Capture-MS), KIAA1033 (Affinity Capture-MS), KIAA1033 (Affinity Capture-MS), KIAA1033 (Affinity Capture-MS), KIAA1033 (Affinity Capture-MS), KIAA1033 (Affinity Capture-MS), KIAA1033 (Affinity Capture-MS), KIAA1033 (Affinity Capture-MS), KIAA1033 (Affinity Capture-MS)

ESM2 similar proteins: A5PJZ5, A9X1A0, B0KWC1, B1MTG7, B2KI64, B3EX61, B4UT09, O02810, O08561, O49160, O54921, O73787, O75694, P58854, Q08CZ0, Q0WQF4, Q15386, Q155U0, Q29RB1, Q2M389, Q3MHG0, Q3SZI7, Q3UMB9, Q3UVG3, Q4V9Y0, Q505L3, Q5R5J6, Q5R7R6, Q5R822, Q641K1, Q66HC5, Q68FP9, Q80U95, Q84K25, Q8BJ71, Q8BKC8, Q8N1F7, Q8R1U1, Q8R3I3, Q96CW5

Diamond homologs: Q2M389, Q3UMB9, Q54R74

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
WASHC4	“form complex”	“WASH complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 79 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
Golgi-to-ER retrograde transport	7	20.2×	6e-06
Intra-Golgi and retrograde Golgi-to-ER traffic	8	18.2×	3e-06
Membrane Trafficking	10	8.1×	3e-05
Vesicle-mediated transport	10	7.6×	4e-05

GO biological processes:

GO term	Partners	Fold	FDR
endocytic recycling	7	27.5×	3e-06
retrograde transport, endosome to Golgi	7	21.2×	1e-05
protein transport	11	7.1×	6e-05
intracellular protein transport	7	6.7×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	10
Uncertain significance	159
Likely benign	33
Benign	10

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
133296	NM_015275.3(WASHC4):c.3056C>G (p.Pro1019Arg)	Pathogenic
1697335	NM_015275.3(WASHC4):c.1324C>T (p.Gln442Ter)	Pathogenic
1697336	NM_015275.3(WASHC4):c.3143A>G (p.Asp1048Gly)	Pathogenic
1804867	NM_015275.3(WASHC4):c.1374del (p.Met458fs)	Likely pathogenic
1878289	NM_015275.3(WASHC4):c.2133dup (p.Ser712fs)	Likely pathogenic
3376285	NM_015275.3(WASHC4):c.1786C>T (p.Arg596Ter)	Likely pathogenic
425017	NM_015275.3(WASHC4):c.1214dup (p.Tyr405Ter)	Likely pathogenic
4292949	NM_015275.3(WASHC4):c.1666C>T (p.Arg556Ter)	Likely pathogenic
4531378	NM_015275.3(WASHC4):c.2556dup (p.Phe853fs)	Likely pathogenic
4845750	NM_015275.3(WASHC4):c.2944C>T (p.Arg982Ter)	Likely pathogenic
4845761	NM_015275.3(WASHC4):c.2611C>T (p.Arg871Ter)	Likely pathogenic
695111	NM_015275.3(WASHC4):c.3236A>G (p.Lys1079Arg)	Likely pathogenic
996910	NM_015275.3(WASHC4):c.1038+1G>T	Likely pathogenic

SpliceAI

5456 predictions. Top by Δscore:

Variant	Effect	Δscore
12:105107857:GCAGA:G	donor_gain	1.0000
12:105107860:GA:G	donor_gain	1.0000
12:105107862:G:GG	donor_gain	1.0000
12:105107867:G:GT	donor_gain	1.0000
12:105111117:A:AG	acceptor_gain	1.0000
12:105114213:TAG:T	acceptor_loss	1.0000
12:105114214:A:AG	acceptor_gain	1.0000
12:105114214:A:AT	acceptor_loss	1.0000
12:105114215:G:GA	acceptor_gain	1.0000
12:105114215:GC:G	acceptor_gain	1.0000
12:105114215:GCT:G	acceptor_gain	1.0000
12:105114215:GCTT:G	acceptor_gain	1.0000
12:105114215:GCTTT:G	acceptor_gain	1.0000
12:105114267:AAGGT:A	donor_loss	1.0000
12:105114270:G:GC	donor_loss	1.0000
12:105114271:T:G	donor_loss	1.0000
12:105115659:A:AG	acceptor_gain	1.0000
12:105115660:G:GT	acceptor_gain	1.0000
12:105115724:TACAG:T	donor_loss	1.0000
12:105115725:ACAG:A	donor_loss	1.0000
12:105115726:CAGGT:C	donor_loss	1.0000
12:105115727:AGGTA:A	donor_loss	1.0000
12:105115728:GG:G	donor_loss	1.0000
12:105115729:G:GA	donor_loss	1.0000
12:105115730:T:A	donor_loss	1.0000
12:105118522:G:GG	donor_gain	1.0000
12:105118529:G:GG	donor_gain	1.0000
12:105122113:TCAAG:T	acceptor_loss	1.0000
12:105122114:CAAG:C	acceptor_loss	1.0000
12:105122115:A:AG	acceptor_gain	1.0000

AlphaMissense

7842 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:105144327:T:C	L684P	1.000
12:105144736:T:C	L733P	1.000
12:105144757:T:C	L740P	1.000
12:105147108:T:C	S826P	1.000
12:105147120:C:G	H830D	1.000
12:105147124:G:A	G831D	1.000
12:105147124:G:T	G831V	1.000
12:105147129:G:A	G833R	1.000
12:105147129:G:C	G833R	1.000
12:105147130:G:A	G833E	1.000
12:105162845:G:C	G1053R	1.000
12:105122132:T:A	V227D	0.999
12:105133804:T:A	W412R	0.999
12:105133804:T:C	W412R	0.999
12:105137886:G:C	G443R	0.999
12:105137977:T:A	V473D	0.999
12:105140364:T:C	L508P	0.999
12:105140375:G:C	A512P	0.999
12:105140397:C:A	A519D	0.999
12:105140948:T:C	L537P	0.999
12:105140953:G:C	A539P	0.999
12:105140954:C:A	A539D	0.999
12:105140957:T:C	L540P	0.999
12:105141002:G:C	R555P	0.999
12:105141034:G:C	G566R	0.999
12:105144318:A:T	E681V	0.999
12:105144329:C:G	R685G	0.999
12:105144330:G:C	R685P	0.999
12:105144333:T:C	L686P	0.999
12:105144769:C:A	A744D	0.999

dbSNP variants (sampled 300 via entrez): RS1000091032 (12:105156495 A>G), RS1000264891 (12:105137457 A>G), RS1000329582 (12:105130998 T>G), RS1000347969 (12:105131733 C>A,G), RS1000353630 (12:105131485 A>T), RS1000402105 (12:105113613 A>G), RS1000512434 (12:105136821 T>G), RS1000574035 (12:105138436 C>T), RS1000591039 (12:105106969 T>C), RS1000595736 (12:105149708 A>G), RS1000669365 (12:105162069 C>A), RS1000685406 (12:105161800 G>A), RS1000704280 (12:105124701 G>A), RS1000745650 (12:105130317 C>T), RS1000865374 (12:105135742 G>A)

Disease associations

OMIM: gene MIM:615748 | disease phenotypes: MIM:615817

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, autosomal recessive 43	Strong	Autosomal recessive
autosomal recessive non-syndromic intellectual disability	Supportive	Autosomal recessive
schizophrenia	No Known Disease Relationship	Unknown

Mondo (4): intellectual disability, autosomal recessive 43 (MONDO:0014354), intellectual disability (MONDO:0001071), schizophrenia (MONDO:0005090), autosomal recessive non-syndromic intellectual disability (MONDO:0019502)

Orphanet (2): Autosomal recessive non-syndromic intellectual disability (Orphanet:88616), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

22 total (22 of 22 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000369	Low-set ears
HP:0000455	Broad nasal tip
HP:0000486	Strabismus
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0002187	Profound intellectual disability
HP:0002553	Highly arched eyebrow
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0004322	Short stature
HP:0010862	Delayed fine motor development
HP:0011220	Prominent forehead
HP:0012736	Profound global developmental delay
HP:0031936	Delayed ability to walk
HP:0034042	Dorsal hirsutism
HP:0100716	Self-injurious behavior

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST010204_27	Low density lipoprotein cholesterol levels	1.000000e-08
GCST010566_8	Benign childhood epilepsy with centro-temporal spikes	9.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement

MeSH disease descriptors (1)

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

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067448 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.72	Kd	18.89	nM	CHEMBL3752910
7.64	ED50	22.93	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149875: Binding affinity to human KIAA1033 incubated for 45 mins by Kinobead based pull down assay	kd	0.0189	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	increases expression, affects expression	3
Acetaminophen	increases expression, affects response to substance	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
dicrotophos	decreases expression	1
testosterone enanthate	affects expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction	1
methylparaben	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
2-palmitoylglycerol	increases expression	1
K 7174	increases expression	1
clothianidin	increases expression	1
bisphenol S	decreases methylation	1
jinfukang	decreases expression	1
(+)-JQ1 compound	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Cadmium	increases abundance, increases expression	1
Caffeine	decreases phosphorylation	1
Cisplatin	decreases expression	1
Coumestrol	decreases 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
CHEMBL5652917	Binding	Binding affinity to human KIAA1033 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety