PACS1

Summary

PACS1 (phosphofurin acidic cluster sorting protein 1, HGNC:30032) is a protein-coding gene on chromosome 11q13.1-q13.2, encoding Phosphofurin acidic cluster sorting protein 1 (Q6VY07). Coat protein that is involved in the localization of trans-Golgi network (TGN) membrane proteins that contain acidic cluster sorting motifs.

This gene encodes a protein with a putative role in the localization of trans-Golgi network (TGN) membrane proteins. Mouse and rat homologs have been identified and studies of the homologous rat protein indicate a role in directing TGN localization of furin by binding to the protease’s phosphorylated cytosolic domain. In addition, the human protein plays a role in HIV-1 Nef-mediated downregulation of cell surface MHC-I molecules to the TGN, thereby enabling HIV-1 to escape immune surveillance.

Source: NCBI Gene 55690 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Schuurs-Hoeijmakers syndrome (Definitive, ClinGen)
• GWAS associations: 18
• Clinical variants (ClinVar): 1,008 total — 1 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 72
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_018026

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30032
Approved symbol	PACS1
Name	phosphofurin acidic cluster sorting protein 1
Location	11q13.1-q13.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10209, KIAA1175
Ensembl gene	ENSG00000175115
Ensembl biotype	protein_coding
OMIM	607492
Entrez	55690

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 8 protein_coding, 6 retained_intron, 2 nonsense_mediated_decay

ENST00000320580, ENST00000524784, ENST00000524815, ENST00000525798, ENST00000527224, ENST00000527380, ENST00000528935, ENST00000529677, ENST00000529757, ENST00000529795, ENST00000531298, ENST00000531597, ENST00000533756, ENST00000533811, ENST00000534273, ENST00000676419

RefSeq mRNA: 1 — MANE Select: NM_018026 NM_018026

CCDS: CCDS8129

Canonical transcript exons

ENST00000320580 — 24 exons

Exon	Start	End
ENSE00001189633	66238804	66238846
ENSE00001189643	66235898	66235940
ENSE00001189648	66235301	66235403
ENSE00001189671	66232172	66232276
ENSE00001189675	66230805	66230940
ENSE00001189680	66230548	66230663
ENSE00001189683	66227504	66227584
ENSE00001189685	66221154	66221247
ENSE00001189699	66216695	66216775
ENSE00001280317	66242912	66243031
ENSE00001331022	66243165	66244744
ENSE00002161316	66070272	66070842
ENSE00003482390	66239142	66239277
ENSE00003487014	66219746	66219805
ENSE00003503980	66216520	66216611
ENSE00003528104	66211134	66211259
ENSE00003538757	66216119	66216263
ENSE00003550954	66220631	66220791
ENSE00003552006	66234132	66234242
ENSE00003570890	66241427	66241653
ENSE00003629361	66233785	66233939
ENSE00003667702	66232960	66233066
ENSE00003683210	66210362	66210451
ENSE00003688801	66193486	66193573

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 96.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 54.3647 / max 543.6498, expressed in 1818 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
115284	47.9960	1816
115283	3.0702	1437
115282	1.4169	813
115286	0.6968	446
115285	0.4784	263
115287	0.4269	224
115281	0.1435	58
115289	0.0641	8
115291	0.0359	5
115290	0.0198	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	96.83	gold quality
minor salivary gland	UBERON:0001830	95.44	gold quality
granulocyte	CL:0000094	95.31	gold quality
saliva-secreting gland	UBERON:0001044	94.88	gold quality
stromal cell of endometrium	CL:0002255	94.32	gold quality
apex of heart	UBERON:0002098	94.16	gold quality
cerebellar hemisphere	UBERON:0002245	94.15	gold quality
cerebellar cortex	UBERON:0002129	94.08	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.08	gold quality
right lung	UBERON:0002167	94.01	gold quality
right coronary artery	UBERON:0001625	93.84	gold quality
popliteal artery	UBERON:0002250	93.78	gold quality
tibial artery	UBERON:0007610	93.78	gold quality
aorta	UBERON:0000947	93.50	gold quality
lymph node	UBERON:0000029	93.47	gold quality
ascending aorta	UBERON:0001496	93.28	gold quality
left lobe of thyroid gland	UBERON:0001120	93.27	gold quality
thoracic aorta	UBERON:0001515	93.27	gold quality
right atrium auricular region	UBERON:0006631	93.15	gold quality
left testis	UBERON:0004533	93.09	gold quality
right lobe of thyroid gland	UBERON:0001119	93.02	gold quality
colonic epithelium	UBERON:0000397	92.96	gold quality
right testis	UBERON:0004534	92.94	gold quality
sural nerve	UBERON:0015488	92.91	gold quality
descending thoracic aorta	UBERON:0002345	92.88	gold quality
blood	UBERON:0000178	92.86	gold quality
endocervix	UBERON:0000458	92.83	gold quality
ectocervix	UBERON:0012249	92.70	gold quality
mouth mucosa	UBERON:0003729	92.68	gold quality
left ovary	UBERON:0002119	92.66	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.50
E-CURD-10	no	93.85

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

131 targeting PACS1, 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-5196-5P	100.00	67.98	2761
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4728-5P	99.85	69.39	4718

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 21)

• PACS-1 along with HIV-1 nef, has a role in downregulating cell surface MHC-I to the trans-Golgi network and usurping the ARF6 endocytic pathway (PMID:12526811)
• subcellular localization and function of polycystin-2 are directed by phosphofurin acidic cluster sorting protein (PACS)-1 and PACS-2 (PMID:15692563)
• casein kinase 2 induces PACS-1 binding of nephrocystin and targeting to cilia (PMID:16308564)
• CK2-activated phosphorylation cascade controlling PACS-1- and GGA3-mediated CI-MPR sorting, is reported. (PMID:16977309)
• PACS-1 mediates phosphorylation-dependent ciliary trafficking of the CNGB1b in olfactory sensory neurons. (PMID:19710307)
• The sites on Nef and the PACS proteins required for their interaction, are identified. (PMID:22496420)
• Our findings suggest that PACS1 is necessary for the formation of craniofacial structures and that perturbation of its functions results in a specific syndromic ID phenotype. (PMID:23159249)
• Single nucleotide polymorphisms in PAKS1 gene is associated with obesity. (PMID:23563609)
• PACS1 plays an important role in protein sorting for amyloidogenic-burden control via both SORLA-dependent and SORLA-independent mechanisms. (PMID:24001769)
• Clinical description of the PACS1-related syndrome has been reported in 19 unrelated patients. (PMID:26842493)
• PCAF and ADA3 transcriptionally regulate PACS1 and PACS1 is a key regulator of BAX/BAK oligomerization and the intrinsic (mitochondrial) pathway to apoptosis. (PMID:28060382)
• Using whole exome sequencing (WES), we identified eight additional individuals with the same p.Arg203Trp missense variant in PACS1 that we demonstrated were de novo in seven individuals with available parental DNA. (PMID:28111752)
• Protein adaptation and the expanding roles of the PACS1 and PACS2 proteins in tissue homeostasis and disease has been summarized. (Review) (PMID:28476937)
• study showed for the first time that the rs564343 in phosphofurin acidic cluster sorting protein 1(PACS1) was associated with risk of severe obesity in Chinese children (PMID:28564656)
• The multifunctional protein PACS-1 is required for HDAC2- and HDAC3-dependent chromatin maturation and genomic stability. (PMID:31988453)
• Dysregulation of hsa-miR-34a and hsa-miR-449a leads to overexpression of PACS-1 and loss of DNA damage response (DDR) in cervical cancer. (PMID:33028635)
• Prenatal and postnatal diagnosis of Schuurs-Hoeijmakers syndrome: Case series and review of the literature. (PMID:33166031)
• Coloboma may be a shared feature in a spectrum of disorders caused by mutations in the WDR37-PACS1-PACS2 axis. (PMID:33369122)
• Schuurs-Hoeijmakers Syndrome (PACS1 Neurodevelopmental Disorder): Seven Novel Patients and a Review. (PMID:34068396)
• Expanding the clinical spectrum associated with the PACS1 p.Arg203Trp mutational hot-spot: Two additional Italian patients. (PMID:36210549)
• Do PACS1 variants impeding adaptor protein binding predispose to syndromic intellectual disability? (PMID:37141437)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	pacs1a	ENSDARG00000044556
		ENSDARG00000113768
mus_musculus	Pacs1	ENSMUSG00000024855
rattus_norvegicus	Pacs1	ENSRNOG00000020350
drosophila_melanogaster	KrT95D	FBGN0020647
caenorhabditis_elegans		WBGENE00044077

Paralogs (1): PACS2 (ENSG00000179364)

Protein

Protein identifiers

Phosphofurin acidic cluster sorting protein 1 — Q6VY07 (reviewed: Q6VY07)

All UniProt accessions (10): B4DF77, E9PNG7, E9PNZ9, E9PPK2, E9PSE1, E9PSG7, H0YCU5, H0YE62, H0YF56, Q6VY07

UniProt curated annotations — full annotation on UniProt →

Function. Coat protein that is involved in the localization of trans-Golgi network (TGN) membrane proteins that contain acidic cluster sorting motifs. Controls the endosome-to-Golgi trafficking of furin and mannose-6-phosphate receptor by connecting the acidic-cluster-containing cytoplasmic domain of these molecules with the adapter-protein complex-1 (AP-1) of endosomal clathrin-coated membrane pits. Involved in HIV-1 nef-mediated removal of MHC-I from the cell surface to the TGN. Required for normal ER Ca2+ handling in lymphocytes. Together with WDR37, it plays an essential role in lymphocyte development, quiescence and survival. Required for stabilizing peripheral lymphocyte populations.

Subunit / interactions. Associates with AP-1 and AP-3 but not with AP-2 complexes. Interacts with FURIN. Forms a ternary complex with FURIN and AP-1. Interacts with NPHP1; the interaction is dependent of NPHP1 phosphorylation by CK2. Interacts with PKD2 (via acidic region). Interacts with SORL1. Interacts with WDR37. (Microbial infection) Interacts with HIV-1 Nef. (Microbial infection) Interacts with Epstein-barr virus protein BBLF1.

Subcellular location. Golgi apparatus. trans-Golgi network.

Disease relevance. Schuurs-Hoeijmakers syndrome (SHMS) [MIM:615009] An autosomal dominant intellectual developmental disorder characterized by intellectual disability in combination with distinct craniofacial features and genital abnormalities. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the PACS family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6VY07-1	1	yes
Q6VY07-2	2

RefSeq proteins (1): NP_060496* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019381	PACS1/2_C	Domain
IPR057541	PACS1/2_N	Domain

Pfam: PF10254, PF25332

UniProt features (39 total): modified residue 14, compositionally biased region 7, region of interest 7, sequence conflict 5, sequence variant 2, initiator methionine 1, chain 1, splice variant 1, coiled-coil region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9Z30	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6VY07-F1	65.81	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 (14): 2, 28, 46, 251, 379, 381, 430, 495, 504, 519, 528, 529, 531, 534

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-164940	Nef mediated downregulation of MHC class I complex cell surface expression

MSigDB gene sets: 370 (showing top): RNGTGGGC_UNKNOWN, PAX4_01, GOBP_LYMPHOCYTE_HOMEOSTASIS, REACTOME_THE_ROLE_OF_NEF_IN_HIV_1_REPLICATION_AND_DISEASE_PATHOGENESIS, TGACCTY_ERR1_Q2, MEF2_02, chr11q13, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, REACTOME_NEF_MEDIATES_DOWN_MODULATION_OF_CELL_SURFACE_RECEPTORS_BY_RECRUITING_THEM_TO_CLATHRIN_ADAPTERS, REACTOME_HIV_INFECTION, GOCC_COATED_VESICLE, MORI_SMALL_PRE_BII_LYMPHOCYTE_DN, GOCC_GOLGI_ASSOCIATED_VESICLE, GOBP_PROTEIN_LOCALIZATION_TO_GOLGI_APPARATUS, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE

GO Biological Process (3): lymphocyte homeostasis (GO:0002260), protein localization to Golgi apparatus (GO:0034067), protein localization to plasma membrane (GO:0072659)

GO Molecular Function (2): transmembrane transporter binding (GO:0044325), protein binding (GO:0005515)

GO Cellular Component (3): Golgi apparatus (GO:0005794), cytosol (GO:0005829), COPI-coated vesicle (GO:0030137)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
leukocyte homeostasis	1
protein localization to organelle	1
protein localization to membrane	1
protein localization to cell periphery	1
protein binding	1
binding	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1
Golgi-associated vesicle	1
coated vesicle	1

Protein interactions and networks

STRING

930 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PACS1	FURIN	P09958	947
PACS1	PKD2	Q13563	856
PACS1	BCAP31	P51572	769
PACS1	TGOLN2	O43493	760
PACS1	CSNK2A1	P19138	739
PACS1	SORL1	Q92673	719
PACS1	ARF6	P26438	595
PACS1	CSNK2A2	P19784	588
PACS1	CPD	O75976	583
PACS1	HCK	P08631	552
PACS1	WDR37	Q9Y2I8	542
PACS1	NPHP4	O75161	530
PACS1	GOLPH3	Q9H4A6	511
PACS1	SNX18	Q96RF0	506
PACS1	ARF1	P10947	477

IntAct

98 interactions, top by confidence:

A	B	Type	Score
SGF29	NDC80	psi-mi:“MI:0914”(association)	0.840
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
CSNK2B	PACS1	psi-mi:“MI:0407”(direct interaction)	0.590
CSNK2B	PACS1	psi-mi:“MI:0915”(physical association)	0.590
PACS1	APBB2	psi-mi:“MI:0915”(physical association)	0.560
	PACS1	psi-mi:“MI:0915”(physical association)	0.560
PACS1		psi-mi:“MI:0915”(physical association)	0.560
PACS1	PMP22	psi-mi:“MI:0915”(physical association)	0.560
SNCA	PACS1	psi-mi:“MI:0915”(physical association)	0.560
HTT	PACS1	psi-mi:“MI:0915”(physical association)	0.560
ATXN1	PACS1	psi-mi:“MI:0915”(physical association)	0.560
TARDBP	PACS1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (63): SORL1 (Affinity Capture-Western), PACS1 (Affinity Capture-MS), PACS1 (Affinity Capture-MS), PACS1 (Proximity Label-MS), PACS1 (Affinity Capture-MS), PACS1 (Affinity Capture-MS), PACS1 (Affinity Capture-MS), PTPRG (Affinity Capture-MS), PACS1 (Affinity Capture-MS), C17orf70 (Affinity Capture-MS), PACS1 (Affinity Capture-MS), PACS1 (Affinity Capture-MS), PACS1 (Affinity Capture-RNA), PACS1 (Affinity Capture-MS), PACS1 (Affinity Capture-MS)

ESM2 similar proteins: A2AF47, B0DOB4, B0R034, E9Q8I9, O15327, O70481, O88588, P50851, P55196, Q0VGW0, Q14B46, Q1JQ19, Q1RLX4, Q32PH0, Q4R4D7, Q5D891, Q5FWH3, Q5JSL3, Q5RA60, Q5U1Z0, Q5U249, Q5XGX5, Q5XIZ9, Q62717, Q6GLR7, Q6P1Y8, Q6VY07, Q80TJ1, Q80TR8, Q8BMG7, Q8BUR4, Q8BZN6, Q8C147, Q8C3J5, Q8IWV7, Q8K212, Q8NF50, Q8R1A4, Q8VDR9, Q91WS7

Diamond homologs: O88588, Q3V3Q7, Q6VY07, Q86VP3, Q8K212

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CSNK2A1	“up-regulates activity”	PACS1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

1008 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	3
Uncertain significance	354
Likely benign	431
Benign	96

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
1686002	NM_018026.4(PACS1):c.1574G>A (p.Arg525Lys)	Pathogenic
1801717	NM_018026.4(PACS1):c.755C>T (p.Ser252Phe)	Likely pathogenic
2571837	NM_018026.4(PACS1):c.2690A>G (p.Glu897Gly)	Likely pathogenic
421421	NM_018026.4(PACS1):c.2656+1G>C	Likely pathogenic

SpliceAI

5232 predictions. Top by Δscore:

Variant	Effect	Δscore
11:66193475:T:A	acceptor_gain	1.0000
11:66193481:TCTA:T	acceptor_loss	1.0000
11:66193482:CTA:C	acceptor_loss	1.0000
11:66193484:A:AG	acceptor_gain	1.0000
11:66193484:AG:A	acceptor_gain	1.0000
11:66193485:G:GT	acceptor_gain	1.0000
11:66193485:GG:G	acceptor_gain	1.0000
11:66193485:GGC:G	acceptor_gain	1.0000
11:66193485:GGCT:G	acceptor_gain	1.0000
11:66193485:GGCTA:G	acceptor_gain	1.0000
11:66193570:GCAG:G	donor_gain	1.0000
11:66193574:G:GG	donor_gain	1.0000
11:66193575:T:A	donor_loss	1.0000
11:66210356:TTTCA:T	acceptor_loss	1.0000
11:66210357:TTCA:T	acceptor_loss	1.0000
11:66210358:TCAG:T	acceptor_loss	1.0000
11:66210360:AG:A	acceptor_gain	1.0000
11:66210360:AGGGT:A	acceptor_loss	1.0000
11:66210361:GG:G	acceptor_gain	1.0000
11:66210448:TCAG:T	donor_loss	1.0000
11:66210449:CAGGT:C	donor_loss	1.0000
11:66210450:AG:A	donor_loss	1.0000
11:66210451:GG:G	donor_loss	1.0000
11:66210452:G:A	donor_loss	1.0000
11:66210453:T:A	donor_loss	1.0000
11:66211130:GTA:G	acceptor_loss	1.0000
11:66211131:TAGT:T	acceptor_loss	1.0000
11:66211132:A:AG	acceptor_gain	1.0000
11:66211132:AGTA:A	acceptor_loss	1.0000
11:66211133:G:GA	acceptor_gain	1.0000

AlphaMissense

6302 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:66070788:T:C	M101T	1.000
11:66070789:G:A	M101I	1.000
11:66070789:G:C	M101I	1.000
11:66070789:G:T	M101I	1.000
11:66070794:T:C	L103P	1.000
11:66070800:C:A	A105D	1.000
11:66070805:T:A	W107R	1.000
11:66070805:T:C	W107R	1.000
11:66070842:G:C	R119T	1.000
11:66070842:G:T	R119M	1.000
11:66193486:G:C	R119S	1.000
11:66193486:G:T	R119S	1.000
11:66193503:T:C	L125P	1.000
11:66193512:T:C	L128P	1.000
11:66193557:T:A	I143N	1.000
11:66193559:G:C	A144P	1.000
11:66193560:C:A	A144D	1.000
11:66210368:A:G	K151E	1.000
11:66210369:A:T	K151I	1.000
11:66210370:A:C	K151N	1.000
11:66210370:A:T	K151N	1.000
11:66210373:A:C	R152S	1.000
11:66210373:A:T	R152S	1.000
11:66210378:T:A	L154H	1.000
11:66210378:T:C	L154P	1.000
11:66210380:C:A	R155S	1.000
11:66210380:C:G	R155G	1.000
11:66210381:G:C	R155P	1.000
11:66210383:T:C	S156P	1.000
11:66210384:C:A	S156Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000016174 (11:66081190 A>G), RS1000032181 (11:66101101 T>C), RS1000037118 (11:66156200 T>A), RS1000040009 (11:66160260 C>T), RS1000063778 (11:66167055 G>A), RS1000066461 (11:66120905 C>A,T), RS1000072338 (11:66159811 A>G), RS1000078154 (11:66081801 A>G,T), RS1000079845 (11:66132040 C>T), RS1000096434 (11:66070877 A>G), RS1000100719 (11:66108377 T>C), RS1000107678 (11:66177255 C>T), RS1000131861 (11:66113473 T>C), RS1000140476 (11:66222195 G>C), RS1000168641 (11:66187415 A>G)

Disease associations

OMIM: gene MIM:607492 | disease phenotypes: MIM:615009, MIM:300633, MIM:181500, MIM:142623

GenCC curated gene-disease

Disease	Classification	Inheritance
Schuurs-Hoeijmakers syndrome	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Schuurs-Hoeijmakers syndrome	Definitive	AD

Mondo (6): Schuurs-Hoeijmakers syndrome (MONDO:0014006), intellectual disability (MONDO:0001071), hypospadias (MONDO:0005345), schizophrenia (MONDO:0005090), neurodevelopmental disorder (MONDO:0700092), Hirschsprung disease (MONDO:0018309)

Orphanet (5): Schuurs-Hoeijmakers syndrome (Orphanet:329224), Hirschsprung disease (Orphanet:388), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), OBSOLETE: Familial hypospadias (Orphanet:440), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

72 total (30 of 72 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000154	Wide mouth
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000294	Low anterior hairline
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000369	Low-set ears
HP:0000400	Macrotia
HP:0000411	Protruding ear
HP:0000414	Bulbous nose
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis
HP:0000527	Long eyelashes
HP:0000545	Myopia
HP:0000589	Coloboma
HP:0000639	Nystagmus
HP:0000664	Synophrys
HP:0000699	Diastema
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0000767	Pectus excavatum
HP:0000954	Single transverse palmar crease
HP:0001176	Large hands
HP:0001195	Single umbilical artery
HP:0001238	Slender finger

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST001241_12	Bipolar disorder	2.000000e-07
GCST001957_15	Obesity (early onset extreme)	2.000000e-09
GCST002481_8	Acne (severe)	3.000000e-11
GCST002709_6	Electroencephalogram traits	4.000000e-06
GCST007294_7	Body fat distribution (trunk fat ratio)	8.000000e-12
GCST007294_75	Body fat distribution (trunk fat ratio)	1.000000e-07
GCST007295_158	Body fat distribution (leg fat ratio)	8.000000e-06
GCST007295_48	Body fat distribution (leg fat ratio)	3.000000e-09
GCST008103_21	Bipolar disorder	2.000000e-08
GCST010512_20	Serum uric acid levels	1.000000e-13
GCST011102_13	Bipolar disorder	2.000000e-08
GCST012227_665	Hip circumference adjusted for BMI	4.000000e-11
GCST012465_11	Bipolar disorder	2.000000e-09
GCST90002387_110	Immature fraction of reticulocytes	5.000000e-10
GCST90020028_1909	Hip circumference adjusted for BMI	7.000000e-13
GCST90020028_1910	Hip circumference adjusted for BMI	2.000000e-10
GCST90020029_333	Waist circumference adjusted for body mass index	1.000000e-12
GCST90020029_335	Waist circumference adjusted for body mass index	2.000000e-08

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004357	electroencephalogram measurement
EFO:0006870	alpha wave measurement
EFO:0006883	alpha peak frequency measurement
EFO:0004341	body fat distribution
EFO:0004761	uric acid measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D006627	Hirschsprung Disease	C06.198.439; C06.405.469.158.701.439; C16.131.314.439
D007021	Hypospadias	C12.050.351.875.466; C12.100.500.494.400; C12.200.294.494.400; C12.200.706.516; C12.800.516; C16.131.939.516
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: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	increases expression	1
ICG 001	decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Temozolomide	decreases expression	1
Acetaminophen	increases expression	1
Cadmium	increases abundance, decreases expression	1
Caffeine	affects phosphorylation	1
Calcitriol	increases expression, affects cotreatment	1
Cisplatin	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Ivermectin	decreases expression	1
Lead	affects expression	1
Ozone	affects expression, increases abundance	1
Plant Extracts	affects cotreatment, decreases expression	1
Dihydrotestosterone	increases expression	1
Testosterone	affects cotreatment, increases expression	1
Tobacco Smoke Pollution	increases methylation	1
Cadmium Chloride	increases abundance, decreases expression	1
Particulate Matter	increases abundance, increases expression	1

Cellosaurus cell lines

11 cell lines: 4 finite cell line, 3 induced pluripotent stem cell, 2 transformed cell line, 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B0IA	GM28206	Transformed cell line	Female
CVCL_B0IB	GM28210	Finite cell line	Female
CVCL_D2ZH	GM28891	Induced pluripotent stem cell	Female
CVCL_D6Y3	GM28584	Transformed cell line	Female
CVCL_E2FT	HAP1 PACS1 (-) 1	Cancer cell line	Male
CVCL_E2FU	HAP1 PACS1 (-) 2	Cancer cell line	Male
CVCL_VI93	GM27159	Finite cell line	Female
CVCL_VI94	GM27161	Finite cell line	Male
CVCL_YN50	GM27650	Finite cell line	Female
CVCL_YZ39	PACS1002i-GM27159	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02848157	PHASE4	COMPLETED	Effects of Dexmedetomidine as Adjunct to Pudendal Block for Pediatric Penile Surgery
NCT02861950	PHASE4	COMPLETED	Does Caudal Block Increase the Incidence of Urethrocutaneous Fistula Formation Following Hypospadias Repair in Infants?
NCT03902249	PHASE4	COMPLETED	Effect of Intravenous Dexamethasone With Pudendal Nerve Block on Postoperative Pain in Pediatric Hypospadias Repair
NCT05708989	PHASE4	WITHDRAWN	Caudal vs. Pudendal Block in Peds GU
NCT05837000	PHASE4	UNKNOWN	Dexmedetomidine, Ketamine and Magnesium Sulphate in Caudal Block for Hypospadias Repair
NCT05922605	PHASE4	UNKNOWN	Analgesic Effects of Caudal S-ketamine for Supplementation of Ropivacaine Caudal Analgesia in Children With Hypospadias
NCT07121764	PHASE4	COMPLETED	Postoperative Pain Relief in Children: Comparing Caudal Bupivacaine Alone Versus Bupivacaine With Dexmedetomidine for Infra-Umbilical Surgeries Under General Anesthesia
NCT07240649	PHASE4	NOT_YET_RECRUITING	Outcomes From Hyperbaric Oxygen (HBO2) Treatment for Emerging Indications
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)
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT01370798	PHASE3	COMPLETED	Local Oestrogen Versus Placebo as Preoperative Treatment in Patients With Severe Hypospadias: Effects on Post-operative Complications
NCT04423107	PHASE3	UNKNOWN	Assessment of Postop Hypospadias Pain
NCT04826484	PHASE3	TERMINATED	Opioid Reduction Initiative During Outpatient Pediatric Urologic Procedures Using Exparel
NCT07197203	PHASE3	NOT_YET_RECRUITING	Comparison of Caudal Block and Sacral Erector Spinae Plane Block With Dexmedetomidine in Pediatric Penile Hypospadias Repair
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05253456	PHASE2	COMPLETED	Modified Second Layer Repair for Distal Penile Hypospadias
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT04479371	PHASE1	WITHDRAWN	Liposomal Bupivacaine vs Standard Penile Block for Hypospadias Repair