GPS2

Summary

GPS2 (G protein pathway suppressor 2, HGNC:4550) is a protein-coding gene on chromosome 17p13.1, encoding G protein pathway suppressor 2 (Q13227). Key regulator of inflammation, lipid metabolism and mitochondrion homeostasis that acts by inhibiting the activity of the ubiquitin-conjugating enzyme UBE2N/Ubc13, thereby inhibiting ‘Lys-63’-linked ubiquitination.

This gene encodes a protein involved in G protein-mitogen-activated protein kinase (MAPK) signaling cascades. When overexpressed in mammalian cells, this gene could potently suppress a RAS- and MAPK-mediated signal and interfere with JNK activity, suggesting that the function of this gene may be signal repression. The encoded protein is an integral subunit of the NCOR1-HDAC3 (nuclear receptor corepressor 1-histone deacetylase 3) complex, and it was shown that the complex inhibits JNK activation through this subunit and thus could potentially provide an alternative mechanism for hormone-mediated antagonism of AP1 (activator protein 1) function.

Source: NCBI Gene 2874 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 56 total — 1 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_004489

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4550
Approved symbol	GPS2
Name	G protein pathway suppressor 2
Location	17p13.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000132522
Ensembl biotype	protein_coding
OMIM	601935
Entrez	2874

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 17 protein_coding, 10 retained_intron

ENST00000380728, ENST00000389167, ENST00000570780, ENST00000571098, ENST00000571569, ENST00000571695, ENST00000571697, ENST00000572172, ENST00000572363, ENST00000572707, ENST00000573059, ENST00000573684, ENST00000573807, ENST00000574201, ENST00000574458, ENST00000577040, ENST00000896390, ENST00000896391, ENST00000896392, ENST00000896393, ENST00000912639, ENST00000912640, ENST00000965307, ENST00000965308, ENST00000965309, ENST00000965310, ENST00000965311

RefSeq mRNA: 1 — MANE Select: NM_004489 NM_004489

CCDS: CCDS11100

Canonical transcript exons

ENST00000380728 — 11 exons

Exon	Start	End
ENSE00002653679	7312661	7312839
ENSE00003463153	7313568	7313721
ENSE00003468466	7313380	7313469
ENSE00003536124	7314488	7314597
ENSE00003548550	7313906	7313988
ENSE00003562540	7313212	7313291
ENSE00003592224	7313029	7313124
ENSE00003642005	7314959	7315119
ENSE00003643808	7314291	7314403
ENSE00003650101	7314080	7314159
ENSE00003849408	7315331	7315360

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 98.75.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 49.3399 / max 398.8763, expressed in 1825 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
164210	46.7987	1824
164209	2.1312	1335
164207	0.3892	179
164208	0.0208	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	98.75	gold quality
right testis	UBERON:0004534	98.70	gold quality
sural nerve	UBERON:0015488	98.43	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.93	gold quality
testis	UBERON:0000473	97.92	gold quality
gastrocnemius	UBERON:0001388	97.86	gold quality
metanephros cortex	UBERON:0010533	97.73	gold quality
pituitary gland	UBERON:0000007	97.69	gold quality
muscle of leg	UBERON:0001383	97.65	gold quality
adenohypophysis	UBERON:0002196	97.63	gold quality
granulocyte	CL:0000094	97.61	gold quality
apex of heart	UBERON:0002098	97.45	gold quality
right lobe of thyroid gland	UBERON:0001119	97.38	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.32	gold quality
mucosa of transverse colon	UBERON:0004991	97.28	gold quality
left lobe of thyroid gland	UBERON:0001120	97.26	gold quality
right adrenal gland	UBERON:0001233	97.19	gold quality
right adrenal gland cortex	UBERON:0035827	97.15	gold quality
skeletal muscle tissue	UBERON:0001134	97.14	gold quality
spleen	UBERON:0002106	97.10	gold quality
body of uterus	UBERON:0009853	97.10	gold quality
thyroid gland	UBERON:0002046	97.09	gold quality
cortex of kidney	UBERON:0001225	97.04	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.03	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.02	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.01	gold quality
cerebellar cortex	UBERON:0002129	97.00	gold quality
cerebellar hemisphere	UBERON:0002245	97.00	gold quality
small intestine Peyer’s patch	UBERON:0003454	97.00	gold quality
lower esophagus	UBERON:0013473	97.00	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.99
E-MTAB-6379	no	175.93

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, GTF3A, KLF10, KLF2, KLF5, PHF20

Literature-anchored findings (GeneRIF, showing 23)

• Results show that the N-CoR-HDAC3 complex inhibits JNK activation through the associated GPS2 subunit and thus could potentially provide an alternative mechanism for hormone-mediated antagonism of AP-1 function. (PMID:11931768)
• the GPS2 might function in concert with hMSH4-hMSH5 during the process of homologous recombination. (PMID:16122992)
• Direct interactions of GPS2 with hnf4alpha and farnesoid x receptor indicate alternative coregulator recruitment strategies to cause differential transcriptional outcomes in governing bile acid biosynthesis. (PMID:17895379)
• GPS2 interacts with RFX4_v3 to modulate transactivation of genes involved in brain morphogenesis, including Cx3Cl1 (PMID:18218630)
• Data describe the requirement of GPS2 for ABCG1 gene transcription and cholesterol efflux from macrophages, and implicate GPS2 in facilitating LXRalpha/beta recruitment to an ABCG1-specific promoter/enhancer unit upon ligand activation. (PMID:19481530)
• G protein pathway suppressor 2 (GPS2) is a transcriptional corepressor important for estrogen receptor alpha-mediated transcriptional regulation. (PMID:19858209)
• Results show for the first time that GPS-2 is differentially methylated at a site that lacks known methylation motifs and that the methylation state is detected by the immune system (PMID:19917673)
• metabolically important coregulator GPS2 functions as a hitherto unrecognized transrepression mediator of interactions between SUMOylated nuclear receptors and the N-CoR corepressor complex (PMID:20159957)
• expression of the transcriptional corepressor complex subunits GPS2 and SMRT was significantly reduced in obese adipose tissue, inversely correlated to inflammatory status (PMID:23221346)
• GPS2 is required for the association of viral NS5A with VAP-A and hepatitis C virus replication. (PMID:24223774)
• Posttranslational modification of GPS2 by SUMOylation may serve as a key factor that regulates the function of GPS2 in vivo. (PMID:24943844)
• Chromosomal translocation in a pediatric undifferentiated spindle cell sarcoma have characterized this alteration to show rearrangement of the MLL4 and GPS2 genes, resulting in fusion gene MLL4-GPS2, the expression of which promotes independent growth. (PMID:25139254)
• regulation of GPS2 by posttranslational modifications provides an effective strategy for modulating its molecular function within the nuclear compartment. (PMID:26070566)
• The study of adipose tissue from humans with and without obesity revealed correlations between reduced GPS2 expression in macrophages, elevated systemic and adipose tissue inflammation, and diabetic status. (PMID:27270589)
• our studies identify GPS2 functions as a tumor suppressor in LPS and its downregulation is correlated to prognosis of LPS. (PMID:27460081)
• These findings, together, reveal an additional layer of regulation of mitochondrial gene transcription, uncover a direct mitochondria-nuclear communication pathway, and indicate that GPS2 retrograde signaling is a key component of the mitochondrial stress response in mammals. (PMID:29499132)
• GPS2 enhances BK channel activity and its protein expression by reducing ERK1/2 signaling-mediated degradation of the channel. (PMID:29767559)
• Because GPS2 expression is down-regulated in some humans with obese and type 2 diabetes, the macrophage GPS-2/ABC-A1 pathway could be altered and contribute to atherogenesis (PMID:30153049)
• GPS2 promotes erythroid differentiation by control of the stability of EKLF protein. (PMID:32384137)
• Loss of G protein pathway suppressor 2 in human adipocytes triggers lipid remodeling by upregulating ATP binding cassette subfamily G member 1. (PMID:32798719)
• G protein pathway suppressor 2 suppresses gastric cancer by destabilizing epidermal growth factor receptor. (PMID:34609770)
• GPS2 promotes erythroid differentiation in K562 erythroleukemia cells primarily via NCOR1. (PMID:38814500)
• Regulation mechanism of GPS2 on PGC-1alpha/Drp1-mediated mitochondrial dynamics in inflammation of acute lung injury. (PMID:39116501)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	gps2	ENSDARG00000035558
mus_musculus	Gps2	ENSMUSG00000023170
rattus_norvegicus	Gps2	ENSRNOG00000016360
drosophila_melanogaster	CG17002	FBGN0033122

Protein

Protein identifiers

G protein pathway suppressor 2 — Q13227 (reviewed: Q13227)

All UniProt accessions (5): Q13227, I3L1H4, I3L242, I3L3Y9, I3L4X7

UniProt curated annotations — full annotation on UniProt →

Function. Key regulator of inflammation, lipid metabolism and mitochondrion homeostasis that acts by inhibiting the activity of the ubiquitin-conjugating enzyme UBE2N/Ubc13, thereby inhibiting ‘Lys-63’-linked ubiquitination. In the nucleus, can both acts as a corepressor and coactivator of transcription, depending on the context. Acts as a transcription coactivator in adipocytes by promoting the recruitment of PPARG to promoters: acts by inhibiting the activity of the ubiquitin-conjugating enzyme UBE2N/Ubc13, leading to stabilization of KDM4A and subsequent histone H3 ‘Lys-9’ (H3K9) demethylation. Promotes cholesterol efflux by acting as a transcription coactivator. Acts as a regulator of B-cell development by inhibiting UBE2N/Ubc13, thereby restricting the activation of Toll-like receptors (TLRs) and B-cell antigen receptors (BCRs) signaling pathways. Acts as a key mediator of mitochondrial stress response: in response to mitochondrial depolarization, relocates from the mitochondria to the nucleus following desumoylation and specifically promotes expression of nuclear-encoded mitochondrial genes. Promotes transcription of nuclear-encoded mitochondrial genes by inhibiting UBE2N/Ubc13. Can also act as a corepressor as part of the N-Cor repressor complex by repressing active PPARG. Plays an anti-inflammatory role in macrophages and is required for insulin sensitivity by acting as a corepressor. Plays an anti-inflammatory role during the hepatic acute phase response by interacting with sumoylated NR1H2 and NR5A2 proteins, thereby preventing N-Cor corepressor complex dissociation. In the cytosol, also plays a non-transcriptional role by regulating insulin signaling and pro-inflammatory pathways. In the cytoplasm, acts as a negative regulator of inflammation by inhibiting the pro-inflammatory TNF pathway; acts by repressing UBE2N/Ubc13 activity. In the cytoplasm of adipocytes, restricts the activation of insulin signaling via inhibition of UBE2N/Ubc13-mediated ubiquitination of AKT. Able to suppress G-protein- and mitogen-activated protein kinase-mediated signal transduction. Acts as a tumor-suppressor in liposarcoma. (Microbial infection) Required for efficient replication of hepatitis C virus (HCV) by promoting the interaction between VAPA and HCV virus protein NS5A.

Subunit / interactions. Component of the N-Cor repressor complex, at least composed of NCOR1, NCOR2, HDAC3, TBL1X, TBL1R, CORO2A and GPS2. Interacts (when sumoylated at Lys-71) with TBL1X; leading to protect GPS2 from degradation by the proteasome. Interacts with UBE2N; leading to inhibit UBE2N/Ubc13 activity. Interacts with TRAF1. Interacts with TRAF2. Interacts with TRAF6. Interacts with PPARG (when in the liganded conformation). Interacts with (sumoylated) NR1H2; interaction with sumoylated NR1H2 and NR5A2 onto hepatic acute phase protein promoters prevents N-Cor corepressor complex dissociation. Interacts with (sumoylated) NR5A2; interaction with sumoylated NR1H2 and NR5A2 onto hepatic acute phase protein promoters prevents N-Cor corepressor complex dissociation. Interacts with NR1H3. Interacts with RFX4. Interacts with ANKRD26. (Microbial infection) Interacts (via coiled coil domain) with hepatitis C virus (HCV) NS5A.

Subcellular location. Nucleus. Mitochondrion. Cytoplasm. Cytosol.

Tissue specificity. Widely expressed.

Post-translational modifications. Sumoylation regulates its subcellular location. Sumoylation at Lys-45 and Lys-71 regulates the shuttling between the cytoplasm and the nucleus. Sumoylation at Lys-71 is required for interaction with TBL1X. Sumoylated at Lys-45 and Lys-71 in mitochondrion. Desumoylation by SENP1 leads to relocation from the mitochondria to the nucleus. Ubiquitinated at the C-terminus by SIAH2; leading to its degradation by the proteasome. Interaction with TBL1X and methylation at Arg-323 protect GPS2 against ubiquitination and degradation. Methylated at Arg-312 and Arg-323 by PRMT6. Methylation at Arg-323 protects from degradation by the proteasome.

Induction. Down-regulated in liposarcoma. Down-regulated in macrophages of patients with adipose tissue inflammation and type-2 diabetes.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13227-1	1	yes
Q13227-2	2

RefSeq proteins (1): NP_004480* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026094	GPS2	Family

Pfam: PF15991

UniProt features (30 total): mutagenesis site 14, region of interest 4, modified residue 3, cross-link 2, compositionally biased region 2, chain 1, splice variant 1, sequence variant 1, helix 1, coiled-coil region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2L5G	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13227-F1	63.77	0.19

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 (5): 323, 45, 71, 312, 323

Mutagenesis-validated functional residues (14):

Position	Phenotype
19–22	abolishes interaction with tbl1x.
45	abolishes sumoylation; when associated with r-71.
61–94	abolishes interaction with sumoylated nr1h2 and nr5a2 proteins.
69–70	weakly affects interaction with sumoylated nr1h2 and nr5a2 proteins.
71	abolishes sumoylation; when associated with r-45.
76–79	weakly affects interaction with sumoylated nr1h2 and nr5a2 proteins.
86–90	weakly affects interaction with sumoylated nr1h2 and nr5a2 proteins.
319	does not affect methylation.
320	does not affect methylation.
321	strongly decreases methylation.
322	strongly decreases methylation.
324	abolishes methylation.
325	abolishes methylation.
327	decreases methylation.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1989781	PPARA activates gene expression
R-HSA-3214815	HDACs deacetylate histones
R-HSA-9022537	Loss of MECP2 binding ability to the NCoR/SMRT complex
R-HSA-9022692	Regulation of MECP2 expression and activity
R-HSA-9029569	NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux
R-HSA-9609690	HCMV Early Events
R-HSA-9841922	MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis

MSigDB gene sets: 256 (showing top): GOBP_REGULATION_OF_B_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, E2F_Q4_01, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_B_CELL_ACTIVATION, GOBP_NEGATIVE_REGULATION_OF_FAT_CELL_DIFFERENTIATION, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_CHOLESTEROL_EFFLUX, GOBP_REGULATION_OF_CHOLESTEROL_EFFLUX, GOBP_NEGATIVE_REGULATION_OF_TOLL_LIKE_RECEPTOR_SIGNALING_PATHWAY, HSIAO_HOUSEKEEPING_GENES

GO Biological Process (17): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of transcription by RNA polymerase II (GO:0006357), JNK cascade (GO:0007254), negative regulation of tumor necrosis factor-mediated signaling pathway (GO:0010804), positive regulation of cholesterol efflux (GO:0010875), regulation of lipid metabolic process (GO:0019216), B cell differentiation (GO:0030183), negative regulation of toll-like receptor signaling pathway (GO:0034122), positive regulation of peroxisome proliferator activated receptor signaling pathway (GO:0035360), regulation of fat cell differentiation (GO:0045598), negative regulation of fat cell differentiation (GO:0045599), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation of JNK cascade (GO:0046329), negative regulation of inflammatory response (GO:0050728), negative regulation of B cell receptor signaling pathway (GO:0050859), response to mitochondrial depolarisation (GO:0098780), negative regulation of protein K63-linked ubiquitination (GO:1900045)

GO Molecular Function (6): transcription coregulator activity (GO:0003712), transcription coactivator activity (GO:0003713), transcription corepressor activity (GO:0003714), GTPase inhibitor activity (GO:0005095), cyclin binding (GO:0030332), protein binding (GO:0005515)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), mitochondrion (GO:0005739), cytosol (GO:0005829), transcription repressor complex (GO:0017053), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Regulation of lipid metabolism by PPARalpha	1
Chromatin modifying enzymes	1
Loss of function of MECP2 in Rett syndrome	1
Transcriptional Regulation by MECP2	1
NR1H2 and NR1H3-mediated signaling	1
HCMV Infection	1
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transcription by RNA polymerase II	3
cellular anatomical structure	3
regulation of transcription by RNA polymerase II	2
negative regulation of DNA-templated transcription	2
fat cell differentiation	2
positive regulation of DNA-templated transcription	2
transcription coregulator activity	2
intracellular membrane-bounded organelle	2
cytoplasm	2
regulation of DNA-templated transcription	1
MAPK cascade	1
negative regulation of cytokine-mediated signaling pathway	1
regulation of tumor necrosis factor-mediated signaling pathway	1
tumor necrosis factor-mediated signaling pathway	1
regulation of cholesterol efflux	1
positive regulation of cholesterol transport	1
cholesterol efflux	1
lipid metabolic process	1
regulation of primary metabolic process	1
lymphocyte differentiation	1
B cell activation	1
toll-like receptor signaling pathway	1
negative regulation of immune system process	1
negative regulation of signal transduction	1
regulation of toll-like receptor signaling pathway	1
peroxisome proliferator activated receptor signaling pathway	1
regulation of peroxisome proliferator activated receptor signaling pathway	1
positive regulation of intracellular signal transduction	1
regulation of cell differentiation	1
negative regulation of cell differentiation	1
regulation of fat cell differentiation	1
JNK cascade	1
negative regulation of MAPK cascade	1
regulation of JNK cascade	1
inflammatory response	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of inflammatory response	1
B cell receptor signaling pathway	1
regulation of B cell receptor signaling pathway	1

Protein interactions and networks

STRING

1289 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GPS2	TBL1Y	Q9BQ87	997
GPS2	TBL1X	O60907	997
GPS2	TBL1XR1	Q9BZK7	996
GPS2	NCOR1	O75376	992
GPS2	GPS1	Q13098	956
GPS2	HDAC3	O15379	944
GPS2	NCOR2	Q9Y618	924
GPS2	TAB2	Q9NYJ8	640
GPS2	EP300	Q09472	544
GPS2	ABCG1	P45844	531
GPS2	CYP8B1	Q9UNU6	506
GPS2	PDE6B	P35913	488
GPS2	CORO2A	Q92828	479
GPS2	ZYX	Q15942	461
GPS2	PROCA1	Q8NCQ7	458

IntAct

268 interactions, top by confidence:

A	B	Type	Score
RALBP1	GPS2	psi-mi:“MI:0915”(physical association)	0.900
GPS2	RALBP1	psi-mi:“MI:0915”(physical association)	0.900
GPS2	HDAC3	psi-mi:“MI:0915”(physical association)	0.900
GPS2	HDAC3	psi-mi:“MI:0914”(association)	0.900
GPS2	ATF4	psi-mi:“MI:0915”(physical association)	0.830
ATF4	GPS2	psi-mi:“MI:0915”(physical association)	0.830
GPS2	NCOR2	psi-mi:“MI:0407”(direct interaction)	0.790
GPS2	NCOR2	psi-mi:“MI:0915”(physical association)	0.790
GPS2	SESTD1	psi-mi:“MI:0915”(physical association)	0.780
SESTD1	GPS2	psi-mi:“MI:0915”(physical association)	0.780
KRT31	GPS2	psi-mi:“MI:0915”(physical association)	0.740
GPS2	KRT31	psi-mi:“MI:0915”(physical association)	0.740
TFIP11	GPS2	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (280): GPS2 (Two-hybrid), KRT31 (Two-hybrid), RALBP1 (Two-hybrid), RBPMS (Two-hybrid), TFIP11 (Two-hybrid), SESTD1 (Two-hybrid), TBL1XR1 (Affinity Capture-MS), TBL1X (Affinity Capture-MS), NCOR1 (Affinity Capture-MS), NCOR2 (Affinity Capture-MS), PPFIA1 (Affinity Capture-MS), PPFIA3 (Affinity Capture-MS), MAPK3 (Affinity Capture-MS), ARMC8 (Affinity Capture-MS), MKLN1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4IBL7, A3RK74, A4L7N3, A5D7F6, B2RWS6, B5DE09, E1BPQ1, G3V7R4, O00512, O43524, P11420, P45481, P78364, Q09472, Q12778, Q13227, Q14686, Q15596, Q17BA4, Q61026, Q64028, Q66JJ0, Q67FY2, Q6AI39, Q6JHU9, Q6T264, Q7ZUK7, Q810W5, Q86UU0, Q8CHH5, Q8CHP6, Q8IXK0, Q8IZL2, Q921N8, Q924H2, Q92585, Q92793, Q961D9, Q96JK9, Q96RN5

Diamond homologs: Q13227, Q921N8

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 80 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
Epigenetic regulation by WDR5-containing histone modifying complexes	5	14.8×	1e-03
Keratinization	11	11.8×	2e-07
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	5	8.0×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
transcription by RNA polymerase II	8	9.2×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	29
Likely benign	0
Benign	2

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
815900	GRCh37/hg19 17p13.1(chr17:6800893-7304696)x1	Pathogenic
562231	Single allele	Likely pathogenic

SpliceAI

1599 predictions. Top by Δscore:

Variant	Effect	Δscore
17:7311345:CCCA:C	acceptor_loss	1.0000
17:7311348:A:AC	acceptor_loss	1.0000
17:7311348:A:AG	acceptor_gain	1.0000
17:7311348:AGCT:A	acceptor_gain	1.0000
17:7311349:G:GA	acceptor_gain	1.0000
17:7311349:GC:G	acceptor_gain	1.0000
17:7311349:GCT:G	acceptor_gain	1.0000
17:7311349:GCTG:G	acceptor_gain	1.0000
17:7311349:GCTGA:G	acceptor_gain	1.0000
17:7311454:G:GT	donor_gain	1.0000
17:7311454:GAA:G	donor_gain	1.0000
17:7311480:TGG:T	donor_loss	1.0000
17:7311481:GGTAT:G	donor_loss	1.0000
17:7311482:G:GG	donor_gain	1.0000
17:7311482:GT:G	donor_loss	1.0000
17:7311483:T:A	donor_loss	1.0000
17:7311567:T:A	acceptor_gain	1.0000
17:7311573:TCCA:T	acceptor_loss	1.0000
17:7311574:CCAG:C	acceptor_loss	1.0000
17:7311575:CA:C	acceptor_loss	1.0000
17:7311576:A:AG	acceptor_gain	1.0000
17:7311577:G:GG	acceptor_gain	1.0000
17:7313122:GGA:G	acceptor_gain	1.0000
17:7313125:C:CC	acceptor_gain	1.0000
17:7313206:A:AC	donor_gain	1.0000
17:7313207:C:CC	donor_gain	1.0000
17:7313207:CT:C	donor_gain	1.0000
17:7313207:CTCA:C	donor_gain	1.0000
17:7313208:TCACT:T	donor_loss	1.0000
17:7313209:CAC:C	donor_loss	1.0000

AlphaMissense

2137 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:7314335:C:A	K91N	1.000
17:7314335:C:G	K91N	1.000
17:7314339:A:G	L90P	1.000
17:7314347:G:C	F87L	1.000
17:7314347:G:T	F87L	1.000
17:7314348:A:G	F87S	1.000
17:7314349:A:G	F87L	1.000
17:7314351:A:G	L86P	1.000
17:7314991:T:G	H21P	1.000
17:7314992:G:C	H21D	1.000
17:7315000:A:G	L18P	1.000
17:7315000:A:T	L18Q	1.000
17:7314327:A:G	L94S	0.999
17:7314336:T:A	K91M	0.999
17:7314336:T:G	K91T	0.999
17:7314337:T:C	K91E	0.999
17:7314342:T:G	Q89P	0.999
17:7314345:A:G	L88P	0.999
17:7314348:A:C	F87C	0.999
17:7314359:C:A	K83N	0.999
17:7314359:C:G	K83N	0.999
17:7314372:A:G	L79P	0.999
17:7314381:A:G	L76P	0.999
17:7314489:T:G	Q68P	0.999
17:7314567:T:G	Q42P	0.999
17:7314583:C:G	D37H	0.999
17:7314961:T:G	Q31P	0.999
17:7314964:C:G	R30P	0.999
17:7314966:C:A	K29N	0.999
17:7314966:C:G	K29N	0.999

dbSNP variants (sampled 300 via entrez): RS1000263544 (17:7315770 G>A), RS1000454241 (17:7315448 G>A), RS1000600861 (17:7314847 C>A,G,T), RS1000800737 (17:7315548 T>G), RS1003523035 (17:7313204 A>G), RS1004186932 (17:7315316 G>A,C,T), RS1004560484 (17:7314089 T>A,C), RS1005601910 (17:7316466 C>A,T), RS1006688948 (17:7313851 G>A), RS1007618216 (17:7312854 GAA>G), RS1008008302 (17:7316485 C>T), RS1008487911 (17:7314901 C>G), RS1009016021 (17:7315406 C>T), RS1009047095 (17:7315289 G>A), RS1010895600 (17:7315558 C>G,T)

Disease associations

OMIM: gene MIM:601935 | disease phenotypes: MIM:261800

GenCC curated gene-disease

Mondo (1): isolated Pierre-Robin syndrome (MONDO:0009869)

Orphanet (1): Isolated Pierre Robin sequence (Orphanet:718)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90013406_265	Liver enzyme levels (alkaline phosphatase)	1.000000e-80

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D010855	Pierre Robin Syndrome	C05.500.460.606; C05.660.207.540.460.606; C07.320.440.606; C07.650.500.460.606; C16.131.621.207.540.460.606; C16.131.850.500.460.606

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	2
Valproic Acid	increases expression, increases methylation, affects cotreatment	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	affects expression	1
afimoxifene	affects binding, increases reaction	1
N-benzyloxycarbonylprolylprolinal	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
14-deoxy-11,12-didehydroandrographolide	decreases expression	1
abrine	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
jinfukang	increases expression	1
Air Pollutants	increases abundance, affects expression	1
Ethanol	increases abundance, increases expression, affects cotreatment	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Catechin	affects cotreatment, increases expression	1
Estradiol	affects binding, increases reaction	1
Gasoline	increases abundance, increases expression, affects cotreatment	1
Hydralazine	affects cotreatment, increases expression	1
Malathion	decreases expression	1
Ozone	affects expression, increases abundance	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, increases abundance, increases expression	1
Smoke	decreases expression	1
Tamoxifen	affects binding, increases reaction	1
Cyclosporine	increases expression	1
Asbestos, Crocidolite	affects expression	1
Thapsigargin	increases expression	1
Okadaic Acid	increases expression	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01690078	Not specified	COMPLETED	Functional Modeling of the Pediatric Airway
NCT02432638	Not specified	WITHDRAWN	Pierre Robin Sequence Outcome Assessment Multi Institutional Study
NCT03423017	Not specified	COMPLETED	Brainstem Dysfunction Involvement in the Pathogenesis of Pierre Robin Sequence
NCT04422067	Not specified	COMPLETED	Usefulness of Cephalometry in the Second and Third Trimester of Pregnancy in the Diagnosis of Fetal Microretrognathia
NCT07257276	Not specified	ACTIVE_NOT_RECRUITING	3D-CT-Based Prediction of Difficult Laryngoscopy in Infants With Pierre Robin Sequence
NCT07604818	Not specified	COMPLETED	Comparison of Sucking in Premature Infants and Infants With Pierre Robin Sequence