GRIP1

Summary

GRIP1 (glutamate receptor interacting protein 1, HGNC:18708) is a protein-coding gene on chromosome 12q14.3, encoding Glutamate receptor-interacting protein 1 (Q9Y3R0). May play a role as a localized scaffold for the assembly of a multiprotein signaling complex and as mediator of the trafficking of its binding partners at specific subcellular location in neurons.

This gene encodes a member of the glutamate receptor interacting protein family. The encoded scaffold protein binds to and mediates the trafficking and membrane organization of a number of transmembrane proteins. Alternatively spliced transcript variants encoding different isoforms have been described.

Source: NCBI Gene 23426 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Fraser syndrome 3 (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 862 total — 18 pathogenic, 17 likely-pathogenic
• Phenotypes (HPO): 1
• MANE Select transcript: NM_001366722

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18708
Approved symbol	GRIP1
Name	glutamate receptor interacting protein 1
Location	12q14.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000155974
Ensembl biotype	protein_coding
OMIM	604597
Entrez	23426

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 16 protein_coding, 2 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000359742, ENST00000398016, ENST00000535002, ENST00000535323, ENST00000535721, ENST00000536215, ENST00000538164, ENST00000538211, ENST00000538373, ENST00000539540, ENST00000540433, ENST00000540854, ENST00000541299, ENST00000541947, ENST00000542021, ENST00000542309, ENST00000543172, ENST00000545666, ENST00000643019, ENST00000696989, ENST00000967087

RefSeq mRNA: 11 — MANE Select: NM_001366722 NM_001178074, NM_001366722, NM_001366723, NM_001366724, NM_001379345, NM_001379346, NM_001379347, NM_001379348, NM_001379349, NM_001379351, NM_021150

CCDS: CCDS41807, CCDS91722

Canonical transcript exons

ENST00000359742 — 25 exons

Exon	Start	End
ENSE00001023693	66465275	66465422
ENSE00001023699	66444584	66444729
ENSE00001023700	66462924	66463093
ENSE00001023701	66445322	66445508
ENSE00001302238	66392677	66392816
ENSE00001303738	66432548	66432628
ENSE00001320083	66394208	66394352
ENSE00001323780	66392308	66392502
ENSE00001323901	66420720	66420789
ENSE00001326760	66371694	66371927
ENSE00001422180	66539078	66539223
ENSE00001428140	66529831	66529914
ENSE00001429206	66347431	66349246
ENSE00001430548	66515619	66515764
ENSE00001431116	66517901	66517976
ENSE00001431604	66377017	66377061
ENSE00003480166	66456187	66456342
ENSE00003511813	66406283	66406428
ENSE00003534066	66353417	66353563
ENSE00003552410	66377174	66377285
ENSE00003575654	66455409	66455564
ENSE00003633888	66541815	66541950
ENSE00003657953	66379280	66379436
ENSE00003671421	66596847	66596927
ENSE00003912333	66678850	66679076

Expression profiles

Bgee: expression breadth ubiquitous, 192 present calls, max score 93.62.

FANTOM5 (CAGE): breadth broad, TPM avg 1.2888 / max 40.7392, expressed in 563 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
131948	0.6010	347
131949	0.2860	152
131950	0.2011	112
131939	0.0861	42
131941	0.0684	24
131938	0.0392	9
131937	0.0070	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	93.62	gold quality
ganglionic eminence	UBERON:0004023	87.42	gold quality
ventricular zone	UBERON:0003053	86.03	gold quality
seminal vesicle	UBERON:0000998	83.20	silver quality
oviduct epithelium	UBERON:0004804	83.09	gold quality
secondary oocyte	CL:0000655	82.46	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.20	gold quality
skin of abdomen	UBERON:0001416	79.54	gold quality
placenta	UBERON:0001987	79.45	gold quality
buccal mucosa cell	CL:0002336	78.64	gold quality
skin of leg	UBERON:0001511	77.97	gold quality
zone of skin	UBERON:0000014	77.19	gold quality
right uterine tube	UBERON:0001302	76.06	gold quality
muscle layer of sigmoid colon	UBERON:0035805	75.99	gold quality
esophagus mucosa	UBERON:0002469	75.49	gold quality
esophagus	UBERON:0001043	75.33	gold quality
colonic epithelium	UBERON:0000397	75.24	gold quality
lower esophagus	UBERON:0013473	75.23	gold quality
lower esophagus muscularis layer	UBERON:0035833	75.19	gold quality
endothelial cell	CL:0000115	74.93	silver quality
minor salivary gland	UBERON:0001830	74.19	gold quality
oocyte	CL:0000023	74.11	silver quality
left lobe of thyroid gland	UBERON:0001120	73.99	gold quality
prefrontal cortex	UBERON:0000451	73.85	gold quality
thyroid gland	UBERON:0002046	73.77	gold quality
lower esophagus mucosa	UBERON:0035834	73.74	gold quality
saliva-secreting gland	UBERON:0001044	73.41	gold quality
islet of Langerhans	UBERON:0000006	73.24	gold quality
fallopian tube	UBERON:0003889	73.15	gold quality
pituitary gland	UBERON:0000007	72.93	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	4653.23
E-HCAD-25	yes	3170.57
E-HCAD-30	yes	2894.80
E-GEOD-180759	yes	2729.44
E-CURD-119	yes	2478.37
E-GEOD-131882	yes	2409.34
E-ANND-3	yes	6.79
E-GEOD-75367	no	62.98

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR2, KAT7, NCOA2, NCOA3, PML

miRNA regulators (miRDB)

189 targeting GRIP1, 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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-12121	99.99	66.64	255
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-12136	99.98	72.81	5713
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-559	99.95	72.28	3609
HSA-LET-7C-3P	99.95	73.42	2862

Literature-anchored findings (GeneRIF, showing 13)

• after regulated endocytosis, binding to GRIP/ABP stabilizes the internalized receptors in an intracellular pool and prevents them from being recycled back to the plasma membrane or entering a degradative pathway. (PMID:12011465)
• GRIP1c 4-7 plays a role not only in glutamatergic synapses but also in GABAergic synapses (PMID:15226318)
• study showed neither single marker nor haplotype analysis revealed an association between variants at GRIP1 locus & schizophrenia; suggests it is unlikely that the GRIP1 polymorphisms investigated play a substantial role in schizophrenia susceptibility (PMID:17303296)
• Supramodular nature of GRIP1 revealed by the structure of its PDZ12 tandem in complex with the carboxyl tail of Fras1. (PMID:18155042)
• GRIP1 splice forms interact with gephyrin and play a role in synaptic function at GABAergic and glycinergic synapses in cultured hippocampal neurons. (PMID:18315564)
• Gain-of-function glutamate receptor interacting protein 1 variants alter GluA2 recycling and surface distribution in patients with autism (PMID:21383172)
• In three unrelated families with parental consanguinity, GRIP1 mutations were found to segregate with Fraser syndrome in an autosomal recessive manner. (PMID:22510445)
• In 15 of 590 families, we identified recessive mutations in the genes FRAS1, FREM2, GRIP1, FREM1, ITGA8, and GREM1, all of which function in the interaction of the ureteric bud and the metanephric mesenchyme. (PMID:24700879)
• the Trip6-GRIP1-myosin VI interaction and its regulation on F-actin network play a significant role in dendritic morphogenesis (PMID:25673849)
• GRIP1 was identified as one of the most important differentially expressed, topologically significant proteins in the protein-protein interaction network in Alzheimer’s disease. (PMID:27425598)
• Data suggest that molecules in the erythropoietin-producing hepatocellular receptor B family (EPHB) / ephrinB (EFNB) signalling pathways, specifically ephrin B3 and GRIP1, are involved blood pressure regulation. (PMID:27941904)
• GRIP1 is phosphorylated at an N-terminal serine cluster by cyclin-dependent kinase-9 (CDK9), which is recruited into GC-induced GR:GRIP1:CDK9 hetero-complexes, producing distinct GRE-specific GRIP1 phospho-isoforms. (PMID:29170386)
• The adaptor proteins HAP1a and GRIP1 collaborate to activate the kinesin-1 isoform KIF5C. (PMID:31757889)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	grip1	ENSDARG00000015053
mus_musculus	Grip1	ENSMUSG00000034813
rattus_norvegicus	Grip1	ENSRNOG00000004013
drosophila_melanogaster	Magi	FBGN0034590
caenorhabditis_elegans		WBGENE00010444

Paralogs (6): MAGI3 (ENSG00000081026), GRIP2 (ENSG00000144596), MAGI1 (ENSG00000151276), SAV1 (ENSG00000151748), MAGI2 (ENSG00000187391), MAGIX (ENSG00000269313)

Protein

Protein identifiers

Glutamate receptor-interacting protein 1 — Q9Y3R0 (reviewed: Q9Y3R0)

All UniProt accessions (15): Q9Y3R0, A0A2R8Y6S7, A0A8V8TLS6, F5H3F9, F5H3G9, F5H424, F5H4M4, F5H4N6, F5H4P8, F5H4Q7, F5H5I0, H0YFK8, H0YFY3, H0YGF1, H0YGM4

UniProt curated annotations — full annotation on UniProt →

Function. May play a role as a localized scaffold for the assembly of a multiprotein signaling complex and as mediator of the trafficking of its binding partners at specific subcellular location in neurons. Through complex formation with NSG1, GRIA2 and STX12 controls the intracellular fate of AMPAR and the endosomal sorting of the GRIA2 subunit toward recycling and membrane targeting.

Subunit / interactions. Interacts with EPHA7, EPHB2, KIF5A, KIF5B, KIF5C, GRIA2, GRIA3, GRIPAP1/GRASP1, PPFIA1, PPFIA4, FRAS1, PLCD4, PTPRF and liprins-alpha. Can form homomultimers or heteromultimers with GRIP2. Forms a ternary complex with GRIA2 and CSPG4. Interacts with ATAD1 in an ATP-dependent manner. ATAD1-catalyzed ATP hydrolysis disrupts binding to ATAD1 and to GRIA2 and leads to AMPAR complex disassembly. Interacts with EFNB1, EFNB3 and the C-terminal tail of PRLHR. Interacts with SLC30A9. Interacts with BUD23. Forms a complex with NSG1, GRIA2 and STX12; controls the intracellular fate of AMPAR and the endosomal sorting of the GRIA2 subunit toward recycling and membrane targeting. Interacts with NSG1.

Subcellular location. Cytoplasmic vesicle. Perikaryon. Cell projection. Dendrite. Cytoplasm. Endomembrane system. Postsynaptic cell membrane. Postsynaptic density. Endoplasmic reticulum membrane.

Disease relevance. Fraser syndrome 3 (FRASRS3) [MIM:617667] A form of Fraser syndrome, an autosomal recessive disorder characterized by cryptophthalmos, cutaneous syndactyly, and urogenital abnormalities including renal agenesis or hypoplasia. Additional features include abnormalities of the larynx, ear malformations, and facial abnormalities. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. PDZ 6 mediates interaction with the PDZ recognition motif of EFNB1 and EPHB2 and with the C-terminus of PPFIA1 and PPFIA4. PDZ 4 and PDZ 5 mediate interaction with the C-terminus of GRIA2 and GRIA3. PDZ 4, PDZ 5 and PDZ 6 mediate homomultimers. PDZ 7 mediates interaction with PDZ domain of GRASP1. PDZ 7 domain binds CSPG4. PDZ 6 mediates interaction with the C-terminus of liprins-alpha. PDZ 1, PDZ 2 and PDZ 3 mediate interaction with the PDZ-binding motif of FRAS1. PDZ 4 and PDZ 5 mediate interaction with PRLHR.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9Y3R0-1	1	yes
Q9Y3R0-2	2
Q9Y3R0-3	3

RefSeq proteins (11): NP_001171545, NP_001353651, NP_001353652, NP_001353653, NP_001366274, NP_001366275, NP_001366276, NP_001366277, NP_001366278, NP_001366280, NP_066973 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001478	PDZ	Domain
IPR036034	PDZ_sf	Homologous_superfamily
IPR041489	PDZ_6	Domain
IPR043545	GRIP1/2	Family

Pfam: PF00595, PF17820

UniProt features (25 total): domain 7, strand 5, region of interest 3, compositionally biased region 2, splice variant 2, helix 2, chain 1, modified residue 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2JIL	X-RAY DIFFRACTION	1.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y3R0-F1	61.50	0.05

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 (1): 43

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-416993	Trafficking of GluR2-containing AMPA receptors

MSigDB gene sets: 369 (showing top): GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_DN, GOBP_NEUROGENESIS, DARWICHE_PAPILLOMA_RISK_HIGH_DN, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_MEMBRANE, GOBP_ENDOCYTIC_RECYCLING, GOCC_NEURON_PROJECTION, GOBP_PROTEIN_LOCALIZATION_TO_SYNAPSE, GOBP_CELL_PROJECTION_ORGANIZATION

GO Biological Process (3): intracellular signal transduction (GO:0035556), neurotransmitter receptor transport, endosome to postsynaptic membrane (GO:0098887), positive regulation of neuron projection arborization (GO:0150012)

GO Molecular Function (3): beta-catenin binding (GO:0008013), signaling receptor complex adaptor activity (GO:0030159), protein binding (GO:0005515)

GO Cellular Component (15): endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), plasma membrane (GO:0005886), postsynaptic density (GO:0014069), dendrite (GO:0030425), cytoplasmic vesicle (GO:0031410), neuron projection (GO:0043005), perikaryon (GO:0043204), postsynaptic membrane (GO:0045211), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), endomembrane system (GO:0012505), membrane (GO:0016020), cell projection (GO:0042995), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Trafficking of AMPA receptors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
cytoplasm	3
intracellular anatomical structure	2
signal transduction	1
intercellular transport	1
neurotransmitter receptor transport to postsynaptic membrane	1
neurotransmitter receptor transport, endosome to plasma membrane	1
positive regulation of cell projection organization	1
positive regulation of developmental process	1
neuron projection arborization	1
regulation of neuron projection arborization	1
protein binding	1
signaling receptor binding	1
signaling adaptor activity	1
binding	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
asymmetric synapse	1
postsynaptic specialization	1
neuron projection	1
dendritic tree	1
intracellular vesicle	1
plasma membrane bounded cell projection	1
neuronal cell body	1
synaptic membrane	1
postsynapse	1
endomembrane system	1
intracellular membrane-bounded organelle	1
vacuole	1
plasma membrane	1
cell junction	1

Protein interactions and networks

STRING

1202 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GRIP1	GRIA2	P42262	997
GRIP1	GRIPAP1	Q4V328	987
GRIP1	GRIA3	P42263	979
GRIP1	PICK1	Q9NRD5	972
GRIP1	GCC2	Q8IWJ2	959
GRIP1	GCC1	Q96CN9	913
GRIP1	PPFIA1	Q13136	908
GRIP1	FREM2	Q5SZK8	874
GRIP1	GRIA1	P42261	869
GRIP1	RGPD1	P0C839	863
GRIP1	FRAS1	Q86XX4	861
GRIP1	RGPD8	O14715	855
GRIP1	FREM1	Q5H8C1	846
GRIP1	RGPD5	Q99666	843
GRIP1	GOLGA4	Q13439	821

IntAct

2264 interactions, top by confidence:

A	B	Type	Score
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
ESR1	GRIP1	psi-mi:“MI:0407”(direct interaction)	0.610
GRIP1	YWHAE	psi-mi:“MI:0915”(physical association)	0.600
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
GRIP1	E6	psi-mi:“MI:0915”(physical association)	0.540
E6	GRIP1	psi-mi:“MI:0407”(direct interaction)	0.540
GRIP1	E6	psi-mi:“MI:0407”(direct interaction)	0.540
YWHAQ	IGLC7	psi-mi:“MI:0914”(association)	0.530
FNTB	BLTP3B	psi-mi:“MI:0914”(association)	0.530
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
YWHAQ	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
SFN	GRIP1	psi-mi:“MI:0915”(physical association)	0.470
NRXN3	GRIP1	psi-mi:“MI:0407”(direct interaction)	0.440
CSPG4	GRIP1	psi-mi:“MI:0407”(direct interaction)	0.440
NECTIN3	GRIP1	psi-mi:“MI:0407”(direct interaction)	0.440
NECTIN1	GRIP1	psi-mi:“MI:0407”(direct interaction)	0.440
E6	GRIP1	psi-mi:“MI:0407”(direct interaction)	0.440
GAS2L2	GRIP1	psi-mi:“MI:0407”(direct interaction)	0.440
ASIC3	GRIP1	psi-mi:“MI:0407”(direct interaction)	0.440
DOCK4	GRIP1	psi-mi:“MI:0407”(direct interaction)	0.440
CNTNAP4	GRIP1	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGEF26	GRIP1	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (136): PPARG (Reconstituted Complex), GRIP1 (Two-hybrid), FLII (Reconstituted Complex), Lrrfip1 (Reconstituted Complex), GRIP1 (Affinity Capture-Western), GRIP1 (Affinity Capture-MS), GRM7 (Two-hybrid), GRIP1 (Reconstituted Complex), GRIP1 (Reconstituted Complex), GRIP1 (Proximity Label-MS), GRIP1 (Proximity Label-MS), GRIP1 (Affinity Capture-Western), DZIP3 (Reconstituted Complex), GRIP1 (Two-hybrid), AGAP2 (Two-hybrid)

ESM2 similar proteins: A0A0G2K2P5, A0JNJ1, B1WAP7, G9CGD6, O14640, O75122, O88382, O95049, O97758, P34908, P39447, P51141, P54792, P70175, Q05AS8, Q07157, Q16825, Q5F488, Q5IS48, Q5SGD7, Q5TCQ9, Q5XI81, Q61062, Q62136, Q62728, Q62936, Q6DKE2, Q6P9H4, Q6ZM86, Q812E4, Q86UL8, Q8BMA3, Q8IVH8, Q8JHI3, Q8TDW5, Q920B0, Q924I2, Q925T6, Q92997, Q95168

Diamond homologs: A1Z9P3, A1ZA47, A2ALU4, A8E0R9, D4A702, E9Q9W7, O00151, O14910, O70209, O70400, O75112, O88952, P36202, P50479, P52944, P70271, P97879, Q01613, Q09JY9, Q0P5E6, Q0P5F3, Q13424, Q13796, Q27IV2, Q28626, Q2M3G4, Q32LM6, Q3SYZ8, Q3T005, Q3T0C8, Q53GG5, Q5E9E1, Q5F425, Q5RAA5, Q5RBI7, Q5SX79, Q61234, Q62920, Q66HS7, Q6AYD6

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
GRIP1	“up-regulates activity”	KIF5C	binding
GRIP1	up-regulates	MEF2C	binding
GRIP1	“up-regulates activity”	GRIPAP1	binding
ERK1/2	“up-regulates activity”	GRIP1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 85 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
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	8	81.4×	1e-11
Activation of BAD and translocation to mitochondria	7	80.8×	2e-10
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	71.2×	4e-10
Activation of BH3-only proteins	7	52.7×	3e-09
RHO GTPases activate PKNs	7	33.6×	7e-08
Intrinsic Pathway for Apoptosis	7	31.1×	1e-07
FOXO-mediated transcription	6	30.5×	1e-06
Apoptosis	9	22.9×	1e-08

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	24.4×	7e-04
intracellular protein localization	7	9.8×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	17
Uncertain significance	273
Likely benign	481
Benign	22

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
2047350	NM_001366722.1(GRIP1):c.2155C>T (p.Arg719Ter)	Pathogenic
2696242	NM_001366722.1(GRIP1):c.1559_1566dup (p.Arg523fs)	Pathogenic
2713892	NM_001366722.1(GRIP1):c.436_437del (p.Val146fs)	Pathogenic
2744863	NM_001366722.1(GRIP1):c.2768_2772delinsCTTGGTAGAACTTTGAGAAACTTTGAGAAAACTTTGAGAAAACTTTGAGAAA (p.Met923_Thr924delinsThrTrpTer)	Pathogenic
2768789	NM_001366722.1(GRIP1):c.505G>T (p.Gly169Ter)	Pathogenic
2788488	NM_001366722.1(GRIP1):c.2775_2776del (p.Leu926fs)	Pathogenic
2792993	NM_001366722.1(GRIP1):c.1633C>T (p.Arg545Ter)	Pathogenic
2835353	NM_001366722.1(GRIP1):c.2885del (p.Pro962fs)	Pathogenic
3063238	GRCh37/hg19 12q14.3(chr12:65462762-66830065)x1	Pathogenic
3244433	NC_000012.11:g.(?67072610)(67072684_?)del	Pathogenic
3244434	NC_000012.11:g.(?66859035)(66859222_?)del	Pathogenic
3244435	NC_000012.11:g.(?66838344)(67072684_?)del	Pathogenic
36970	NM_001366722.1(GRIP1):c.2269+1G>C	Pathogenic
36971	NM_001366722.1(GRIP1):c.1337_1340del (p.Lys446fs)	Pathogenic
3717575	NM_001366722.1(GRIP1):c.672_675del (p.Lys224fs)	Pathogenic
3726914	NM_001366722.1(GRIP1):c.2749del (p.Arg917fs)	Pathogenic
4682806	GRCh37/hg19 12q14.3(chr12:65953394-66867963)x1	Pathogenic
974698	NM_001366722.1(GRIP1):c.1930C>T (p.Gln644Ter)	Pathogenic
1878400	NM_001366722.1(GRIP1):c.10_13del (p.Val4fs)	Likely pathogenic
2768364	NM_001366722.1(GRIP1):c.503-2del	Likely pathogenic
2802784	NM_001366722.1(GRIP1):c.1199-2del	Likely pathogenic
2805894	NM_001366722.1(GRIP1):c.1199-1G>A	Likely pathogenic
2838526	NM_001366722.1(GRIP1):c.1769-1G>A	Likely pathogenic
2987018	NM_001366722.1(GRIP1):c.137-1G>A	Likely pathogenic
3575200	NM_021150.4(GRIP1):c.1618_1619insTATATCTCCATTATTACAGCACCAT	Likely pathogenic
3575202	NM_001366722.1(GRIP1):c.1688-1G>C	Likely pathogenic
3575209	NM_001366722.1(GRIP1):c.1285del (p.Leu429fs)	Likely pathogenic
3575210	NM_001366722.1(GRIP1):c.1279C>T (p.Arg427Ter)	Likely pathogenic
3575215	NM_001366722.1(GRIP1):c.1199-2A>G	Likely pathogenic
3575234	NM_001366722.1(GRIP1):c.206C>A (p.Ser69Ter)	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

7382 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:66349167:A:G	L1080P	1.000
12:66349173:A:G	L1078P	1.000
12:66353418:T:G	Q1053P	1.000
12:66353421:A:G	L1052S	1.000
12:66353430:T:A	D1049V	1.000
12:66353484:A:T	V1031D	1.000
12:66353494:C:G	G1028R	1.000
12:66353494:C:T	G1028R	1.000
12:66353523:A:G	F1018S	1.000
12:66353526:C:T	G1017E	1.000
12:66377214:A:G	L898S	1.000
12:66377217:T:C	D897G	1.000
12:66377223:A:G	L895P	1.000
12:66377236:A:G	W891R	1.000
12:66377236:A:T	W891R	1.000
12:66392694:A:C	I751S	1.000
12:66392694:A:G	I751T	1.000
12:66392694:A:T	I751N	1.000
12:66392700:A:C	L749W	1.000
12:66392700:A:G	L749S	1.000
12:66392706:A:T	V747D	1.000
12:66392724:T:G	Q741P	1.000
12:66392727:A:G	L740S	1.000
12:66392736:A:T	I737N	1.000
12:66392739:G:T	A736D	1.000
12:66392740:C:G	A736P	1.000
12:66392748:A:G	L733P	1.000
12:66392748:A:T	L733Q	1.000
12:66392763:A:C	L728W	1.000
12:66392763:A:G	L728S	1.000

dbSNP variants (sampled 300 via entrez): RS1000001383 (12:66949644 G>A,T), RS1000004543 (12:66486631 C>G), RS1000010541 (12:66390345 G>A,C), RS1000010867 (12:66563649 TG>T), RS1000012184 (12:66860006 T>C,G), RS1000017688 (12:66650287 G>A), RS1000027771 (12:66603519 T>A), RS1000036019 (12:66718143 T>C,G), RS1000036187 (12:66476461 T>A), RS1000037089 (12:66894247 C>T), RS1000048540 (12:67060456 T>C), RS1000049831 (12:66476354 T>C), RS1000052741 (12:66593721 C>G), RS1000058384 (12:66517288 T>C), RS1000058681 (12:66568285 T>G)

Disease associations

OMIM: gene MIM:604597 | disease phenotypes: MIM:617667, MIM:219000

GenCC curated gene-disease

Disease	Classification	Inheritance
Fraser syndrome 3	Strong	Autosomal recessive
Fraser syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Fraser syndrome 3	Definitive	AR

Mondo (5): Fraser syndrome 3 (MONDO:0054739), Fraser syndrome 1 (MONDO:0054737), intellectual disability (MONDO:0001071), microcephaly (MONDO:0001149), Fraser syndrome (MONDO:0009046)

Orphanet (2): Fraser syndrome (Orphanet:2052), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000252	Microcephaly

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D058497	Fraser Syndrome	C05.116.099.370.894.819.428; C05.660.585.800.428; C05.660.906.819.428; C11.250.390; C12.050.351.875.397; C12.200.706.410; C12.800.410; C16.131.077.371; C16.131.384.442; C16.131.621.585.800.428; C16.131.621.906.819.428; C16.131.939.410
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects expression	3
Cisplatin	affects cotreatment, decreases expression	2
Aflatoxin B1	decreases expression, increases methylation	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
methyleugenol	decreases expression	1
pirinixic acid	increases activity, increases expression, affects binding	1
bisphenol A	increases expression	1
lead acetate	decreases expression	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	increases expression	1
coumarin	affects phosphorylation	1
PK 11195	affects binding, decreases reaction	1
2,3,4,5-tetrachlorophenate	affects response to substance	1
3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone	affects response to substance	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	affects binding, decreases reaction	1
CGP 52608	affects binding, increases reaction	1
entinostat	decreases expression	1
abrine	increases expression	1
bisphenol S	increases methylation	1
jinfukang	affects cotreatment, decreases expression	1
Air Pollutants	decreases expression	1
Amiloride	affects response to substance	1
Vehicle Emissions	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Cadmium	increases abundance, decreases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Doxorubicin	affects expression	1
Endosulfan	increases expression	1
Estradiol	affects response to substance	1

Clinical trials (associated diseases)

198 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
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
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
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)
NCT00032877	Not specified	COMPLETED	Genetic Analysis of Fraser Syndrome and Fryns Syndrome
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability