GIGYF2

Summary

GIGYF2 (GRB10 interacting GYF protein 2, HGNC:11960) is a protein-coding gene on chromosome 2q37.1, encoding GRB10-interacting GYF protein 2 (Q6Y7W6). Key component of the 4EHP-GYF2 complex, a multiprotein complex that acts as a repressor of translation initiation.

This gene contains CAG trinucleotide repeats and encodes a protein containing several stretches of polyglutamine residues. The encoded protein may be involved in the regulation of tyrosine kinase receptor signaling. This gene is located in a chromosomal region that was genetically linked to Parkinson disease type 11, and mutations in this gene were thought to be causative for this disease. However, more recent studies in different populations have been unable to replicate this association. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 26058 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Parkinson disease 11, autosomal dominant, susceptibility to (Moderate, GenCC)
• GWAS associations: 14
• Clinical variants (ClinVar): 484 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 35
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001103146

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11960
Approved symbol	GIGYF2
Name	GRB10 interacting GYF protein 2
Location	2q37.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0642, GYF2
Ensembl gene	ENSG00000204120
Ensembl biotype	protein_coding
OMIM	612003
Entrez	26058

Gene structure

Transcript identifiers

Ensembl transcripts: 73 — 60 protein_coding, 6 protein_coding_CDS_not_defined, 5 retained_intron, 2 nonsense_mediated_decay

ENST00000373563, ENST00000409196, ENST00000409451, ENST00000409480, ENST00000409547, ENST00000421433, ENST00000423659, ENST00000424038, ENST00000425040, ENST00000426102, ENST00000427233, ENST00000428883, ENST00000429187, ENST00000430720, ENST00000440945, ENST00000456491, ENST00000458528, ENST00000463554, ENST00000464402, ENST00000464805, ENST00000469843, ENST00000471011, ENST00000473170, ENST00000474312, ENST00000474465, ENST00000475359, ENST00000475530, ENST00000476995, ENST00000482666, ENST00000482952, ENST00000483164, ENST00000484409, ENST00000488629, ENST00000488734, ENST00000489328, ENST00000490229, ENST00000490612, ENST00000492910, ENST00000629305, ENST00000676848, ENST00000677450, ENST00000677591, ENST00000678230, ENST00000678339, ENST00000678466, ENST00000678885, ENST00000869690, ENST00000869691, ENST00000869692, ENST00000869693, ENST00000869694, ENST00000869695, ENST00000869696, ENST00000869697, ENST00000933239, ENST00000933240, ENST00000933241, ENST00000933242, ENST00000933243, ENST00000933244, ENST00000933245, ENST00000933246, ENST00000933247, ENST00000933248, ENST00000933249, ENST00000961216, ENST00000961217, ENST00000961218, ENST00000961219, ENST00000961220, ENST00000961221, ENST00000961222, ENST00000961223

RefSeq mRNA: 4 — MANE Select: NM_001103146 NM_001103146, NM_001103147, NM_001103148, NM_015575

CCDS: CCDS33401, CCDS46542, CCDS46543

Canonical transcript exons

ENST00000373563 — 29 exons

Exon	Start	End
ENSE00001460931	232703424	232703489
ENSE00002222816	232806491	232806657
ENSE00002223979	232794748	232794944
ENSE00002243044	232791008	232791170
ENSE00002276408	232796062	232796221
ENSE00003470192	232791258	232791446
ENSE00003471479	232816871	232817032
ENSE00003472423	232747615	232747744
ENSE00003475391	232815637	232815737
ENSE00003483160	232809720	232809811
ENSE00003495643	232847348	232847571
ENSE00003500523	232839849	232839971
ENSE00003520865	232812391	232812491
ENSE00003521038	232735155	232735238
ENSE00003527336	232850262	232850409
ENSE00003529396	232832857	232833093
ENSE00003542333	232856793	232860605
ENSE00003551667	232756223	232756334
ENSE00003556003	232760480	232760591
ENSE00003556363	232844369	232844574
ENSE00003567198	232761396	232761436
ENSE00003580657	232811244	232811351
ENSE00003607002	232790698	232790915
ENSE00003621346	232748987	232749082
ENSE00003645587	232787150	232787329
ENSE00003661405	232819827	232819985
ENSE00003667886	232844046	232844255
ENSE00003692650	232845732	232845886
ENSE00003899004	232697331	232697392

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 99.16.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 42.5026 / max 1248.7644, expressed in 1818 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
26011	40.3787	1818
26012	2.0955	1050
26014	0.0170	8
26013	0.0114	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	99.16	gold quality
sural nerve	UBERON:0015488	98.01	gold quality
colonic epithelium	UBERON:0000397	97.45	gold quality
adrenal tissue	UBERON:0018303	96.27	gold quality
tendon	UBERON:0000043	94.92	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	94.20	gold quality
right testis	UBERON:0004534	94.02	gold quality
left testis	UBERON:0004533	93.72	gold quality
corpus callosum	UBERON:0002336	93.15	gold quality
testis	UBERON:0000473	93.05	gold quality
islet of Langerhans	UBERON:0000006	92.79	gold quality
bone marrow cell	CL:0002092	92.71	gold quality
cortical plate	UBERON:0005343	92.47	gold quality
ventricular zone	UBERON:0003053	92.14	gold quality
muscle of leg	UBERON:0001383	91.66	gold quality
gastrocnemius	UBERON:0001388	91.59	gold quality
pancreas	UBERON:0001264	91.26	gold quality
body of pancreas	UBERON:0001150	91.14	gold quality
ganglionic eminence	UBERON:0004023	90.76	gold quality
skin of leg	UBERON:0001511	90.63	gold quality
skin of abdomen	UBERON:0001416	90.39	gold quality
muscle organ	UBERON:0001630	90.28	gold quality
tonsil	UBERON:0002372	90.27	gold quality
stromal cell of endometrium	CL:0002255	90.06	gold quality
buccal mucosa cell	CL:0002336	89.82	silver quality
adrenal gland	UBERON:0002369	89.65	gold quality
left ovary	UBERON:0002119	89.56	gold quality
right adrenal gland cortex	UBERON:0035827	89.47	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.40	gold quality
rectum	UBERON:0001052	89.19	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7303	no	232.01
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

239 targeting GIGYF2, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
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-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 32)

• These data strongly support GIGYF2 as a PARK11 gene with a causal role in familial Parkinson disease. (PMID:18358451)
• Mutations in GIGYF2 are not strongly related to the development of the Parkinson’s disease in Portuguese and North American populations. (PMID:18923002)
• This study suggested that reported mutations in GIGYF2 are not a common cause of Parkinson’s disease in Norway and United States. (PMID:19133664)
• The results of this study concluded that neither of Asn56Ser and Asn457Thr variants plays a major role in the pathogenesis of parkinson disease. (PMID:19250854)
• We believe that variation in a gene other than GIGYF2 accounts for the previously reported linkage finding on chromosome 2q36-37. (PMID:19279319)
• The results of this study did not support a role for GIGYF2 in the genetic etiology of Belgian Parkinson disease. (PMID:19321232)
• The current genetic evidence suggestes that GIGYF2 is not a common cause od parkinson disease in several Caucasian. (PMID:19348706)
• GIGYF2 Asn56Ser and Asn457Thr mutations are a rare cause of PD in North American Caucasian population (PMID:19429085)
• analysis of GIGYF2 variants in Parkinson’s disease from two Asian populations (PMID:19449032)
• GIGYF2 mutations are not a frequent cause of Parkinson’s disease (PMID:19482505)
• This letter suggested that GIGYF2 is neither responsible for PARK11 nor a gene implicated in Parkinson disease. (PMID:19562763)
• The GIGYF2 Asn56Ser mutation is rare in Chinese PD patients. (PMID:19638301)
• our findings suggest that GIGYF2 variants are not a frequent cause of Parkinson’s disease in the Spanish population, since we found no clearly segregating GIGYF2 variants (PMID:19845746)
• The results of this study do not support a major role of GIGYF2 in parkinson disease. (PMID:20004041)
• GIGYF2 variants are not associated with Parkinson’s disease in the mainland Chinese Population. (PMID:20044296)
• These data, together with those recently reported by other groups, suggest that GIGYF2 is unlikely to be the PARK11 gene. (PMID:20060621)
• We identified nine novel variants in GIGYF2 gene, which might be associated with PD in the Chinese population. (PMID:20178831)
• GIGYF2 is unlikely to play a major role in PD in Japanese patients, similar to other populations. (PMID:20641165)
• No clearly pathogenic mutations are identified in GIGYF2 and ATP13A2 in Brazilian patients with early-onset Parkinson’s disease. (PMID:20816920)
• within the Chinese population, the c.297T>C p.Ala99Ala polymorphism of the GIGYF2 gene may be associated with an increased risk of developing Parkinson disease. (PMID:22115759)
• Our result indicated that SCNA, LRRK2, UCHL1, HtrA2 and GIGYF2 genes’ mutations might not be a main reason for Chinese Autosomal dorminant Parkinson’s disease (PMID:22503729)
• GIGYF2 and the zinc finger protein 598 (ZNF598) are identified as components of the 4EHP complex. (PMID:22751931)
• required, this finding may shed light on the GIGYF2-associated mechanisms that lead to PD and suggests insulin dysregulation as a disease-specific mechanism for both PD and cognitive dysfunction. (PMID:26134514)
• Results suggest that the N56S and N457T of GIGYF2 are risk factors for Parkinson’s disease in Caucasians, but not in Asians (PMID:26152800)
• Full-length GIGYF2 coimmunoprecipitates with AGO2 in human cells, and upon tethering to a reporter mRNA, GIGYF2 exhibits strong, dose-dependent silencing activity, involving both mRNA destabilization and translational repression. (PMID:27157137)
• genetic analyses of indel loci in ACE, DJ-1, and GIGYF2 genes, was performed to explore the potential contribution of insertion (I)/deletion (D) polymorphisms (indels) to the risk of PD in a Chinese population. (PMID:28873462)
• GIGYF2 has two distinct mechanisms of repression: one depends on 4EHP binding and mainly affects translation; the other is 4EHP-independent and involves the CCR4/NOT complex and its deadenylation activity. (PMID:29554310)
• GIGYF2 and 4EHP Inhibit Translation Initiation of Defective Messenger RNAs to Assist Ribosome-Associated Quality Control. (PMID:32726578)
• 4EHP and GIGYF1/2 Mediate Translation-Coupled Messenger RNA Decay. (PMID:33053355)
• Association study of DNAJC13, UCHL1, HTRA2, GIGYF2, and EIF4G1 with Parkinson’s disease. (PMID:33239198)
• Translational repression of NMD targets by GIGYF2 and EIF4E2. (PMID:34665823)
• RNA-binding protein GIGYF2 orchestrates hepatic insulin resistance through STAU1/PTEN-mediated disruption of the PI3K/AKT signaling cascade. (PMID:39138413)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	gigyf2	ENSDARG00000009735
mus_musculus	Gigyf2	ENSMUSG00000048000
rattus_norvegicus	Gigyf2	ENSRNOG00000023577
drosophila_melanogaster	Gyf	FBGN0039936
caenorhabditis_elegans		WBGENE00016002

Paralogs (1): GIGYF1 (ENSG00000146830)

Protein

Protein identifiers

GRB10-interacting GYF protein 2 — Q6Y7W6 (reviewed: Q6Y7W6)

Alternative names: PERQ amino acid-rich with GYF domain-containing protein 2, Trinucleotide repeat-containing gene 15 protein

All UniProt accessions (19): A0A7I2V361, A0A7I2V3H0, A0A7I2V3H7, A0A7I2V3X3, A0A7I2V516, A0A7I2YQP8, C9J0V6, C9JC65, C9JHT0, C9JHW1, C9JPV7, C9JRZ2, C9JW88, C9JXQ0, E7ESB6, Q6Y7W6, F8WBF1, F8WCD5, I1E4Y6

UniProt curated annotations — full annotation on UniProt →

Function. Key component of the 4EHP-GYF2 complex, a multiprotein complex that acts as a repressor of translation initiation. In the 4EHP-GYF2 complex, acts as a factor that bridges EIF4E2 to ZFP36/TTP, linking translation repression with mRNA decay. Also recruits and bridges the association of the 4EHP complex with the decapping effector protein DDX6, which is required for the ZFP36/TTP-mediated down-regulation of AU-rich mRNA. May act cooperatively with GRB10 to regulate tyrosine kinase receptor signaling, including IGF1 and insulin receptors. In association with EIF4E2, assists ribosome-associated quality control (RQC) by sequestering the mRNA cap, blocking ribosome initiation and decreasing the translational load on problematic messages. Part of a pathway that works in parallel to RQC-mediated degradation of the stalled nascent polypeptide. GIGYF2 and EIF4E2 work downstream and independently of ZNF598, which seems to work as a scaffold that can recruit them to faulty mRNA even if alternative recruitment mechanisms may exist. (Microbial infection) Upon SARS coronavirus-2/SARS-CoV-2 infection, the interaction with non-structural protein 2 (nsp2) enhances GIGYF2 binding to EIF4E2 and increases repression of translation initiation of genes involved in antiviral innate immune response such as IFNB1.

Subunit / interactions. Component of the 4EHP-GYF2 complex, at least composed of EIF4E2, GIGYF2 and ZNF598. Interacts (via the 4EHP-binding motif) with EIF4E2; the interaction is direct. Interacts with ZFP36/TTP (via P-P-P-P-G repeats); the interaction is direct. Interacts with GRB10. Interacts (via DDX6 motif) with DDX6 (via RecA-like domain 2). (Microbial infection) Interacts with SARS coronavirus-2/SARS-CoV-2 non-structural protein 2 (nsp2); the interaction enhances GIGYF2 binding to EIF4E2.

Disease relevance. Parkinson disease 11 (PARK11) [MIM:607688] A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability, as well as by a clinically significant response to treatment with levodopa. The pathology involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. Disease susceptibility may be associated with variants affecting the gene represented in this entry. Its association with Parkinson disease is however unclear. According to a number of studies, variations affecting this gene are not a frequent cause of Parkinson disease, suggesting that GIGYF2 does not play a major role in Parkinson disease etiology.

Similarity. Belongs to the GIGYF family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q6Y7W6-1	1	yes
Q6Y7W6-3	2
Q6Y7W6-4	3
Q6Y7W6-5	4

RefSeq proteins (4): NP_001096616, NP_001096617, NP_001096618, NP_056390 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003169	GYF	Domain
IPR035445	GYF-like_dom_sf	Homologous_superfamily
IPR051640	GRB10-interact_GYF	Family

Pfam: PF02213

UniProt features (101 total): sequence variant 27, modified residue 17, region of interest 15, compositionally biased region 13, helix 8, splice variant 4, mutagenesis site 4, strand 4, sequence conflict 3, short sequence motif 2, initiator methionine 1, chain 1, domain 1, cross-link 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
7RUP	X-RAY DIFFRACTION	1.23
5NVM	X-RAY DIFFRACTION	2
5NVL	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6Y7W6-F1	57.36	0.06

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 (18): 2, 19, 26, 30, 107, 118, 120, 139, 149, 160, 189, 236, 382, 388, 593, 993, 1284, 1123

Mutagenesis-validated functional residues (4):

Position	Phenotype
41–49	abolishes interaction with eif4e2.
288	abolishes interaction with ddx6.
300	abolishes interaction with ddx6; when associated with a-306.
306	abolishes interaction with ddx6; when associated with a-300.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 382 (showing top): GOBP_SPINAL_CORD_DEVELOPMENT, RNGTGGGC_UNKNOWN, GOBP_BEHAVIOR, PAX4_01, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_RESPONSE_TO_PEPTIDE, GCANCTGNY_MYOD_Q6, GOBP_ADULT_BEHAVIOR, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_GROWTH, GOBP_RESPONSE_TO_TYPE_I_INTERFERON, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_INNATE_IMMUNE_RESPONSE, GOBP_TRANSLATIONAL_INITIATION, GOBP_NEUROGENESIS

GO Biological Process (16): feeding behavior (GO:0007631), adult locomotory behavior (GO:0008344), post-embryonic development (GO:0009791), post-transcriptional gene silencing (GO:0016441), negative regulation of translation (GO:0017148), spinal cord motor neuron differentiation (GO:0021522), mitotic G1 DNA damage checkpoint signaling (GO:0031571), multicellular organism growth (GO:0035264), negative regulation of translational initiation (GO:0045947), insulin-like growth factor receptor signaling pathway (GO:0048009), homeostasis of number of cells within a tissue (GO:0048873), musculoskeletal movement (GO:0050881), neuromuscular process controlling balance (GO:0050885), negative regulation of type I interferon-mediated signaling pathway (GO:0060339), mRNA destabilization (GO:0061157), rescue of stalled cytosolic ribosome (GO:0072344)

GO Molecular Function (5): RNA binding (GO:0003723), cadherin binding (GO:0045296), molecular adaptor activity (GO:0060090), proline-rich region binding (GO:0070064), protein binding (GO:0005515)

GO Cellular Component (11): endosome (GO:0005768), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), cytosol (GO:0005829), cytoplasmic stress granule (GO:0010494), membrane (GO:0016020), vesicle (GO:0031982), protein-containing complex (GO:0032991), perikaryon (GO:0043204), proximal dendrite (GO:1990635), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
negative regulation of gene expression	3
endomembrane system	3
cytoplasm	3
multicellular organismal process	2
neuromuscular process	2
binding	2
intracellular membrane-bounded organelle	2
behavior	1
locomotory behavior	1
adult behavior	1
multicellular organism development	1
post-transcriptional regulation of gene expression	1
translation	1
regulation of translation	1
negative regulation of protein metabolic process	1
cell differentiation in spinal cord	1
ventral spinal cord development	1
central nervous system neuron differentiation	1
mitotic G1 phase	1
mitotic DNA damage checkpoint signaling	1
mitotic G1/S transition checkpoint signaling	1
developmental growth	1
translational initiation	1
regulation of translational initiation	1
negative regulation of translation	1
cell surface receptor protein tyrosine kinase signaling pathway	1
tissue homeostasis	1
homeostasis of number of cells	1
multicellular organismal movement	1
musculoskeletal movement	1
negative regulation of cytokine-mediated signaling pathway	1
negative regulation of innate immune response	1
type I interferon-mediated signaling pathway	1
regulation of type I interferon-mediated signaling pathway	1
regulation of mRNA stability	1
RNA destabilization	1
positive regulation of mRNA catabolic process	1
cytoplasmic translational elongation	1
ribosome disassembly	1

Protein interactions and networks

STRING

2370 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GIGYF2	EIF4E2	O60573	984
GIGYF2	GRB10	Q13322	963
GIGYF2	ZNF598	Q86UK7	929
GIGYF2	FBXO7	Q9Y3I1	857
GIGYF2	PLA2G6	O60733	802
GIGYF2	HTRA2	O43464	794
GIGYF2	UCHL1	P09936	791
GIGYF2	SNCA	P37840	769
GIGYF2	LRRK2	Q5S007	732
GIGYF2	PARK7	Q99497	727
GIGYF2	PINK1	Q9BXM7	721
GIGYF2	ATP13A2	Q9NQ11	702
GIGYF2	GBA1	P04062	685
GIGYF2	GIGYF1	O75420	655
GIGYF2	ZFP36	P26651	643

IntAct

187 interactions, top by confidence:

A	B	Type	Score
RFX5	RFXAP	psi-mi:“MI:0914”(association)	0.880
EIF4E2	GIGYF1	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
EIF4E2	EIF4EBP1	psi-mi:“MI:0914”(association)	0.670
EXOSC5	ZFC3H1	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAB	BLTP3B	psi-mi:“MI:0914”(association)	0.610
GIGYF2	EIF4E2	psi-mi:“MI:0407”(direct interaction)	0.590
EIF4E2	GIGYF2	psi-mi:“MI:0915”(physical association)	0.590
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
YWHAZ	GIGYF2	psi-mi:“MI:0915”(physical association)	0.560
GIGYF2	SNRPC	psi-mi:“MI:0915”(physical association)	0.550
EXOSC4	MTREX	psi-mi:“MI:0914”(association)	0.530
rep	SLC27A2	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
SNRPC	SNRPGP15	psi-mi:“MI:0914”(association)	0.530
PIP	TBKBP1	psi-mi:“MI:0914”(association)	0.530
DIS3L	EIF4E2	psi-mi:“MI:0914”(association)	0.530
GIGYF2		psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (357): GIGYF2 (Affinity Capture-MS), GIGYF2 (Affinity Capture-MS), GIGYF2 (Affinity Capture-MS), GIGYF2 (Affinity Capture-MS), GIGYF2 (Affinity Capture-MS), GIGYF2 (Affinity Capture-MS), GIGYF2 (Proximity Label-MS), GIGYF2 (Proximity Label-MS), GIGYF2 (Affinity Capture-MS), GIGYF2 (Affinity Capture-MS), GIGYF2 (Affinity Capture-MS), GIGYF2 (Affinity Capture-MS), GIGYF2 (Affinity Capture-MS), GIGYF2 (Affinity Capture-MS), GIGYF2 (Affinity Capture-MS)

ESM2 similar proteins: A2AG50, A2AUY4, D4A4L4, E7F5E1, O13024, O60237, O60293, O75167, O88735, O94885, P12957, P53352, P62025, Q05682, Q0IHP2, Q14244, Q2MJV9, Q2YDJ0, Q32N93, Q3KQW7, Q3MHH7, Q3UH68, Q4G0F8, Q501J7, Q5R7F9, Q5RG44, Q5U236, Q5ZIA2, Q62736, Q6Y7W6, Q6Y7W8, Q80ST9, Q80TN7, Q80Z38, Q86VQ0, Q8BG95, Q8IVL0, Q8IVL1, Q8IWC1, Q8K298

Diamond homologs: C6KRN1, O75420, Q4KME6, Q5U236, Q6Y7W6, Q6Y7W8, Q99MR1, O36025, P32909, Q02875, Q7KQM6, Q9FMM3, Q9SIV5, Q09237, Q9FT92, O88491, O96028, Q08747, Q6P2L6, Q8BVE8, Q96L73, Q9BZ95, Q9SD34

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
CNOT9	“up-regulates activity”	GIGYF2	binding
GIGYF2	“form complex”	“EIF4E2/GIGYF2 complex”	binding
GIGYF2	“up-regulates activity”	GRB10	binding
MAPK1	unknown	GIGYF2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 209 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	6	29.2×	6e-06
Activation of BAD and translocation to mitochondria	5	27.6×	4e-05
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	5	24.3×	8e-05
Activation of BH3-only proteins	5	18.0×	3e-04
RHO GTPases activate PKNs	6	13.8×	2e-04
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S	6	11.8×	4e-04
SARS-CoV-1-host interactions	9	11.5×	1e-05
Eukaryotic Translation Initiation	5	11.2×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
RNA catabolic process	5	12.4×	1e-02
negative regulation of translation	8	8.5×	2e-03
RNA processing	7	8.3×	6e-03
intracellular protein localization	11	6.3×	2e-03
rRNA processing	8	6.2×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	280
Likely benign	77
Benign	48

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
191155	NM_002242.4(KCNJ13):c.359T>C (p.Ile120Thr)	Pathogenic
30331	NM_002242.4(KCNJ13):c.496C>T (p.Arg166Ter)	Pathogenic
978432	NM_002242.4(KCNJ13):c.494del (p.Asn165fs)	Pathogenic
2571128	NM_002242.4(KCNJ13):c.403del (p.Ile135fs)	Likely pathogenic

SpliceAI

6388 predictions. Top by Δscore:

Variant	Effect	Δscore
2:232703419:TACA:T	acceptor_loss	1.0000
2:232703422:A:AG	acceptor_gain	1.0000
2:232703422:AGC:A	acceptor_gain	1.0000
2:232703423:G:A	acceptor_loss	1.0000
2:232703423:G:GA	acceptor_gain	1.0000
2:232703423:GC:G	acceptor_gain	1.0000
2:232703423:GCG:G	acceptor_gain	1.0000
2:232703423:GCGT:G	acceptor_gain	1.0000
2:232703423:GCGTT:G	acceptor_gain	1.0000
2:232735235:AATGG:A	donor_loss	1.0000
2:232735237:TGGTG:T	donor_loss	1.0000
2:232735238:GGTGA:G	donor_loss	1.0000
2:232735239:G:C	donor_loss	1.0000
2:232735240:T:G	donor_loss	1.0000
2:232735241:GAG:G	donor_loss	1.0000
2:232747608:A:AG	acceptor_gain	1.0000
2:232747611:CTA:C	acceptor_loss	1.0000
2:232747612:TAG:T	acceptor_loss	1.0000
2:232747613:A:AG	acceptor_gain	1.0000
2:232747613:AG:A	acceptor_gain	1.0000
2:232747614:G:A	acceptor_loss	1.0000
2:232747614:G:GT	acceptor_gain	1.0000
2:232747614:GG:G	acceptor_gain	1.0000
2:232747614:GGC:G	acceptor_gain	1.0000
2:232747614:GGCT:G	acceptor_gain	1.0000
2:232747614:GGCTC:G	acceptor_gain	1.0000
2:232747743:AGG:A	donor_loss	1.0000
2:232747745:G:GC	donor_loss	1.0000
2:232747746:T:A	donor_loss	1.0000
2:232748976:T:TA	acceptor_gain	1.0000

AlphaMissense

8533 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:232735225:T:C	F10L	1.000
2:232735227:T:A	F10L	1.000
2:232735227:T:G	F10L	1.000
2:232735229:G:A	G11E	1.000
2:232735237:T:A	W14R	1.000
2:232735237:T:C	W14R	1.000
2:232747615:G:C	W14C	1.000
2:232747615:G:T	W14C	1.000
2:232747617:T:C	L15P	1.000
2:232790847:T:A	W288R	1.000
2:232790847:T:C	W288R	1.000
2:232790849:G:C	W288C	1.000
2:232790849:G:T	W288C	1.000
2:232790883:T:C	F300L	1.000
2:232790884:T:C	F300S	1.000
2:232790884:T:G	F300C	1.000
2:232790885:T:A	F300L	1.000
2:232790885:T:G	F300L	1.000
2:232790896:G:A	G304E	1.000
2:232790901:T:C	F306L	1.000
2:232790902:T:C	F306S	1.000
2:232790903:C:A	F306L	1.000
2:232790903:C:G	F306L	1.000
2:232796188:T:A	W536R	1.000
2:232796188:T:C	W536R	1.000
2:232796189:G:C	W536S	1.000
2:232796190:G:C	W536C	1.000
2:232796190:G:T	W536C	1.000
2:232796194:T:C	Y538H	1.000
2:232796194:T:G	Y538D	1.000

dbSNP variants (sampled 300 via entrez): RS1000029477 (2:232810705 T>C), RS1000036503 (2:232755918 T>C), RS1000071374 (2:232792100 T>C), RS1000074266 (2:232708179 T>C), RS1000090912 (2:232713899 T>C,G), RS1000093855 (2:232732877 AC>A), RS1000095919 (2:232859823 AG>A), RS1000096682 (2:232816766 A>C,G), RS1000123279 (2:232791911 T>C), RS1000130391 (2:232835655 A>G,T), RS1000130586 (2:232801904 A>C,G), RS1000156818 (2:232723270 T>C), RS1000157635 (2:232769258 T>A), RS1000168706 (2:232855005 T>C,G), RS1000182602 (2:232749784 A>T)

Disease associations

OMIM: gene MIM:612003 | disease phenotypes: MIM:193230, MIM:607688, MIM:614186, MIM:204000

GenCC curated gene-disease

Disease	Classification	Inheritance
Parkinson disease 11, autosomal dominant, susceptibility to	Moderate	Autosomal dominant

Mondo (5): snowflake vitreoretinal degeneration (MONDO:0008663), inherited retinal dystrophy (MONDO:0019118), Parkinson disease 11, autosomal dominant, susceptibility to (MONDO:0011896), Leber congenital amaurosis 16 (MONDO:0013613), Leber congenital amaurosis (MONDO:0018998)

Orphanet (4): Snowflake vitreoretinal degeneration (Orphanet:91496), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Hereditary late-onset Parkinson disease (Orphanet:411602), Leber congenital amaurosis (Orphanet:65)

HPO phenotypes

35 total (30 of 35 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000338	Hypomimic face
HP:0000651	Diplopia
HP:0000713	Agitation
HP:0000716	Depression
HP:0000726	Dementia
HP:0000741	Apathy
HP:0000744	Low frustration tolerance
HP:0001268	Mental deterioration
HP:0001300	Parkinsonism
HP:0001332	Dystonia
HP:0001824	Weight loss
HP:0002015	Dysphagia
HP:0002063	Rigidity
HP:0002067	Bradykinesia
HP:0002120	Cerebral cortical atrophy
HP:0002171	Gliosis
HP:0002172	Postural instability
HP:0002304	Akinesia
HP:0002322	Resting tremor
HP:0002359	Frequent falls
HP:0002360	Sleep disturbance
HP:0002362	Shuffling gait
HP:0002367	Visual hallucination
HP:0002548	Parkinsonism with favorable response to dopaminergic medication
HP:0003394	Muscle spasm
HP:0004409	Hyposmia
HP:0004926	Orthostatic hypotension due to autonomic dysfunction
HP:0005340	Spastic/hyperactive bladder
HP:0012450	Chronic constipation

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST002149_18	Schizophrenia	2.000000e-08
GCST002539_44	Schizophrenia	2.000000e-12
GCST004521_189	Autism spectrum disorder or schizophrenia	3.000000e-10
GCST004521_38	Autism spectrum disorder or schizophrenia	1.000000e-08
GCST004787_50	Coronary artery disease (myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, angina or chromic ischemic heart disease)	2.000000e-06
GCST005196_218	Coronary artery disease	3.000000e-10
GCST006803_9	Schizophrenia	4.000000e-16
GCST008559_2	Anxiety and stress-related disorders	1.000000e-06
GCST008595_74	Cognitive ability, years of educational attainment or schizophrenia (pleiotropy)	1.000000e-14
GCST010479_63	Coronary artery disease	4.000000e-08
GCST010866_46	Coronary artery disease	1.000000e-08
GCST011365_87	Myocardial infarction	3.000000e-07
GCST90000025_713	Appendicular lean mass	2.000000e-23
GCST90020028_721	Hip circumference adjusted for BMI	1.000000e-12

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0010098	stress-related disorder
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0004980	appendicular lean mass
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D057130	Leber Congenital Amaurosis	C11.270.516; C11.768.364
D058499	Retinal Dystrophies	C11.768.585.658
C564345	Parkinson Disease 11 (supp.)
C536677	Snowflake vitreoretinal degeneration (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2331055 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
6.73	Kd	186	nM	CHEMBL2337520

PubChem BioAssay actives

1 with measured affinity, of 10 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
[3-[1,1-bis[4-(2-pyrrolidin-1-ylethoxy)phenyl]but-1-en-2-yl]phenyl] 6-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]hexanoate	731987: Binding affinity to recombinant His-tagged Grb10 interacting GYF protein 2 (745-1030 amino acids) (unknown origin) by surface plasmon resonance analysis	kd	0.1860	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	3
Acetaminophen	decreases expression, increases expression	2
Valproic Acid	affects expression, decreases methylation	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	decreases expression, increases oxidation, increases abundance, affects cotreatment	1
beta-lapachone	increases expression	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
Poly(amidoamine)	increases expression	1
bisphenol S	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Arsenic Trioxide	increases expression	1
Acrolein	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
Air Pollutants	decreases expression, increases abundance, increases oxidation, affects cotreatment	1
Vehicle Emissions	increases abundance, decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Caffeine	affects phosphorylation	1
Demecolcine	increases expression	1
Succimer	decreases expression, affects cotreatment	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Formaldehyde	increases expression	1
Gallic Acid	decreases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	increases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2339070	Binding	Inhibition of Grb10 interacting GYF protein 2 (unknown origin) expressed in HEK293T cells exposed to serum depletion for 20 hrs assessed as reduction in IGF1-stimulated Akt Ser473 phosphorylation pre-treated for 4 hrs followed by IGF1 stimu	Ridaifen B, a tamoxifen derivative, directly binds to Grb10 interacting GYF protein 2. — Bioorg Med Chem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A5EG	HEK293T-GIGYF1/2-null	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT00999609	PHASE3	ACTIVE_NOT_RECRUITING	Safety and Efficacy Study in Subjects With Leber Congenital Amaurosis
NCT06891443	PHASE3	RECRUITING	Study to Evaluate Sepofarsen in Subjects With Leber Congenital Amaurosis (LCA) Type 10 (HYPERION)
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT06455826	PHASE1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)
NCT00516477	PHASE1	COMPLETED	Safety Study in Subjects With Leber Congenital Amaurosis
NCT00821340	PHASE1	COMPLETED	Clinical Trial of Gene Therapy for Leber Congenital Amaurosis Caused by RPE65 Mutations
NCT04855045	PHASE2/PHASE3	UNKNOWN	An Open-label, Dose Escalation and Double-masked, Randomized, Controlled Trial Evaluating Safety and Tolerability of Sepofarsen in Children (<8 Years of Age) With LCA10 Caused by Mutations in the CEP290 Gene.
NCT03872479	PHASE1/PHASE2	UNKNOWN	Single Ascending Dose Study in Participants With LCA10
NCT04123626	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Safety and Tolerability of QR-1123 in Subjects With Autosomal Dominant Retinitis Pigmentosa Due to the P23H Mutation in the RHO Gene
NCT04545736	PHASE1/PHASE2	RECRUITING	Oral Metformin for Treatment of ABCA4 Retinopathy
NCT06212297	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Fellow-eye Study (FE) of LX101 in Subjects With Inherited Retinal Dystrophy
NCT06852963	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Repeat-Dose, Open-Label, Two Arm Safety and Efficacy Study of Two Doses of VP-001 Administered Intravitreally in Participants With Confirmed PRPF31 Mutation-Associated Retinal Dystrophy, Including Participants Previously Treated With VP001
NCT07177196	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Personalized Antisense Oligonucleotide Therapy for a Single Participant With PRPH2 Mutation Associated With Retinal Dystrophy
NCT07063030	EARLY_PHASE1	RECRUITING	A Study of LX107 Gene Therapy in AIPL1-IRD Patients
NCT01546181	Not specified	COMPLETED	Retinal Imaging by Adaptive Optics in Healthy Eyes and During Retinal and General Diseases
NCT01876147	Not specified	COMPLETED	Visual and Functional Assessment in Low Vision Patients
NCT01920867	Not specified	UNKNOWN	Stem Cell Ophthalmology Treatment Study
NCT02014389	Not specified	RECRUITING	Evaluation of Objective Perimetry Using Chromatic Multifocal Pupillometer
NCT02983305	Not specified	COMPLETED	Optical Head-Mounted Display Technology for Low Vision Rehabilitation
NCT03592017	Not specified	COMPLETED	Performance of Long-wavelength Autofluorescence Imaging
NCT03662386	Not specified	TERMINATED	Prospective Analysis of Genotype-phenotype Correlations Observed in a Large Cohort of Patients With Hereditary Retinal Dystrophies - GEPHIRD
NCT03691168	Not specified	UNKNOWN	Multi-center Observation of the Natural Course of Inherited Retinal Dystrophies
NCT03843840	Not specified	COMPLETED	Dual Wavelength OCT
NCT03853252	Not specified	COMPLETED	iPS Cells of Patients for Models of Retinal Dystrophies
NCT05130385	Not specified	UNKNOWN	High Resolution Optical Coherence Tomography
NCT05294978	Not specified	RECRUITING	EyeConic: Qualification for Cone-Optogenetics
NCT05573984	Not specified	ACTIVE_NOT_RECRUITING	Natural History of PRPF31 Mutation-Associated Retinal Dystrophy
NCT05793515	Not specified	COMPLETED	Mechanisms of Inherited Retinal Dystrophies Using Whole Genome Sequencing and in Vitro and in Vivo Models
NCT05820100	Not specified	COMPLETED	Observational Study to Assess the Reliability and Validity of the MLYMT and MLSDT
NCT05976139	Not specified	RECRUITING	Micropulsed Laser in Patients With Macular Oedema in Retinal Dystrophies
NCT06162585	Not specified	ACTIVE_NOT_RECRUITING	Non-Interventional Long Term Follow-up Study of Participants Previously Enrolled in the RESTORE Study
NCT06177977	Not specified	RECRUITING	SS-HH-OCT as a Novel Diagnostic Modality for Early-Onset Retinal Dystrophies (EORDs)
NCT06375239	Not specified	RECRUITING	Observational Study to Assess Endpoint Operational Feasibility & Measurement Properties in Patients with Retinal Degeneration
NCT06908161	Not specified	NOT_YET_RECRUITING	Functional Assessments in Vision Impairment