WIPI2

Summary

WIPI2 (WD repeat domain, phosphoinositide interacting 2, HGNC:32225) is a protein-coding gene on chromosome 7p22.1, encoding WD repeat domain phosphoinositide-interacting protein 2 (Q9Y4P8). Component of the autophagy machinery that controls the major intracellular degradation process by which cytoplasmic materials are packaged into autophagosomes and delivered to lysosomes for degradation.

WD40 repeat proteins are key components of many essential biologic functions. They regulate the assembly of multiprotein complexes by presenting a beta-propeller platform for simultaneous and reversible protein-protein interactions. Members of the WIPI subfamily of WD40 repeat proteins, such as WIPI2, have a 7-bladed propeller structure and contain a conserved motif for interaction with phospholipids (Proikas-Cezanne et al., 2004 [PubMed 15602573]).

Source: NCBI Gene 26100 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual developmental disorder with short stature and variable skeletal anomalies (Strong, GenCC)
• GWAS associations: 11
• Clinical variants (ClinVar): 108 total — 3 pathogenic
• Phenotypes (HPO): 15
• MANE Select transcript: NM_015610

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:32225
Approved symbol	WIPI2
Name	WD repeat domain, phosphoinositide interacting 2
Location	7p22.1
Locus type	gene with protein product
Status	Approved
Aliases	ATG21, CGI-50, FLJ12979, FLJ14217, FLJ42984, DKFZP434J154, DKFZp686P02188, ATG18B
Ensembl gene	ENSG00000157954
Ensembl biotype	protein_coding
OMIM	609225
Entrez	26100

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 11 protein_coding, 5 retained_intron, 4 protein_coding_CDS_not_defined

ENST00000288828, ENST00000382384, ENST00000401525, ENST00000404704, ENST00000465102, ENST00000466014, ENST00000471851, ENST00000475309, ENST00000479690, ENST00000480238, ENST00000484262, ENST00000485854, ENST00000488359, ENST00000496867, ENST00000880937, ENST00000880938, ENST00000880939, ENST00000928759, ENST00000951748, ENST00000951749

RefSeq mRNA: 6 — MANE Select: NM_015610 NM_001033518, NM_001033519, NM_001033520, NM_001278299, NM_015610, NM_016003

CCDS: CCDS34593, CCDS47531, CCDS47532, CCDS47533, CCDS5339

Canonical transcript exons

ENST00000288828 — 13 exons

Exon	Start	End
ENSE00001826879	5230835	5233840
ENSE00001926181	5190233	5190493
ENSE00003463293	5227180	5227344
ENSE00003492065	5216563	5216659
ENSE00003545818	5199576	5199658
ENSE00003561739	5225823	5225930
ENSE00003562738	5217090	5217187
ENSE00003572460	5228104	5228211
ENSE00003593182	5217922	5218014
ENSE00003626936	5193118	5193171
ENSE00003627316	5214535	5214704
ENSE00003678499	5222602	5222672
ENSE00003689323	5229608	5229738

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 98.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.4645 / max 201.6748, expressed in 1824 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
77089	33.8476	1824
77090	0.6169	345

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	98.83	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.90	gold quality
nipple	UBERON:0002030	97.63	gold quality
olfactory bulb	UBERON:0002264	97.50	gold quality
adult organism	UBERON:0007023	97.16	gold quality
type B pancreatic cell	CL:0000169	97.12	gold quality
inferior vagus X ganglion	UBERON:0005363	96.75	gold quality
ventral tegmental area	UBERON:0002691	96.74	gold quality
parotid gland	UBERON:0001831	96.72	gold quality
pons	UBERON:0000988	96.54	gold quality
endothelial cell	CL:0000115	96.46	gold quality
amniotic fluid	UBERON:0000173	96.38	gold quality
male germ cell	CL:0000015	96.29	gold quality
cardia of stomach	UBERON:0001162	96.27	gold quality
renal medulla	UBERON:0000362	96.25	gold quality
stromal cell of endometrium	CL:0002255	96.18	gold quality
secondary oocyte	CL:0000655	96.15	gold quality
entorhinal cortex	UBERON:0002728	96.15	gold quality
sperm	CL:0000019	96.11	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.04	gold quality
lateral globus pallidus	UBERON:0002476	95.96	gold quality
pylorus	UBERON:0001166	95.94	gold quality
superior vestibular nucleus	UBERON:0007227	95.94	gold quality
penis	UBERON:0000989	95.92	gold quality
right testis	UBERON:0004534	95.88	gold quality
skin of leg	UBERON:0001511	95.87	gold quality
occipital lobe	UBERON:0002021	95.87	gold quality
left testis	UBERON:0004533	95.87	gold quality
trigeminal ganglion	UBERON:0001675	95.86	gold quality
dorsal root ganglion	UBERON:0000044	95.78	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.83
E-MTAB-7303	no	731.22

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SMCR8

miRNA regulators (miRDB)

100 targeting WIPI2, 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-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-1252-5P	100.00	69.80	2774
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-6077	99.99	68.04	2299
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-570-3P	99.96	72.41	4910
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-497-5P	99.92	71.83	2674

Literature-anchored findings (GeneRIF, showing 18)

• A role for WIPI2 in the progression of omegasomes into autophagosomes, is reported. (PMID:20505359)
• WIPI2 is a phosphatidylinsitol-3-phosphate binding protein required for starvation induced autophagy. (PMID:20505359)
• Freeze-fracture replica immunolabelling reveals WD-repeat protein interacting with phosphoinositides 1 and 2 (WIPI-1 and WIPI-2) as membrane components of autophagosomes and the plasma membrane (PM). (PMID:21564513)
• WIPI2b binds the membrane surrounding Salmonella and recruits the Atg12-5-16L1 complex, initiating LC3 conjugation, autophagosomal membrane formation, and engulfment of Salmonella. (PMID:24954904)
• WIPI-1 and WIPI-2 are functionally required in mediating the PI3P signal at the onset of autophagy in NB4 cells. (PMID:24991767)
• Data suggest that WIPI2b directly interacts with dimer of ATG16L1 (autophagy related 16-like 1) and this interaction is linked to production of phosphatidylinositol 3-phosphate in endoplasmic reticulum triggered by autophagosome formation. [REVIEW] (PMID:25233411)
• Data suggest WIPI1/WIPI2 co-localize with microtubule-associated light chain 3 and autophagy related proteins 2/14L, participate in biogenesis of phagosomes, autophagy, and mobilization of lipids to/from intracellular droplets. [review-like article] (PMID:25233424)
• The specific autophagosomal localization of both WIPI1 and WIPI2 (refered to as WIPI puncta) has been employed to assess autophagy using fluorescence microscopy methods, such as confocal and live-cell video microscopy (PMID:25462558)
• Here the authors show that recruitment of WIPI2, itself essential for anti-bacterial autophagy, is dependent on the localization of catalytically active TBK1 to the vicinity of cytosolic bacteria. (PMID:27370208)
• Data suggest that, in patients with diabetic kidney disease, urinary excretion of mRNAs for MAP1LC3A, WIPI2, and RB1CC1 is down-regulated as compared to healthy control subjects; these transcripts may serve as urinary autophagy biomarkers. (MAP1LC3A = microtubule associated protein 1 light chain 3; WIPI2 = WD repeat domain phosphoinositide-interacting protein 2; RB1CC1 = RB1 inducible coiled-coil 1) (PMID:28760651)
• Results suggest that Optn potentiates LC3-II production and maturation of the phagophore into the autophagosome, by facilitating the recruitment of the Atg12-5-16L1 complex to Wipi2-positive phagophores. (PMID:29133525)
• Regulation of the intracellular WIPI2 protein level by mTORC1 and HUWE1 is a key determinant of autophagy flux. (PMID:30340022)
• A mutation in a highly conserved region of WIPI2 is an essential requirement for autophagy to proceed and is found in a large pedigree with global developmental abnormalities. (PMID:30968111)
• WIPI2 depletion inhibits the growth of hepatocellular carcinoma cells through the AMPK signaling pathway. (PMID:32323845)
• A PI3K-WIPI2 positive feedback loop allosterically activates LC3 lipidation in autophagy. (PMID:32437499)
• Structural basis for membrane recruitment of ATG16L1 by WIPI2 in autophagy. (PMID:34505572)
• STING directly recruits WIPI2 for autophagosome formation during STING-induced autophagy. (PMID:36872914)
• WIPI2b recruitment to phagophores and ATG16L1 binding are regulated by ULK1 phosphorylation. (PMID:39152217)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	wipi2	ENSDARG00000037871
mus_musculus	Wipi2	ENSMUSG00000029578
rattus_norvegicus	Wipi2	ENSRNOG00000001114

Paralogs (3): WIPI1 (ENSG00000070540), WDR45B (ENSG00000141580), WDR45 (ENSG00000196998)

Protein

Protein identifiers

WD repeat domain phosphoinositide-interacting protein 2 — Q9Y4P8 (reviewed: Q9Y4P8)

Alternative names: WIPI49-like protein 2

All UniProt accessions (1): Q9Y4P8

UniProt curated annotations — full annotation on UniProt →

Function. Component of the autophagy machinery that controls the major intracellular degradation process by which cytoplasmic materials are packaged into autophagosomes and delivered to lysosomes for degradation. Involved in an early step of the formation of preautophagosomal structures. Binds and is activated by phosphatidylinositol 3-phosphate (PtdIns3P) forming on membranes of the endoplasmic reticulum upon activation of the upstream ULK1 and PI3 kinases. Mediates ER-isolation membranes contacts by interacting with the ULK1:RB1CC1 complex and PtdIns3P. Once activated, WIPI2 recruits at phagophore assembly sites the ATG12-ATG5-ATG16L1 complex that directly controls the elongation of the nascent autophagosomal membrane. Recruits the ATG12-ATG5-ATG16L1 complex to omegasomes and preautophagosomal structures, resulting in ATG8 family proteins lipidation and starvation-induced autophagy. Isoform 4 is also required for autophagic clearance of pathogenic bacteria. Isoform 4 binds the membrane surrounding Salmonella and recruits the ATG12-5-16L1 complex, initiating LC3 conjugation, autophagosomal membrane formation, and engulfment of Salmonella.

Subunit / interactions. Interacts with TECPR1. Interacts with ATG16L1. Interacts with ATG5. Interacts with WIPI1. Interacts with WDR45. May interact with NUDC. Interacts with ULK1 and RB1CC1.

Subcellular location. Preautophagosomal structure membrane.

Tissue specificity. Ubiquitously expressed (at protein level). Highly expressed in heart, skeletal muscle and pancreas. Expression is down-regulated in pancreatic and in kidney tumors.

Disease relevance. Intellectual developmental disorder with short stature and variable skeletal anomalies (IDDSSA) [MIM:618453] An autosomal recessive disorder characterized by severe intellectual disability, speech and language impairment, developmental delay, and cardiac, thyroid and skeletal abnormalities. Skeletal features include short stature, camptodactyly, fifth finger clinodactyly, thumb hypoplasia, overlapping toes, and kyphosis or lumbar vertebral abnormalities. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The L/FRRG motif is required for recruitment to PtdIns3P.

Induction. Expression is repressed by ZKSCAN3.

Similarity. Belongs to the WD repeat PROPPIN family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q9Y4P8-1	1, WIPI-2 alpha, WIPI2a	yes
Q9Y4P8-2	2, WIPI-2 beta, WIPI2d
Q9Y4P8-3	3, WIPI2e
Q9Y4P8-4	4, WIPI2b
Q9Y4P8-5	5, WIPI-2 delta
Q9Y4P8-6	6, WIPI2c

RefSeq proteins (6): NP_001028690, NP_001028691, NP_001028692, NP_001265228, NP_056425, NP_057087 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR048720	PROPPIN	Family

Pfam: PF21032

UniProt features (58 total): strand 30, repeat 7, splice variant 5, turn 5, mutagenesis site 4, sequence conflict 3, chain 1, sequence variant 1, short sequence motif 1, modified residue 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
7F69	X-RAY DIFFRACTION	1.5
7XFR	X-RAY DIFFRACTION	1.76
7MU2	X-RAY DIFFRACTION	1.85

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y4P8-F1	76.73	0.60

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): 413

Mutagenesis-validated functional residues (4):

Position	Phenotype
126	impairs interaction with atg16l1.
143	decreasess interaction with atg16l1.
242	impairs preautophagosomal localization; when associated with t-243.
243	impairs preautophagosomal localization; when associated with t-242.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1632852	Macroautophagy

MSigDB gene sets: 277 (showing top): GGGACCA_MIR133A_MIR133B, FREAC2_01, GOBP_VACUOLE_ORGANIZATION, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOCC_VACUOLAR_MEMBRANE, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MORF_RAD21, FOXO1_01, YY1_Q6, chr7p22, GOBP_MACROAUTOPHAGY, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GTGCCTT_MIR506, GOBP_POLYSACCHARIDE_CATABOLIC_PROCESS

GO Biological Process (9): autophagosome assembly (GO:0000045), autophagy of mitochondrion (GO:0000422), pexophagy (GO:0000425), cellular response to starvation (GO:0009267), protein localization to phagophore assembly site (GO:0034497), nucleophagy (GO:0044804), glycophagy (GO:0061723), autophagy (GO:0006914), response to stress (GO:0006950)

GO Molecular Function (6): phosphatidylinositol-5-phosphate binding (GO:0010314), protein-macromolecule adaptor activity (GO:0030674), phosphatidylinositol-3-phosphate binding (GO:0032266), phosphatidylinositol-3,5-bisphosphate binding (GO:0080025), protein binding (GO:0005515), lipid binding (GO:0008289)

GO Cellular Component (7): phagophore assembly site (GO:0000407), autophagosome membrane (GO:0000421), nucleoplasm (GO:0005654), cytosol (GO:0005829), protein-containing complex (GO:0032991), phagophore assembly site membrane (GO:0034045), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Autophagy	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
macroautophagy	3
phosphatidylinositol phosphate binding	3
binding	2
cytoplasm	2
Atg12 activating enzyme activity	1
protein-phosphatidylethanolamide deconjugating activity	1
Atg12 conjugating enzyme activity	1
Atg12 ligase activity	1
organelle assembly	1
Atg1/ULK1 kinase complex assembly	1
autophagosome organization	1
autophagy	1
autophagy of peroxisome	1
cellular response to nutrient levels	1
cellular response to stress	1
response to starvation	1
autophagosome assembly	1
intracellular protein localization	1
glycogen catabolic process	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
response to stimulus	1
anion binding	1
protein binding	1
molecular adaptor activity	1
phosphatidylinositol bisphosphate binding	1
vacuolar membrane	1
autophagosome	1
nuclear lumen	1
cellular_component	1
phagophore assembly site	1
membrane	1

Protein interactions and networks

STRING

1666 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WIPI2	ATG16L1	Q676U5	994
WIPI2	ATG12	O94817	988
WIPI2	TECPR1	Q7Z6L1	977
WIPI2	ATG5	Q9H1Y0	974
WIPI2	PIK3C3	Q8NEB9	944
WIPI2	RB1CC1	Q8TDY2	915
WIPI2	ATG2A	Q2TAZ0	910
WIPI2	ATG14	Q6ZNE5	870
WIPI2	ZFYVE1	Q9HBF4	870
WIPI2	OTUD7B	Q6GQQ9	864
WIPI2	BECN1	Q14457	857
WIPI2	GABARAPL2	P60520	853
WIPI2	ATG2B	Q96BY7	804
WIPI2	ATG13	O75143	801
WIPI2	ATG3	Q9NT62	792
WIPI2	ATG101	Q9BSB4	792

IntAct

34 interactions, top by confidence:

A	B	Type	Score
PSMC3	PSMD9	psi-mi:“MI:0914”(association)	0.940
WIPI2	BNIP3L	psi-mi:“MI:0914”(association)	0.640
IFT57	IFT56	psi-mi:“MI:0914”(association)	0.640
IFT81	NDC80	psi-mi:“MI:0914”(association)	0.640
WIPI2	ARL6IP1	psi-mi:“MI:0915”(physical association)	0.560
RABAC1	WIPI2	psi-mi:“MI:0915”(physical association)	0.560
WIPI2	PHAF1	psi-mi:“MI:0914”(association)	0.530
PLTP	SEL1L3	psi-mi:“MI:0914”(association)	0.530
POT1	WIPI2	psi-mi:“MI:0915”(physical association)	0.510
WIPI2	BLMH	psi-mi:“MI:0915”(physical association)	0.400
WIPI2	TERF2IP	psi-mi:“MI:0915”(physical association)	0.370
COPS5	FBLL1	psi-mi:“MI:0914”(association)	0.350
BBS7	PER1	psi-mi:“MI:0914”(association)	0.350
P		psi-mi:“MI:0914”(association)	0.350
IMMP2L	ANKHD1-EIF4EBP3	psi-mi:“MI:0914”(association)	0.350
WIPI2	VTN	psi-mi:“MI:0914”(association)	0.350
WIPI2	PFKP	psi-mi:“MI:0914”(association)	0.350
WIPI2	AIP	psi-mi:“MI:0914”(association)	0.350
BBS7	TARS3	psi-mi:“MI:0914”(association)	0.350
DDB2	LONP1	psi-mi:“MI:0914”(association)	0.350
VIPR2	SLC33A1	psi-mi:“MI:0914”(association)	0.350
SWSAP1	NACA	psi-mi:“MI:2364”(proximity)	0.270
WIPI2	PLEKHG3	psi-mi:“MI:2364”(proximity)	0.270
WIPI2	POT1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (142): WIPI2 (Affinity Capture-MS), ATG16L1 (Affinity Capture-Western), ATG5 (Affinity Capture-Western), ATG12 (Affinity Capture-Western), WIPI2 (Two-hybrid), WIPI2 (Two-hybrid), C16orf70 (Affinity Capture-MS), BCAS3 (Affinity Capture-MS), NAGK (Affinity Capture-MS), RABGAP1 (Affinity Capture-MS), ATG16L1 (Affinity Capture-MS), DPH1 (Affinity Capture-MS), BNIP3L (Affinity Capture-MS), ATG5 (Affinity Capture-MS), DPH2 (Affinity Capture-MS)

ESM2 similar proteins: A0A2R8QFQ6, A0A2R8RWN9, D3Z7P3, E9PV86, G3MWR8, O54865, O60907, O89050, O94925, P13264, P16068, P20595, P58058, Q02153, Q08211, Q12800, Q13042, Q14722, Q28141, Q28D01, Q3MHJ2, Q3ULA2, Q4R8H1, Q4ZHR9, Q5R874, Q5RB35, Q5SP67, Q5SRY7, Q5ZHN3, Q6DN14, Q7RTP6, Q7T2U9, Q7Z6J6, Q8BTG7, Q8C6G8, Q8CJ19, Q8K4Q0, Q8N122, Q8N2K0, Q8R349

Diamond homologs: A1CBB8, A1DE24, A2RAG5, A3GFE3, A5DHI9, A5DVU7, A6QTX7, A6SJ85, A7A258, A7EW77, A7KAM8, A7TPY4, I1RKA1, O16466, P0CS28, P0CS29, P43601, P50079, Q0CW30, Q0U2J8, Q0WPK3, Q1DKJ3, Q2GV40, Q2U6D5, Q4P4N1, Q4WVD0, Q524W4, Q54NA2, Q59P11, Q5ABA6, Q5BH53, Q5MNZ6, Q5MNZ9, Q5QA94, Q5QJC0, Q5R7W0, Q5ZHN3, Q5ZL16, Q640T2, Q68F45

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
PIP3	up-regulates	WIPI2	“chemical activation”
SMCR8	“up-regulates quantity”	WIPI2	“transcriptional regulation”
WIPI2	“up-regulates quantity”	ATG16L1	binding
Cullin4-RBX1-DDB1	“down-regulates quantity by destabilization”	WIPI2	polyubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	51
Likely benign	17
Benign	12

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1315583	NM_015610.4(WIPI2):c.551T>G (p.Val184Gly)	Pathogenic
1330190	GRCh37/hg19 7p22.1(chr7:5096876-5569338)x1	Pathogenic
633591	NM_015610.4(WIPI2):c.745G>A (p.Val249Met)	Pathogenic

SpliceAI

2803 predictions. Top by Δscore:

Variant	Effect	Δscore
7:5190492:ACGT:A	donor_loss	1.0000
7:5190494:G:GG	donor_gain	1.0000
7:5190494:GTAAG:G	donor_loss	1.0000
7:5190495:T:G	donor_loss	1.0000
7:5199656:GCA:G	donor_gain	1.0000
7:5199659:G:GG	donor_gain	1.0000
7:5214526:T:TA	acceptor_gain	1.0000
7:5214529:TTTCA:T	acceptor_loss	1.0000
7:5214530:TTCA:T	acceptor_loss	1.0000
7:5214531:TCA:T	acceptor_loss	1.0000
7:5214533:A:AG	acceptor_gain	1.0000
7:5214533:A:G	acceptor_loss	1.0000
7:5214533:AGCC:A	acceptor_gain	1.0000
7:5214534:G:GT	acceptor_gain	1.0000
7:5214534:GC:G	acceptor_gain	1.0000
7:5214534:GCC:G	acceptor_gain	1.0000
7:5214534:GCCG:G	acceptor_gain	1.0000
7:5214534:GCCGA:G	acceptor_gain	1.0000
7:5214701:GCAG:G	donor_gain	1.0000
7:5214702:CAGG:C	donor_loss	1.0000
7:5214705:G:A	donor_loss	1.0000
7:5214705:G:GG	donor_gain	1.0000
7:5214706:T:G	donor_loss	1.0000
7:5216556:C:CA	acceptor_gain	1.0000
7:5216558:CCTA:C	acceptor_loss	1.0000
7:5216560:TA:T	acceptor_loss	1.0000
7:5216561:A:AG	acceptor_gain	1.0000
7:5216561:AGAG:A	acceptor_gain	1.0000
7:5216562:G:GG	acceptor_gain	1.0000
7:5216562:GA:G	acceptor_gain	1.0000

AlphaMissense

2973 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:5214570:T:A	F83I	1.000
7:5214570:T:C	F83L	1.000
7:5214572:C:A	F83L	1.000
7:5214572:C:G	F83L	1.000
7:5214577:G:T	S85I	1.000
7:5214579:A:C	S86R	1.000
7:5214580:G:T	S86I	1.000
7:5214581:C:A	S86R	1.000
7:5214581:C:G	S86R	1.000
7:5214583:T:A	L87Q	1.000
7:5214583:T:C	L87P	1.000
7:5214588:G:C	A89P	1.000
7:5214589:C:A	A89D	1.000
7:5214595:T:A	V91D	1.000
7:5214613:G:C	R97T	1.000
7:5214613:G:T	R97M	1.000
7:5214619:T:C	L99P	1.000
7:5214630:C:G	H103D	1.000
7:5214632:C:A	H103Q	1.000
7:5214632:C:G	H103Q	1.000
7:5214633:T:C	F104L	1.000
7:5214635:T:A	F104L	1.000
7:5214635:T:G	F104L	1.000
7:5214652:T:A	I110N	1.000
7:5214652:T:C	I110T	1.000
7:5214652:T:G	I110S	1.000
7:5214655:G:A	C111Y	1.000
7:5214666:T:C	Y115H	1.000
7:5214666:T:G	Y115D	1.000
7:5214678:A:T	I119F	1.000

dbSNP variants (sampled 300 via entrez): RS1000037123 (7:5196239 C>A,T), RS1000110177 (7:5195962 C>T), RS1000169238 (7:5229238 G>A), RS1000178500 (7:5201321 A>G), RS1000217302 (7:5212123 C>T), RS1000234248 (7:5234143 G>A), RS1000234801 (7:5206161 A>T), RS1000275191 (7:5205332 G>A,T), RS1000303225 (7:5226357 T>C), RS1000304941 (7:5205154 T>C), RS1000335208 (7:5191443 G>A), RS1000466320 (7:5225714 C>T), RS1000516012 (7:5200247 T>C,G), RS1000533320 (7:5209990 C>G,T), RS1000626200 (7:5200798 A>G,T)

Disease associations

OMIM: gene MIM:609225 | disease phenotypes: MIM:618453, MIM:160700, MIM:603047

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual developmental disorder with short stature and variable skeletal anomalies	Strong	Autosomal recessive

Mondo (3): intellectual developmental disorder with short stature and variable skeletal anomalies (MONDO:0032759), myopia (MONDO:0001384), astigmatism (MONDO:0011284)

Orphanet (0):

HPO phenotypes

15 total (17 of 15 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000750	Delayed speech and language development
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001845	Overlapping toe
HP:0002059	Cerebral atrophy
HP:0002465	Poor speech
HP:0002808	Kyphosis
HP:0004209	Clinodactyly of the 5th finger
HP:0004322	Short stature
HP:0009778	Short thumb
HP:0010864	Severe intellectual disability
HP:0011675	Arrhythmia
HP:0012385	Camptodactyly
HP:0100660	Dyskinesia
HP:0000545	Myopia
HP:0000483	Astigmatism

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST004602_126	Mean corpuscular volume	2.000000e-09
GCST004628_89	Immature fraction of reticulocytes	2.000000e-12
GCST004630_256	Mean corpuscular hemoglobin	1.000000e-13
GCST006132_1	Bone mineral density x blood lead interaction in current smokers (1df test)	4.000000e-07
GCST006133_1	Bone mineral density x blood lead interaction in current smokers (2df test)	2.000000e-06
GCST90002385_176	High light scatter reticulocyte count	5.000000e-13
GCST90002387_374	Immature fraction of reticulocytes	2.000000e-33
GCST90002390_236	Mean corpuscular hemoglobin	1.000000e-52
GCST90002391_215	Mean corpuscular hemoglobin concentration	4.000000e-17
GCST90002392_711	Mean corpuscular volume	2.000000e-40
GCST90002403_193	Red blood cell count	3.000000e-19

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007986	reticulocyte count
EFO:0004527	mean corpuscular hemoglobin
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0004305	erythrocyte count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D001251	Astigmatism	C11.744.212
D009216	Myopia	C11.744.636

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	2
cobaltous chloride	increases expression	2
Acetaminophen	increases expression, affects response to substance	2
GSK-J4	increases expression	1
FR900359	decreases phosphorylation	1
bisphenol F	affects cotreatment, increases methylation	1
triphenyl phosphate	affects expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
apilimod	increases expression	1
bisphenol S	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cisplatin	increases expression	1
Coumestrol	decreases expression	1
Diazinon	increases methylation	1
Dietary Carbohydrates	decreases expression	1
Hydrogen Peroxide	affects expression	1
Lead	affects splicing	1
Urethane	increases expression	1
Valproic Acid	affects expression	1
Vitamin E	decreases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	decreases expression, increases methylation, increases expression	1
Lactic Acid	decreases expression	1

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_5A21	HEK293A/GFP-WIPI2	Transformed cell line	Female
CVCL_E6FD	HeLa S3 WIPI2 KO clone #7	Cancer cell line	Female
CVCL_TY04	HAP1 WIPI2 (-) 1	Cancer cell line	Male
CVCL_XV13	HAP1 WIPI2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00347204	PHASE4	COMPLETED	Comparison of Acular LS Versus Nevanac for Pain Control in Eyes Undergoing PRK
NCT00349843	PHASE4	COMPLETED	Investigation of Multi-Purpose Solution-Based Corneal Staining and Ocular Comfort
NCT00349882	PHASE4	COMPLETED	Effects of Contact Lens Care Regimens on the Corneal Epithelium
NCT00350246	PHASE4	COMPLETED	Long-term Effects of Laser Refractive Surgery
NCT00404105	PHASE4	COMPLETED	A Comparison of PRK and LASIK for Correction of Myopia
NCT00455455	PHASE4	COMPLETED	Corneal and Conjunctival Sensitivity and Staining Study
NCT00541177	PHASE4	UNKNOWN	Study of Myopia Prevention in Children With Low Concentration of Atropine
NCT00627302	PHASE4	COMPLETED	Efficacy of PEG-400 and Systane Artificial Tears (Alcon) on Quality of Vision
NCT00640341	PHASE4	COMPLETED	Comparative Performance of PureVision, Acuvue Oasys and O2Optix
NCT00770094	PHASE4	UNKNOWN	Multi Laser Platform Comparison Study for LASIK
NCT00821236	PHASE4	COMPLETED	Contralateral Comparison of Three Excimer Laser Systems in Performing LASIK
NCT00889941	PHASE4	COMPLETED	Effect of Preoperative Pupil Size on Quality of Vision After Wavefront-Guided LASIK
NCT00937105	PHASE4	COMPLETED	Daily Wear Corneal Infiltrative Event Study
NCT01173198	PHASE4	COMPLETED	An Evaluation of Outcomes Following Wavefront Optimized or Wavefront Guided Lasik Procedure in Low to Moderate Myopic Patients
NCT01250925	PHASE4	COMPLETED	Effect of Contact Lens Wear on Immune Cell Density and Morphology of the Ocular Surface
NCT01387360	PHASE4	COMPLETED	Presbyopic Supracor Treatment for Near Myopic/Hyperopic Pseudophakic Eyes
NCT01454843	PHASE4	COMPLETED	LASIK Using the Alcon Allegretto Wavefront-Guided Excimer Laser vs AMO Visx Wavefront-Guided Excimer Laser
NCT01693939	PHASE4	COMPLETED	Evaluation of the Post-LASIK Flap Thickness of the FS200 Femtosecond Laser Flap
NCT01706237	PHASE4	WITHDRAWN	Visual Outcomes And Contrast Sensitivity After Myopic Wavefront-Optimized Lasik With Nexisvision Shield Or Bandage Contact Lens
NCT01746589	PHASE4	COMPLETED	Visual Outcomes and Contrast Sensitivity After Myopic LASIK
NCT01977807	PHASE4	UNKNOWN	A Prospective Safety and Effectiveness Study of the 500 Hz Technolas Perfect Vision Excimer Laser in Asian Eyes Using LASIK
NCT02071576	PHASE4	UNKNOWN	A Prospective Safety and Effectiveness Study of the 500 Hz Technolas Perfect Vision Excimer Laser Using LASIK
NCT02112968	PHASE4	UNKNOWN	A Prospective Safety and Effectiveness Study of a New High Repetition Rate Excimer Laser Using LASIK for the Correction of Ammetropia and Presbyopia
NCT02186184	PHASE4	COMPLETED	Effect of Orthokeratology Versus Spectacles on Myopia Progression in Chinese Children: A Crossover Trial
NCT02544529	PHASE4	WITHDRAWN	Echothiophate Iodide for the Prevention of Progression of Myopia
NCT03001401	PHASE4	UNKNOWN	Comparison of Next Generation Laser Techniques of Myopia Correction: iDesign vs. SMILE
NCT03158142	PHASE4	COMPLETED	The Influence of Atropine on Choroidal Thickness
NCT03544827	PHASE4	COMPLETED	The Effects of Low Dose Atropine on Choroidal Thickness
NCT03881670	PHASE4	COMPLETED	On-Eye Optical Quality of Lotrafilcon B Lenses Over 12 Hours
NCT03949101	PHASE4	UNKNOWN	Atropine for Children and Adolescent Myopia Progression Study
NCT04208750	PHASE4	COMPLETED	Clinical Investigation of the Vision-R800 Device.
NCT04283331	PHASE4	UNKNOWN	Anesthetic Impregnated Bandage Soft Contact Lens (BSCL) in Pain Management After Photorefractive Keratectomy (PRK)
NCT05357326	PHASE4	UNKNOWN	Myopia Intervention in Children and Adolescents and Establishment of a Precise Intervention Model
NCT05448989	PHASE4	UNKNOWN	Efficacy and Safety of 1% Atropine 5+3 Regimen in Children and Adolescents Controlling Myopia
NCT05449015	PHASE4	UNKNOWN	Study on the Effect of Two Ways of Cycloplegia on Biological Parameters of Ciliary Muscle
NCT05733741	PHASE4	COMPLETED	Preservative-free Topical Anesthetics for Post-PRK Pain
NCT05803863	PHASE4	UNKNOWN	Efficacy Comparison of 2 Low-dose Atropine Eye Drops in Vietnamese Children Myopia Management
NCT06431841	PHASE4	ACTIVE_NOT_RECRUITING	Atropine and Spectacle Combination Treatment (ASPECT): 12-month Results of a Randomized Clinical Trial for Myopia Control
NCT06450132	PHASE4	ACTIVE_NOT_RECRUITING	Changes in Eye Shape With Myopia Management Interventions
NCT06553404	PHASE4	ACTIVE_NOT_RECRUITING	Myoslow Lens Study to Control Myopia in Children