WDFY3

Summary

WDFY3 (WD repeat and FYVE domain containing 3, HGNC:20751) is a protein-coding gene on chromosome 4q21.23, encoding WD repeat and FYVE domain-containing protein 3 (Q8IZQ1). Required for selective macroautophagy (aggrephagy). It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a phosphatidylinositol 3-phosphate-binding protein that functions as a master conductor for aggregate clearance by autophagy. This protein shuttles from the nuclear membrane to colocalize with aggregated proteins, where it complexes with other autophagic components to achieve macroautophagy-mediated clearance of these aggregated proteins. However, it is not necessary for starvation-induced macroautophagy.

Source: NCBI Gene 23001 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic intellectual disability (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 1,052 total — 44 pathogenic, 46 likely-pathogenic
• Phenotypes (HPO): 4
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_014991

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20751
Approved symbol	WDFY3
Name	WD repeat and FYVE domain containing 3
Location	4q21.23
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0993, ALFY, ZFYVE25
Ensembl gene	ENSG00000163625
Ensembl biotype	protein_coding
OMIM	617485
Entrez	23001

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 5 protein_coding, 5 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000295888, ENST00000425179, ENST00000426414, ENST00000502713, ENST00000504839, ENST00000504990, ENST00000505923, ENST00000509172, ENST00000509825, ENST00000512267, ENST00000514071, ENST00000514711

RefSeq mRNA: 1 — MANE Select: NM_014991 NM_014991

CCDS: CCDS3609

Canonical transcript exons

ENST00000295888 — 68 exons

Exon	Start	End
ENSE00001355814	84896911	84897010
ENSE00001355827	84932270	84932363
ENSE00001591323	84708909	84709028
ENSE00001592502	84718422	84718570
ENSE00001592723	84756926	84757161
ENSE00001608589	84696732	84696823
ENSE00001640107	84713159	84713239
ENSE00001666001	84695970	84696182
ENSE00001687765	84709293	84709347
ENSE00001689111	84715298	84715383
ENSE00001689813	84704338	84704444
ENSE00001715967	84705394	84705511
ENSE00001729953	84721409	84721572
ENSE00001740880	84724426	84724594
ENSE00001753420	84716896	84717016
ENSE00001761719	84702353	84702506
ENSE00001765243	84726861	84726911
ENSE00001767915	84692885	84693032
ENSE00001904973	84669597	84672991
ENSE00002033038	84691631	84691785
ENSE00002063062	84733382	84733609
ENSE00003472698	84860412	84860622
ENSE00003484723	84841154	84841263
ENSE00003494676	84836929	84837090
ENSE00003557339	84849902	84850025
ENSE00003557527	84831413	84831605
ENSE00003580185	84829004	84829190
ENSE00003587362	84826815	84826981
ENSE00003610470	84821084	84821551
ENSE00003899672	84966209	84966690
ENSE00003994508	84751483	84751716
ENSE00003994509	84682374	84682470
ENSE00003994510	84688086	84688265
ENSE00003994511	84787482	84787713
ENSE00003994512	84677199	84677396
ENSE00003994513	84778503	84778655
ENSE00003994514	84678919	84679242
ENSE00003994515	84797996	84798108
ENSE00003994516	84755266	84755400
ENSE00003994517	84789726	84789907
ENSE00003994518	84735043	84735120
ENSE00003994519	84774820	84774981
ENSE00003994520	84820085	84820186
ENSE00003994522	84765810	84766027
ENSE00003994524	84794879	84794979
ENSE00003994525	84736170	84736327
ENSE00003994526	84780108	84780298
ENSE00003994527	84678168	84678279
ENSE00003994528	84801650	84801864
ENSE00003994529	84808334	84808417
ENSE00003994530	84796521	84796752
ENSE00003994531	84775065	84775138
ENSE00003994532	84743700	84743799
ENSE00003994533	84803290	84803467
ENSE00003994534	84785979	84786139
ENSE00003994535	84739010	84739119
ENSE00003994536	84737184	84737366
ENSE00003994537	84766252	84766372
ENSE00003994538	84809887	84810344
ENSE00003994539	84817392	84817585
ENSE00003994540	84794519	84794737
ENSE00003994541	84772835	84772929
ENSE00003994542	84683943	84684125
ENSE00003994543	84741761	84741921
ENSE00003994544	84782963	84783074
ENSE00003994546	84740187	84740416
ENSE00003994547	84690506	84690664
ENSE00003994548	84753697	84753876

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 96.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.6518 / max 284.6526, expressed in 1698 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
52953	11.2521	1692
52954	0.9775	376
52948	0.4222	119

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	96.43	gold quality
calcaneal tendon	UBERON:0003701	95.58	gold quality
corpus callosum	UBERON:0002336	94.41	gold quality
adrenal tissue	UBERON:0018303	94.35	gold quality
inferior olivary complex	UBERON:0002127	94.13	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	93.83	gold quality
ventricular zone	UBERON:0003053	93.31	gold quality
medial globus pallidus	UBERON:0002477	92.84	gold quality
cortical plate	UBERON:0005343	92.61	gold quality
ganglionic eminence	UBERON:0004023	92.47	gold quality
colonic epithelium	UBERON:0000397	92.45	gold quality
tendon	UBERON:0000043	92.12	gold quality
globus pallidus	UBERON:0001875	92.06	gold quality
cranial nerve II	UBERON:0000941	91.18	gold quality
postcentral gyrus	UBERON:0002581	91.16	gold quality
blood vessel layer	UBERON:0004797	90.42	gold quality
skin of hip	UBERON:0001554	90.14	gold quality
cerebellar vermis	UBERON:0004720	90.00	gold quality
Brodmann (1909) area 23	UBERON:0013554	89.99	gold quality
entorhinal cortex	UBERON:0002728	89.53	gold quality
parietal lobe	UBERON:0001872	89.51	gold quality
primary visual cortex	UBERON:0002436	89.41	gold quality
subthalamic nucleus	UBERON:0001906	89.36	gold quality
superior frontal gyrus	UBERON:0002661	89.33	gold quality
prefrontal cortex	UBERON:0000451	89.26	gold quality
islet of Langerhans	UBERON:0000006	88.92	gold quality
upper leg skin	UBERON:0004262	88.90	gold quality
middle temporal gyrus	UBERON:0002771	88.77	gold quality
stromal cell of endometrium	CL:0002255	88.49	gold quality
inferior vagus X ganglion	UBERON:0005363	88.27	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.16
E-CURD-10	no	366.48

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

361 targeting WDFY3, 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-MIR-3646	100.00	73.56	5283
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4668-3P	100.00	68.74	2635
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-3163	100.00	77.23	8605
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 13)

• Alfy might target cytosolic protein aggregates for autophagic degradation. (PMID:15292400)
• Data suggest that p62 and ALFY interact to organize misfolded, ubiquitinated proteins into protein bodies that become degraded by autophagy. (PMID:20168092)
• The selective macroautophagic degradation of aggregated proteins requires the PI3P-binding protein Alfy. (PMID:20417604)
• increasing Alfy-mediated protein degradation may be beneficial in some organs, but may be detrimental in others (PMID:21150266)
• ALFY binds selectively to LC3C and the GABARAPs through a LC3-interacting region in its WD40 domain. (PMID:24668264)
• we demonstrate that normally ALFY attenuates the canonical Wnt signaling pathway via autophagy-dependent removal specifically of aggregates of DVL3 and not of Dvl1 or Dvl2. (PMID:27008544)
• The Autophagy linked FYVE protein (Alfy), also known as WDFY3, is required for development of the central nervous system (CNS) in mice. (PMID:27648578)
• a crucial role for ALFY in retinoid triggered maturation of acute myeloid leukemia cells, is reported. (PMID:29021535)
• Proliferating cortical neural progenitors of human embryonic brain regions highly express WDFY3. (PMID:31327001)
• Alfy is required in the adult brain for the autophagy-dependent clearance of proteinaceous deposits, and its depletion in neurons derived from Huntington’s disease patient fibroblasts accelerates the aberrant accumulation of this pathological hallmark shared across adult-onset neurodegenerative diseases. (PMID:31899071)
• A highly conserved glutamic acid in ALFY inhibits membrane binding to aid in aggregate clearance. (PMID:33225481)
• ALFY localizes to early endosomes and cellular protrusions to facilitate directional cell migration. (PMID:35099014)
• A genome-wide CRISPR screen identifies WDFY3 as a regulator of macrophage efferocytosis. (PMID:36566259)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	wdfy3	ENSDARG00000078890
mus_musculus	Wdfy3	ENSMUSG00000043940
rattus_norvegicus	Wdfy3	ENSRNOG00000061121
drosophila_melanogaster	bchs	FBGN0043362
caenorhabditis_elegans		WBGENE00004760
caenorhabditis_elegans		WBGENE00007752

Paralogs (7): NSMAF (ENSG00000035681), WDFY4 (ENSG00000128815), LYST (ENSG00000143669), NBEAL1 (ENSG00000144426), NBEAL2 (ENSG00000160796), NBEA (ENSG00000172915), LRBA (ENSG00000198589)

Protein

Protein identifiers

WD repeat and FYVE domain-containing protein 3 — Q8IZQ1 (reviewed: Q8IZQ1)

Alternative names: Autophagy-linked FYVE protein

All UniProt accessions (5): A0A1D5RMR8, Q8IZQ1, D6RJE4, H0Y9T6, H0YAD8

UniProt curated annotations — full annotation on UniProt →

Function. Required for selective macroautophagy (aggrephagy). Acts as an adapter protein by linking specific proteins destined for degradation to the core autophagic machinery members, such as the ATG5-ATG12-ATG16L E3-like ligase, SQSTM1 and LC3. Along with p62/SQSTM1, involved in the formation and autophagic degradation of cytoplasmic ubiquitin-containing inclusions (p62 bodies, ALIS/aggresome-like induced structures). Along with SQSTM1, required to recruit ubiquitinated proteins to PML bodies in the nucleus. Important for normal brain development. Essential for the formation of axonal tracts throughout the brain and spinal cord, including the formation of the major forebrain commissures. Involved in the ability of neural cells to respond to guidance cues. Required for cortical neurons to respond to the trophic effects of netrin-1/NTN1. Regulates Wnt signaling through the removal of DVL3 aggregates, likely in an autophagy-dependent manner. This process may be important for the determination of brain size during embryonic development. May regulate osteoclastogenesis by acting on the TNFSF11/RANKL - TRAF6 pathway. After cytokinetic abscission, involved in midbody remnant degradation. In vitro strongly binds to phosphatidylinositol 3-phosphate (PtdIns3P).

Subunit / interactions. Directly interacts with ATG5 and associates with the ATG12-ATG5-ATG16L complex. Interacts with p62/SQSTM1; this interaction is required to recruit WDFY3 to cytoplasmic bodies and to PML bodies. Directly interacts with GABARAP, GABARAPL1 and GABARAPL2; the interaction with GABARAP is required for WDFY3 recruitment to MAP1LC3B-positive p62/SQSTM1 bodies. Weakly interacts with MAP1LC3C; this interaction is direct. Does not interact with MAP1LC3A, nor MAP1LC3B. Interacts with TRAF6.

Subcellular location. Nucleus membrane. Cytoplasm. Cytosol. Nucleus. PML body. Membrane. Perikaryon. Cell projection. Axon.

Tissue specificity. Expressed in osteoclast and their mononuclear precursors (at protein level).

Disease relevance. Microcephaly 18, primary, autosomal dominant (MCPH18) [MIM:617520] A form of microcephaly, a disease defined as a head circumference more than 3 standard deviations below the age, sex and ethnically matched mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small. MCPH18 affected individuals manifest microcephaly with mild to moderate intellectual disability. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The LIR (LC3-interacting region) motif mediates the interaction with MAP1LC3C and other ATG8 family members. The FYVE domain mediates binding to phosphatidylinositol 3-phosphate (PtdIns3P).

Isoforms (2)

UniProt ID	Names	Canonical?
Q8IZQ1-1	1	yes
Q8IZQ1-2	2

RefSeq proteins (1): NP_055806* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000306	Znf_FYVE	Domain
IPR000409	BEACH_dom	Domain
IPR001680	WD40_rpt	Repeat
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR011989	ARM-like	Homologous_superfamily
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR017455	Znf_FYVE-rel	Domain
IPR019775	WD40_repeat_CS	Conserved_site
IPR023362	PH-BEACH_dom	Domain
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR036372	BEACH_dom_sf	Homologous_superfamily
IPR051944	BEACH_domain_protein	Family
IPR056252	Alfy-like_Arm-like	Domain

Pfam: PF00400, PF01363, PF02138, PF14844, PF23295

UniProt features (56 total): binding site 8, strand 8, region of interest 7, mutagenesis site 7, modified residue 5, repeat 5, domain 2, compositionally biased region 2, sequence variant 2, sequence conflict 2, turn 2, helix 2, chain 1, short sequence motif 1, splice variant 1, zinc finger region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3WIM	X-RAY DIFFRACTION	2.6
6W9N	SOLUTION NMR

Predicted structure (AlphaFold)

No AlphaFold model available for Q8IZQ1 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (8): 3460; 3463; 3476; 3479; 3484; 3487; 3506; 3509

Post-translational modifications (5): 1942, 2278, 2492, 3335, 3339

Mutagenesis-validated functional residues (7):

Position	Phenotype
3343	decreased interaction with gabarap, no effect on interaction with map1lc3b; when associated with a-3344 and a-3351.
3344	decreased interaction with gabarap, no effect on interaction with map1lc3b; when associated with a-3343 and a-3351.
3346	abolishes interaction with gabarap and map1lc3c.
3347	decreases interaction with gabarap and map1lc3c.
3348	decreases interaction with gabarap and map1lc3c.
3349	decreases interaction with gabarap and map1lc3c.
3351	decreased interaction with gabarap, no effect on interaction with map1lc3b; when associated with a-3343 and a-3344.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 0 (showing top):

GO Biological Process (3): aggrephagy (GO:0035973), autophagy (GO:0006914), macroautophagy (GO:0016236)

GO Molecular Function (5): 1-phosphatidylinositol binding (GO:0005545), zinc ion binding (GO:0008270), protein binding (GO:0005515), lipid binding (GO:0008289), metal ion binding (GO:0046872)

GO Cellular Component (17): autophagosome membrane (GO:0000421), nuclear envelope (GO:0005635), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), autophagosome (GO:0005776), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), inclusion body (GO:0016234), PML body (GO:0016605), axon (GO:0030424), nuclear membrane (GO:0031965), perikaryon (GO:0043204), nucleus (GO:0005634), Atg12-Atg5-Atg16 complex (GO:0034274), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
binding	2
nucleus	2
nuclear lumen	2
intracellular anatomical structure	2
cytoplasm	2
macroautophagy	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
autophagosome assembly	1
autophagy	1
phospholipid binding	1
transition metal ion binding	1
cation binding	1
vacuolar membrane	1
autophagosome	1
endomembrane system	1
organelle envelope	1
intracellular membraneless organelle	1
vacuole	1
membrane	1
cell periphery	1
nuclear body	1
neuron projection	1
nuclear envelope	1
organelle membrane	1
neuronal cell body	1
intracellular membrane-bounded organelle	1
transferase complex	1

Protein interactions and networks

STRING

1488 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WDFY3	ATG5	Q9H1Y0	990
WDFY3	SQSTM1	Q13501	972
WDFY3	MAP1LC3C	Q9BXW4	899
WDFY3	ATG12	O94817	898
WDFY3	ATG16L1	Q676U5	879
WDFY3	TRAF6	Q9Y4K3	840
WDFY3	NBR1	Q14596	829
WDFY3	GABARAP	O95166	734
WDFY3	F5GZY7	F5GZY7	728
WDFY3	GABARAPL2	P60520	724
WDFY3	CD300C	Q08708	682
WDFY3	HTT	P42858	596
WDFY3	MAP1LC3B	Q9GZQ8	582
WDFY3	CALCOCO2	Q13137	572
WDFY3	OPTN	Q96CV9	543

IntAct

146 interactions, top by confidence:

A	B	Type	Score
MAP1LC3C	SQSTM1	psi-mi:“MI:0914”(association)	0.900
HTT	SQSTM1	psi-mi:“MI:0914”(association)	0.770
HTT	SQSTM1	psi-mi:“MI:0403”(colocalization)	0.770
MAP1LC3B	ATG7	psi-mi:“MI:0914”(association)	0.740
MAP1LC3B	WDFY3	psi-mi:“MI:0407”(direct interaction)	0.710
WDFY3	MAP1LC3B	psi-mi:“MI:0403”(colocalization)	0.710
MAP1LC3B	WDFY3	psi-mi:“MI:0403”(colocalization)	0.710
WDFY3	SQSTM1	psi-mi:“MI:0403”(colocalization)	0.710
WDFY3	SQSTM1	psi-mi:“MI:0915”(physical association)	0.710
WDFY3	SQSTM1	psi-mi:“MI:0407”(direct interaction)	0.710
WDFY3	GABARAP	psi-mi:“MI:0915”(physical association)	0.660
WDFY3	GABARAP	psi-mi:“MI:0407”(direct interaction)	0.660
GABARAP	WDFY3	psi-mi:“MI:0407”(direct interaction)	0.660

BioGRID (146): ZBTB44 (Two-hybrid), TRIM39 (Two-hybrid), CEP76 (Two-hybrid), WDFY3 (Affinity Capture-RNA), WDFY3 (Affinity Capture-RNA), WDFY3 (Affinity Capture-RNA), WDFY3 (Affinity Capture-MS), WDFY3 (Affinity Capture-MS), WDFY3 (Affinity Capture-Western), WDFY3 (Affinity Capture-Western), WDFY3 (Affinity Capture-Western), WDFY3 (Affinity Capture-Western), WDFY3 (Reconstituted Complex), WDFY3 (Reconstituted Complex), WDFY3 (Reconstituted Complex)

ESM2 similar proteins: A0A0R4IES7, A0JN62, A0JNW5, A2AAE1, A2AGL3, A2RSJ4, A2RT67, A2RUS2, A2RV80, B0LPN4, B1H2P5, E7F240, E9Q401, O00507, O94967, P30957, P48553, P51593, Q14161, Q2LD37, Q3TLI0, Q3UHE1, Q3UVG3, Q3UX43, Q5F361, Q5M7Q1, Q5RAQ5, Q5ZJK1, Q658Y4, Q68CL5, Q6BDS2, Q6P6Y1, Q6TEP1, Q6VNB8, Q7TMY8, Q7TSG1, Q7Z6Z7, Q8BHY8, Q8CB44, Q8CGF6

Diamond homologs: A0A0D1E015, A0JMD2, A1CEK1, A1DFP5, A2QWA2, A4QTV1, A8QCE4, A8XJZ8, B0G126, B0WAQ0, B3MT31, B3P851, B4G2G5, B4IC49, B4JHI7, B4K982, B4M140, B4NFJ7, B4PRU6, D2H5P6, D3ZVP7, D4A8G9, E1BLZ4, F1MM41, F7EP40, O13821, O14964, O59722, O76902, O95405, O96838, P0CS26, P0CS27, P34756, P40343, Q05B78, Q08CN9, Q0CJV3, Q0P4S0, Q0U4Z8

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
WDFY3	“up-regulates quantity”	ATG5	binding
SQSTM1	“up-regulates quantity”	WDFY3	binding
WDFY3	“down-regulates quantity by destabilization”	DVL3	relocalization
WDFY3	up-regulates	Autophagy
MAP1LC3C	“up-regulates activity”	WDFY3	binding
WDFY3	“down-regulates quantity by destabilization”	GABARAP	binding
TFEB	“up-regulates quantity by expression”	WDFY3	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 121 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
Macroautophagy	9	14.2×	6e-06
SLC transporter disorders	5	14.0×	3e-03
Autophagy	6	12.2×	2e-03
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	8	9.6×	5e-04

GO biological processes:

GO term	Partners	Fold	FDR
mitophagy	9	26.5×	2e-08
autophagosome maturation	5	16.2×	3e-03
autophagosome assembly	7	14.6×	1e-04
response to ischemia	5	11.6×	8e-03
macroautophagy	5	11.2×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1052 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	44
Likely pathogenic	46
Uncertain significance	735
Likely benign	101
Benign	47

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1174114	NM_014991.6(WDFY3):c.4063-1G>T	Pathogenic
1208615	NM_014991.6(WDFY3):c.8941C>T (p.Arg2981Ter)	Pathogenic
1253820	NM_014991.6(WDFY3):c.8094G>A (p.Trp2698Ter)	Pathogenic
1341159	GRCh37/hg19 4q21.23(chr4:85592482-85651685)x1	Pathogenic
1343934	NM_014991.6(WDFY3):c.3442C>T (p.Arg1148Ter)	Pathogenic
1805197	NM_014991.6(WDFY3):c.3579G>A (p.Trp1193Ter)	Pathogenic
2112856	NM_014991.6(WDFY3):c.3877A>C (p.Ser1293Arg)	Pathogenic
2229123	NM_014991.6(WDFY3):c.9597del (p.Asn3200fs)	Pathogenic
2497719	NM_014991.6(WDFY3):c.7917C>A (p.Tyr2639Ter)	Pathogenic
2497964	NM_014991.6(WDFY3):c.3382C>T (p.Arg1128Ter)	Pathogenic
2498167	NM_014991.6(WDFY3):c.2345+1G>A	Pathogenic
3189729	NM_014991.6(WDFY3):c.2883del (p.Lys961fs)	Pathogenic
3236646	NM_014991.6(WDFY3):c.7297_7298insC (p.Val2433fs)	Pathogenic
3254937	NM_014991.6(WDFY3):c.3547C>T (p.Arg1183Ter)	Pathogenic
3340633	NM_014991.6(WDFY3):c.4141C>T (p.Arg1381Trp)	Pathogenic
3343050	NM_014991.6(WDFY3):c.10153C>T (p.Arg3385Ter)	Pathogenic
3364140	NM_014991.6(WDFY3):c.235C>T (p.Gln79Ter)	Pathogenic
3369613	NM_014991.6(WDFY3):c.2707C>T (p.Arg903Ter)	Pathogenic
3377092	NM_014991.6(WDFY3):c.10117G>T (p.Glu3373Ter)	Pathogenic
3381423	NM_014991.6(WDFY3):c.8758C>T (p.Gln2920Ter)	Pathogenic
3469097	NM_014991.6(WDFY3):c.7949_7950del (p.Lys2650fs)	Pathogenic
3469098	NM_014991.6(WDFY3):c.5593C>T (p.Arg1865Ter)	Pathogenic
3649969	NM_014991.6(WDFY3):c.4826_4829del (p.Asn1609fs)	Pathogenic
3893336	NM_014991.6(WDFY3):c.4660C>T (p.Arg1554Ter)	Pathogenic
3899503	NM_014991.6(WDFY3):c.6739_6740del (p.Cys2247fs)	Pathogenic
3900265	NM_014991.6(WDFY3):c.3414C>A (p.Cys1138Ter)	Pathogenic
4075483	NM_014991.6(WDFY3):c.1702C>T (p.Arg568Ter)	Pathogenic
4077201	NM_014991.6(WDFY3):c.6874C>T (p.Arg2292Ter)	Pathogenic
4081929	NM_014991.6(WDFY3):c.6913C>T (p.Gln2305Ter)	Pathogenic
4200304	NM_014991.6(WDFY3):c.7282C>T (p.Arg2428Ter)	Pathogenic

SpliceAI

11869 predictions. Top by Δscore:

Variant	Effect	Δscore
4:84677193:T:C	donor_gain	1.0000
4:84677197:A:AC	donor_gain	1.0000
4:84677198:C:CC	donor_gain	1.0000
4:84677198:CTT:C	donor_gain	1.0000
4:84677200:T:TA	donor_gain	1.0000
4:84677395:CC:C	acceptor_gain	1.0000
4:84677396:CC:C	acceptor_gain	1.0000
4:84678161:CACTT:C	donor_loss	1.0000
4:84678164:TTA:T	donor_loss	1.0000
4:84678165:TA:T	donor_loss	1.0000
4:84678166:A:AC	donor_gain	1.0000
4:84678167:C:CT	donor_gain	1.0000
4:84682376:A:AC	donor_gain	1.0000
4:84682397:T:TA	donor_gain	1.0000
4:84682468:AAA:A	acceptor_gain	1.0000
4:84682471:C:CC	acceptor_gain	1.0000
4:84683937:ACTT:A	donor_loss	1.0000
4:84683938:CTTA:C	donor_loss	1.0000
4:84683939:TTA:T	donor_loss	1.0000
4:84683940:T:TG	donor_loss	1.0000
4:84683941:A:AC	donor_gain	1.0000
4:84683941:A:AG	donor_loss	1.0000
4:84683941:AC:A	donor_gain	1.0000
4:84683942:C:CC	donor_gain	1.0000
4:84683942:CC:C	donor_gain	1.0000
4:84684121:TCCCC:T	acceptor_gain	1.0000
4:84684122:CCCC:C	acceptor_gain	1.0000
4:84684122:CCCCC:C	acceptor_gain	1.0000
4:84684123:CCC:C	acceptor_gain	1.0000
4:84684123:CCCC:C	acceptor_gain	1.0000

AlphaMissense

23172 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:84672922:A:C	C3509W	1.000
4:84672923:C:G	C3509S	1.000
4:84672924:A:G	C3509R	1.000
4:84672924:A:T	C3509S	1.000
4:84672931:A:C	C3506W	1.000
4:84672932:C:G	C3506S	1.000
4:84672932:C:T	C3506Y	1.000
4:84672933:A:G	C3506R	1.000
4:84672933:A:T	C3506S	1.000
4:84672935:A:T	V3505D	1.000
4:84672939:G:T	R3504S	1.000
4:84672989:C:G	C3487S	1.000
4:84672990:A:G	C3487R	1.000
4:84672990:A:T	C3487S	1.000
4:84677204:G:C	C3484W	1.000
4:84677205:C:G	C3484S	1.000
4:84677205:C:T	C3484Y	1.000
4:84677206:A:G	C3484R	1.000
4:84677206:A:T	C3484S	1.000
4:84677220:C:T	C3479Y	1.000
4:84677221:A:G	C3479R	1.000
4:84677225:C:A	R3477S	1.000
4:84677225:C:G	R3477S	1.000
4:84677226:C:A	R3477M	1.000
4:84677226:C:G	R3477T	1.000
4:84677228:G:C	C3476W	1.000
4:84677229:C:A	C3476F	1.000
4:84677229:C:G	C3476S	1.000
4:84677229:C:T	C3476Y	1.000
4:84677230:A:G	C3476R	1.000

dbSNP variants (sampled 300 via entrez): RS1000008372 (4:84863044 T>C), RS1000010736 (4:84905126 A>C), RS1000013388 (4:84771564 T>C), RS1000036584 (4:84765402 G>A), RS1000036769 (4:84724191 A>G), RS1000048158 (4:84904961 G>A), RS1000062370 (4:84684422 GAA>G), RS1000063276 (4:84905470 A>G), RS1000097105 (4:84674129 T>C), RS1000101171 (4:84693899 A>G), RS1000133329 (4:84948280 T>C), RS1000142093 (4:84835247 A>G), RS1000145125 (4:84717557 G>A,C), RS1000151877 (4:84875796 C>G), RS1000158478 (4:84783520 G>T)

Disease associations

OMIM: gene MIM:617485 | disease phenotypes: MIM:617520, MIM:156200, MIM:189960

GenCC curated gene-disease

Disease	Classification	Inheritance
microcephaly 18, primary, autosomal dominant	Strong	Autosomal dominant
autism spectrum disorder	Moderate	Autosomal dominant
complex neurodevelopmental disorder	Moderate	Autosomal dominant
neurodevelopmental disorder	Moderate	Autosomal dominant
syndromic intellectual disability	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
syndromic intellectual disability	Definitive	AD

Mondo (9): microcephaly 18, primary, autosomal dominant (MONDO:0054593), neurodevelopmental disorder (MONDO:0700092), prostate cancer (MONDO:0008315), intellectual disability, autosomal dominant 1 (MONDO:0007974), autism spectrum disorder (MONDO:0005258), syndromic intellectual disability (MONDO:0000508), microcephaly (MONDO:0001149), esophageal atresia/tracheoesophageal fistula (MONDO:0008586), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (5): Familial prostate cancer (Orphanet:1331), 2q23.1 microdeletion syndrome (Orphanet:228402), Rare genetic syndromic intellectual disability (Orphanet:183763), Esophageal atresia (Orphanet:1199), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

4 total (4 of 4 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000252	Microcephaly
HP:0001249	Intellectual disability
HP:0001999	Abnormal facial shape

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST003073_12	Cerebral amyloid deposition (PET imaging)	3.000000e-06
GCST003073_2	Cerebral amyloid deposition (PET imaging)	1.000000e-07
GCST003859_12	Oropharynx cancer	1.000000e-06
GCST90002394_60	Monocyte percentage of white cells	4.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007707	cerebral amyloid deposition measurement
EFO:0007989	monocyte percentage of leukocytes

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D065886	Neurodevelopmental Disorders	F03.625
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
C531835	Esophageal atresia with or without tracheoesophageal fistula (supp.)
C566947	Mental Retardation, Autosomal Dominant 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects cotreatment, decreases expression	6
Benzo(a)pyrene	decreases expression, decreases methylation	3
bisphenol A	decreases methylation, affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Aflatoxin B1	increases methylation	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	decreases expression	1
manganese chloride	decreases expression, increases abundance	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
aflatoxin B2	increases methylation	1
1-nitropyrene	increases expression	1
epigallocatechin gallate	decreases expression, increases expression, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
calfactant	affects cotreatment, increases expression	1
entinostat	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
bisphenol S	decreases expression, affects cotreatment	1
jinfukang	affects cotreatment, decreases expression	1
Fulvestrant	decreases methylation	1
Vorinostat	decreases expression	1
Arsenic	affects methylation	1
Cisplatin	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy