WDFY3

protein-coding

WD repeat and FYVE domain containing 3, the group of Armadillo like helical domain containing|BEACH domain containing |Zinc fingers FYVE-type|WD repeat domain containing

Gene summary

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. [provided by RefSeq, May 2010]

MANE transcript

NM_014991.6

Inheritance

ClinVar variants

P:109U:855B:143

Top phenotype

Microcephaly 18, primary, autosomal dominant

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr4:84,668,765-84,966,690

External References & Databases

Ensembl (ENSG00000163625)

Transcript & Mutation Effects

hg38 • Region Span ~297.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

microcephaly 18, primary, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0054593

Submitter: PanelApp Australia

autism spectrum disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0005258

Submitter: Ambry Genetics

syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: ClinGen

The *WDFY3* gene encodes a large multidomain scaffolding protein implicated in the selective degradation of ubiquitinated protein aggregates by autophagy. A *WDFY3* missense variant in the PH domain of the protein was reported in 2016 in a large family with autosomal dominant microcephaly and mild to moderate intellectual disability (Kadir et al., PMID: 27008544). Since then, several mostly *de novo* variants in *WDFY3* have been reported, including nonsense, frameshift, splice, and missense variants. Affected individuals present with developmental delay, intellectual disability, autism spectrum disorder, hypotonia, seizures, and abnormal head size, either microcephaly or macrocephaly (PMIDs: 27824329, 28263302, 30564305, 31130284, 31327001). It has been suggested that *WDFY3* haploinsufficiency leads to macrocephaly or large-normal head size, while missense variants in the PH domain of WDFY3 cause microcephaly (two such variants reported) through opposing effects on the Wnt pathway (PMID: 31327001). Although this hypothesis appears to be supported by a transgenic fly model overexpressing a human *WDFY3* mutant (PMID: 27008544) and several *Wdfy3* loss-of-function mouse models (PMID: 25198012, 27648578, 31327001), further evidence is needed to clarify the effect of *WDFY3* variants on head size and the mechanisms involved. In summary, there is definitive evidence supporting the relationship between *WDFY3* and autosomal dominant syndromic intellectual disability. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on January 19, 2022 (SOP Version 8). Data provided by the ClinGen Prenatal GCEP from April 8, 2025 secondary analysis: There is no clear evidence for prenatal phenotypes in WDFY3-syndromic intellectual disability at the time of this curation. The only reported prenatal phenotype is hypoplastic left heart found in a fetus with a de novo WDFY3 frameshift variant (PMID: 33898534). No cases with fetal hydrops have been reported.

complex neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

microcephaly 18, primary, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0054593

Submitter: G2P

neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: Orphanet

Clinical Genomic Database (CGD)

Microcephaly 18, primary, autosomal dominantAD

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 27008544

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to WDFY3 variants in ClinVar

20 Conditions Cataloged

not providedTotal: 626

Inborn genetic diseasesTotal: 321

Microcephaly 18, primary, autosomal dominantTotal: 99

not specifiedTotal: 92

WDFY3-related disorderTotal: 87

Neurodevelopmental delayTotal: 13

Neurodevelopmental disorderTotal: 11

See casesTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014991.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			13 clinvar	79 clinvar	3 clinvar	95
missense	3 clinvar	13 clinvar	803 clinvar	58 clinvar	3 clinvar	880
nonsense	19 clinvar	25 clinvar	8 clinvar			52
start loss						0
frameshift	12 clinvar	25 clinvar	10 clinvar			47
splice donor/acceptor (+/-2bp)	3 clinvar	9 clinvar	21 clinvar			33
Total	37	72	855	137	6	1107

Highest pathogenic variant AF is 0.000006568921

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 36 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014991.6	RefSeq	NP_055806.2	65	MANE Select
ENST00000295888.9	Ensembl	ENSP00000295888.4	65	MANE Select
ENST00000502713.1	Ensembl	ENSP00000422741.1	1	Standard
ENST00000509172.1	Ensembl	ENSP00000425699.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

multicellular organism development
aggrephagy

Molecular Function

beta-N-acetylglucosaminylglycopeptide beta-1,4-galactosyltransferase activity
protein binding
1-phosphatidylinositol binding
metal ion binding

Cellular Component

nucleus
nuclear envelope
nucleolus
cytoplasm
autophagosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000295888
Coding exons: 65
Length: 296841
Individuals with no LoFs: 125727
Homozygous LoFs: 0
Heterozygous LoFs: 21
Defined: 125748
p: 0.0000835

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	5.82	1176	1.89e+3	0.623	0.000101	23100
Missense (PolyPhen)		183	467.77	0.39122		5820
Synonymous	-0.358	708	696	1.02	0.0000384	6866
Loss of Function	12.1	7	184	0.0380	0.0000104	2146

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00012	0.00012	rare
South Asian	0.00010	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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 (PubMed:20417604). 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 (PubMed:20168092). 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 (By similarity). 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 (PubMed:27008544). May regulate osteoclastogenesis by acting on the TNFSF11/RANKL - TRAF6 pathway (By similarity). After cytokinetic abscission, involved in midbody remnant degradation (PubMed:24128730). In vitro strongly binds to phosphatidylinositol 3-phosphate (PtdIns3P) (PubMed:15292400). {ECO:0000250|UniProtKB:Q6VNB8, ECO:0000269|PubMed:15292400, ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:20417604, ECO:0000269|PubMed:24128730, ECO:0000269|PubMed:27008544}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:27008544}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.114

Intolerance Scores

LoFtool: 0.279
RVIS EVS: -2.82
RVIS percentile EVS: 0.63

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.224

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium