WDFY3

Chr 4AD

WD repeat and FYVE domain containing 3

Also known as: ALFY, BCHS, MCPH18, ZFYVE25

NCBI Gene: 23001ENSG00000163625UniProt: Q8IZQ1

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]

Primary Disease Associations & Inheritance

?Microcephaly 18, primary, autosomal dominantMIM #617520
AD
631
ClinVar variants
50
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— WDFY3
🧬
Gene-Disease Validity (ClinGen)
syndromic intellectual disability · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
50 Pathogenic / Likely Pathogenic· 486 VUS of 631 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.07LOEUF
pLI 1.000
Z-score 12.10
OE 0.04 (0.02–0.07)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
5.82Z-score
OE missense 0.62 (0.59–0.65)
1176 obs / 1887.2 exp
Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.04 (0.02–0.07)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.62 (0.59–0.65)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.02
0≤1.21.6
LoF obs/exp: 7 / 184.3Missense obs/exp: 1176 / 1887.2Syn Z: -0.36

ClinVar Variant Classifications

631 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic29
Likely Pathogenic21
VUS486
Likely Benign84
Benign7
Conflicting4
29
Pathogenic
21
Likely Pathogenic
486
VUS
84
Likely Benign
7
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
7
1
21
0
29
Likely Pathogenic
7
6
8
0
21
VUS
8
454
20
4
486
Likely Benign
0
34
7
43
84
Benign
0
1
2
4
7
Conflicting
—4
Total224965851631

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

WDFY3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

WDFY3-related primary microcephaly or macrocephaly with developmental delay

strong
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Microcephaly 18, primary, autosomal dominant

MIM #617520

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
De novo genic mutations among a Chinese autism spectrum disorder cohort.
Wang T et al.·Nat Commun
2016Cohort
Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.
Guo H et al.·Mol Autism
2018Functional
Pathogenic WDFY3 variants cause neurodevelopmental disorders and opposing effects on brain size.
Le Duc D et al.·Brain
2019
The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy.
Deneubourg C et al.·Autophagy
2022
WDFY3-AS2: A Potential Prognostic Factor and Therapeutic Target Related to Cancer.
Mou J et al.·Curr Med Chem
2023Review
Targeted proteomics addresses selectivity and complexity of protein degradation by autophagy.
Leytens A et al.·Autophagy
2025
A rare genetic variant confers resistance to neurodegeneration across multiple neurological disorders by augmenting selective autophagy.
Croce KR et al.·Neuron
2025
WDFY3 Haploinsufficiency Is Associated With Autosomal Dominant Neurodevelopmental Disorders and Macrocephaly.
Graziani L et al.·Clin Genet
2025Case report
WDFY3 mutation alters laminar position and morphology of cortical neurons.
Schaaf ZA et al.·Mol Autism
2022
LncRNA WDFY3-AS2 suppresses proliferation and invasion in oesophageal squamous cell carcinoma by regulating miR-2355-5p/SOCS2 axis.
Zhang Q et al.·J Cell Mol Med
2020
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10

External Resources

Links to major genomics databases and tools