WDFY3

Chr 4

WD repeat and FYVE domain containing 3

Also known as: ALFY, BCHS, MCPH18, ZFYVE25

NCBI Gene: 23001 ENSG00000163625 UniProt: Q8IZQ1

The protein encoded by this gene binds phosphatidylinositol 3-phosphate and functions as an adapter protein that links aggregated proteins to the autophagy machinery for selective clearance, playing an essential role in brain development including formation of axonal tracts and major forebrain commissures. Mutations cause primary microcephaly 18 with autosomal dominant inheritance. This gene is highly constrained against loss-of-function variants (pLI = 1, LOEUF = 0.071), consistent with its essential role in early brain development.

ResearchSummary from RefSeq, OMIM, UniProt

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]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.07

Clinical Summary— WDFY3

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Gene-Disease Validity (ClinGen)

syndromic intellectual disability · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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ClinVar Variants

92 unique Pathogenic / Likely Pathogenic· 755 VUS of 1084 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.04 (0.02–0.07)

0≤0.351.4

Missense OE?0.62 (0.59–0.65)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 7 / 184.3Missense obs/exp: 1176 / 1887.2Syn Z: -0.36

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongWDFY3-related primary microcephaly or macrocephaly with developmental delayLOFAD

This gene — mechanism propensity

0.2599th %ile

GOF

0.2895th %ile

LOF

0.75top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 83% of P/LP variants are LoF · LOEUF 0.07 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFConsequently, we propose that in humans WDFY3 loss-of-function variants lead to macrocephaly via downregulation of the Wnt pathway.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 31327001 ↗

ClinVar Variant Classifications

1084 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic41

Likely Pathogenic51

VUS755

Likely Benign105

Benign51

Conflicting12

Pathogenic

Likely Pathogenic

755

VUS

105

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	37	3	1	0	41
Likely Pathogenic	39	12	0	0	51
VUS	22	707	21	5	755
Likely Benign	0	48	11	46	105
Benign	0	3	40	8	51
Conflicting	—				12
Total	98	773	73	59	1,015

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

View in ClinVar →

38 pathogenic / likely-pathogenic (of 44) ClinVar copy-number / structural variants overlap WDFY3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →