WDR45

Chr XXLD

WD repeat domain 45

Also known as: JM5, NBIA4, NBIA5, WDRX1, WIPI-4, WIPI4

NCBI Gene: 11152ENSG00000196998UniProt: Q9Y484OMIM: 300526

The encoded protein binds phosphatidylinositol 3-phosphate and controls autophagosome assembly and size regulation, working downstream of WIPI2 and promoting ATG2-mediated lipid transfer in the autophagy pathway. Loss-of-function mutations cause neurodegeneration with brain iron accumulation 5 (NBIA5), which follows X-linked dominant inheritance and predominantly affects females due to male lethality. The gene is highly constrained against loss-of-function variants, consistent with pathogenicity through haploinsufficiency.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
LOFmechanismXLDLOEUF 0.211 OMIM phenotype
Clinical Summary— WDR45
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Gene-Disease Validity (ClinGen)
X-linked complex neurodevelopmental disorder · XLDefinitive

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 0.99). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
102 unique Pathogenic / Likely Pathogenic· 65 VUS of 300 total submissions
Explore recent and relevant literature in Research Assistant →
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GeneReview available — WDR45
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.21LOEUF
pLI 0.991
Z-score 3.50
OE 0.00 (0.00–0.21)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
2.02Z-score
OE missense 0.56 (0.47–0.66)
92 obs / 164.8 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.00 (0.00–0.21)
0≤0.351.4
Missense OE0.56 (0.47–0.66)
0≤0.61.4
Synonymous OE0.72
0≤1.21.6
LoF obs/exp: 0 / 14.3Missense obs/exp: 92 / 164.8Syn Z: 1.78
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveWDR45-related neurodegeneration with brain iron accumulationLOFmonoallelic_X_heterozygous
DN
0.3097th %ile
GOF
0.3292th %ile
LOF
0.77top 5%

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

LOFprediction above median · 68% of P/LP variants are LoF · LOEUF 0.21

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

ClinVar Variant Classifications

300 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic77
Likely Pathogenic25
VUS65
Likely Benign81
Benign13
Conflicting12
77
Pathogenic
25
Likely Pathogenic
65
VUS
81
Likely Benign
13
Benign
12
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
58
1
18
0
77
Likely Pathogenic
11
11
3
0
25
VUS
1
54
8
2
65
Likely Benign
0
17
39
25
81
Benign
0
0
10
3
13
Conflicting
—12
Total70837830273

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

View in ClinVar →

Protein Context — Lollipop Plot

WDR45 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Generation of six hiPSC lines from patients with WDR45-related neurodegenerative disease (Beta-propeller Protein-Associated Neurodegeneration, BPAN).
Tournois J et al.·Stem Cell Res
2026Cohort
Generation of two human iPSC lines from fibroblasts of BPAN patients carrying pathogenic variants in the WDR45 gene.
Gasparini G et al.·Stem Cell Res
2026Cohort
Generation of two induced pluripotent stem cell lines (FDCHi011-A and FDCHi016-A) from different patients with NBIA5 syndrome carrying WDR45 m.700C > T and m.888G > A mutation.
Yin T et al.·Stem Cell Res
2025Cohort
WDR45 deficiency shortens axon length in dopaminergic neurons from patient-derived iPSCs.
Huang N et al.·Hum Mol Genet
2025
β-propeller protein-associated neurodegeneration protein WDR45 regulates stress granule disassembly via phase separation with Caprin-1.
Li Y et al.·Nat Commun
2025Open Access
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients