WDR5
Chr 9WD repeat domain 5
Also known as: BIG-3, BIG3, CFAP89, SWD3
This protein contributes to histone modification by positioning histone H3 for efficient trimethylation at lysine-4 and stimulating histone methyltransferase activities as part of the MLL1/MLL complex and NSL complex, which are essential for epigenetic transcriptional activation. Mutations cause an autosomal dominant neurodevelopmental disorder through loss-of-function mechanisms. The gene is highly intolerant to loss-of-function variants, indicating haploinsufficiency as the primary pathogenic mechanism.
Limited evidence — not for standalone diagnostic reporting
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Among the most LoF-intolerant genes (~top 3%)
Highly missense-constrained (top ~0.1%)
This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Literature Evidence
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
107 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 2 | 39 | 0 | 41 |
Likely Pathogenic | 0 | 1 | 1 | 0 | 2 |
VUS | 1 | 30 | 7 | 0 | 38 |
Likely Benign | 0 | 0 | 1 | 3 | 4 |
Benign | 0 | 0 | 0 | 0 | 0 |
Conflicting | — | 1 | |||
| Total | 1 | 33 | 48 | 3 | 86 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
WDR5 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools