FZD4
Chr 11ADfrizzled class receptor 4
Also known as: CD344, EVR1, FEVR, FZD4S, Fz-4, Fz4, FzE4, GPCR
FZD4 encodes a seven-transmembrane receptor for Wnt proteins and norrin that activates beta-catenin signaling and plays a critical role in retinal vascularization. Mutations cause exudative vitreoretinopathy and retinopathy of prematurity with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants, indicating strong selective pressure for normal protein function.
Definitive — sufficient evidence for diagnostic panels
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Mild missense constraint
This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
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
475 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 | 42 | 9 | 14 | 0 | 65 |
Likely Pathogenic | 6 | 9 | 1 | 0 | 16 |
VUS | 3 | 218 | 32 | 0 | 253 |
Likely Benign | 0 | 6 | 10 | 81 | 97 |
Benign | 0 | 0 | 29 | 2 | 31 |
Conflicting | — | 9 | |||
| Total | 51 | 242 | 86 | 83 | 471 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
FZD4 · 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