FZD4

Chr 11

frizzled class receptor 4

Also known as: CD344, EVR1, FEVR, FZD4S, Fz-4, Fz4, FzE4, GPCR

NCBI Gene: 8322 ENSG00000174804 UniProt: Q9ULV1

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.

ResearchSummary from RefSeq, OMIM, UniProt

This gene is a member of the frizzled gene family. Members of this family encode seven-transmembrane domain proteins that are receptors for the Wingless type MMTV integration site family of signaling proteins. Most frizzled receptors are coupled to the beta-catenin canonical signaling pathway. This protein may play a role as a positive regulator of the Wingless type MMTV integration site signaling pathway. A transcript variant retaining intronic sequence and encoding a shorter isoform has been described, however, its expression is not supported by other experimental evidence. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtVitreoretinopathy, exudative 1

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · FZD4-related exudative vitreoretinopathy · AD · ClinGen 2024

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.31

LOEUF· LoF intol.

LOF

Mechanism· G2P

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.31LOEUF

pLI 0.970

Z-score 3.38

OE 0.07 (0.02–0.31)

Highly constrained

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

Missense Constraint?

0.73Z-score

OE missense 0.88 (0.79–0.97)

255 obs / 290.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.07 (0.02–0.31)

0≤0.351.4

Missense OE?0.88 (0.79–0.97)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 1 / 15.2Missense obs/exp: 255 / 290.1Syn Z: -0.57

Background carrier burden — how many people carry a rare variant somewhere in FZD4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 96

637 rare PASS variants

Rare truncating (LoF)

1 in 5,200

51 rare PASS variants

Rare synonymous (reference)

1 in 230

271 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FZD4. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 130	1 in 5,200
South Asian	~43k	1 in 150	≈ 1 in 10,000
Remaining (unassigned)	~30k	1 in 110	≈ 1 in 7,500
European (Finnish)	~27k	1 in 220	1 in 2,200
Admixed American	~22k	1 in 110	≈ 1 in 22,000
African / African American	~21k	1 in 99	1 in 2,500
East Asian	~20k	1 in 120	≈ 1 in 6,600
Ashkenazi Jewish	~13k	1 in 350	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 160	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 2 coding exons well covered in gnomAD exomes and genomes.? see exons ↓