FZD5

Chr 2AD

frizzled class receptor 5

Also known as: C2orf31, HFZ5, MCOPCB11

NCBI Gene: 7855 ENSG00000163251 OMIM: 601723

FZD5 encodes a 7-transmembrane domain receptor for Wnt signaling proteins that functions in the canonical Wnt/beta-catenin pathway and plays roles in synaptic formation, tissue morphogenesis, and ocular development. Mutations cause autosomal dominant coloboma with or without other eye abnormalities. The gene is highly constrained against loss-of-function variants, indicating that such mutations are likely to have significant clinical consequences.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

Members of the 'frizzled' gene family encode 7-transmembrane domain proteins that are receptors for Wnt signaling proteins. The FZD5 protein is believed to be the receptor for the Wnt5A ligand. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismADLOEUF 0.281 OMIM phenotype

Clinical Summary— FZD5

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

10 unique Pathogenic / Likely Pathogenic· 100 VUS of 140 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — FZD5

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?

0.28LOEUF

pLI 0.983

Z-score 3.56

OE 0.06 (0.02–0.28)

Highly constrained

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

Missense Constraint?

3.00Z-score

OE missense 0.57 (0.51–0.64)

222 obs / 388.1 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.06 (0.02–0.28)

0≤0.351.4

Missense OE?0.57 (0.51–0.64)

0≤0.61.4

Synonymous OE?0.84

0≤1.21.6

LoF obs/exp: 1 / 16.7Missense obs/exp: 222 / 388.1Syn Z: 1.78

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongFZD5-related colobomaDNAD

This gene — mechanism propensity

0.5181th %ile

GOF

0.6833th %ile

LOF

0.50top 25%

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.

LOF60% of P/LP variants are LoF · LOEUF 0.28

GOFprediction above median

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.

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

140 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic5

VUS100

Likely Benign13

Benign13

Conflicting2

Pathogenic

Likely Pathogenic

100

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	1	0	0	5
Likely Pathogenic	2	3	0	0	5
VUS	15	85	0	0	100
Likely Benign	0	4	0	9	13
Benign	0	3	0	10	13
Conflicting	—				2
Total	21	96	0	19	138

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

View in ClinVar →

26 pathogenic / likely-pathogenic (of 28) ClinVar copy-number / structural variants overlap FZD5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →