FZD3

Chr 8

frizzled class receptor 3

Also known as: Fz-3

NCBI Gene: 7976 ENSG00000104290 UniProt: Q9NPG1 OMIM: 606143

The FZD3 protein is a seven-transmembrane receptor for Wnt signaling proteins that controls axon growth and guidance during development of major central nervous system fiber tracts including the corpus callosum, corticospinal tract, and thalamocortical connections, as well as peripheral motor nerves and neural tube closure. Mutations cause autosomal recessive developmental and epileptic encephalopathy with microcephaly, intellectual disability, seizures, and structural brain abnormalities including agenesis of the corpus callosum. This gene is highly intolerant to loss-of-function mutations, indicating that complete loss of protein function is likely pathogenic.

OMIM ResearchSummary from RefSeq, 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. The function of this protein is unknown, although it may play a role in mammalian hair follicle development. Alternative splicing results in multiple transcript variants. This gene is a susceptibility locus for schizophrenia. [provided by RefSeq, Dec 2010]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.62

Clinical Summary— FZD3

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 66 VUS of 82 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.62LOEUF

pLI 0.000

Z-score 3.14

OE 0.37 (0.23–0.62)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.64Z-score

OE missense 0.62 (0.56–0.69)

240 obs / 385.7 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.37 (0.23–0.62)

0≤0.351.4

Missense OE?0.62 (0.56–0.69)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 11 / 29.4Missense obs/exp: 240 / 385.7Syn Z: 0.29

This gene — mechanism propensity

0.76top 25%

GOF

0.77top 25%

LOF

0.2679th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction 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.

ClinVar Variant Classifications

82 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic1

VUS66

Likely Benign1

Benign3

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Synonymous	Total
Pathogenic	1	0	0	1
Likely Pathogenic	1	0	0	1
VUS	0	66	0	66
Likely Benign	0	1	0	1
Benign	0	0	3	3
Total	2	67	3	72

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

View in ClinVar →

73 pathogenic / likely-pathogenic (of 80) ClinVar copy-number / structural variants overlap FZD3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →