FZD7

Chr 2

frizzled class receptor 7

Also known as: FzE3

NCBI Gene: 8324 ENSG00000155760 UniProt: O75084 OMIM: 603410

The FZD7 protein is a seven-transmembrane receptor for Wnt signaling proteins that activates the canonical beta-catenin pathway and non-canonical Wnt responses involved in cell polarity and tissue morphogenesis. Mutations cause autosomal recessive retinal dystrophy, with patients developing progressive vision loss typically beginning in childhood. FZD7 is moderately constrained against loss-of-function variants, reflecting its important role in retinal development and maintenance.

OMIM ResearchSummary from RefSeq, UniProt

Members of the 'frizzled' gene family encode 7-transmembrane domain proteins that are receptors for Wnt signaling proteins. The FZD7 protein contains an N-terminal signal sequence, 10 cysteine residues typical of the cysteine-rich extracellular domain of Fz family members, 7 putative transmembrane domains, and an intracellular C-terminal tail with a PDZ domain-binding motif. FZD7 gene expression may downregulate APC function and enhance beta-catenin-mediated signals in poorly differentiated human esophageal carcinomas. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.61

Clinical Summary— FZD7

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.29) despite low pLI — interpret in context.

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ClinVar Variants

60 VUS of 63 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.61LOEUF

pLI 0.088

Z-score 2.75

OE 0.29 (0.15–0.61)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.03Z-score

OE missense 0.70 (0.63–0.78)

257 obs / 366.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.29 (0.15–0.61)

0≤0.351.4

Missense OE?0.70 (0.63–0.78)

0≤0.61.4

Synonymous OE?1.21

0≤1.21.6

LoF obs/exp: 5 / 17.4Missense obs/exp: 257 / 366.5Syn Z: -2.14

This gene — mechanism propensity

0.7229th %ile

GOF

0.78top 25%

LOF

0.2484th %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

63 submitted variants in ClinVar

ClinVar

Classification Summary

VUS60

Likely Benign1

Benign2

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	60	0	60
Likely Benign	0	1	1
Benign	1	1	2
Total	61	2	63

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

View in ClinVar →

31 pathogenic / likely-pathogenic (of 34) ClinVar copy-number / structural variants overlap FZD7 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →