FZD2

Chr 17AD

frizzled class receptor 2

Also known as: Fz2, OMOD2, fz-2, fzE2, hFz2

NCBI Gene: 2535 ENSG00000180340 UniProt: Q14332

This intronless 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. This gene encodes a protein that is coupled to the beta-catenin canonical signaling pathway. Competition between the wingless-type MMTV integration site family, member 3A and wingless-type MMTV integration site family, member 5A gene products for binding of this protein is thought to regulate the beta-catenin-dependent and -independent pathways. [provided by RefSeq, Dec 2010]

Primary Disease Associations & Inheritance

Omodysplasia 2MIM #164745

Active trials

Pathogenic / LP

250

ClinVar variants

Pubs (1 yr)

3.7

Missense Z· constrained

0.47

LOEUF

Clinical Summary— FZD2

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.65) — some intolerance to loss-of-function variants.

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ClinVar Variants

19 Pathogenic / Likely Pathogenic· 163 VUS of 250 total submissions

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GeneReview available — FZD2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.47LOEUF

pLI 0.653

Z-score 3.08

OE 0.18 (0.08–0.47)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

3.67Z-score

OE missense 0.46 (0.40–0.52)

165 obs / 361.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.18 (0.08–0.47)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.46 (0.40–0.52)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.82

0≤1.21.6

LoF obs/exp: 3 / 16.5Missense obs/exp: 165 / 361.1Syn Z: 1.81

0.5378th %ile

GOF

0.6832th %ile

LOF

0.4430th %ile

The highest-scoring mechanism for this gene is gain-of-function.

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.