SFRP4

Chr 7AR

secreted frizzled related protein 4

Also known as: FRP-4, FRPHE, FRZB-2, PYL, sFRP-4

NCBI Gene: 6424ENSG00000106483UniProt: Q6FHJ7

Secreted frizzled-related protein 4 (SFRP4) is a member of the SFRP family that contains a cysteine-rich domain homologous to the putative Wnt-binding site of Frizzled proteins. SFRPs act as soluble modulators of Wnt signaling. The expression of SFRP4 in ventricular myocardium correlates with apoptosis related gene expression. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Pyle diseaseMIM #265900
AR
194
ClinVar variants
34
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— SFRP4
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
34 Pathogenic / Likely Pathogenic· 87 VUS of 194 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.95LOEUF
pLI 0.000
Z-score 1.72
OE 0.54 (0.33–0.95)
Tolerant

Typical tolerance to LoF variation

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.
0.05Z-score
OE missense 0.99 (0.89–1.11)
210 obs / 211.9 exp
Tolerant

Mild missense constraint

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.0.54 (0.33–0.95)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.99 (0.89–1.11)
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.0.97
0≤1.21.6
LoF obs/exp: 9 / 16.6Missense obs/exp: 210 / 211.9Syn Z: 0.19

ClinVar Variant Classifications

194 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27
Likely Pathogenic7
VUS87
Likely Benign64
Benign9
27
Pathogenic
7
Likely Pathogenic
87
VUS
64
Likely Benign
9
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
0
22
0
27
Likely Pathogenic
2
2
3
0
7
VUS
2
79
5
1
87
Likely Benign
0
2
22
40
64
Benign
0
2
1
6
9
Total9855347194

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

View in ClinVar →

Protein Context — Lollipop Plot

SFRP4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Pyle disease

MIM #265900

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Exome-wide association study identifies KDELR3 mutations in extreme myopia.
Yuan J et al.·Nat Commun
2024
Fibroblast Subpopulations in Systemic Sclerosis: Functional Implications of Individual Subpopulations and Correlations with Clinical Features.
Zhu H et al.·J Invest Dermatol
2024Functional
Secreted frizzled-related protein 4 (sFRP4) in cancer - Dual roles in tumorigenesis and therapeutic potential: A review.
Jiang Y et al.·Biomol Biomed
2025Review
Premature cell senescence promotes vascular smooth muscle cell phenotypic modulation and resistance to re-differentiation.
Kaistha A et al.·Cardiovasc Res
2025
RUNX2-related metaphyseal dysplasia with maxillary hypoplasia: A rare skeletal disorder resembling SFRP4-related Pyle disease.
Hordyjewska-Kowalczyk E et al.·Clin Genet
2024Review
PKA-Mediated Phosphorylation of SFRP4 Promotes Wnt/β-Catenin Activation and Cancer Stemness in Gastric Cancer.
Jhe YL et al.·Int J Mol Sci
2025
Identification of 10 differentially expressed genes involved in the tumorigenesis of cervical cancer via next-generation sequencing.
Xu J et al.·PeerJ
2024
SFRP4 gene expression is increased in aggressive prostate cancer.
Sandsmark E et al.·Sci Rep
2017
The adipokine sFRP4 induces insulin resistance and lipogenesis in the liver.
Hörbelt T et al.·Biochim Biophys Acta Mol Basis Dis
2019
MeCP2 attenuates inflammation and regulates T cell phenotype via SFRP4 suppression in preeclampsia.
Peng M et al.·Mol Cell Endocrinol
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools