The SFRP4 gene spans 10.99 kb on the short arm of chromosome 7 and is transcribed from the minus strand in the centromere-to-telomere orientation. The gene is encoded by six exons with the translation initiation codon in the first exon.

The SFRP4 mRNA transcript is 2974 bp, 1041 bp are coding sequence. Ensembl data predicts a second transcript from the SFRP4 gene, lacking the 81 bp exon 2, although this has not been demonstrated.

SFRP4 protein is comprised of 346 amino acids with a predicted molecular weight of 39.9 kDa and an actual molecular weight of approximately 50-55 kDa.
SFRP4 belongs to a family of five SFRPs; these proteins fold into two independent domains. The N-terminus contains a secretion signal peptide followed by a ~120 amino acid cysteine-rich domain (CRD). The CRD is 30-50% identical to the extracellular putative Wnt-binding domain of frizzled (Fzd) receptors and is characterized by the presence of ten cysteine residues at conserved positions. These cysteines form a pattern of disulfide bridges. The C-terminal portion of the SFRP protein is characterized by segments of positively charged residues that appear to confer heparin-binding properties in at least two SFRPs (SFRP1 and SFRP3) and contains a netrin-related motif (NTR) with six cysteine residues that most likely form three disulfide bridges. NTR domains with similar features are found in a wide range of unrelated proteins, including Netrin-1, tissue inhibitors of metallo-proteinases (TIMPs), complement proteins and type I procollagen C-proteinase enhancer proteins (PCOLCEs). The six conserved cysteines in the NTR of SFRP4 share a similar spacing to SFRP3, whereas those of the SFRP1/SFRP2/SFRP5 subgroup are distinctively different, indicating a disparity in disulfide bond formation. Uniquely, SFRP4 contains two additional cysteine residues. The overall function of the NTR is unknown, yet there is some evidence that the NTR may also play a role in Wnt binding. This implies that multiple Wnt binding sites may exist on SFRP molecules and/or that SFRPs exhibit differential affinities for Wnt ligands according to the different SFRP conformational and post-translational modifications.

SFRP4 is expressed in various normal tissues including endometrium (specifically stromal cells with higher expression during proliferative phase of menstrual cycle), ovary, kidney, heart, brain, mammary gland, cervix, pancreas, stomach, colon, lung, skeletal muscle, testis, eye, bone, prostate, and liver.

Secreted from cell; extracellular matrix; bound to plasma membrane.

Since SFRPs share a similar CRD with the Fzd family of receptors; it is believed that SFRPs may act as soluble modulators that compete with Fzd to bind the Wnt ligands, thereby altering the Wnt signal. Individual SFRPs also have distinct binding specificity for distinct Wnt ligands. Reports have demonstrated that SFRP4 binds Wnt7a and there is conflicting data for SFRP4 binding to Wnt3a. SFRP4 expression is regulated by estrogen and progesterone and may act as a regulator of adult uterine morphology and function. SFRP4 has been shown to increase apoptosis during ovulation. Transgenic studies have found that SFRP4 decreases bone formation and inhibits osteoblast proliferation by attenuating canonical/beta-catenin-Wnt signaling. SFRP4 reportedly exhibits phosphaturic effects by specifically inhibiting sodium-dependent phosphate uptake.

Of the five human SFRPs (SFRP1, SFRP2, SFRP3, SFRP4, SFRP5), SFRP4 shares most significant homology with SFRP3.

It was reported that the T allele of the SFRP4 gene polymorphism ARG262 (CGC to CGT) of exon4 is associated with decreased bone mineral density in post-menopausal Japanese women.