SFRP4

Summary

SFRP4 (secreted frizzled related protein 4, HGNC:10778) is a protein-coding gene on chromosome 7p14.1, encoding Secreted frizzled-related protein 4 (Q6FHJ7). Soluble frizzled-related proteins (sFRPS) function as modulators of Wnt signaling through direct interaction with Wnts.

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.

Source: NCBI Gene 6424 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Pyle disease (Strong, GenCC)
• GWAS associations: 9
• Clinical variants (ClinVar): 178 total — 12 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 34
• MANE Select transcript: NM_003014

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10778
Approved symbol	SFRP4
Name	secreted frizzled related protein 4
Location	7p14.1
Locus type	gene with protein product
Status	Approved
Aliases	frpHE, FRP-4, FRPHE, FRZB-2
Ensembl gene	ENSG00000106483
Ensembl biotype	protein_coding
OMIM	606570
Entrez	6424

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 retained_intron

ENST00000436072, ENST00000447200, ENST00000478975, ENST00000881887, ENST00000960683, ENST00000960684

RefSeq mRNA: 1 — MANE Select: NM_003014 NM_003014

CCDS: CCDS5453

Canonical transcript exons

ENST00000436072 — 6 exons

Exon	Start	End
ENSE00000678500	37909617	37909680
ENSE00000678504	37912119	37912317
ENSE00000678507	37914213	37914278
ENSE00000678509	37914373	37914453
ENSE00001870633	37905932	37907664
ENSE00001952939	37916093	37916817

Expression profiles

Bgee: expression breadth ubiquitous, 221 present calls, max score 99.32.

FANTOM5 (CAGE): breadth broad, TPM avg 13.4334 / max 1000.1617, expressed in 540 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
83653	13.4334	540

Top tissues by expression

281 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	99.32	gold quality
endocervix	UBERON:0000458	98.81	gold quality
ectocervix	UBERON:0012249	97.59	gold quality
vena cava	UBERON:0004087	96.69	gold quality
tibial nerve	UBERON:0001323	96.68	gold quality
dorsal root ganglion	UBERON:0000044	96.65	gold quality
calcaneal tendon	UBERON:0003701	96.24	gold quality
right ovary	UBERON:0002118	95.99	gold quality
left ovary	UBERON:0002119	95.39	gold quality
adult organism	UBERON:0007023	95.24	gold quality
smooth muscle tissue	UBERON:0001135	94.58	gold quality
left uterine tube	UBERON:0001303	94.55	gold quality
endometrium	UBERON:0001295	94.06	gold quality
trigeminal ganglion	UBERON:0001675	93.92	gold quality
ascending aorta	UBERON:0001496	93.28	gold quality
uterus	UBERON:0000995	93.24	gold quality
body of uterus	UBERON:0009853	93.24	gold quality
thoracic aorta	UBERON:0001515	93.19	gold quality
mammary duct	UBERON:0001765	92.97	gold quality
uterine cervix	UBERON:0000002	92.83	gold quality
mammalian vulva	UBERON:0000997	92.25	gold quality
parietal pleura	UBERON:0002400	92.22	gold quality
aorta	UBERON:0000947	92.15	gold quality
myometrium	UBERON:0001296	92.09	gold quality
saphenous vein	UBERON:0007318	91.83	gold quality
pleura	UBERON:0000977	91.56	gold quality
popliteal artery	UBERON:0002250	91.49	gold quality
tibial artery	UBERON:0007610	91.47	gold quality
vagina	UBERON:0000996	91.46	gold quality
skin of hip	UBERON:0001554	91.43	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-MTAB-9841	yes	12648.61
E-MTAB-10287	yes	11998.39
E-CURD-126	yes	2134.96
E-GEOD-135922	yes	51.54
E-GEOD-134144	yes	31.66
E-CURD-112	yes	4.55
E-MTAB-9543	no	1.22
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPB, CTNNB1, DNMT3B, GATA1, STAT3

miRNA regulators (miRDB)

70 targeting SFRP4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-8084	99.73	69.57	1760
HSA-MIR-548M	99.70	68.87	1749
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-519A-3P	99.67	71.67	1868
HSA-MIR-519B-3P	99.67	71.67	1868
HSA-MIR-519C-3P	99.67	71.67	1870
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-5700	99.64	69.88	2280
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-4753-5P	99.54	68.51	1356
HSA-MIR-5571-5P	99.49	66.99	1764
HSA-MIR-4696	99.48	67.48	1040
HSA-MIR-657	99.48	66.02	848
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-4762-3P	99.43	69.72	2363

Literature-anchored findings (GeneRIF, showing 40)

• sFRP-4 displays phosphatonin-like properties. (PMID:12952927)
• lack of secreted frizzled-related protein 4 leads to progression of prostate cancer (PMID:14760084)
• Methylation silencing of SFRP4 may play an important role in aberrant Wnt activation in mesothelioma even in the absence of beta-catenin (PMID:15705870)
• sFRP-4 increases renal P(i) excretion by reducing Na(+)-P(i)-IIa transporter abundance in the brush border of the proximal tubule through enhanced internalization of the protein. (PMID:16151791)
• In contrast to other sFRP family members, sFRP-4 expression appears to be upregulated in colorectal carcinoma (PMID:16356838)
• The SFRP4 protein gene plays an important role in the pathogenesis of bladder tumor and can be detected using cellular DNA extracted from urine samples. (PMID:16609023)
• sFRP4 is an inhibitor of prostate cancer growth and invasion in vitro independent of androgen receptor (AR) signaling. (PMID:17476687)
• Reduced tumor expression of Wnt inhibitory factor-1 (WIF1), sFRP2, and sFRP4 mRNA was confirmed in all pituitary tumors. (PMID:18079202)
• Hypermethylation and aberrant expression of SFRP genes are common in pancreatic cancer, which may be involved in pancreatic carcinogenesis. (PMID:18528941)
• Ectopic expression of SFRPs downregulated T-cell factor transcriptional activity in liver cancer cells, while overexpression of a beta-catenin mutant and depletion of SFRP1 using siRNA synergistically upregulated TCF/LEF transcriptional activity. (PMID:18592156)
• These data suggest sFRP4 promotes epidermal differentiation. (PMID:18938133)
• sFRP4 may be a potential biomarker for monitoring the progression of ADPKD. (PMID:18945944)
• Dkk1 and sFRP4 perform an important function in adipogenesis in human adipose tissue-derived mesenchymal stem cells. (PMID:19040566)
• sFRP4 has a role in placental development and implantation, and may be an important factor in the development of the decidual fibrinoid zone, and in trophoblast apoptosis and a band of apoptosis in the underlying decidua deep into the trophoblast. (PMID:19146776)
• In multiple myeloma cell lines, aberrant promoter hypermethylation of the secreted Frizzled-related protein genes was a common event. The frequency of aberrant methylation of SFRP4 was 1.3% (PMID:19299079)
• Elevated SFRP4 expression in serous ovarian tumours appears to correlate with reduced beta-catenin expression but long-term survival appears unaffected by this. (PMID:19480240)
• SFRP1 and SFRP4 appear to be candidate markers for colorectal carcinoma. Unlike SFRP1 as a negative regulator for CRC carcinogenesis, SFRP4 may play quite different biological role in CRC. (PMID:19730886)
• Methylation and unmethylation of SFRP4 were both detected in CA46, HL60 and U937 cell lines. (PMID:20030932)
• SFRP4 promoter methylation is aberrant in mesothelioma. (PMID:20596629)
• the secreted frizzled-related protein (sFRP4) c1019G>A polymorphism may be one of the genetic factors affecting lumbar spine Bone minera density in postmenopausal Korean women. Risk AA genotype was 6.39 times higher than GG (PMID:20613673)
• This study suggests that a cause of catenin delocalization in oral cancer could be due to WNT pathway activation, by epigenetic alterations of SFRP-1, SFRP-2, SFRP-4, SFRP-5, WIF-1, DKK-3 genes (PMID:20811686)
• sFRP4 is expressed in human GCs and its expression declines during late antral follicular growth (PMID:21307090)
• results indicate that the coding regions of INHBA, SFRP4 and HOXA10 do not harbour mutations responsible for linkage to endometriosis in the families studied (PMID:21576276)
• Data show that decidualization was associated with increased expression of 428 genes including SCARA5 (181-fold), DKK1 (71-fold) and PROK1 (32-fold), and decreased expression of 230 genes including MMP-7 (35-fold) and SFRP4 (21-fold). (PMID:21858178)
• These results support a role for SFRP4 as a tumor suppressor gene in ovarian cancers. (PMID:22363760)
• genetic variation in sFRP4 has an influence on hip fracture risk, percentage body fat and height in a Danish male population. However, we were unable to replicate these results in an independent Belgian population. (PMID:22608881)
• haplotype genotypes of secreted frizzled-related protein 4 (sFRP4) c.958C>A and c.1019G>A polymorphisms are genetic factors that affect changes in bone mineral density of the femoral neck after hormone therapy in postmenopausal Korean women (PMID:22668815)
• sFRP4’s cysteine-rich domain was seen to inhibit tube formation of endothelial cells. In addition, the netrin-like domain promoted endothelial cell death and may also inhibit angiogenesis. (PMID:23035359)
• SFRP4 caused reduced glucose tolerance through decreased islet expression of Ca(2+) channels and suppressed insulin exocytosis. (PMID:23140642)
• Decreased placental expression of Wnt2 and increased placental expression of sFRP4 may be associated with the pathogenesis of severe preeclampsia. (PMID:23322712)
• This raises the possibility that SFRP4 may be used both diagnostically and therapeutically in epithelial ovarian cancer. (PMID:23326605)
• Our results suggest that the sFRP3 c.970C>G and sFRP4 c.958C>A polymorphisms may be genetic factors associated with the prevalence of osteoporosis at the femoral neck in postmenopausal Korean women. (PMID:24662300)
• High SFRP4 gene methylation is associated with ovarian cancer infected with high risk human papillomavirus. (PMID:24761891)
• ZAR1 and SFRP4 qMSP could be used as potential biomarker for CC diagnosis (PMID:24787227)
• sFRP4 expression is inversely related to the aggressiveness of pituitary adenomas, and acts as a tumor suppressor. (PMID:24917361)
• total of three potential inhibitors of SFRP4 were found, namely cyclothiazide, clopamide and perindopril. These inhibitors showed significant interactions with SFRP4 as compared to other inhibitors as well as control (acetohexamide). (PMID:25019556)
• Serum WISP2 correlated directly with fatty acid binding protein 4. Serum SFRP5 did not differ between obese (n=32) vs. nonobese (n=25) PCOS women, but reference women had lower SFRP5 (p<5x10(-6) as compared to both PCOS groups). (PMID:25089371)
• Aberrant methylation of APC gene was statistically significant associated with age over 50, DDK3 with male, SFRP4, WIF1, and WNT5a with increasing tumor stage SFRP4 and WIF1 with tumor differentiation and SFRP2 and SFRP5 with histological type (PMID:25107489)
• Abdominal adipose tissue is a major contributor for circulating-SFRP4; SFRP4 has an important role in obese adipose tissue pathophysiology. (PMID:25322919)
• SFRP4 concentrations are associated with impaired glucose and triglyceride metabolism (PMID:25408147)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
mus_musculus	Sfrp4	ENSMUSG00000021319
rattus_norvegicus	Sfrp4	ENSRNOG00000054957
drosophila_melanogaster	fz2	FBGN0016797
drosophila_melanogaster	fz3	FBGN0027343
caenorhabditis_elegans		WBGENE00000478
caenorhabditis_elegans		WBGENE00022242

Paralogs (15): FZD3 (ENSG00000104290), SFRP1 (ENSG00000104332), FZD10 (ENSG00000111432), SFRP5 (ENSG00000120057), SMO (ENSG00000128602), SFRP2 (ENSG00000145423), FZD7 (ENSG00000155760), FZD1 (ENSG00000157240), FRZB (ENSG00000162998), FZD5 (ENSG00000163251), FZD6 (ENSG00000164930), FZD4 (ENSG00000174804), FZD8 (ENSG00000177283), FZD2 (ENSG00000180340), FZD9 (ENSG00000188763)

Protein

Protein identifiers

Secreted frizzled-related protein 4 — Q6FHJ7 (reviewed: Q6FHJ7)

Alternative names: Frizzled protein, human endometrium

All UniProt accessions (2): Q6FHJ7, C9JMJ2

UniProt curated annotations — full annotation on UniProt →

Function. Soluble frizzled-related proteins (sFRPS) function as modulators of Wnt signaling through direct interaction with Wnts. They have a role in regulating cell growth and differentiation in specific cell types. SFRP4 plays a role in bone morphogenesis. May also act as a regulator of adult uterine morphology and function. May also increase apoptosis during ovulation possibly through modulation of FZ1/FZ4/WNT4 signaling. Has phosphaturic effects by specifically inhibiting sodium-dependent phosphate uptake.

Subcellular location. Secreted.

Tissue specificity. Expressed in mesenchymal cells. Highly expressed in the stroma of proliferative endometrium. Expressed in cardiomyocytes. Shows moderate to strong expression in ovarian tumors with expression increasing as the tumor stage increases. In ovarian tumors, expression levels are inversely correlated with expression of CTNNB1 (at protein level).

Disease relevance. Pyle disease (PYL) [MIM:265900] A disorder characterized by cortical-bone thinning, limb deformity, bone fragility and fractures. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The FZ domain is involved in binding with Wnt ligands.

Induction. Increased levels in failing myocardium. Up-regulated in several tumor types including ostomalacia-associated tumors and endometrial and breast carcinomas.

Similarity. Belongs to the secreted frizzled-related protein (sFRP) family.

RefSeq proteins (1): NP_003005* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001134	Netrin_domain	Domain
IPR008993	TIMP-like_OB-fold	Homologous_superfamily
IPR015526	Frizzled/SFRP	Family
IPR018933	Netrin_module_non-TIMP	Domain
IPR020067	Frizzled_dom	Domain
IPR036790	Frizzled_dom_sf	Homologous_superfamily

Pfam: PF01392, PF01759

UniProt features (23 total): glycosylation site 5, disulfide bond 5, sequence conflict 3, compositionally biased region 3, sequence variant 2, domain 2, signal peptide 1, chain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6FHJ7-F1	78.60	0.41

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (5): 24–85, 32–78, 69–108, 97–136, 101–125

Glycosylation sites (5): 116, 194, 240, 38, 68

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 298 (showing top): GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_EPITHELIAL_CELL_APOPTOTIC_PROCESS, BENPORATH_ES_WITH_H3K27ME3, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, MCLACHLAN_DENTAL_CARIES_UP, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_EPIDERMIS_DEVELOPMENT, GOBP_NON_CANONICAL_WNT_SIGNALING_PATHWAY, MODULE_64, GOBP_REGULATION_OF_NON_CANONICAL_WNT_SIGNALING_PATHWAY, GOCC_CELL_SURFACE, GOBP_INORGANIC_ANION_TRANSPORT, SMID_BREAST_CANCER_RELAPSE_IN_LUNG_DN

GO Biological Process (22): negative regulation of transcription by RNA polymerase II (GO:0000122), positive regulation of receptor internalization (GO:0002092), negative regulation of cell population proliferation (GO:0008285), response to hormone (GO:0009725), positive regulation of gene expression (GO:0010628), cell differentiation (GO:0030154), negative regulation of Wnt signaling pathway (GO:0030178), regulation of BMP signaling pathway (GO:0030510), non-canonical Wnt signaling pathway (GO:0035567), positive regulation of apoptotic process (GO:0043065), positive regulation of epidermal cell differentiation (GO:0045606), phosphate ion homeostasis (GO:0055062), canonical Wnt signaling pathway (GO:0060070), bone morphogenesis (GO:0060349), negative regulation of canonical Wnt signaling pathway (GO:0090090), positive regulation of canonical Wnt signaling pathway (GO:0090263), positive regulation of keratinocyte apoptotic process (GO:1902174), negative regulation of non-canonical Wnt signaling pathway (GO:2000051), negative regulation of sodium-dependent phosphate transport (GO:2000119), skeletal system development (GO:0001501), animal organ morphogenesis (GO:0009887), Wnt signaling pathway (GO:0016055)

GO Molecular Function (2): Wnt-protein binding (GO:0017147), protein binding (GO:0005515)

GO Cellular Component (5): obsolete extracellular space (GO:0005615), nucleus (GO:0005634), cytoplasm (GO:0005737), cell surface (GO:0009986), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
Wnt signaling pathway	3
cellular anatomical structure	3
negative regulation of Wnt signaling pathway	2
canonical Wnt signaling pathway	2
regulation of canonical Wnt signaling pathway	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
regulation of receptor internalization	1
receptor internalization	1
positive regulation of receptor-mediated endocytosis	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
response to endogenous stimulus	1
response to chemical	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
cellular developmental process	1
negative regulation of signal transduction	1
regulation of Wnt signaling pathway	1
BMP signaling pathway	1
regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
regulation of cellular response to growth factor stimulus	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
epidermal cell differentiation	1
positive regulation of epithelial cell differentiation	1
regulation of epidermal cell differentiation	1
positive regulation of epidermis development	1
inorganic ion homeostasis	1
animal organ morphogenesis	1
skeletal system morphogenesis	1
bone development	1
positive regulation of Wnt signaling pathway	1
keratinocyte apoptotic process	1
regulation of keratinocyte apoptotic process	1
positive regulation of epithelial cell apoptotic process	1

Protein interactions and networks

STRING

1900 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SFRP4	PDP1	Q9P0J1	837
SFRP4	MEPE	Q9NQ76	770
SFRP4	CTNNB1	P35222	768
SFRP4	WNT3A	P56704	759
SFRP4	SNRK	Q9NRH2	720
SFRP4	LRP5	O75197	713
SFRP4	WNT4	P56705	712
SFRP4	DKK3	Q9UBP4	698
SFRP4	ZNF346	Q9UL40	696
SFRP4	LRP6	O75581	681
SFRP4	DKK1	O94907	680
SFRP4	SOST	Q9BQB4	678
SFRP4	WNT7A	O00755	674
SFRP4	WIF1	Q9Y5W5	672
SFRP4	WNT1	P04628	667

IntAct

37 interactions, top by confidence:

A	B	Type	Score
SFRP4	AQP6	psi-mi:“MI:0915”(physical association)	0.560
SFRP4	HSD17B11	psi-mi:“MI:0915”(physical association)	0.560
AQP6	SFRP4	psi-mi:“MI:0915”(physical association)	0.560
SFRP4	JPH3	psi-mi:“MI:0915”(physical association)	0.560
SFRP4	H2BC20P	psi-mi:“MI:0915”(physical association)	0.400
SFRP4	H2BC21	psi-mi:“MI:0915”(physical association)	0.400
AP2M1	SFRP4	psi-mi:“MI:0915”(physical association)	0.370
CKMT1A	SFRP4	psi-mi:“MI:0915”(physical association)	0.370
NARF	SFRP4	psi-mi:“MI:0915”(physical association)	0.370
SFRP4	PFKM	psi-mi:“MI:0915”(physical association)	0.370
AURKA	SFRP4	psi-mi:“MI:0915”(physical association)	0.370
SFRP4	BMPR1A	psi-mi:“MI:0915”(physical association)	0.370
SFRP4	BUB1	psi-mi:“MI:0915”(physical association)	0.370
SFRP4	CDKN2A	psi-mi:“MI:0915”(physical association)	0.370
SFRP4	CTNNA1	psi-mi:“MI:0915”(physical association)	0.370
DLC1	SFRP4	psi-mi:“MI:0915”(physical association)	0.370
ERBB2	SFRP4	psi-mi:“MI:0915”(physical association)	0.370
MCC	SFRP4	psi-mi:“MI:0915”(physical association)	0.370
NRAS	SFRP4	psi-mi:“MI:0915”(physical association)	0.370
SFRP4	PDGFRL	psi-mi:“MI:0915”(physical association)	0.370
SFRP4	PIK3CA	psi-mi:“MI:0915”(physical association)	0.370
SFRP4	PMS2	psi-mi:“MI:0915”(physical association)	0.370
PTPN12	SFRP4	psi-mi:“MI:0915”(physical association)	0.370
SFRP4	PTPRJ	psi-mi:“MI:0915”(physical association)	0.370
SFRP4	SMAD4	psi-mi:“MI:0915”(physical association)	0.370
SFRP4		psi-mi:“MI:0915”(physical association)	0.370
SFRP4	ANKRD17	psi-mi:“MI:0914”(association)	0.350

BioGRID (65): ANKHD1 (Affinity Capture-MS), ANKRD17 (Affinity Capture-MS), AKAP11 (Affinity Capture-MS), PASK (Affinity Capture-MS), PPP2R3A (Affinity Capture-MS), DICER1 (Affinity Capture-MS), FBN2 (Affinity Capture-MS), TUBB1 (Affinity Capture-MS), SIRT1 (Affinity Capture-MS), UBE2O (Affinity Capture-MS), PRKAR1B (Affinity Capture-MS), DCAF16 (Affinity Capture-MS), KBTBD7 (Affinity Capture-MS), B3GALNT2 (Affinity Capture-MS), FBLN1 (Affinity Capture-MS)

ESM2 similar proteins: A0A2D0TC04, A1A4K5, A7E2Z9, A8MWY0, F1QR43, J3SBP3, J3SEZ3, O14638, O15041, O18756, O94923, O95461, P06802, P0DQQ4, P15396, P22413, P79948, P97675, Q13219, Q13822, Q3UZV7, Q5M900, Q5NDE3, Q5NDE4, Q5NDE5, Q5NDE8, Q5R5M5, Q64610, Q66PG1, Q66PG2, Q66PG3, Q6DYE8, Q6FHJ7, Q6GMK0, Q6NRQ1, Q6P9A2, Q8C1F4, Q8JHF2, Q8K1B9, Q8N6G5

Diamond homologs: A0A0K3AWM6, B3DIG4, G5ECQ2, O00144, O19116, O42579, O57328, O57329, O60353, O70421, O75084, O93274, P18537, P58421, P97299, P97401, Q08463, Q08464, Q13467, Q14332, Q24760, Q498S8, Q5BL72, Q5RCN4, Q5RF67, Q5T4F7, Q61086, Q61088, Q61089, Q61090, Q61091, Q6FHJ7, Q7YRN1, Q80YN4, Q863H1, Q8AVJ9, Q8BKG4, Q8C4U3, Q8CHL0, Q8K4C8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

178 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	4
Uncertain significance	83
Likely benign	64
Benign	9

Top pathogenic / likely-pathogenic (16)

Variant ID	HGVS	Classification
1367322	NM_003014.4(SFRP4):c.73G>T (p.Glu25Ter)	Pathogenic
1424941	NM_003014.4(SFRP4):c.617del (p.Val206fs)	Pathogenic
1983442	NM_003014.4(SFRP4):c.184G>T (p.Glu62Ter)	Pathogenic
242995	NM_003014.4(SFRP4):c.499dup (p.Asp167fs)	Pathogenic
242996	NM_003014.3(SFRP4):c.694C>T	Pathogenic
242997	NM_003014.4(SFRP4):c.481_487del (p.Val161fs)	Pathogenic
2970935	NM_003014.4(SFRP4):c.72C>A (p.Cys24Ter)	Pathogenic
3621877	NM_003014.4(SFRP4):c.180_182dup (p.Tyr61Ter)	Pathogenic
3686505	NM_003014.4(SFRP4):c.111del (p.Pro36_Trp37insTer)	Pathogenic
3893232	NM_003014.4(SFRP4):c.433del (p.Asp145fs)	Pathogenic
4720407	NM_003014.4(SFRP4):c.50_65del (p.Leu17fs)	Pathogenic
4819365	NM_003014.4(SFRP4):c.180del (p.Gln60fs)	Pathogenic
2860973	NM_003014.4(SFRP4):c.792-1G>A	Likely pathogenic
3775097	NM_003014.4(SFRP4):c.445+1G>A	Likely pathogenic
989454	NM_003014.4(SFRP4):c.161C>A (p.Ala54Asp)	Likely pathogenic
989455	NM_003014.4(SFRP4):c.373T>A (p.Cys125Ser)	Likely pathogenic

SpliceAI

1144 predictions. Top by Δscore:

Variant	Effect	Δscore
7:37914206:GACTT:G	donor_loss	1.0000
7:37914207:ACTTA:A	donor_loss	1.0000
7:37914208:CTTA:C	donor_loss	1.0000
7:37914209:TTA:T	donor_loss	1.0000
7:37914210:TA:T	donor_loss	1.0000
7:37914211:A:AC	donor_gain	1.0000
7:37914212:C:CC	donor_gain	1.0000
7:37914274:CCGAT:C	acceptor_gain	1.0000
7:37914275:CGAT:C	acceptor_gain	1.0000
7:37914275:CGATC:C	acceptor_gain	1.0000
7:37914278:TC:T	acceptor_loss	1.0000
7:37914279:C:CA	acceptor_loss	1.0000
7:37914279:C:CC	acceptor_gain	1.0000
7:37914280:T:A	acceptor_loss	1.0000
7:37916091:AC:A	donor_gain	1.0000
7:37916092:CC:C	donor_gain	1.0000
7:37921206:GAG:G	donor_gain	1.0000
7:37949018:G:GT	donor_gain	1.0000
7:37949031:GAAA:G	donor_gain	1.0000
7:37949032:A:T	donor_gain	1.0000
7:37949035:G:GG	donor_gain	1.0000
7:37949040:C:G	donor_gain	1.0000
7:37949045:TCCT:T	donor_gain	1.0000
7:37949049:G:GG	donor_gain	1.0000
7:37950197:TAGAT:T	acceptor_loss	1.0000
7:37950198:A:AG	acceptor_gain	1.0000
7:37950198:A:T	acceptor_loss	1.0000
7:37950199:G:GG	acceptor_gain	1.0000
7:37950199:GAT:G	acceptor_gain	1.0000
7:37907660:CACTG:C	acceptor_gain	0.9900

AlphaMissense

2297 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:37912136:A:C	C258W	1.000
7:37916130:G:C	C136W	1.000
7:37916131:C:A	C136F	1.000
7:37916131:C:G	C136S	1.000
7:37916131:C:T	C136Y	1.000
7:37916132:A:G	C136R	1.000
7:37916132:A:T	C136S	1.000
7:37916181:C:A	W119C	1.000
7:37916181:C:G	W119C	1.000
7:37916183:A:G	W119R	1.000
7:37916183:A:T	W119R	1.000
7:37916214:G:C	C108W	1.000
7:37916215:C:G	C108S	1.000
7:37916215:C:T	C108Y	1.000
7:37916216:A:T	C108S	1.000
7:37916236:C:G	C101S	1.000
7:37916237:A:T	C101S	1.000
7:37916248:C:G	C97S	1.000
7:37916248:C:T	C97Y	1.000
7:37916249:A:T	C97S	1.000
7:37916283:G:C	C85W	1.000
7:37916284:C:T	C85Y	1.000
7:37916406:G:C	N44K	1.000
7:37916406:G:T	N44K	1.000
7:37916427:C:A	W37C	1.000
7:37916427:C:G	W37C	1.000
7:37916429:A:G	W37R	1.000
7:37916429:A:T	W37R	1.000
7:37909659:G:C	C271W	0.999
7:37912137:C:T	C258Y	0.999

dbSNP variants (sampled 300 via entrez): RS1000040121 (7:37917595 A>G), RS1000217330 (7:37913135 G>A), RS1000289110 (7:37912287 C>A,T), RS1000669793 (7:37908118 T>C,G), RS1001181334 (7:37914689 A>G), RS1001331407 (7:37913031 T>C), RS1001386879 (7:37912751 C>T), RS1001676289 (7:37909758 T>C), RS1001786363 (7:37915898 G>C), RS1001896620 (7:37918405 C>A), RS1002217281 (7:37915688 A>G), RS1003168929 (7:37905720 C>T), RS1003184677 (7:37906004 G>C), RS1003198806 (7:37916878 G>T), RS1003570406 (7:37907923 G>A)

Disease associations

OMIM: gene MIM:606570 | disease phenotypes: MIM:265900

GenCC curated gene-disease

Disease	Classification	Inheritance
Pyle disease	Strong	Autosomal recessive

Mondo (1): Pyle disease (MONDO:0009943)

Orphanet (1): Pyle disease (Orphanet:3005)

HPO phenotypes

34 total (30 of 34 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000303	Mandibular prognathia
HP:0000411	Protruding ear
HP:0000670	Carious teeth
HP:0000684	Delayed eruption of teeth
HP:0000689	Dental malocclusion
HP:0000696	Delayed eruption of permanent teeth
HP:0000765	Abnormal thorax morphology
HP:0000926	Platyspondyly
HP:0001324	Muscle weakness
HP:0001377	Limited elbow extension
HP:0002645	Wormian bones
HP:0002650	Scoliosis
HP:0002659	Increased susceptibility to fractures
HP:0002684	Thickened calvaria
HP:0002689	Absent paranasal sinuses
HP:0002738	Hypoplastic frontal sinuses
HP:0002753	Thin bony cortex
HP:0002829	Arthralgia
HP:0002857	Genu valgum
HP:0002967	Cubitus valgus
HP:0003016	Metaphyseal widening
HP:0003051	Enlarged metaphyses
HP:0003418	Back pain
HP:0003581	Adult onset
HP:0003621	Juvenile onset
HP:0004349	Reduced bone mineral density
HP:0004975	Erlenmeyer flask deformity of the femurs
HP:0005464	Craniofacial osteosclerosis
HP:0006335	Persistence of primary teeth

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001144_3	Dupuytren’s disease	6.000000e-39
GCST004858_5	Dupuytren’s disease	2.000000e-44
GCST004858_6	Dupuytren’s disease	3.000000e-81
GCST006288_148	Heel bone mineral density	1.000000e-14
GCST006288_643	Heel bone mineral density	1.000000e-31
GCST006288_750	Heel bone mineral density	1.000000e-19
GCST006585_1314	Blood protein levels	2.000000e-18
GCST006979_345	Heel bone mineral density	2.000000e-114
GCST012316_5	ghrelin levels	1.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004229	Dupuytren Contracture
EFO:0009270	heel bone mineral density
EFO:0600001	ghrelin measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536252	Pyle disease (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

44 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	4
Decitabine	affects cotreatment, increases expression, affects expression, affects methylation	2
Air Pollutants	decreases expression, increases abundance	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Polyamines	increases expression, affects expression	2
cyclothiazide	affects binding	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
phytosphingosine	decreases reaction, increases phosphorylation, increases expression, affects cotreatment, decreases phosphorylation	1
terbufos	decreases methylation	1
trichostatin A	increases expression, affects cotreatment	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ormosil	affects binding, decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression, decreases expression	1
incobotulinumtoxinA	increases expression	1
Acetaminophen	increases expression	1
Glyphosate	decreases expression	1
Arsenic	affects expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Biguanides	affects expression	1
Buserelin	decreases expression, affects cotreatment	1
Calcitriol	decreases expression	1
Cisplatin	affects cotreatment, increases expression	1
Clopamide	affects binding	1
Bucladesine	increases phosphorylation, affects cotreatment, decreases phosphorylation, decreases reaction	1
Diethylstilbestrol	decreases expression	1
Doxorubicin	decreases expression	1
Dust	increases abundance, decreases expression	1

Clinical trials (associated diseases)

1 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05046977	Not specified	UNKNOWN	Double Osteotomy for Deformity Correction in Pyle Disease