PORCN

Summary

PORCN (porcupine O-acyltransferase, HGNC:17652) is a protein-coding gene on chromosome Xp11.23, encoding Protein-serine O-palmitoleoyltransferase porcupine (Q9H237). Protein-serine O-palmitoleoyltransferase that acts as a key regulator of the Wnt signaling pathway by mediating the attachment of palmitoleate, a 16-carbon monounsaturated fatty acid (C16:1(9Z)), to Wnt proteins.

This gene belongs to the evolutionarily conserved porcupine (Porc) gene family. Genes of the porcupine family encode endoplasmic reticulum proteins with multiple transmembrane domains. Porcupine proteins are involved in the processing of Wnt (wingless and int homologue) proteins. Disruption of this gene is associated with focal dermal hypoplasia, and the encoded protein has been implicated in cancer. Multiple alternatively spliced transcript variants encoding distinct isoforms have been observed.

Source: NCBI Gene 64840 — RefSeq curated summary.

At a glance

• Gene–disease (curated): focal dermal hypoplasia (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 21
• Clinical variants (ClinVar): 1,164 total — 101 pathogenic, 60 likely-pathogenic
• Phenotypes (HPO): 284
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_203475

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17652
Approved symbol	PORCN
Name	porcupine O-acyltransferase
Location	Xp11.23
Locus type	gene with protein product
Status	Approved
Aliases	MG61, PORC, PPN, por
Ensembl gene	ENSG00000102312
Ensembl biotype	protein_coding
OMIM	300651
Entrez	64840

Gene structure

Transcript identifiers

Ensembl transcripts: 39 — 29 protein_coding, 5 retained_intron, 3 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000326194, ENST00000355961, ENST00000359882, ENST00000361988, ENST00000367574, ENST00000459953, ENST00000470275, ENST00000472520, ENST00000485288, ENST00000486272, ENST00000489940, ENST00000491243, ENST00000528612, ENST00000537758, ENST00000682661, ENST00000683804, ENST00000683923, ENST00000684722, ENST00000908862, ENST00000908863, ENST00000916265, ENST00000916266, ENST00000916267, ENST00000916268, ENST00000916269, ENST00000965635, ENST00000965636, ENST00000965637, ENST00000965638, ENST00000965639, ENST00000965640, ENST00000965641, ENST00000965642, ENST00000965643, ENST00000965644, ENST00000965645, ENST00000965646, ENST00000965647, ENST00000965648

RefSeq mRNA: 5 — MANE Select: NM_203475 NM_001282167, NM_022825, NM_203473, NM_203474, NM_203475

CCDS: CCDS14296, CCDS14297, CCDS14298, CCDS14299

Canonical transcript exons

ENST00000326194 — 15 exons

Exon	Start	End
ENSE00000669527	48511295	48511487
ENSE00001664402	48512835	48512852
ENSE00001714331	48514127	48514141
ENSE00001874768	48520375	48520808
ENSE00001943050	48508992	48509103
ENSE00003468117	48511892	48511935
ENSE00003538819	48516061	48516146
ENSE00003577991	48512326	48512507
ENSE00003587113	48514525	48514625
ENSE00003616342	48515890	48515953
ENSE00003624378	48517183	48517293
ENSE00003633841	48512589	48512719
ENSE00003677153	48509784	48509956
ENSE00003678662	48514240	48514365
ENSE00003692629	48515717	48515793

Expression profiles

Bgee: expression breadth ubiquitous, 184 present calls, max score 96.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.0613 / max 247.6030, expressed in 1687 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196244	7.9866	1684
196246	0.0412	10
196245	0.0335	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	96.60	gold quality
right adrenal gland cortex	UBERON:0035827	95.87	gold quality
right adrenal gland	UBERON:0001233	95.70	gold quality
left adrenal gland cortex	UBERON:0035825	95.05	gold quality
left adrenal gland	UBERON:0001234	94.99	gold quality
adrenal cortex	UBERON:0001235	93.97	gold quality
adrenal gland	UBERON:0002369	92.09	gold quality
right hemisphere of cerebellum	UBERON:0014890	91.67	gold quality
cerebellar hemisphere	UBERON:0002245	90.95	gold quality
cerebellar cortex	UBERON:0002129	90.85	gold quality
cerebellum	UBERON:0002037	89.18	gold quality
right frontal lobe	UBERON:0002810	87.65	gold quality
stromal cell of endometrium	CL:0002255	86.75	gold quality
esophagus mucosa	UBERON:0002469	86.46	gold quality
anterior cingulate cortex	UBERON:0009835	86.20	gold quality
cingulate cortex	UBERON:0003027	86.05	gold quality
right atrium auricular region	UBERON:0006631	85.85	gold quality
prefrontal cortex	UBERON:0000451	85.60	gold quality
granulocyte	CL:0000094	85.56	gold quality
apex of heart	UBERON:0002098	85.34	gold quality
cortical plate	UBERON:0005343	85.13	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	84.95	gold quality
Brodmann (1909) area 9	UBERON:0013540	84.83	gold quality
esophagus	UBERON:0001043	84.75	gold quality
secondary oocyte	CL:0000655	84.74	gold quality
nucleus accumbens	UBERON:0001882	84.34	gold quality
mucosa of stomach	UBERON:0001199	84.23	gold quality
cardiac atrium	UBERON:0002081	84.17	gold quality
heart left ventricle	UBERON:0002084	84.16	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.14	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.46

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

22 targeting PORCN, 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-6867-5P	100.00	82.21	3464
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-9851-3P	99.63	69.68	1110
HSA-MIR-3685	99.62	68.83	1621
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-593-5P	99.34	69.50	965
HSA-MIR-6803-5P	99.19	63.90	1026
HSA-MIR-3127-3P	98.94	67.34	1055
HSA-MIR-6756-3P	98.94	66.79	1104
HSA-MIR-6747-3P	97.73	64.84	1596
HSA-MIR-6729-3P	96.91	66.79	703
HSA-MIR-5194	96.77	63.91	1021
HSA-MIR-6738-5P	96.33	63.61	815
HSA-MIR-1914-3P	95.07	63.37	762

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 37)

• Sequence deletions and point mutations cause focal dermal hypoplasia. (PMID:17546030)
• PORCN, encoding a putative O-acyltransferase potentially crucial for cellular export of Wnt signaling proteins, is the gene mutated in focal dermal hypoplasia. (PMID:17546031)
• Overexpression of PORCN is associated with lung cancer (PMID:18193088)
• 3 novel mutations in PORCN, c.373+1G>A, c.737_738insA & c.1094G>A (p.R365Q), were identified in focal dermal hypoplasia patients(FDH); study shows PORCN is gene responsible for FDH in different populations & extends number of confirmed mutations to 26 (PMID:18325042)
• defective PORCN does not lead to selective growth disadvantage (PMID:19277062)
• Molecular characterization of 24 unrelated patients from different ethnic backgrounds revealed 23 different mutations of the PORCN gene in Xp11.23. (PMID:19309688)
• Mutations within the PORCN gene are associated with Goltz-Gorlin syndrome. (PMID:19586929)
• Focal dermal hypoplasia illustrates the phenotypic consequences of defective modulation of Wnt signaling in utero and highlights the important roles of PORCN and Wnt signaling pathways in embryogenesis. (PMID:19681149)
• Three de novo mutations were identified in PORCN gene in patients with focal dermal hypoplasia. (PMID:19863546)
• Porcupine might contribute to non-small cell lung carcinoma development by ranscriptional activation of cancer-related genes such as s100P. (PMID:20198348)
• 12 novel PORCN mutations and 6 previously reported mutations were found in 53 unrelated focal dermal hypoplasia patients. (PMID:20854095)
• review of the published mutations in the PORCN gene and report on 7 new mutations identified in Goltz-Gorlin syndrome patients (PMID:21472892)
• PORCN protein thus appears to moonlight in a novel signaling pathway that is rate-limiting for cancer cell growth and tumorigenesis independent of its enzymatic function in Wnt biosynthesis and secretion (PMID:22509316)
• To the best of our knowledge, this is the second case report that reveals a mutation of the PORCN gene in a patient with almost unilateral focal dermal hypoplasia. (PMID:22735390)
• We report a typical focal dermal hypoplasia (FDH) patient with a recurrent PORCN mutation, which was previously identified, and a second female, with an almost unilateral FDH and a novel postzygotic PORCN mutation. (PMID:23399492)
• a novel variant in the PORCN gene (c.1250T>C:p.F417S) in the focal dermal hypoplasia with spinal anomaly (PMID:23696273)
• porcupine-mediated production of Wnts is context dependent and is not required for all Wnts production, suggesting that alternative mechanisms exist for Wnts production. (PMID:24647048)
• We describe the ophthalmologic findings in an 18-month-old boy with mosaicism of a novel mutation in PORCN. (PMID:24698628)
• We describe the first case of non-mosaic males affected with syndromic microphthalmia because of a non-synonymous variant in the PORCN gene. (PMID:25026905)
• the Wnt amino acid residues required for recognition and palmitoylation by PORCN (PMID:25451226)
• three distinct members [porcupine (PORCN), hedgehog (Hh) acyltransferase (HHAT) and ghrelin O-acyltransferase (GOAT)] have been shown to acylate specific proteins or peptides. (PMID:25849925)
• Inhibition of Wnt signaling by PORCN inhibition holds promise as differentiation therapy in genetically defined human cancers (PMID:26257057)
• Case Report: mosaicism for PORCN mutations in focal dermal hypoplasia (Goltz Syndrome). (PMID:28293688)
• Data suggest that PORCN exhibits substrate specificity that includes a Wnt3a peptide fragment (residues 199-219, with disulfide bonds); recombinant PORCN containing a point mutation (R228C) associated with focal dermal hypoplasia exhibits impaired acylation activity toward Wnt3a peptide fragment. (PORCN = porcupine O-acyltransferase; Wnt3a = Wnt family member 3A) (PMID:28655768)
• Together, these results provide discrete, high-resolution biochemical insights into the mechanism of PORCN-mediated Wnt acylation and pave the way for further detailed biochemical and structural studies. (PMID:30420431)
• Targeting Porcupine or the CBP/beta-catenin interaction seems to be an effective strategy for the inhibition of canonical Wnt signaling in head and neck carcinoma cells. (PMID:31089983)
• findings demonstrate that dual PORCN and PI3K/mTOR inhibition is a potential strategy for treating Wnt-driven pancreatic cancers (PMID:31391551)
• Porcupine Inhibitor LGK974 Downregulates the Wnt Signaling Pathway and Inhibits Clear Cell Renal Cell Carcinoma. (PMID:32104684)
• Non-syndromic anophthalmia/microphthalmia can be caused by a PORCN variant inherited in X-linked recessive manner. (PMID:33111437)
• De Novo PORCN and ZIC2 Mutations in a Highly Consanguineous Family. (PMID:33557041)
• Responses of Porcupine and Wntless proteins to oxidative, hypoxic and endoplasmic reticulum stresses. (PMID:34015469)
• Two new patients with focal dermal hypoplasia: A novel PORCN variant and insights on the diagnostic considerations. (PMID:34962003)
• A novel intronic PORCN variant creating an alternative splice acceptor site in a mother and her daughter with focal dermal hypoplasia. (PMID:35005837)
• Mechanisms and inhibition of Porcupine-mediated Wnt acylation. (PMID:35831507)
• Suppression of Wnt/beta-Catenin Signaling Is Associated with Downregulation of Wnt1, PORCN, and Rspo2 in Alzheimer’s Disease. (PMID:36215026)
• A novel large deletion mutation involving the PORCN gene in a Chinese patient with focal dermal hypoplasia and literature review. (PMID:36880456)
• Inhibition of PORCN Blocks Wnt Signaling to Attenuate Progression of Oral Carcinogenesis. (PMID:37812478)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	porcnl	ENSDARG00000052455
danio_rerio	porcn	ENSDARG00000052558
mus_musculus	Porcn	ENSMUSG00000031169
rattus_norvegicus	Porcn	ENSRNOG00000004819
drosophila_melanogaster	por	FBGN0004957
caenorhabditis_elegans		WBGENE00003394

Paralogs (5): LPCAT3 (ENSG00000111684), MBOAT7 (ENSG00000125505), MBOAT2 (ENSG00000143797), MBOAT1 (ENSG00000172197), MBOAT4 (ENSG00000177669)

Protein

Protein identifiers

Protein-serine O-palmitoleoyltransferase porcupine — Q9H237 (reviewed: Q9H237)

Alternative names: Protein MG61

All UniProt accessions (4): Q9H237, C9JWI5, F2Z360, F8WEW7

UniProt curated annotations — full annotation on UniProt →

Function. Protein-serine O-palmitoleoyltransferase that acts as a key regulator of the Wnt signaling pathway by mediating the attachment of palmitoleate, a 16-carbon monounsaturated fatty acid (C16:1(9Z)), to Wnt proteins. Serine palmitoleoylation of WNT proteins is required for efficient binding to frizzled receptors.

Subunit / interactions. Interacts with WNT1, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT6, WNT7A and WNT7B.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Isoform 1 is expressed in fetal brain, brain, amygdala, caudate nucleus, cerebellum, hippocampus, pituitary, thalamus, heart, skeletal muscle and testis. Isoform 4 is expressed in amygdala, corpus callosum, hippocampus, spinal cord, kidney, liver, lung, spleen, uterus, testis. Isoform 2 and isoform 3 are expressed in substantia negra, spinal cord, heart and lung.

Disease relevance. Focal dermal hypoplasia (FODH) [MIM:305600] A rare congenital ectomesodermal disorder characterized by a combination of skin defects, skeletal abnormalities, and ocular anomalies. Affected individuals have patchy dermal hypoplasia, often in a distribution pattern following the Blaschko lines, and areas of subcutaneous fat herniation or deposition of fat into the dermis. In addition, sparse and brittle hair, hypoplastic nails and papillomas have been described. Skeletal abnormalities usually comprise syndactyly, ectrodactyly, and brachydactyly, and in some cases osteopathia striata has been seen. Patients frequently have ocular anomalies, including microphthalmia/ anophthalmia, coloboma, pigmentary and vascularization defects of the retina. Dental abnormalities are often present. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the membrane-bound acyltransferase family. Porcupine subfamily.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9H237-1	1, D	yes
Q9H237-2	2, B
Q9H237-3	3, C
Q9H237-4	4, A
Q9H237-5	5

RefSeq proteins (5): NP_001269096, NP_073736, NP_982299, NP_982300, NP_982301* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004299	MBOAT_fam	Family
IPR049941	LPLAT_7/PORCN-like	Family

Pfam: PF03062

Enzyme classification (BRENDA):

• EC 2.3.1.250 — [Wnt protein] O-palmitoleoyl transferase (BRENDA: 7 organisms, 33 substrates, 45 inhibitors, 1 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
(9Z)-HEXADEC-9-ENOYL-COA	0.0143	1

Catalyzed reactions (Rhea), 1 shown:

• [Wnt protein]-L-serine + (9Z)-hexadecenoyl-CoA = [Wnt protein]-O-(9Z)-hexadecenoyl-L-serine + CoA (RHEA:45336)

UniProt features (77 total): helix 23, sequence variant 16, topological domain 9, transmembrane region 8, turn 5, strand 5, splice variant 4, mutagenesis site 2, sequence conflict 2, chain 1, active site 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
9OO6	ELECTRON MICROSCOPY	2.39
9OO7	ELECTRON MICROSCOPY	2.61
7URD	ELECTRON MICROSCOPY	2.92
7URA	ELECTRON MICROSCOPY	3.11
7URC	ELECTRON MICROSCOPY	3.14
7URE	ELECTRON MICROSCOPY	3.19
9OO8	ELECTRON MICROSCOPY	3.32

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H237-F1	89.95	0.72

Antibody-complex structures (SAbDab): 4 — 7URA, 7URC, 7URD, 7URE

Functional residue map

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

Catalytic / active sites (1): 341

Post-translational modifications (1): 187

Mutagenesis-validated functional residues (2):

Position	Phenotype
187	drastic loss of palmitoylation.
341	loss of function.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-3238698	WNT ligand biogenesis and trafficking
R-HSA-5340573	LGK974 inhibits PORCN

MSigDB gene sets: 444 (showing top): GOBP_LIPID_MODIFICATION, MODULE_255, GOBP_LIPOPROTEIN_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, MODULE_317, AP2_Q3, BEIER_GLIOMA_STEM_CELL_DN, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_CELL_CELL_SIGNALING, MODULE_301, GOBP_LIPOPROTEIN_BIOSYNTHETIC_PROCESS, GOBP_SECRETION, GOBP_SIGNAL_RELEASE

GO Biological Process (7): protein lipidation (GO:0006497), glycoprotein metabolic process (GO:0009100), Wnt signaling pathway (GO:0016055), lipid modification (GO:0030258), protein palmitoleylation (GO:0045234), Wnt protein secretion (GO:0061355), regulation of postsynaptic membrane neurotransmitter receptor levels (GO:0099072)

GO Molecular Function (5): Wnt-protein binding (GO:0017147), palmitoleoyltransferase activity (GO:1990698), protein binding (GO:0005515), transferase activity (GO:0016740), acyltransferase activity (GO:0016746)

GO Cellular Component (5): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), AMPA glutamate receptor complex (GO:0032281), glutamatergic synapse (GO:0098978)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Signaling by WNT	1
Signaling by WNT in cancer	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein modification process	1
lipoprotein biosynthetic process	1
protein metabolic process	1
carbohydrate derivative metabolic process	1
cell surface receptor signaling pathway	1
lipid metabolic process	1
protein lipidation	1
protein acylation	1
protein secretion	1
signal release	1
regulation of biological quality	1
protein binding	1
acyltransferase activity, transferring groups other than amino-acyl groups	1
binding	1
catalytic activity	1
transferase activity	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1
ionotropic glutamate receptor complex	1
synapse	1

Protein interactions and networks

STRING

792 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PORCN	WNT1	P04628	849
PORCN	WNT7A	O00755	759
PORCN	WLS	Q5T9L3	710
PORCN	WNT3	P56703	690
PORCN	HPRT1	P00492	635
PORCN	HHAT	Q5VTY9	628
PORCN	FZD6	O60353	614
PORCN	CTNNB1	P35222	608
PORCN	RNF43	Q68DV7	608
PORCN	AXIN2	Q9Y2T1	599
PORCN	RSPO3	Q9BXY4	598
PORCN	WNT3A	P56704	595
PORCN	WNT5A	P41221	584
PORCN	TNKS	O95271	582
PORCN	TNKS2	Q9H2K2	577

IntAct

3 interactions, top by confidence:

A	B	Type	Score
GRIK5	ADCY6	psi-mi:“MI:0914”(association)	0.350
SLC9A6	GOLIM4	psi-mi:“MI:0914”(association)	0.350

BioGRID (7): PORCN (Affinity Capture-RNA), PORCN (Two-hybrid), APOC2 (Two-hybrid), APOC4 (Two-hybrid), PORCN (Affinity Capture-MS), WLS (Affinity Capture-Western), PORCN (Affinity Capture-MS)

ESM2 similar proteins: A0A8C2M425, A1A5Z0, A9ULG4, B1Q005, B1Q006, D3ZI76, O75908, O77759, O88908, P0C7A3, Q07175, Q148G2, Q14DK4, Q1XHX8, Q32LM8, Q49LS0, Q5D0E6, Q5KR61, Q5TM67, Q5U2T1, Q5U4T9, Q60850, Q641Y9, Q643R3, Q6AZ83, Q6MG14, Q6NSQ9, Q6NUI2, Q6NVG1, Q6PJN8, Q767L9, Q7SZQ0, Q7TN58, Q7TPN3, Q7TQM4, Q8BPS4, Q8CIP5, Q8IXM6, Q8VC65, Q96T53

Diamond homologs: A8WZ09, Q22329, Q9H237, Q9JJJ7, Q7Q3N5, Q9VWV9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PORCN	“up-regulates activity”	WNT3A	palmitoylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

1164 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	101
Likely pathogenic	60
Uncertain significance	306
Likely benign	469
Benign	57

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
10700	NM_203475.3(PORCN):c.1059_1071dup (p.Thr358fs)	Pathogenic
10701	NM_203475.3(PORCN):c.178G>A (p.Gly60Arg)	Pathogenic
10702	NM_203475.3(PORCN):c.370C>T (p.Arg124Ter)	Pathogenic
10703	NM_203475.3(PORCN):c.222G>A (p.Trp74Ter)	Pathogenic
1315505	NM_203475.3(PORCN):c.374-2A>G	Pathogenic
1371874	NM_203475.3(PORCN):c.566G>A (p.Trp189Ter)	Pathogenic
1379019	NM_001395413.1(POR):c.1676_1679dup (p.Leu561fs)	Pathogenic
1405328	NM_001395413.1(POR):c.723-2A>T	Pathogenic
1410449	NM_203475.3(PORCN):c.935G>A (p.Trp312Ter)	Pathogenic
1441030	NM_203475.3(PORCN):c.983C>A (p.Ser328Ter)	Pathogenic
1454456	NM_001395413.1(POR):c.1406_1407del (p.Val469fs)	Pathogenic
1684295	NM_001395413.1(POR):c.1166dup (p.Ala390fs)	Pathogenic
16901	NM_001395413.1(POR):c.1466T>A (p.Val489Glu)	Pathogenic
16904	NM_001395413.1(POR):c.1813G>T (p.Val605Phe)	Pathogenic
16905	NM_001395413.1(POR):c.722+1G>A	Pathogenic
16906	NM_001395413.1(POR):c.532T>G (p.Tyr178Asp)	Pathogenic
16911	NM_001395413.1(POR):c.1724A>G (p.Tyr575Cys)	Pathogenic
16914	NM_001395413.1(POR):c.559_571dup (p.Arg191fs)	Pathogenic
16915	NM_001395413.1(POR):c.1606G>A (p.Gly536Arg)	Pathogenic
1704345	GRCh37/hg19 Xp22.33-q28(chrX:61545-155226048)x2	Pathogenic
1758058	NM_203475.3(PORCN):c.727C>T (p.Arg243Ter)	Pathogenic
1920714	NM_001395413.1(POR):c.64_65del (p.Leu22fs)	Pathogenic
2065334	NM_001395413.1(POR):c.1795C>T (p.Gln599Ter)	Pathogenic
242872	NM_203475.3(PORCN):c.268C>T (p.Arg90Ter)	Pathogenic
2502299	NM_203475.3(PORCN):c.137-1G>C	Pathogenic
2626788	NM_001395413.1(POR):c.1675dup (p.Glu559fs)	Pathogenic
2628346	NM_203475.3(PORCN):c.502G>A (p.Gly168Arg)	Pathogenic
2628347	NM_203475.3(PORCN):c.846-2A>G	Pathogenic
2631169	NM_203475.3(PORCN):c.661del (p.Leu221fs)	Pathogenic
2671905	NM_203475.3(PORCN):c.1076dup (p.Tyr359Ter)	Pathogenic

SpliceAI

5133 predictions. Top by Δscore:

Variant	Effect	Δscore
7:75953983:TAACA:T	acceptor_loss	1.0000
7:75953984:A:AG	acceptor_gain	1.0000
7:75953985:ACAGT:A	acceptor_loss	1.0000
7:75953986:CAGTT:C	acceptor_loss	1.0000
7:75953987:A:AG	acceptor_gain	1.0000
7:75953987:A:C	acceptor_loss	1.0000
7:75953988:G:GA	acceptor_gain	1.0000
7:75953988:GT:G	acceptor_gain	1.0000
7:75953988:GTT:G	acceptor_gain	1.0000
7:75953988:GTTT:G	acceptor_gain	1.0000
7:75953988:GTTTC:G	acceptor_gain	1.0000
7:75954176:ACATT:A	donor_gain	1.0000
7:75954177:CATT:C	donor_gain	1.0000
7:75954177:CATTG:C	donor_loss	1.0000
7:75954178:ATT:A	donor_gain	1.0000
7:75954178:ATTGT:A	donor_loss	1.0000
7:75954179:TT:T	donor_gain	1.0000
7:75954179:TTGTA:T	donor_loss	1.0000
7:75954180:TGTA:T	donor_loss	1.0000
7:75954181:G:GG	donor_gain	1.0000
7:75954181:GTAAG:G	donor_loss	1.0000
7:75954182:TAAG:T	donor_loss	1.0000
7:75972407:TTGCA:T	acceptor_loss	1.0000
7:75972408:TGCA:T	acceptor_loss	1.0000
7:75972409:GCA:G	acceptor_loss	1.0000
7:75972410:CA:C	acceptor_loss	1.0000
7:75972411:A:AG	acceptor_gain	1.0000
7:75972412:G:C	acceptor_loss	1.0000
7:75972412:G:GT	acceptor_gain	1.0000
7:75972412:GGA:G	acceptor_gain	1.0000

AlphaMissense

2980 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:48511393:A:C	S79R	0.999
X:48511395:C:A	S79R	0.999
X:48511395:C:G	S79R	0.999
X:48511920:T:A	W120R	0.999
X:48511920:T:C	W120R	0.999
X:48511922:G:C	W120C	0.999
X:48511922:G:T	W120C	0.999
X:48512455:G:A	G168E	0.999
X:48514271:T:C	F251L	0.999
X:48514273:C:A	F251L	0.999
X:48514273:C:G	F251L	0.999
X:48514592:T:A	W305R	0.999
X:48514592:T:C	W305R	0.999
X:48514594:G:C	W305C	0.999
X:48514594:G:T	W305C	0.999
X:48515779:A:C	S337R	0.999
X:48515781:C:A	S337R	0.999
X:48515781:C:G	S337R	0.999
X:48520405:T:A	W439R	0.999
X:48520405:T:C	W439R	0.999
X:48511337:G:A	G60E	0.998
X:48511935:G:A	G125R	0.998
X:48511935:G:C	G125R	0.998
X:48512335:T:C	M128T	0.998
X:48512335:T:G	M128R	0.998
X:48512351:G:C	K133N	0.998
X:48512351:G:T	K133N	0.998
X:48512421:G:C	G157R	0.998
X:48512460:T:A	W170R	0.998
X:48512460:T:C	W170R	0.998

dbSNP variants (sampled 300 via entrez): RS1000312686 (X:48515415 A>C), RS1000972966 (X:48507638 G>A), RS1001259749 (X:48508077 C>T), RS1001856118 (X:48510164 A>G), RS1001972417 (X:48509656 C>T), RS1002349147 (X:48519880 C>G,T), RS1002872236 (X:48520529 T>C), RS1003871090 (X:48514890 G>A), RS1005865660 (X:48518919 G>A), RS1005919465 (X:48518284 G>A,C), RS1005980635 (X:48519498 G>A), RS1006565969 (X:48508916 C>G,T), RS1006923083 (X:48521207 C>T), RS1008111146 (X:48513519 C>A), RS1008581183 (X:48513808 C>G,T)

Disease associations

OMIM: gene MIM:300651 | disease phenotypes: MIM:305600, MIM:613571, MIM:201750, MIM:207410, MIM:601353, MIM:308350, MIM:309800, MIM:142623

GenCC curated gene-disease

Disease	Classification	Inheritance
focal dermal hypoplasia	Definitive	X-linked
Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis	Definitive	Autosomal recessive
congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency	Strong	Autosomal recessive
microphthalmia, isolated, with coloboma	Supportive	Autosomal dominant
Antley-Bixler syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
focal dermal hypoplasia	Definitive	XL
Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis	Definitive	AR

Mondo (14): focal dermal hypoplasia (MONDO:0010592), congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency (MONDO:0013310), Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (MONDO:0008726), congenital adrenal hyperplasia (MONDO:0018479), Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis (MONDO:0020667), Klinefelter syndrome (MONDO:0006823), 46 XY differences of sex development (MONDO:0020040), Fine-Lubinsky syndrome (MONDO:0011049), genetic developmental and epileptic encephalopathy (MONDO:0100062), syndromic microphthalmia (MONDO:0016073), Hirschsprung disease (MONDO:0018309), primary ovarian failure (MONDO:0005387), microphthalmia, isolated, with coloboma (MONDO:0000170), Antley-Bixler syndrome (MONDO:0008803)

Orphanet (12): Focal dermal hypoplasia (Orphanet:2092), Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency (Orphanet:95699), Microphthalmia-anophthalmia-coloboma (Orphanet:98555), Congenital adrenal hyperplasia (Orphanet:418), Antley-Bixler syndrome without genital anomaly or disorder of steroidogenesis (Orphanet:596008), Antley-Bixler syndrome with genital anomaly and disorder of steroidogenesis (Orphanet:63269), Antley-Bixler syndrome (Orphanet:83), 46,XY difference of sex development (Orphanet:98085), Aymé-Gripp syndrome (Orphanet:1272), Syndromic microphthalmia-anophthalmia-coloboma (Orphanet:202948), Hirschsprung disease (Orphanet:388), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

284 total (30 of 284 shown, HPO-id order):

HPO	Term
HP:0000003	Multicystic kidney dysplasia
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000013	Hypoplasia of the uterus
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000032	Abnormal male external genitalia morphology
HP:0000041	Chordee
HP:0000046	Small scrotum
HP:0000047	Hypospadias
HP:0000048	Bifid scrotum
HP:0000054	Micropenis
HP:0000055	Abnormal female external genitalia morphology
HP:0000059	Hypoplastic labia majora
HP:0000060	Clitoral hypoplasia
HP:0000062	Ambiguous genitalia
HP:0000063	Fused labia minora
HP:0000066	Labial hypoplasia
HP:0000073	Ureteral duplication
HP:0000076	Vesicoureteral reflux
HP:0000079	Abnormality of the urinary system
HP:0000085	Horseshoe kidney
HP:0000122	Unilateral renal agenesis
HP:0000126	Hydronephrosis
HP:0000138	Ovarian cyst
HP:0000144	Decreased fertility
HP:0000147	Polycystic ovaries
HP:0000148	Vaginal atresia
HP:0000160	Narrow mouth
HP:0000164	Abnormality of the dentition

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST002650_4	Coffee consumption (cups per day)	4.000000e-11
GCST002651_1	Coffee consumption	1.000000e-09
GCST008058_99	Estimated glomerular filtration rate	4.000000e-19
GCST008361_9	Response to cognitive-behavioural therapy in major depressive disorder	6.000000e-06
GCST008521_18	Bitter beverage consumption	3.000000e-16
GCST008524_23	Bitter non-alcoholic beverage consumption	4.000000e-23
GCST008526_80	Coffee consumption	1.000000e-33
GCST008747_126	Estimated glomerular filtration rate	7.000000e-11
GCST008747_22	Estimated glomerular filtration rate	1.000000e-07
GCST008794_19	Urinary albumin-to-creatinine ratio	3.000000e-08
GCST009391_43	Metabolite levels	3.000000e-06
GCST009801_10	Coffee consumption	1.000000e-08
GCST010108_16	Coffee consumption (cups per day)	8.000000e-20
GCST010204_137	Low density lipoprotein cholesterol levels	1.000000e-11
GCST011124_4	Caffeine consumption from tea	7.000000e-22
GCST011125_7	Caffeine consumption from coffee	6.000000e-22
GCST011126_17	Caffeine consumption from coffee or tea	4.000000e-56
GCST90002382_151	Eosinophil percentage of white cells	1.000000e-12
GCST90002385_140	High light scatter reticulocyte count	2.000000e-09
GCST90002402_22	Platelet count	7.000000e-10
GCST90002405_482	Reticulocyte count	3.000000e-09

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0004330	coffee consumption
EFO:0006782	cups of coffee per day measurement
EFO:0007820	cognitive behavioural therapy
EFO:0010089	bitter beverage consumption measurement
EFO:0010093	bitter non-alcoholic beverage consumption measurement
EFO:0006781	coffee consumption measurement
EFO:0007778	urinary albumin to creatinine ratio
EFO:0010114	citrate measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0010091	tea consumption measurement
EFO:0007991	eosinophil percentage of leukocytes
EFO:0007986	reticulocyte count
EFO:0004309	platelet count

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D000312	Adrenal Hyperplasia, Congenital	C12.050.351.875.253.090.500; C12.200.706.316.090.500; C12.800.316.090.500; C16.131.939.316.129.500; C16.320.033; C16.320.565.925.249; C18.452.648.925.249; C19.053.440; C19.391.119.090.500
D058490	Disorder of Sex Development, 46,XY	C12.050.351.875.253.096; C12.200.706.316.096; C12.800.316.096; C16.131.939.316.096; C19.391.119.096
D005489	Focal Dermal Hypoplasia	C05.116.099.370.380; C16.131.077.350.424; C16.131.831.350.424; C16.320.322.186; C16.320.850.250.424; C17.800.804.350.424; C17.800.827.250.424
D006627	Hirschsprung Disease	C06.198.439; C06.405.469.158.701.439; C16.131.314.439
D007713	Klinefelter Syndrome	C12.050.351.875.253.795.500; C12.200.706.316.795.500; C12.800.316.795.500; C16.131.260.830.835.500; C16.131.939.316.795.500; C16.320.180.830.835.500; C19.391.119.795.500; C19.391.482.629
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750
C537933	Fine-Lubinsky syndrome (supp.)
C537463	Microphthalmia associated with colobomatous cyst (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1255163 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,483 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL3188386	WNT-974	2	1,238
CHEMBL3633802	ETC-159	1	245

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Membrane bound O-acyltransferases

Most potent curated ligand interactions (5 total), top 5:

Ligand	Action	Affinity	Parameter
Wnt-C59	Inhibition	10.13	pIC50
GNF-6231	Inhibition	9.1	pIC50
LGK974	Inhibition	9.0	pIC50
ETC-1922159	Inhibition	8.54	pIC50
GNF-1331	Inhibition	8.1	pIC50

ChEMBL bioactivities

64 potent at pChembl≥5 of 65 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.13	IC50	0.074	nM	CHEMBL2139947
9.96	IC50	0.11	nM	CHEMBL3623895
9.72	IC50	0.19	nM	CHEMBL3623894
9.64	IC50	0.23	nM	CHEMBL3623875
9.42	IC50	0.38	nM	CHEMBL3623896
9.40	IC50	0.4	nM	WNT-974
9.40	IC50	0.4	nM	CHEMBL4080208
9.30	IC50	0.5	nM	CHEMBL3633801
9.28	IC50	0.53	nM	CHEMBL3623893
9.24	IC50	0.57	nM	CHEMBL3623896
9.17	IC50	0.67	nM	CHEMBL3623892
9.02	IC50	0.96	nM	CHEMBL3623891
9.00	IC50	1	nM	CHEMBL4088716
9.00	IC50	1	nM	CHEMBL4080842
9.00	IC50	1	nM	CHEMBL4096728
9.00	IC50	1	nM	CHEMBL4080021
8.70	IC50	2	nM	CHEMBL4070649
8.66	IC50	2.2	nM	CHEMBL3623874
8.57	IC50	2.7	nM	CHEMBL3623887
8.54	IC50	2.9	nM	ETC-159
8.40	IC50	4	nM	CHEMBL4099279
8.30	IC50	5	nM	CHEMBL3623873
8.30	IC50	5	nM	CHEMBL3633804
8.30	IC50	5	nM	CHEMBL4084739
8.22	IC50	6	nM	CHEMBL4069295
8.15	IC50	7	nM	CHEMBL4089128
8.10	IC50	8	nM	CHEMBL4104447
8.10	IC50	8	nM	CHEMBL4540197
8.05	IC50	9	nM	CHEMBL4066589
8.00	IC50	10	nM	CHEMBL4098880
7.96	IC50	11	nM	CHEMBL4096529
7.96	IC50	11	nM	CHEMBL4095609
7.92	IC50	12	nM	CHEMBL4066796
7.92	IC50	12	nM	CHEMBL4087906
7.92	IC50	12	nM	CHEMBL4103356
7.82	IC50	15	nM	CHEMBL4097104
7.82	IC50	15	nM	CHEMBL4061069
7.82	IC50	15	nM	CHEMBL4094309
7.62	IC50	24	nM	CHEMBL3623889
7.62	IC50	24	nM	CHEMBL4066798
7.57	IC50	27	nM	CHEMBL3633800
7.54	IC50	29	nM	CHEMBL4104257
7.54	IC50	29	nM	CHEMBL4075204
7.52	IC50	30	nM	CHEMBL3623879
7.52	IC50	30	nM	CHEMBL4081262
7.40	IC50	40	nM	CHEMBL3623878
7.40	IC50	40	nM	CHEMBL4096832
7.38	IC50	42	nM	CHEMBL4063419
7.38	IC50	42	nM	CHEMBL4102043
7.22	IC50	60	nM	CHEMBL1257063

PubChem BioAssay actives

65 with measured affinity, of 135 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[4-(2-methyl-4-pyridinyl)phenoxy]-N-(5-pyrazin-2-yl-2-pyridinyl)propanamide	1252015: Inhibition of porcupine (unknown origin) expressed in mouse L Wnt3A cells co-cultured with TM3 cells harboring luciferase reporter gene assessed as reduction in Wnt ligand-driven LEF/TCF-dependent transcriptional activity	ic50	0.0001	uM
2-[4-(2-methyl-4-pyridinyl)phenyl]-N-(4-pyridin-3-ylphenyl)acetamide	1257057: Inhibition of porcupine activity (unknown origin) expressed in human HT1080 cells assessed as suppression of Wnt3A-mediated super top flash activity by STF luciferase assay	ic50	0.0001	uM
[4-(2-methyl-4-pyridinyl)phenyl] N-(5-pyrazin-2-yl-2-pyridinyl)carbamate	1252015: Inhibition of porcupine (unknown origin) expressed in mouse L Wnt3A cells co-cultured with TM3 cells harboring luciferase reporter gene assessed as reduction in Wnt ligand-driven LEF/TCF-dependent transcriptional activity	ic50	0.0002	uM
3-[4-(2-methyl-4-pyridinyl)phenyl]-N-(5-pyrazin-2-yl-2-pyridinyl)propanamide	1252015: Inhibition of porcupine (unknown origin) expressed in mouse L Wnt3A cells co-cultured with TM3 cells harboring luciferase reporter gene assessed as reduction in Wnt ligand-driven LEF/TCF-dependent transcriptional activity	ic50	0.0002	uM
2-[5-methyl-6-(6-methyl-3-pyridinyl)-3-pyridinyl]-N-(5-pyrazin-2-yl-2-pyridinyl)acetamide	1252029: Inhibition of porcupine (unknown origin)	ic50	0.0004	uM
2-[5-methyl-6-(2-methyl-4-pyridinyl)-3-pyridinyl]-N-(5-pyrazin-2-yl-2-pyridinyl)acetamide	1257057: Inhibition of porcupine activity (unknown origin) expressed in human HT1080 cells assessed as suppression of Wnt3A-mediated super top flash activity by STF luciferase assay	ic50	0.0004	uM
2-(1,3-dimethyl-2,6-dioxopurin-7-yl)-N-(4-thiophen-3-ylphenyl)acetamide	1457595: Inhibition of porcupine (unknown origin) expressed in HEK293 cells after day 1 post treatment by Super-top flash reporter gene assay	ic50	0.0004	uM
2-[4-(2-methyl-4-pyridinyl)phenyl]sulfanyl-N-(5-pyrazin-2-yl-2-pyridinyl)acetamide	1252015: Inhibition of porcupine (unknown origin) expressed in mouse L Wnt3A cells co-cultured with TM3 cells harboring luciferase reporter gene assessed as reduction in Wnt ligand-driven LEF/TCF-dependent transcriptional activity	ic50	0.0005	uM
(2S)-2-(1,3-dimethyl-2,6-dioxopurin-7-yl)-N-(4-thiophen-3-ylphenyl)propanamide	1257058: Inhibition of porcupine in human HEK293 cells assessed as reduction in Wnt secretion by measuring suppression of beta-catenin reporter activity after 24 hrs by STF reporter assay	ic50	0.0005	uM
2-[N-methyl-4-(2-methyl-4-pyridinyl)anilino]-N-(5-pyrazin-2-yl-2-pyridinyl)acetamide	1252015: Inhibition of porcupine (unknown origin) expressed in mouse L Wnt3A cells co-cultured with TM3 cells harboring luciferase reporter gene assessed as reduction in Wnt ligand-driven LEF/TCF-dependent transcriptional activity	ic50	0.0007	uM
2-(6-methyl-5,7-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b]pyridin-1-yl)-N-(5-phenyl-2-pyridinyl)acetamide	1457595: Inhibition of porcupine (unknown origin) expressed in HEK293 cells after day 1 post treatment by Super-top flash reporter gene assay	ic50	0.0010	uM
2-(6-methyl-5,7-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b]pyridin-1-yl)-N-(6-phenylpyridazin-3-yl)acetamide	1457595: Inhibition of porcupine (unknown origin) expressed in HEK293 cells after day 1 post treatment by Super-top flash reporter gene assay	ic50	0.0010	uM
2-[4-(2-methyl-4-pyridinyl)anilino]-N-(5-pyrazin-2-yl-2-pyridinyl)acetamide	1252015: Inhibition of porcupine (unknown origin) expressed in mouse L Wnt3A cells co-cultured with TM3 cells harboring luciferase reporter gene assessed as reduction in Wnt ligand-driven LEF/TCF-dependent transcriptional activity	ic50	0.0010	uM
(2S)-2-[[6-(2-methylpyrazol-3-yl)-3-pyridinyl]amino]-N-(5-phenyl-2-pyridinyl)propanamide	1433103: Inhibition of porcupine (unknown origin) expressed in HEK293-STF3A cells assessed as inhibition of Wnt signaling by measuring decrease in beta-catenin-mediated transcriptional activity after 24 hrs by Steady-Glo luciferase assay	ic50	0.0010	uM
(2S)-2-[[6-(2-methylpyrazol-3-yl)-3-pyridinyl]amino]-N-(5-pyridin-3-yl-2-pyridinyl)propanamide	1433103: Inhibition of porcupine (unknown origin) expressed in HEK293-STF3A cells assessed as inhibition of Wnt signaling by measuring decrease in beta-catenin-mediated transcriptional activity after 24 hrs by Steady-Glo luciferase assay	ic50	0.0010	uM
2-[4-(2-methylimidazol-1-yl)phenoxy]-N-(4-phenylphenyl)acetamide	1433103: Inhibition of porcupine (unknown origin) expressed in HEK293-STF3A cells assessed as inhibition of Wnt signaling by measuring decrease in beta-catenin-mediated transcriptional activity after 24 hrs by Steady-Glo luciferase assay	ic50	0.0020	uM
[4-(2-methyl-4-pyridinyl)phenyl] N-(4-pyridin-3-ylphenyl)carbamate	1252015: Inhibition of porcupine (unknown origin) expressed in mouse L Wnt3A cells co-cultured with TM3 cells harboring luciferase reporter gene assessed as reduction in Wnt ligand-driven LEF/TCF-dependent transcriptional activity	ic50	0.0022	uM
2-(6-cyanonaphthalen-2-yl)oxy-N-(5-pyrazin-2-yl-2-pyridinyl)acetamide	1252015: Inhibition of porcupine (unknown origin) expressed in mouse L Wnt3A cells co-cultured with TM3 cells harboring luciferase reporter gene assessed as reduction in Wnt ligand-driven LEF/TCF-dependent transcriptional activity	ic50	0.0027	uM
2-(1,3-dimethyl-2,6-dioxopurin-7-yl)-N-(6-phenylpyridazin-3-yl)acetamide	1257058: Inhibition of porcupine in human HEK293 cells assessed as reduction in Wnt secretion by measuring suppression of beta-catenin reporter activity after 24 hrs by STF reporter assay	ic50	0.0029	uM
2-[4-(2-methylpyrazol-3-yl)phenoxy]-N-(4-phenylphenyl)acetamide	1433103: Inhibition of porcupine (unknown origin) expressed in HEK293-STF3A cells assessed as inhibition of Wnt signaling by measuring decrease in beta-catenin-mediated transcriptional activity after 24 hrs by Steady-Glo luciferase assay	ic50	0.0040	uM
[4-(2-methyl-4-pyridinyl)phenyl] N-(4-phenylphenyl)carbamate	1252015: Inhibition of porcupine (unknown origin) expressed in mouse L Wnt3A cells co-cultured with TM3 cells harboring luciferase reporter gene assessed as reduction in Wnt ligand-driven LEF/TCF-dependent transcriptional activity	ic50	0.0050	uM
2-[(8S)-2,4-dimethyl-1,3-dioxo-7,8-dihydro-6H-purino[7,8-a]pyrrol-8-yl]-N-(6-phenylpyridazin-3-yl)acetamide	1257062: Inhibition of porcupine in human HEK293 cells by STF reporter assay	ic50	0.0050	uM
(2S)-2-(4-imidazol-1-ylanilino)-N-(5-phenyl-2-pyridinyl)propanamide	1433103: Inhibition of porcupine (unknown origin) expressed in HEK293-STF3A cells assessed as inhibition of Wnt signaling by measuring decrease in beta-catenin-mediated transcriptional activity after 24 hrs by Steady-Glo luciferase assay	ic50	0.0050	uM
2-(6-methyl-5,7-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b]pyridin-1-yl)-N-(6-phenyl-3-pyridinyl)acetamide	1457595: Inhibition of porcupine (unknown origin) expressed in HEK293 cells after day 1 post treatment by Super-top flash reporter gene assay	ic50	0.0060	uM
(2S)-2-(4-imidazol-1-ylphenoxy)-N-(4-phenylphenyl)propanamide	1433103: Inhibition of porcupine (unknown origin) expressed in HEK293-STF3A cells assessed as inhibition of Wnt signaling by measuring decrease in beta-catenin-mediated transcriptional activity after 24 hrs by Steady-Glo luciferase assay	ic50	0.0070	uM
2-(6-methyl-5,7-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b]pyridin-1-yl)-N-(4-pyridin-3-ylphenyl)acetamide	1457595: Inhibition of porcupine (unknown origin) expressed in HEK293 cells after day 1 post treatment by Super-top flash reporter gene assay	ic50	0.0080	uM
N-(6-methoxy-1,3-benzothiazol-2-yl)-2-[(4-propyl-5-pyridin-4-yl-1,2,4-triazol-3-yl)sulfanyl]acetamide	1627468: Displacement of [3H]-GNF-1331 from human PORCN after 3 hrs by scintillation counting analysis	ic50	0.0080	uM
N-[6-(5-fluoro-3-pyridinyl)pyridazin-3-yl]-2-(6-methyl-5,7-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b]pyridin-1-yl)acetamide	1457595: Inhibition of porcupine (unknown origin) expressed in HEK293 cells after day 1 post treatment by Super-top flash reporter gene assay	ic50	0.0090	uM
(2S)-2-[[6-(2-methylpyrazol-3-yl)-3-pyridinyl]amino]-N-(6-pyridin-3-yl-3-pyridinyl)propanamide	1433103: Inhibition of porcupine (unknown origin) expressed in HEK293-STF3A cells assessed as inhibition of Wnt signaling by measuring decrease in beta-catenin-mediated transcriptional activity after 24 hrs by Steady-Glo luciferase assay	ic50	0.0100	uM
2-(6-methyl-5,7-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b]pyridin-1-yl)-N-(6-pyridin-3-yl-3-pyridinyl)acetamide	1457595: Inhibition of porcupine (unknown origin) expressed in HEK293 cells after day 1 post treatment by Super-top flash reporter gene assay	ic50	0.0110	uM
2-(6-cyclopropyl-5,7-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b]pyridin-1-yl)-N-[6-(5-fluoro-3-pyridinyl)pyridazin-3-yl]acetamide	1457595: Inhibition of porcupine (unknown origin) expressed in HEK293 cells after day 1 post treatment by Super-top flash reporter gene assay	ic50	0.0110	uM
2-(6-cyclopropyl-5,7-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b]pyridin-1-yl)-N-[6-(6-methyl-3-pyridinyl)pyridazin-3-yl]acetamide	1457595: Inhibition of porcupine (unknown origin) expressed in HEK293 cells after day 1 post treatment by Super-top flash reporter gene assay	ic50	0.0120	uM
2-(6-methyl-5,7-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b]pyridin-1-yl)-N-(4-phenylphenyl)acetamide	1457595: Inhibition of porcupine (unknown origin) expressed in HEK293 cells after day 1 post treatment by Super-top flash reporter gene assay	ic50	0.0120	uM
2-(6-cyclopropyl-5,7-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b]pyridin-1-yl)-N-(6-pyridin-3-ylpyridazin-3-yl)acetamide	1457595: Inhibition of porcupine (unknown origin) expressed in HEK293 cells after day 1 post treatment by Super-top flash reporter gene assay	ic50	0.0120	uM
2-(6-methyl-5,7-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b]pyridin-1-yl)-N-[4-(1,3-thiazol-2-yl)phenyl]acetamide	1457595: Inhibition of porcupine (unknown origin) expressed in HEK293 cells after day 1 post treatment by Super-top flash reporter gene assay	ic50	0.0150	uM
2-(2-methyl-1,3-dioxoisoindol-4-yl)-N-[4-(1,3-thiazol-2-yl)phenyl]acetamide	1457595: Inhibition of porcupine (unknown origin) expressed in HEK293 cells after day 1 post treatment by Super-top flash reporter gene assay	ic50	0.0150	uM
2-(4-imidazol-1-ylphenoxy)-N-(4-phenylphenyl)acetamide	1433103: Inhibition of porcupine (unknown origin) expressed in HEK293-STF3A cells assessed as inhibition of Wnt signaling by measuring decrease in beta-catenin-mediated transcriptional activity after 24 hrs by Steady-Glo luciferase assay	ic50	0.0150	uM
2-[(2-acetyl-3,4-dihydro-1H-isoquinolin-7-yl)oxy]-N-(5-pyrazin-2-yl-2-pyridinyl)acetamide	1252015: Inhibition of porcupine (unknown origin) expressed in mouse L Wnt3A cells co-cultured with TM3 cells harboring luciferase reporter gene assessed as reduction in Wnt ligand-driven LEF/TCF-dependent transcriptional activity	ic50	0.0240	uM
2-(1,3-dimethyl-2,6-dioxopurin-7-yl)-N-[4-(1,3-thiazol-2-yl)phenyl]acetamide	1457595: Inhibition of porcupine (unknown origin) expressed in HEK293 cells after day 1 post treatment by Super-top flash reporter gene assay	ic50	0.0240	uM
2-[[3-(4-fluoro-2-methoxyphenyl)-4-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl]sulfanyl]-N-(6-methyl-1,3-benzothiazol-2-yl)acetamide	1257057: Inhibition of porcupine activity (unknown origin) expressed in human HT1080 cells assessed as suppression of Wnt3A-mediated super top flash activity by STF luciferase assay	ic50	0.0270	uM
2-(6-methyl-5,7-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b]pyridin-1-yl)-N-[6-(6-methyl-3-pyridinyl)pyridazin-3-yl]acetamide	1457595: Inhibition of porcupine (unknown origin) expressed in HEK293 cells after day 1 post treatment by Super-top flash reporter gene assay	ic50	0.0290	uM
2-(6-methyl-5,7-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b]pyridin-1-yl)-N-(6-pyridin-3-ylpyridazin-3-yl)acetamide	1457595: Inhibition of porcupine (unknown origin) expressed in HEK293 cells after day 1 post treatment by Super-top flash reporter gene assay	ic50	0.0290	uM
2-isoquinolin-7-yloxy-N-(5-pyrazin-2-yl-2-pyridinyl)acetamide	1252015: Inhibition of porcupine (unknown origin) expressed in mouse L Wnt3A cells co-cultured with TM3 cells harboring luciferase reporter gene assessed as reduction in Wnt ligand-driven LEF/TCF-dependent transcriptional activity	ic50	0.0300	uM
2-(4-imidazol-1-ylanilino)-N-(4-phenylphenyl)acetamide	1433103: Inhibition of porcupine (unknown origin) expressed in HEK293-STF3A cells assessed as inhibition of Wnt signaling by measuring decrease in beta-catenin-mediated transcriptional activity after 24 hrs by Steady-Glo luciferase assay	ic50	0.0300	uM
(2S)-1-(4-imidazol-1-ylphenyl)-N-(4-phenylphenyl)pyrrolidine-2-carboxamide	1433103: Inhibition of porcupine (unknown origin) expressed in HEK293-STF3A cells assessed as inhibition of Wnt signaling by measuring decrease in beta-catenin-mediated transcriptional activity after 24 hrs by Steady-Glo luciferase assay	ic50	0.0400	uM
2-[3-(2-methyl-4-pyridinyl)phenyl]sulfanyl-N-(5-pyrazin-2-yl-2-pyridinyl)acetamide	1252015: Inhibition of porcupine (unknown origin) expressed in mouse L Wnt3A cells co-cultured with TM3 cells harboring luciferase reporter gene assessed as reduction in Wnt ligand-driven LEF/TCF-dependent transcriptional activity	ic50	0.0400	uM
2-[4-(1,3-oxazol-5-yl)phenoxy]-N-(4-phenylphenyl)acetamide	1433103: Inhibition of porcupine (unknown origin) expressed in HEK293-STF3A cells assessed as inhibition of Wnt signaling by measuring decrease in beta-catenin-mediated transcriptional activity after 24 hrs by Steady-Glo luciferase assay	ic50	0.0420	uM
2,4-dimethyl-1,3-dioxo-N-[4-(1,3-thiazol-2-yl)phenyl]-7,8-dihydro-6H-purino[7,8-a]pyrrole-8-carboxamide	1457595: Inhibition of porcupine (unknown origin) expressed in HEK293 cells after day 1 post treatment by Super-top flash reporter gene assay	ic50	0.0420	uM
N-(6-methoxy-1,3-benzothiazol-2-yl)-2-[[3-(4-methoxyphenyl)-4-oxophthalazin-1-yl]methylamino]acetamide	1457594: Inhibition of porcupine (unknown origin)	ic50	0.0600	uM
N-[2-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-2-oxoethyl]-3-(4-methoxyphenyl)-4-oxophthalazine-1-carboxamide	1257057: Inhibition of porcupine activity (unknown origin) expressed in human HT1080 cells assessed as suppression of Wnt3A-mediated super top flash activity by STF luciferase assay	ic50	0.0600	uM

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic	decreases expression, increases abundance, increases expression	2
Estradiol	affects cotreatment, decreases expression, increases expression	2
Smoke	increases expression	2
Sodium Selenite	increases expression	2
Particulate Matter	increases expression	2
aristolochic acid I	increases expression	1
titanium dioxide	affects binding, increases expression	1
beta-lapachone	increases expression	1
sodium arsenite	increases abundance, increases expression	1
nickel sulfate	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
palbociclib	increases expression	1
jinfukang	increases expression, affects cotreatment	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	decreases expression, increases abundance	1
Cisplatin	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Phenobarbital	affects expression	1
Progesterone	decreases expression, affects cotreatment	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
Vanadates	increases expression	1
Vitallium	affects binding, increases expression	1
Cadmium Chloride	decreases expression, increases abundance	1

ChEMBL screening assays

31 unique, capped per target: 31 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1267179	Binding	Displacement of IWP-PB from porcn in HEK293 lysate by Western blot analysis	Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. — Nat Chem Biol

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2BL	Abcam HeLa PORCN KO	Cancer cell line	Female
CVCL_D7Y1	Ubigene A-549 PORCN KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03760835	PHASE4	RECRUITING	Congenital Adrenal Hyperplasia Once Daily Hydrocortisone Treatment
NCT04536662	PHASE4	UNKNOWN	Comparisons of Different Forms of Glucocorticoid on the Recovery of Reproductive Function in Patients With 21α-hydroxylase Deficiency
NCT02408445	PHASE4	COMPLETED	Body Composition in Infants With Klinefelter Syndrome and Effects of Testosterone Treatment
NCT03325647	PHASE4	COMPLETED	TESTO: Testosterone Effects on Short-Term Outcomes in Infants With XXY
NCT05498090	PHASE4	UNKNOWN	Interrogating Fatty Acid Metabolism Impairment and Clinical Correlates in Males with Klinefelter Syndrome
NCT06294990	PHASE4	RECRUITING	Klinefelter Syndrome and Testosterone Treatment in Puberty
NCT02343562	PHASE4	UNKNOWN	Probiotics for Prophylaxis of Postoperative Hirschsprungs Associated Enterocolitis
NCT07186647	PHASE4	COMPLETED	Laparoscopic-Assisted Transanal Pull-Through for Hirschsprung Disease in Pediatric:Short and Intermediate Outcomes of Two Different Techniques
NCT00001521	PHASE3	COMPLETED	Three Drug Combination Therapy Versus Conventional Treatment of Children With Congenital Adrenal Hyperplasia
NCT02716818	PHASE3	COMPLETED	Comparison of Chronocort® With Standard Glucocorticoid Therapy in Patients With Congenital Adrenal Hyperplasia
NCT03062280	PHASE3	COMPLETED	A Study of the Efficacy, Safety and Tolerability of Chronocort in Treating CAH
NCT03532022	PHASE3	WITHDRAWN	Open-label Comparison of Chronocort® Versus Standard Glucocorticoid Replacement Therapy
NCT04490915	PHASE3	ACTIVE_NOT_RECRUITING	Global Safety and Efficacy Registration Study of Crinecerfont for Congenital Adrenal Hyperplasia
NCT04806451	PHASE3	ACTIVE_NOT_RECRUITING	Global Safety and Efficacy Registration Study of Crinecerfont in Pediatric Participants With Classic Congenital Adrenal Hyperplasia (CAHtalyst Pediatric Study)
NCT05063994	PHASE3	COMPLETED	Comparison of Chronocort Versus Standard Hydrocortisone Replacement Therapy in Participants Aged 16 Years and Over With Congenital Adrenal Hyperplasia
NCT05299554	PHASE3	COMPLETED	Long-term Safety Study of Chronocort in the Treatment of Participants With Congenital Adrenal Hyperplasia
NCT07144163	PHASE3	RECRUITING	A Study to Evaluate Atumelnant in Adults With Congenital Adrenal Hyperplasia
NCT05586802	PHASE3	RECRUITING	Sex Steroids Balance for Metabolic and Reproductive Health in Klinefelter Syndrome
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT00621985	PHASE2	COMPLETED	Dexamethasone Treatment of Congenital Adrenal Hyperplasia
NCT01735617	PHASE2	COMPLETED	Pilot Study to Characterize and Examine the Pharmacokinetics and Efficacy of Chronocort® in Adults With CAH
NCT01771328	PHASE2	UNKNOWN	Continuous Subcutaneous Hydrocortisone Infusion in Congenital Adrenal Hyperplasia
NCT01859312	PHASE2	COMPLETED	Comparison of Cortisol Pump With Standard Treatment for Congenital Adrenal Hyperplasia
NCT02804178	PHASE2	COMPLETED	A Study of ATR-101 for the Treatment of Congenital Adrenal Hyperplasia
NCT03257462	PHASE2	COMPLETED	Study of SPR001 in Adults With Classic Congenital Adrenal Hyperplasia
NCT03548246	PHASE2	WITHDRAWN	Androgen Reduction in Congenital Adrenal Hyperplasia
NCT03669549	PHASE2	TERMINATED	Nevanimibe HCl for the Treatment of Classic CAH
NCT03687242	PHASE2	COMPLETED	Study to Evaluate the Safety and Efficacy of SPR001 in Subjects With Classic Congenital Adrenal Hyperplasia
NCT04457336	PHASE2	TERMINATED	A Ph2b to Evaluate Clinical Efficacy and Safety of Tildacerfont in Adult CAH
NCT04544410	PHASE2	TERMINATED	A Ph2b to Evaluate Tildacerfont in the Reduction of Glucocorticoid Steroid Doses in Adult CAH
NCT05128942	PHASE2	TERMINATED	A Phase 2 Study to Evaluate the Safety, Efficacy and PK of Tildacerfont in Children Aged 2-17 Years With CAH
NCT05907291	PHASE2	COMPLETED	Evaluate the Safety, Efficacy, and Pharmacokinetics of CRN04894 in Participants With Congenital Adrenal Hyperplasia (TouCAHn)
NCT06712823	PHASE2	RECRUITING	An Extension Study to Evaluate Safety and Efficacy in Participants Treated With CRN04894
NCT07187375	PHASE2	RECRUITING	Pharmacokinetics, Safety and Tolerability of Crinecerfont in Participants With Congenital Adrenal Hyperplasia Who Are Less Than 2 Years Old
NCT07536269	PHASE2	NOT_YET_RECRUITING	Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Crinecerfont in Participants With Classic Congenital Adrenal Hyperplasia (CAH) Who Are Less Than 4 Years Old
NCT00348946	PHASE2	COMPLETED	Androgen Effect on Klinefelter Syndrome Motor Outcome
NCT02061384	PHASE2	COMPLETED	RA-2 13-cis Retinoic Acid (Isotretinoin)
NCT05626634	PHASE2	COMPLETED	Open-label, Long-term Safety Study of LP352 in Subjects With Developmental and Epileptic Encephalopathy
NCT02349503	PHASE1	WITHDRAWN	Safety, Pharmacokinetics and Pharmacodynamics of NBI-77860 in Adolescent Females With Congenital Adrenal Hyperplasia