GeneBe

PORCN

protein-coding

porcupine O-acyltransferase, the group of Membrane bound O-acyltransferase family

Gene summary

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. [provided by RefSeq, Aug 2013]

Previous symbols:
  • DHOF

MANE transcript

NM_203475.3

Inheritance

XL, AD

ClinVar variants

P:78U:125B:60

Top phenotype

Focal dermal hypoplasia

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:48,508,959-48,520,814

External References & Databases

Ensembl (ENSG00000102312)NCBI Gene (64840)OMIM (300651)HGNC:17652GenCCUniProt (Q9H237)AlphaFoldClinVar (PORCN)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~11.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

focal dermal hypoplasiaDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010592

Submitter: G2P

focal dermal hypoplasiaSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010592

Submitter: PanelApp Australia

focal dermal hypoplasiaDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010592

Submitter: Ambry Genetics

microphthalmia, isolated, with colobomaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000170

Submitter: Orphanet

focal dermal hypoplasiaSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010592

Submitter: Orphanet

focal dermal hypoplasiaDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010592

Submitter: ClinGen

*PORCN* is located on chromosome Xp11.23 and encodes a membrane bound O-acyl transferase that acts as a key regulator of the Wnt signaling pathway. *PORCN* was first reported in relation to X-linked focal dermal hypoplasia in 2007 (Wang et al., PMID: 17546030; Grzeschik et al., PMID: 17546031). Focal dermal hypoplasia (FDH) is a highly variable multisystem disorder with X-linked dominant inheritance. Females (90% of affected individuals) are heterozygous or mosaic; non-mosaic variants in males result in *in utero* lethality, and surviving males (10% of affected individuals) exhibit somatic mosaicism. FDH is characterized by skin abnormalities, including congenital patchy skin aplasia, nodular fat herniations, and pigmentary changes; limb malformations; ocular defects; dysmorphic facial features; dental anomalies; and patchy alopecia. Psychomotor development is usually normal but some individuals have cognitive impairment and/or behavioral problems. A 1990 review of 91 FDH cases reported a 15% prevalence of intellectual disability (PMID: 2325092); a more recent publication reported a similar rate, with 18% (3/17) individuals exhibiting borderline to impaired cognitive ability (PMID: 26818018). Twenty variants (nonsense, frameshift, splice, start loss, and missense) reported in 20 probands in 4 publications (PMIDs: 19277062, 19292719, 21472892, 26603014) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by a mouse model (PMID: 22412863). In summary, there is definitive evidence supporting the relationship between *PORCN* and X-linked focal dermal hypoplasia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 19, 2019 (SOP Version 7). As of August 2026, this record underwent administrative updates to edit the evidence summary and update scoring to be consistent with SOP Version 12. No new evidence was added, and the classification remains the same.

focal dermal hypoplasiaSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010592

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Focal dermal hypoplasiaXL

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Dental; Dermatologic; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 13948891; 1190805; 843447; 17546031; 17546030; 18325042; 19309688; 19863546; 19586929; 20420028; 21332693; 21472892; 21484999; 21732017; 22414489; 22250236; 22735390; 23131169; 23399492Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PORCN variants in ClinVar

11 Conditions Cataloged
not providedTotal: 141
Focal dermal hypoplasiaTotal: 57
Inborn genetic diseasesTotal: 45
PORCN-related disorderTotal: 20
not specifiedTotal: 17
PORCN-Related Developmental DisordersTotal: 2
Genetic developmental and epileptic encephalopathyTotal: 1
History of neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_203475.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
2
clinvar
7
clinvar
31
clinvar
7
clinvar
 47
missense
5
clinvar
18
clinvar
101
clinvar
21
clinvar
1
clinvar
 146
nonsense
14
clinvar
6
clinvar
3
clinvar
 23
start loss
2
clinvar
 2
frameshift
10
clinvar
3
clinvar
1
clinvar
 14
splice donor/acceptor (+/-2bp)
9
clinvar
9
clinvar
13
clinvar
 31
Total3840125528263
Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 95 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_203475.3RefSeqNP_982301.114MANE Select
ENST00000326194.11EnsemblENSP00000322304.614MANE Select
NM_001282167.2RefSeqNP_001269096.111Standard
NM_001441333.1RefSeqNP_001428262.113Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
porcnDanio rerio

Structure: neural tube

Quality: shortened

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Wnt signaling pathway - Homo sapiens (human)
  • Wnt Signaling Pathway
  • Disease
  • Signaling by WNT
  • Signal Transduction

Biological Process

  • protein lipidation
  • glycoprotein metabolic process
  • Wnt signaling pathway
  • protein palmitoleylation
  • canonical Wnt signaling pathway

Molecular Function

  • Wnt-protein binding
  • palmitoleoyltransferase activity

Cellular Component

  • endoplasmic reticulum
  • endoplasmic reticulum membrane
  • integral component of endoplasmic reticulum membrane
  • AMPA glutamate receptor complex
  • glutamatergic synapse

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000326194
Coding exons
14
Length
11853
Individuals with no LoFs
0
Homozygous LoFs
0
Heterozygous LoFs
0
Defined
0
p
0.00
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.371122080.5380.00001862975
Missense (PolyPhen)2874.7710.374481087
Synonymous2.276188.20.6920.00000798953
Loss of Function4.35022.10.000.00000175293

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
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), to Wnt proteins. Serine palmitoleylation of WNT proteins is required for efficient binding to frizzled receptors. {ECO:0000250|UniProtKB:Q9JJJ7, ECO:0000269|PubMed:12034504, ECO:0000269|PubMed:20826466, ECO:0000269|PubMed:24292069}.;

Recessive Scores

pRec
0.290

Intolerance Scores

RVIS EVS
-0.52
RVIS percentile EVS
21.2

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.238

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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