POFUT1
protein-codingprotein O-fucosyltransferase 1, the group of Fucosyltransferases|MicroRNA protein coding host genes
Gene summary
This gene encodes a member of the glycosyltransferase O-Fuc family. This enzyme adds O-fucose through an O-glycosidic linkage to conserved serine or threonine residues in the epidermal growth factor-like repeats of a number of cell surface and secreted proteins. O-fucose glycans are involved in ligand-induced receptor signaling. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~30.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0008371
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014130
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0015286
Submitter: ClinGen
*POFUT1* was first reported in relation to autosomal recessive congenital disorder of glycosylation in 2018 (Takeuchi et al., PMID: 29452367). The proband presented with a syndromic condition characterized by recessive microcephaly, global developmental delay, and cardiac and vascular features. Variants in *POFUT1* have also been reported in individuals with Dowling-Degos disease 2 (OMIM: 615327). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into two disease entities. The split curation for autosomal dominant Dowling-Degos disease 2 has been curated separately. One missense variant that has been reported in humans is included in this curation. The mechanism for disease is unknown. This gene-disease relationship is supported by two animal models (PMID: 19161597, 12697902) and a cell culture rescue study (PMID: 29452367). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on the meeting date December 15, 2025 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0014130
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014130
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0014130
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0100038
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0014130
Submitter: ClinGen
Variants in *POFUT1* have primarily been reported in relation to autosomal dominant Dowling-Degos disease 2. A single case presenting with microcephaly, global developmental delay, cardiac defects, and failure to thrive with biallelic *POFUT1* variants has been reported (PMID: 29452367). This association will be assessed separately. *POFUT1* was first reported in relation to autosomal dominant Dowling-Degos disease 2 in 2013 (Li et al., PMID: 23684010). Twelve variants (nonsense, missense, frameshift, splice) that have been reported in twelve probands in five publications (PMIDs: 23684010, 25229252, 32258313, 25157627, 25639155) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be heterozygous loss of function. This gene-disease relationship is also supported by a knockout zebrafish model (PMID: 23684010). In summary, there is definitive evidence supporting the relationship between *POFUT1* and autosomal dominant Dowling-Degos disease 2. 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 Congenital Disorders of Glycosylation GCEP on the meeting date October 20, 2025 (SOP Version 11).
Clinical Genomic Database (CGD)
Manifestation: Dermatologic
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to POFUT1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_015352.2. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 24 | 5 | 30 | ||
| missense | 70 | 4 | 2 | 76 | ||
| nonsense | 3 | 1 | 1 | 5 | ||
| start loss | 0 | |||||
| frameshift | 2 | 2 | ||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 5 | 1 | 72 | 28 | 7 | 113 |
Highest pathogenic variant AF is 0.0000020530733
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_056167.1 | 7 | MANE Select | |
| Ensembl | ENSP00000364902.3 | 7 | MANE Select | |
| RefSeq | NP_758436.1 | 5 | Standard | |
| Ensembl | ENSP00000364882.3 | 5 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| pofut1 | Danio rerio | Structure: whole organism Quality: decreased pigmentation abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Other types of O-glycan biosynthesis - Homo sapiens (human)
- NOTCH-Ncore
- Notch
- Signal Transduction
- Pre-NOTCH Processing in the Endoplasmic Reticulum
Biological Process
- angiogenesis
- somitogenesis
- fucose metabolic process
- regulation of transcription, DNA-templated
- protein O-linked glycosylation
Molecular Function
- fucosyltransferase activity
- peptide-O-fucosyltransferase activity
Cellular Component
- endoplasmic reticulum
- membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000375749
- Coding exons
- 7
- Length
- 30788
- Individuals with no LoFs
- 125744
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 4
- Defined
- 125748
- p
- 0.0000159
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.952 | 190 | 231 | 0.824 | 0.0000134 | 2528 |
| Missense (PolyPhen) | 88 | 106.99 | 0.82253 | 1097 | ||
| Synonymous | 0.333 | 94 | 98.2 | 0.957 | 0.00000624 | 772 |
| Loss of Function | 3.62 | 2 | 19.1 | 0.105 | 9.71e-7 | 200 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalyzes the reaction that attaches fucose through an O-glycosidic linkage to a conserved serine or threonine residue found in the consensus sequence C2-X(4,5)-[S/T]-C3 of EGF domains, where C2 and C3 are the second and third conserved cysteines. Specifically uses GDP-fucose as donor substrate and proper disulfide pairing of the substrate EGF domains is required for fucose transfer. Plays a crucial role in NOTCH signaling. Initial fucosylation of NOTCH by POFUT1 generates a substrate for FRINGE/RFNG, an acetylglucosaminyltransferase that can then extend the fucosylation on the NOTCH EGF repeats. This extended fucosylation is required for optimal ligand binding and canonical NOTCH signaling induced by DLL1 or JAGGED1. Fucosylates AGRN and determines its ability to cluster acetylcholine receptors (AChRs). {ECO:0000269|PubMed:11524432, ECO:0000269|PubMed:28334865, ECO:0000269|PubMed:8358148}.;
- Disease
- DISEASE: Dowling-Degos disease 2 (DDD2) [MIM:615327]: An autosomal dominant genodermatosis. Affected individuals develop a postpubertal reticulate hyperpigmentation that is progressive and disfiguring, and small hyperkeratotic dark brown papules that affect mainly the flexures and great skin folds. Patients usually show no abnormalities of the hair or nails. {ECO:0000269|PubMed:23684010}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.132
Intolerance Scores
- LoFtool
- 0.447
- RVIS EVS
- -0.09
- RVIS percentile EVS
- 46.92
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.997
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |