POFUT1

Chr 20AD

protein O-fucosyltransferase 1

Also known as: DDD2, FUT12, O-FUT, O-Fuc-T, O-FucT-1, OFUCT1

The POFUT1 protein is a glycosyltransferase that adds fucose to epidermal growth factor-like repeats on cell surface proteins, playing a crucial role in NOTCH signaling pathway regulation. Mutations cause Dowling-Degos disease 2, an autosomal dominant genodermatosis. This gene is highly constrained against loss-of-function mutations (pLI 0.96), indicating that such variants are likely to have significant functional consequences.

Summary from RefSeq, OMIM, UniProt
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Primary Disease Associations & Inheritance

Dowling-Degos disease 2MIM #615327
AD
0
Active trials
6
Pubs (1 yr)
0
P/LP submissions
P/LP missense
0.33
LOEUF· LoF intol.
Multiple*
Mechanism· predicted
Clinical SummaryPOFUT1
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Gene-Disease Validity (ClinGen)
Dowling-Degos disease 2 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.96). One damaged copy is likely sufficient to cause disease.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

LoF intolerant — likely haploinsufficient
LoF Constraint
0.33LOEUF
pLI 0.963
Z-score 3.62
OE 0.10 (0.040.33)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
0.95Z-score
OE missense 0.82 (0.730.93)
190 obs / 230.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.10 (0.040.33)
00.351.4
Missense OE0.82 (0.730.93)
00.61.4
Synonymous OE0.96
01.21.6
LoF obs/exp: 2 / 19.1Missense obs/exp: 190 / 230.7Syn Z: 0.33
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
strongPOFUT1-related Dowling-Degos diseaseOTHERAD
DN
0.3495th %ile
GOF
0.3986th %ile
LOF
0.55top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · LOEUF 0.33
GOF1 literature citation

Literature Evidence

GOFThis study provides insights on the possible involvement of these seven missense mutations in colorectal tumors. The hyperactive forms could lead to an increased O-fucosylation of POFUT1 protein targets such as NOTCH receptors in CRC patients, thereby leading to a NOTCH signaling dysregulation. It iPMID:32486426
LOFHaploinsufficiency of POFUT1 has been linked to adult-onset Dowling Degos Disease (DDD) with hyperpigmentation defects.PMID:29452367

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

POFUT1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

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Clinical Literature
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