POFUT1

Summary

POFUT1 (protein O-fucosyltransferase 1, HGNC:14988) is a protein-coding gene on chromosome 20q11.21, encoding GDP-fucose protein O-fucosyltransferase 1 (Q9H488). 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.

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.

Source: NCBI Gene 23509 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Dowling-Degos disease 2 (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 154 total — 6 pathogenic
• Phenotypes (HPO): 29
• MANE Select transcript: NM_015352

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14988
Approved symbol	POFUT1
Name	protein O-fucosyltransferase 1
Location	20q11.21
Locus type	gene with protein product
Status	Approved
Aliases	O-FUT, O-Fuc-T, KIAA0180, FUT12
Ensembl gene	ENSG00000101346
Ensembl biotype	protein_coding
OMIM	607491
Entrez	23509

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 9 protein_coding, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000375730, ENST00000375749, ENST00000434904, ENST00000465791, ENST00000486717, ENST00000706471, ENST00000706472, ENST00000910316, ENST00000910317, ENST00000921349, ENST00000921350, ENST00000955935, ENST00000955936, ENST00000955937

RefSeq mRNA: 2 — MANE Select: NM_015352 NM_015352, NM_172236

CCDS: CCDS13198, CCDS13199

Canonical transcript exons

ENST00000375749 — 7 exons

Exon	Start	End
ENSE00001154695	32210071	32210192
ENSE00003645457	32216609	32216721
ENSE00003663515	32215269	32215451
ENSE00003995918	32230819	32231061
ENSE00003995919	32207880	32208065
ENSE00003995920	32228263	32228455
ENSE00003995923	32234473	32238658

Expression profiles

Bgee: expression breadth ubiquitous, 160 present calls, max score 92.24.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 36.9158 / max 155.3265, expressed in 1811 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
184031	36.1843	1811
184030	0.7315	502

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	92.24	gold quality
ventricular zone	UBERON:0003053	89.17	gold quality
adrenal tissue	UBERON:0018303	88.94	gold quality
islet of Langerhans	UBERON:0000006	88.84	gold quality
smooth muscle tissue	UBERON:0001135	88.26	gold quality
right lobe of liver	UBERON:0001114	87.87	gold quality
rectum	UBERON:0001052	87.57	gold quality
calcaneal tendon	UBERON:0003701	86.13	gold quality
right coronary artery	UBERON:0001625	85.90	gold quality
thoracic aorta	UBERON:0001515	85.50	gold quality
ascending aorta	UBERON:0001496	85.37	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.18	gold quality
descending thoracic aorta	UBERON:0002345	85.09	gold quality
aorta	UBERON:0000947	84.93	gold quality
popliteal artery	UBERON:0002250	84.93	gold quality
tibial artery	UBERON:0007610	84.93	gold quality
hindlimb stylopod muscle	UBERON:0004252	84.89	gold quality
monocyte	CL:0000576	84.85	gold quality
left coronary artery	UBERON:0001626	84.78	gold quality
leukocyte	CL:0000738	84.69	gold quality
transverse colon	UBERON:0001157	84.65	gold quality
right atrium auricular region	UBERON:0006631	84.62	gold quality
apex of heart	UBERON:0002098	84.61	gold quality
right ovary	UBERON:0002118	84.55	gold quality
pancreas	UBERON:0001264	84.18	gold quality
left ovary	UBERON:0002119	84.01	gold quality
mucosa of transverse colon	UBERON:0004991	84.01	gold quality
colonic epithelium	UBERON:0000397	83.83	gold quality
vermiform appendix	UBERON:0001154	83.64	gold quality
gall bladder	UBERON:0002110	83.63	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.77

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1

miRNA regulators (miRDB)

95 targeting POFUT1, 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-6873-3P	100.00	71.42	2626
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-370-5P	99.78	66.81	706
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-10393-5P	99.65	68.01	1368
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-1251-3P	99.64	67.21	1408
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-497-3P	99.61	69.71	1990

Literature-anchored findings (GeneRIF, showing 27)

• fucosyltransferases, O-FucT-1 is a soluble protein that localizes to the endoplasmic reticulum and recognizes properly folded epidermal growth factor-like repeats. (PMID:15653671)
• Pofut1 and O-fucose have roles in mammalian Notch signaling (PMID:18347015)
• The protein product of POFUT1 plays a significant and conserved role in melanin synthesis and transport. (PMID:23684010)
• POFUT1 expression can contribute to cancer progression and that POFUT1 may serve as a diagnostic marker and a therapeutic target for OSCCs. (PMID:24064921)
• Silencing of Pofut1 expression exerted antiproliferative and antiadhesive effects on hepatocytes. (PMID:25107841)
• Only a novel 1-bp deletion (c.246+5delG) in POFUT1 was found in a Chinese family with Dowling-Degos disease (DDD). No other novel mutation or this deletion was detected in POFUT1 in a second DDD family and a sporadic DDD case by Sanger Sequencing. (PMID:25157627)
• The upregulation of poFUT1 by LIF facilitated trophoblast cell migration and invasion through activating the PI3K/Akt signaling pathway. (PMID:25165882)
• Identification of six pathogenic POFUT1 mutations in Dowling-Degos disease patients of different ethnic origin. (PMID:25229252)
• POFUT1, POGLUT1 and ADAM10 are processing enzymes that are involved in different steps of Notch receptor activation in the epidermis[10]; the roles of these unique enzymes in a single pathway may explain both the overlapping and distinct clinical features of DDD and RAK patients (PMID:26486618)
• High expression of POFUT1 correlates with aggressive clinicopathological characteristics and poor prognosis of hepatocellular carcinoma patients. (PMID:27003260)
• POFUT1 gene expression in gastric cancer (PMID:28040433)
• the reported Dowling-Degos mutations of POFUT1, except for M262T, fail to rescue Notch1 signaling efficiently in the CRISPR-engineered POFUT1-/- background; these studies identify POFUT1 as a potential target for cancers driven by Notch1 mutations and provide a structural roadmap for its inhibition (PMID:28334865)
• Our findings suggested that overexpression of Pofut1 and activated Notch1 signaling may be associated with a poor prognosis in breast cancer. (PMID:28709865)
• The results suggest that this N-glycan of POFUT1 is not required for its proper enzymatic function, and that the p.Ser162Leu mutation of POFUT1 likely causes global developmental delay, microcephaly with vascular and cardiac defects. (PMID:29452367)
• heterozygous nonsense POFUT1 mutations c.210G>A (p.Trp70*) and c.871C>T (p.Gln291*) were identified in Probands 1 and 2, respectively. The mutations segregated perfectly with the phenotypes in both families. (PMID:29797344)
• POFUT1 is a tumor activating gene during colorectal cancer development, which positively regulates colorectal cancer tumor progression through activating Notch1. (PMID:30250219)
• we revealed that poFUT1 was increased in the secretory phase compared to the proliferative phase. Meanwhile, poFUT1 was expressed at lower levels in the uterine endometrium of miscarriage patients than that in normal early pregnancies. Moreover, we provides novel evidence showing that poFUT1 controls the O-fucosylation and activation ofNotch1. (PMID:31201143)
• Our team identified for the first time a bidirectional promoter pair oncogene, PLAGL2-POFUT1, in colorectal cancer (CRC). (PMID:31279780)
• High POFUT1 expression was also associated with Notch signaling enrichment and with decreased goblet cells differentiation. In-depth molecular characterization of colorectal adenomas revealed POFUT1 and Notch signaling as potential drivers of tumor progression. (PMID:31411736)
• poFUT1 promotes uterine angiogenesis and vascular remodeling via enhancing the O-fucosylation on uPA. (PMID:31601791)
• PLAGL2 and POFUT1 were common and upregulated in tumor samples in colorectal cancer (CRC). Survival analysis of PLAGL2 and POFUT1 expression revealed differences between proximal and distal CRC. PLAGL2 and POFUT1, which have the highest correlation with tumor location, may serve as biomarkers and therapeutic targets for the precise diagnosis and treatment of CRC in the future. (PMID:31638246)
• POFUT1 acts as a tumor promoter in glioblastoma by enhancing the activation of Notch signaling. (PMID:34251584)
• Circular RNA circPOFUT1 enhances malignant phenotypes and autophagy-associated chemoresistance via sequestrating miR-488-3p to activate the PLAG1-ATG12 axis in gastric cancer. (PMID:36624091)
• Preliminary study on the mechanism of POFUT1 in colorectal cancer. (PMID:37432515)
• Overexpression of POFUT1 promotes malignant phenotype and mediates perineural invasion in head and neck squamous cell carcinoma. (PMID:37641160)
• POFUT1 and PLAGL2 are characteristic markers of mucinous colorectal cancer associated with MUC2 expression. (PMID:38500386)
• Analysis of endogenous NOTCH1 from POFUT1 S162L patient fibroblasts reveals the importance of the O-fucose modification on EGF12 in human development. (PMID:38976017)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pofut1	ENSDARG00000008953
mus_musculus	Pofut1	ENSMUSG00000046020
rattus_norvegicus	Pofut1	ENSRNOG00000010104
drosophila_melanogaster	O-fut1	FBGN0033901
caenorhabditis_elegans		WBGENE00015793

Protein

Protein identifiers

GDP-fucose protein O-fucosyltransferase 1 — Q9H488 (reviewed: Q9H488)

Alternative names: Peptide-O-fucosyltransferase 1

All UniProt accessions (3): Q9H488, A0A9L9PX68, A0A9L9PY15

UniProt curated annotations — full annotation on UniProt →

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).

Subcellular location. Endoplasmic reticulum.

Tissue specificity. Highly expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.

Post-translational modifications. N-glycosylated.

Disease relevance. 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. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein glycosylation.

Similarity. Belongs to the glycosyltransferase 65 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H488-1	1	yes
Q9H488-2	2

RefSeq proteins (2): NP_056167, NP_758436 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019378	GDP-Fuc_O-FucTrfase	Family
IPR039922	POFUT1	Family

Pfam: PF10250

Enzyme classification (BRENDA):

• EC 2.4.1.221 — peptide-O-fucosyltransferase (BRENDA: 12 organisms, 68 substrates, 3 inhibitors, 15 Km, 2 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GDP-BETA-L-FUCOSE	0.001–0.0368	6
FACTOR VII EGF	0.006–0.015	2
GDP-L-FUCOSE	0.013–0.015	2
GLCNACBETA(1-2)MANALPHA(1-6)[GLCNACBETA(1-2)MANA	0.15–0.154	2
GDP-FUCOSE	0.0098	1
TSR4	0.0295	1

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + GDP-beta-L-fucose = 3-O-(alpha-L-fucosyl)-L-seryl-[protein] + GDP + H(+) (RHEA:63644)
• L-threonyl-[protein] + GDP-beta-L-fucose = 3-O-(alpha-L-fucosyl)-L-threonyl-[protein] + GDP + H(+) (RHEA:70491)

UniProt features (62 total): helix 20, strand 18, disulfide bond 4, mutagenesis site 4, binding site 4, turn 4, sequence variant 2, glycosylation site 2, signal peptide 1, chain 1, splice variant 1, short sequence motif 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
5UX6	X-RAY DIFFRACTION	2.09
5UXH	X-RAY DIFFRACTION	2.41

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H488-F1	93.39	0.88

Functional residue map

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

Ligand- & substrate-binding residues (4): 43–46; 238–240; 340; 357–358

Disulfide bonds (4): 126–140, 249–283, 267–354, 38–40

Glycosylation sites (2): 62, 160

Mutagenesis-validated functional residues (4):

Position	Phenotype
240	strongly impaired ability to activate notch signaling.
262	no effect on ability to activate notch signaling.
356	abolishes ability to activate notch signaling.
366	strongly impaired ability to activate notch signaling.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1912399	Pre-NOTCH Processing in the Endoplasmic Reticulum

MSigDB gene sets: 225 (showing top): REACTOME_SIGNALING_BY_NOTCH, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, PAX4_01, GCANCTGNY_MYOD_Q6, SP3_Q3, AREB6_03, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, MEF2_02, AP2_Q3, AAAYRNCTG_UNKNOWN, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, PATIL_LIVER_CANCER, MYOD_01

GO Biological Process (9): angiogenesis (GO:0001525), somitogenesis (GO:0001756), fucose metabolic process (GO:0006004), Notch signaling pathway (GO:0007219), nervous system development (GO:0007399), heart development (GO:0007507), regulation of Notch signaling pathway (GO:0008593), protein O-linked glycosylation via fucose (GO:0036066), obsolete protein glycosylation (GO:0006486)

GO Molecular Function (3): peptide-O-fucosyltransferase activity (GO:0046922), transferase activity (GO:0016740), glycosyltransferase activity (GO:0016757)

GO Cellular Component (2): endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Pre-NOTCH Expression and Processing	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure formation involved in morphogenesis	2
blood vessel morphogenesis	1
anterior/posterior pattern specification	1
segmentation	1
chordate embryonic development	1
somite development	1
hexose metabolic process	1
cell surface receptor signaling pathway	1
system development	1
animal organ development	1
circulatory system development	1
Notch signaling pathway	1
regulation of signal transduction	1
protein O-linked glycosylation	1
fucosyltransferase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
transferase activity	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1138 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POFUT1	POFUT2	Q9Y2G5	868
POFUT1	POGLUT1	Q8NBL1	860
POFUT1	PLAGL2	Q9UPG8	794
POFUT1	LFNG	Q8NES3	755
POFUT1	EOGT	Q5NDL2	749
POFUT1	KIF3B	O15066	748
POFUT1	FUT8	Q9BYC5	730
POFUT1	RBPJ	Q06330	714
POFUT1	JAG1	P78504	672
POFUT1	MFNG	O00587	670
POFUT1	XXYLT1	Q8NBI6	669
POFUT1	NOTCH2	Q04721	664
POFUT1	FUT1	P19526	664
POFUT1	TM9SF4	Q92544	651
POFUT1	MAML1	Q92585	649

IntAct

33 interactions, top by confidence:

A	B	Type	Score
C1QTNF9	C1QTNF9B	psi-mi:“MI:0914”(association)	0.780
FBXO6	MAN2B1	psi-mi:“MI:0914”(association)	0.640
	PLOD2	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
CGREF1	TNKS	psi-mi:“MI:0914”(association)	0.530
CNPY3	LRIG2	psi-mi:“MI:0914”(association)	0.530
POFUT1	AKT2	psi-mi:“MI:0915”(physical association)	0.370
LRRK2		psi-mi:“MI:0914”(association)	0.350
H2AX	ANXA6	psi-mi:“MI:0914”(association)	0.350
	PLOD3	psi-mi:“MI:0914”(association)	0.350
CCL3	KRBA1	psi-mi:“MI:0914”(association)	0.350
FBLN7	CIBAR1	psi-mi:“MI:0914”(association)	0.350
WDR54	OSCP1	psi-mi:“MI:0914”(association)	0.350
A2M	SRPX2	psi-mi:“MI:0914”(association)	0.350
ASGR2	SCAMP2	psi-mi:“MI:0914”(association)	0.350
AZU1	UBA6	psi-mi:“MI:0914”(association)	0.350
C1orf54	QSOX1	psi-mi:“MI:0914”(association)	0.350
C1QTNF9B	DNASE2	psi-mi:“MI:0914”(association)	0.350
DDX28	UBA6	psi-mi:“MI:0914”(association)	0.350
FBXO6	TMEM131L	psi-mi:“MI:0914”(association)	0.350
HPN	DDX39A	psi-mi:“MI:0914”(association)	0.350
LCN6	HIGD1C	psi-mi:“MI:0914”(association)	0.350
MRPL49	UBA6	psi-mi:“MI:0914”(association)	0.350
OAS1	UBA6	psi-mi:“MI:0914”(association)	0.350
PEX7	UBA6	psi-mi:“MI:0914”(association)	0.350

BioGRID (56): POFUT1 (Affinity Capture-RNA), POFUT1 (Affinity Capture-RNA), POFUT1 (Affinity Capture-RNA), POFUT1 (Affinity Capture-MS), ACAA2 (Co-fractionation), POFUT1 (Co-fractionation), POFUT1 (Proximity Label-MS), POFUT1 (Affinity Capture-MS), POFUT1 (Affinity Capture-MS), POFUT1 (Affinity Capture-MS), POFUT1 (Affinity Capture-MS), POFUT1 (Proximity Label-MS), POFUT1 (Affinity Capture-MS), POFUT1 (Affinity Capture-MS), POFUT1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0D3QS99, A4IID1, A5D7I4, A7MB73, A9X1C8, G5E897, O60568, O95461, O97583, P24802, P52849, P52850, P58242, P83337, P97464, Q13822, Q16394, Q566E5, Q5IGR6, Q5IGR7, Q5IGR8, Q5M854, Q5M900, Q5NDE9, Q5NDF2, Q5R6K5, Q5RBC3, Q5T4B2, Q5U367, Q66PG3, Q66PG4, Q6EV69, Q6EV70, Q6GMK0, Q6GQI7, Q6IS24, Q6KFX9, Q6P9A2, Q6UW63, Q7Z4H8

Diamond homologs: P83337, Q18014, Q6EV69, Q6EV70, Q91ZW2, Q9H488, Q9V6X7

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
POFUT1	up-regulates	NOTCH1	binding
POFUT1	up-regulates	NOTCH	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	0
Uncertain significance	73
Likely benign	37
Benign	28

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
1344696	NM_015352.2(POFUT1):c.889_890del (p.Trp297fs)	Pathogenic
2636247	NM_015352.2(POFUT1):c.397C>T (p.Arg133Ter)	Pathogenic
3252104	NM_015352.2(POFUT1):c.246+5del	Pathogenic
56808	NM_015352.2(POFUT1):c.430G>T (p.Glu144Ter)	Pathogenic
56809	NM_015352.2(POFUT1):c.482del (p.Lys161fs)	Pathogenic
574378	NM_015352.2(POFUT1):c.289C>T (p.Gln97Ter)	Pathogenic

SpliceAI

1500 predictions. Top by Δscore:

Variant	Effect	Δscore
20:32215266:TA:T	acceptor_loss	1.0000
20:32215267:A:AC	acceptor_loss	1.0000
20:32215267:A:AG	acceptor_gain	1.0000
20:32215268:G:GC	acceptor_gain	1.0000
20:32215268:GCTC:G	acceptor_gain	1.0000
20:32215268:GCTCC:G	acceptor_gain	1.0000
20:32215429:A:G	donor_gain	1.0000
20:32215452:G:GA	donor_loss	1.0000
20:32215453:T:A	donor_loss	1.0000
20:32230814:CGTAG:C	acceptor_loss	1.0000
20:32230817:A:AG	acceptor_gain	1.0000
20:32230817:AG:A	acceptor_loss	1.0000
20:32230818:G:A	acceptor_loss	1.0000
20:32230818:G:GT	acceptor_gain	1.0000
20:32230818:GA:G	acceptor_gain	1.0000
20:32230818:GAA:G	acceptor_gain	1.0000
20:32230818:GAAGA:G	acceptor_gain	1.0000
20:32231057:GGAAG:G	donor_gain	1.0000
20:32231058:G:T	donor_gain	1.0000
20:32231058:GAAG:G	donor_gain	1.0000
20:32231058:GAAGG:G	donor_gain	1.0000
20:32231059:A:T	donor_gain	1.0000
20:32231061:GGT:G	donor_loss	1.0000
20:32231062:G:C	donor_loss	1.0000
20:32231063:T:G	donor_loss	1.0000
20:32234468:TGCA:T	acceptor_loss	1.0000
20:32234469:GCA:G	acceptor_loss	1.0000
20:32234470:CA:C	acceptor_loss	1.0000
20:32234471:A:AC	acceptor_loss	1.0000
20:32234471:A:AG	acceptor_gain	1.0000

AlphaMissense

2550 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:32216635:G:C	W152C	1.000
20:32216635:G:T	W152C	1.000
20:32228315:T:C	F199L	1.000
20:32228317:C:A	F199L	1.000
20:32228317:C:G	F199L	1.000
20:32208053:T:C	C38R	0.999
20:32208054:G:A	C38Y	0.999
20:32208055:C:G	C38W	0.999
20:32208060:G:A	C40Y	0.999
20:32208061:C:G	C40W	0.999
20:32208065:G:A	G42R	0.999
20:32208065:G:C	G42R	0.999
20:32210084:C:A	N46K	0.999
20:32210084:C:G	N46K	0.999
20:32210134:G:C	R63P	0.999
20:32210146:T:A	V67D	0.999
20:32210154:T:A	W70R	0.999
20:32210154:T:C	W70R	0.999
20:32215399:G:A	C126Y	0.999
20:32215400:C:G	C126W	0.999
20:32215440:T:A	C140S	0.999
20:32215440:T:C	C140R	0.999
20:32215441:G:C	C140S	0.999
20:32216633:T:A	W152R	0.999
20:32216633:T:C	W152R	0.999
20:32228316:T:G	F199C	0.999
20:32228453:T:A	W245R	0.999
20:32228453:T:C	W245R	0.999
20:32228455:G:C	W245C	0.999
20:32228455:G:T	W245C	0.999

dbSNP variants (sampled 300 via entrez): RS1000054382 (20:32234786 G>A), RS1000206191 (20:32228106 C>A), RS1000280910 (20:32228140 G>A,C,T), RS1000355981 (20:32213988 T>A), RS1000388757 (20:32234803 A>T), RS1000607279 (20:32233729 T>C), RS1000617183 (20:32229727 G>C), RS1000649953 (20:32226480 A>G,T), RS1000664361 (20:32233276 G>A), RS1000738757 (20:32234447 T>G), RS1000774914 (20:32215144 C>T), RS1000815784 (20:32208817 CAG>C), RS1000895059 (20:32213542 G>C), RS1001206995 (20:32229802 A>G,T), RS1001321718 (20:32229541 G>A,C)

Disease associations

OMIM: gene MIM:607491 | disease phenotypes: MIM:615327

GenCC curated gene-disease

Disease	Classification	Inheritance
Dowling-Degos disease 2	Definitive	Autosomal dominant
Dowling-Degos disease	Supportive	Autosomal dominant
complex neurodevelopmental disorder	Limited	Autosomal recessive
congenital disorder of glycosylation	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
Dowling-Degos disease 2	Definitive	AD
congenital disorder of glycosylation	Limited	AR

Mondo (4): Dowling-Degos disease 2 (MONDO:0014130), complex neurodevelopmental disorder (MONDO:0100038), congenital disorder of glycosylation (MONDO:0015286), Dowling-Degos disease (MONDO:0008371)

Orphanet (1): Dowling-Degos disease (Orphanet:79145)

HPO phenotypes

29 total (29 of 29 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000464	Abnormality of the neck
HP:0000962	Hyperkeratosis
HP:0000989	Pruritus
HP:0001034	Hypermelanotic macule
HP:0001155	Abnormality of the hand
HP:0001231	Abnormal fingernail morphology
HP:0001369	Arthritis
HP:0002046	Heat intolerance
HP:0007456	Progressive reticulate hyperpigmentation
HP:0007502	Follicular hyperkeratosis
HP:0007588	Reticular hyperpigmentation
HP:0009123	Mixed hypo- and hyperpigmentation of the skin
HP:0009719	Hypomelanotic macule
HP:0010610	Palmar pits
HP:0011354	Generalized abnormality of skin
HP:0012855	Scrotal hyperpigmentation
HP:0020073	Hypopigmented macule
HP:0025473	Hyperpigmented papule
HP:0030052	Inguinal freckling
HP:0030350	Erythematous papule
HP:0030442	Anal margin squamous cell carcinoma
HP:0031293	Digital pitting scar
HP:0031447	Penile freckling
HP:0031525	Keratoacanthoma
HP:0040154	Acne inversa
HP:0045059	Hyperkeratotic papule
HP:0200037	Skin vesicle
HP:0200040	Epidermoid cyst

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST004131_132	Inflammatory bowel disease	6.000000e-06
GCST004147_17	Chronic obstructive pulmonary disease	8.000000e-07
GCST006585_245	Blood protein levels	2.000000e-14
GCST007611_4	Chronic obstructive pulmonary disease or high blood pressure (pleiotropy)	4.000000e-08

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D018981	Congenital Disorders of Glycosylation	C16.320.565.202.125; C18.452.648.202.125
C562924	Dowling-Degos Disease (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, decreases reaction, increases abundance	3
sodium arsenite	decreases expression, increases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
ginger extract	increases expression, decreases reaction, increases abundance	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
chloropicrin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
enzalutamide	affects expression	1
LDN 193189	affects cotreatment, increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Calcitriol	increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ivermectin	decreases expression	1
Oils, Volatile	increases abundance, increases expression, decreases reaction	1
Progesterone	decreases expression	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Valproic Acid	decreases methylation	1
Aflatoxin B1	decreases methylation	1
Asbestos, Crocidolite	decreases expression	1
Cadmium Chloride	decreases expression	1
Copper Sulfate	decreases expression	1
Genistein	decreases expression, increases reaction	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07572825	PHASE1	NOT_YET_RECRUITING	Assessing the Safety and Tolerability of NMN in DHDDS-CDG
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT02089789	Not specified	RECRUITING	Clinical and Basic Investigations Into Known and Suspected Congenital Disorders of Glycosylation
NCT02503267	Not specified	UNKNOWN	Incidence and Consequences of Disorders of Glycosylation in Patients With Conotruncal and Septal Heart Defects
NCT02955264	Not specified	COMPLETED	Using D-Galactose as a Food Supplement in Congenital Disorders of Glycosylation
NCT03250728	Not specified	COMPLETED	Role of the Endothelium in Stroke-like Episode Among CDG Patients
NCT03560570	Not specified	COMPLETED	Study of Hemostasis in Patients With Congenital Disorder of Glycosylation
NCT04198987	Not specified	COMPLETED	Dietary Monosaccharide Supplementation in Patients With Congenital Disorders of Glycosylation
NCT04199000	Not specified	RECRUITING	Clinical and Basic Investigations Into Congenital Disorders of Glycosylation
NCT04201067	Not specified	COMPLETED	Large-Scale Metabolomic Profiling for the Diagnosis of Inborn Errors of Metabolism