RFNG

Summary

RFNG (RFNG O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase, HGNC:9974) is a protein-coding gene on chromosome 17q25.3, encoding Beta-1,3-N-acetylglucosaminyltransferase radical fringe (Q9Y644). Glycosyltransferase that initiates the elongation of O-linked fucose residues attached to EGF-like repeats in the extracellular domain of Notch molecules.

Predicted to enable O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase activity. Predicted to be involved in regulation of Notch signaling pathway. Predicted to act upstream of or within positive regulation of Notch signaling pathway. Predicted to be located in extracellular region.

Source: NCBI Gene 5986 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 64 total
• MANE Select transcript: NM_002917

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9974
Approved symbol	RFNG
Name	RFNG O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase
Location	17q25.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000169733
Ensembl biotype	protein_coding
OMIM	602578
Entrez	5986

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 7 retained_intron, 5 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000310496, ENST00000429557, ENST00000578356, ENST00000578676, ENST00000580793, ENST00000580928, ENST00000580953, ENST00000582478, ENST00000583784, ENST00000584463, ENST00000584515, ENST00000584838, ENST00000901399, ENST00000901400

RefSeq mRNA: 1 — MANE Select: NM_002917 NM_002917

CCDS: CCDS32773

Canonical transcript exons

ENST00000310496 — 8 exons

Exon	Start	End
ENSE00002222540	82051500	82051811
ENSE00003463247	82049918	82050006
ENSE00003536991	82047902	82048807
ENSE00003545106	82051294	82051342
ENSE00003571946	82050402	82050555
ENSE00003574223	82050662	82050764
ENSE00003623205	82049031	82049116
ENSE00003688505	82049677	82049842

Expression profiles

Bgee: expression breadth ubiquitous, 237 present calls, max score 95.64.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.3780 / max 108.5483, expressed in 1804 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
168896	21.5626	1804
168895	0.4934	305
168894	0.2346	110
168893	0.0873	31

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	95.64	gold quality
right ovary	UBERON:0002118	94.77	gold quality
lower esophagus mucosa	UBERON:0035834	94.66	gold quality
left ovary	UBERON:0002119	94.65	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.05	gold quality
stromal cell of endometrium	CL:0002255	93.91	gold quality
body of pancreas	UBERON:0001150	93.81	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.66	gold quality
adenohypophysis	UBERON:0002196	93.50	gold quality
right uterine tube	UBERON:0001302	93.43	gold quality
endocervix	UBERON:0000458	93.35	gold quality
apex of heart	UBERON:0002098	93.08	gold quality
body of stomach	UBERON:0001161	92.90	gold quality
cerebellar hemisphere	UBERON:0002245	92.77	gold quality
cerebellar cortex	UBERON:0002129	92.57	gold quality
body of uterus	UBERON:0009853	92.56	gold quality
tibial nerve	UBERON:0001323	92.43	gold quality
gastrocnemius	UBERON:0001388	92.40	gold quality
muscle layer of sigmoid colon	UBERON:0035805	92.27	gold quality
left uterine tube	UBERON:0001303	92.12	gold quality
pituitary gland	UBERON:0000007	92.10	gold quality
right frontal lobe	UBERON:0002810	92.10	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.08	gold quality
right lobe of thyroid gland	UBERON:0001119	91.99	gold quality
skin of leg	UBERON:0001511	91.98	gold quality
right coronary artery	UBERON:0001625	91.91	gold quality
lower esophagus	UBERON:0013473	91.89	gold quality
lower esophagus muscularis layer	UBERON:0035833	91.89	gold quality
right adrenal gland cortex	UBERON:0035827	91.75	gold quality
ascending aorta	UBERON:0001496	91.71	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.41

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

16 targeting RFNG, 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-4283	100.00	66.42	2097
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-4755-3P	98.77	65.59	1915
HSA-MIR-4726-3P	98.49	63.89	1385
HSA-MIR-1199-5P	98.44	66.51	829
HSA-MIR-6751-3P	98.44	66.35	835
HSA-MIR-6867-3P	98.12	66.07	1305
HSA-MIR-505-5P	97.01	65.54	778
HSA-MIR-6805-5P	95.79	64.86	670
HSA-MIR-6820-5P	94.04	61.13	161

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	rfng	ENSDARG00000019746
mus_musculus	Rfng	ENSMUSG00000025158
rattus_norvegicus	Rfng	ENSRNOG00000050298
drosophila_melanogaster	fng	FBGN0011591

Paralogs (3): MFNG (ENSG00000100060), LFNG (ENSG00000106003), B3GLCT (ENSG00000187676)

Protein

Protein identifiers

Beta-1,3-N-acetylglucosaminyltransferase radical fringe — Q9Y644 (reviewed: Q9Y644)

Alternative names: O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase

All UniProt accessions (3): Q9Y644, F5H3H7, J3QLN0

UniProt curated annotations — full annotation on UniProt →

Function. Glycosyltransferase that initiates the elongation of O-linked fucose residues attached to EGF-like repeats in the extracellular domain of Notch molecules. Modulates NOTCH1 activity by modifying O-fucose residues at specific EGF-like domains resulting in enhancement of NOTCH1 activation by DLL1 and JAG1. May be involved in limb formation and in neurogenesis.

Subcellular location. Golgi apparatus membrane.

Cofactor. Has some activity with cobalt but not with magnesium, calcium and zinc.

Similarity. Belongs to the glycosyltransferase 31 family.

RefSeq proteins (1): NP_002908* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003378	Fringe-like_glycosylTrfase	Domain
IPR017374	Fringe	Family

Pfam: PF02434

Enzyme classification (BRENDA):

• EC 2.4.1.222 — O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase (BRENDA: 8 organisms, 66 substrates, 5 inhibitors, 20 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
P-NITROPHENYL-ALPHA-L-FUCOSE	0.0012–0.129	15
UDP-BETA-D-GLCNAC	0.0343–0.0707	5

Catalyzed reactions (Rhea), 2 shown:

• 3-O-(alpha-L-fucosyl)-L-seryl-[EGF-like domain protein] + UDP-N-acetyl-alpha-D-glucosamine = 3-O-(N-acetyl-beta-D-glucosaminyl-(1->3)-alpha-L-fucosyl)-L-seryl-[EGF-like domain protein] + UDP + H(+) (RHEA:70511)
• 3-O-(alpha-L-fucosyl)-L-threonyl-[EGF-like domain protein] + UDP-N-acetyl-alpha-D-glucosamine = 3-O-(N-acetyl-beta-D-glucosaminyl-(1->3)-alpha-L-fucosyl)-L-threonyl-[EGF-like domain protein] + UDP + H(+) (RHEA:70531)

UniProt features (16 total): binding site 4, disulfide bond 3, topological domain 2, chain 1, glycosylation site 1, sequence conflict 1, transmembrane region 1, region of interest 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y644-F1	88.28	0.76

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): 237

Ligand- & substrate-binding residues (4): 261; 74; 147; 148

Disulfide bonds (3): 114–125, 143–207, 311–320

Glycosylation sites (1): 113

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1912420	Pre-NOTCH Processing in Golgi

MSigDB gene sets: 92 (showing top): REACTOME_SIGNALING_BY_NOTCH, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_POSITIVE_REGULATION_OF_NOTCH_SIGNALING_PATHWAY, MAYBURD_RESPONSE_TO_L663536_UP, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, BLALOCK_ALZHEIMERS_DISEASE_UP, SHIN_B_CELL_LYMPHOMA_CLUSTER_2, GOBP_REGULATION_OF_NOTCH_SIGNALING_PATHWAY, BOGNI_TREATMENT_RELATED_MYELOID_LEUKEMIA_UP, NIKOLSKY_BREAST_CANCER_17Q21_Q25_AMPLICON, DURCHDEWALD_SKIN_CARCINOGENESIS_DN, BENPORATH_OCT4_TARGETS, GOMF_HEXOSYLTRANSFERASE_ACTIVITY, GOMF_GLYCOSYLTRANSFERASE_ACTIVITY

GO Biological Process (6): pattern specification process (GO:0007389), nervous system development (GO:0007399), regulation of Notch signaling pathway (GO:0008593), animal organ morphogenesis (GO:0009887), cell differentiation (GO:0030154), positive regulation of Notch signaling pathway (GO:0045747)

GO Molecular Function (4): O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase activity (GO:0033829), metal ion binding (GO:0046872), transferase activity (GO:0016740), glycosyltransferase activity (GO:0016757)

GO Cellular Component (5): Golgi membrane (GO:0000139), extracellular region (GO:0005576), Golgi apparatus (GO:0005794), endomembrane system (GO:0012505), 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
cellular anatomical structure	3
Notch signaling pathway	2
multicellular organism development	1
multicellular organismal process	1
system development	1
regulation of signal transduction	1
anatomical structure morphogenesis	1
animal organ development	1
cellular developmental process	1
regulation of Notch signaling pathway	1
positive regulation of signal transduction	1
acetylglucosaminyltransferase activity	1
cation binding	1
catalytic activity	1
transferase activity	1
Golgi apparatus	1
bounding membrane of organelle	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

692 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RFNG	POFUT1	Q9H488	643
RFNG	DLL3	Q9NYJ7	567
RFNG	EGF	P01133	566
RFNG	B3GALT9	A8MXE2	506
RFNG	NOTCH3	Q9UM47	500
RFNG	LRRC42	Q9Y546	478
RFNG	B3GNT5	Q9BYG0	469
RFNG	POGLUT1	Q8NBL1	462
RFNG	SRRT	Q9BXP5	447
RFNG	SGCA	Q16586	434
RFNG	B4GALT1	P15291	428
RFNG	MPLKIP	Q8TAP9	423
RFNG	JAG1	P78504	405
RFNG	DTX1	Q86Y01	398
RFNG	DLL1	O00548	398
RFNG	EOGT	Q5NDL2	398

IntAct

5 interactions, top by confidence:

A	B	Type	Score
CLEC12B	GXYLT2	psi-mi:“MI:0914”(association)	0.350
ST14	LIPT2	psi-mi:“MI:0914”(association)	0.350
TMEM106A	RTL8C	psi-mi:“MI:0914”(association)	0.350
SCGB2A2	RTL8C	psi-mi:“MI:0914”(association)	0.350
HTR1B	SCAMP2	psi-mi:“MI:0914”(association)	0.350

BioGRID (6): RFNG (Affinity Capture-MS), RFNG (Affinity Capture-MS), RFNG (Affinity Capture-MS), RFNG (Affinity Capture-MS), RFNG (Affinity Capture-MS), RFNG (Proximity Label-MS)

ESM2 similar proteins: A5D7I4, A5PK45, A7MB73, A9X1C8, O09009, O09010, O12971, O12972, O60568, O97583, P16442, P52848, P52849, P52850, P97464, Q02353, Q16394, Q2KJ92, Q3UHN9, Q5IGR7, Q5IGR8, Q5R6K5, Q5RBC3, Q5T4B2, Q5U367, Q5U4X8, Q6GQK9, Q6IS24, Q6ZQ11, Q6ZRP7, Q7Z4H8, Q812F8, Q86X52, Q8K297, Q8NBJ5, Q8NES3, Q8R087, Q8VHI3, Q924T4, Q9EQH7

Diamond homologs: O00587, O09008, O09009, O09010, O12971, O12972, P79948, P79949, Q24342, Q2KJ92, Q5IS64, Q5YB40, Q6KFX9, Q8JHF2, Q8NES3, Q924T4, Q9R1U9, Q9Y644, Q9YHB3, Q5F3G7

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
RFNG	up-regulates	NOTCH1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	43
Likely benign	8
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1059 predictions. Top by Δscore:

Variant	Effect	Δscore
17:82049025:A:AC	donor_gain	1.0000
17:82049026:C:CC	donor_gain	1.0000
17:82049026:CTCA:C	donor_gain	1.0000
17:82049027:TCACC:T	donor_loss	1.0000
17:82049029:A:AC	donor_gain	1.0000
17:82049029:A:C	donor_loss	1.0000
17:82049029:AC:A	donor_gain	1.0000
17:82049030:C:CC	donor_gain	1.0000
17:82049030:CC:C	donor_gain	1.0000
17:82049030:CCGT:C	donor_gain	1.0000
17:82049116:CCTGG:C	acceptor_loss	1.0000
17:82049117:C:CC	acceptor_gain	1.0000
17:82049671:CTGTA:C	donor_loss	1.0000
17:82049672:TGTA:T	donor_loss	1.0000
17:82049673:GTAC:G	donor_loss	1.0000
17:82049674:TACCT:T	donor_loss	1.0000
17:82049675:A:AG	donor_loss	1.0000
17:82049676:C:CA	donor_loss	1.0000
17:82049676:CCTG:C	donor_gain	1.0000
17:82049679:G:A	donor_gain	1.0000
17:82049838:CCAGG:C	acceptor_gain	1.0000
17:82049839:CAGG:C	acceptor_gain	1.0000
17:82049839:CAGGC:C	acceptor_gain	1.0000
17:82049843:C:CC	acceptor_gain	1.0000
17:82050304:ATGC:A	donor_gain	1.0000
17:82050325:T:A	donor_gain	1.0000
17:82050331:C:CA	donor_gain	1.0000
17:82050400:A:AC	donor_gain	1.0000
17:82050401:C:CC	donor_gain	1.0000
17:82050401:CAGTT:C	donor_gain	1.0000

AlphaMissense

2134 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:82050554:A:G	W141R	0.996
17:82050554:A:T	W141R	0.996
17:82050552:C:A	W141C	0.995
17:82050552:C:G	W141C	0.995
17:82050679:G:C	F134L	0.995
17:82050679:G:T	F134L	0.995
17:82050681:A:G	F134L	0.995
17:82049953:G:C	S209R	0.994
17:82049953:G:T	S209R	0.994
17:82049955:T:G	S209R	0.994
17:82049983:A:C	F199L	0.994
17:82049983:A:T	F199L	0.994
17:82049985:A:G	F199L	0.994
17:82051523:A:G	W82R	0.993
17:82051523:A:T	W82R	0.993
17:82049959:G:C	C207W	0.992
17:82049933:A:C	M216R	0.990
17:82049960:C:T	C207Y	0.990
17:82049989:G:C	F197L	0.990
17:82049989:G:T	F197L	0.990
17:82049991:A:G	F197L	0.990
17:82049933:A:T	M216K	0.989
17:82049954:C:A	S209I	0.989
17:82050467:A:C	Y170D	0.989
17:82051521:C:A	W82C	0.989
17:82051521:C:G	W82C	0.989
17:82049942:G:T	A213D	0.987
17:82049961:A:G	C207R	0.987
17:82050548:A:G	C143R	0.987
17:82051570:G:A	T66I	0.987

dbSNP variants (sampled 300 via entrez): RS1000349452 (17:82052652 C>A,T), RS1000364181 (17:82052246 C>T), RS1001509222 (17:82047882 T>G), RS1001889356 (17:82051306 C>G,T), RS1001912810 (17:82048055 T>C), RS1001955385 (17:82053146 C>T), RS1001983007 (17:82048031 C>T), RS1002035521 (17:82047876 G>A), RS1002256662 (17:82051094 G>A,C), RS1003079366 (17:82049589 G>A,T), RS1003588624 (17:82047413 T>C), RS1004005110 (17:82051345 G>A), RS1004306877 (17:82048072 G>A), RS1004391283 (17:82051140 G>A,C,T), RS1004859808 (17:82047427 C>T)

Disease associations

OMIM: gene MIM:602578 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006979_259	Heel bone mineral density	2.000000e-17
GCST90020028_1294	Hip circumference adjusted for BMI	3.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	increases abundance, increases expression, affects expression	2
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Ozone	increases abundance, affects cotreatment, increases expression, affects expression	2
Particulate Matter	increases abundance, increases expression, affects cotreatment	2
bisphenol F	affects cotreatment, increases expression	1
bufotalin	decreases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
methacrylaldehyde	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	decreases expression	1
jinfukang	increases expression, affects cotreatment	1
picoxystrobin	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	increases expression	1
Acrolein	affects cotreatment, increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Diethylhexyl Phthalate	increases abundance, increases methylation	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Gasoline	increases expression, affects cotreatment, increases abundance	1
Indomethacin	affects cotreatment, increases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, increases abundance, increases expression	1

Clinical trials (associated diseases)

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