SUMF1

Summary

SUMF1 (sulfatase modifying factor 1, HGNC:20376) is a protein-coding gene on chromosome 3p26.1, encoding Formylglycine-generating enzyme (Q8NBK3). Oxidase that catalyzes the conversion of cysteine to 3-oxoalanine on target proteins, using molecular oxygen and an unidentified reducing agent. 3-oxoalanine modification, which is also named formylglycine (fGly), occurs in the maturation of arylsulfatases and some alkaline phos….

This gene encodes an enzyme that catalyzes the hydrolysis of sulfate esters by oxidizing a cysteine residue in the substrate sulfatase to an active site 3-oxoalanine residue, which is also known as C-alpha-formylglycine. Mutations in this gene cause multiple sulfatase deficiency, a lysosomal storage disorder. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 285362 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mucosulfatidosis (Definitive, ClinGen)
• GWAS associations: 15
• Clinical variants (ClinVar): 734 total — 58 pathogenic, 51 likely-pathogenic
• Phenotypes (HPO): 50
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_182760

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20376
Approved symbol	SUMF1
Name	sulfatase modifying factor 1
Location	3p26.1
Locus type	gene with protein product
Status	Approved
Aliases	FGE, UNQ3037
Ensembl gene	ENSG00000144455
Ensembl biotype	protein_coding
OMIM	607939
Entrez	285362

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 12 protein_coding, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000272902, ENST00000383843, ENST00000405420, ENST00000448413, ENST00000458465, ENST00000469888, ENST00000470751, ENST00000484993, ENST00000881800, ENST00000881801, ENST00000881802, ENST00000881803, ENST00000933293, ENST00000948920, ENST00000948921, ENST00000948922

RefSeq mRNA: 3 — MANE Select: NM_182760 NM_001164674, NM_001164675, NM_182760

CCDS: CCDS2564, CCDS54548, CCDS54549

Canonical transcript exons

ENST00000272902 — 9 exons

Exon	Start	End
ENSE00000965223	4452876	4453049
ENSE00001072608	4361146	4362254
ENSE00001173755	4376330	4376389
ENSE00001173758	4410865	4410978
ENSE00001173766	4417128	4417242
ENSE00001173770	4418010	4418132
ENSE00001173775	4420064	4420146
ENSE00001173781	4449266	4449340
ENSE00001939829	4466976	4467269

Expression profiles

Bgee: expression breadth ubiquitous, 258 present calls, max score 97.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.9706 / max 227.5841, expressed in 1818 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
40830	23.9706	1818

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
kidney epithelium	UBERON:0004819	97.60	gold quality
renal medulla	UBERON:0000362	97.52	gold quality
upper arm skin	UBERON:0004263	97.04	gold quality
layer of synovial tissue	UBERON:0007616	96.63	gold quality
oviduct epithelium	UBERON:0004804	96.06	gold quality
synovial joint	UBERON:0002217	95.62	gold quality
tibia	UBERON:0000979	94.62	gold quality
penis	UBERON:0000989	94.59	gold quality
esophagus squamous epithelium	UBERON:0006920	94.54	gold quality
upper leg skin	UBERON:0004262	94.48	gold quality
nipple	UBERON:0002030	94.23	gold quality
stromal cell of endometrium	CL:0002255	93.90	gold quality
pylorus	UBERON:0001166	93.66	gold quality
bronchial epithelial cell	CL:0002328	93.61	gold quality
urethra	UBERON:0000057	93.60	gold quality
epithelial cell of pancreas	CL:0000083	93.57	gold quality
bronchus	UBERON:0002185	93.53	gold quality
mammalian vulva	UBERON:0000997	93.35	gold quality
ileal mucosa	UBERON:0000331	93.19	gold quality
trachea	UBERON:0003126	93.12	gold quality
decidua	UBERON:0002450	93.03	gold quality
skin of hip	UBERON:0001554	92.94	gold quality
visceral pleura	UBERON:0002401	92.94	gold quality
parietal pleura	UBERON:0002400	92.66	gold quality
nasal cavity epithelium	UBERON:0005384	92.53	gold quality
buccal mucosa cell	CL:0002336	92.36	gold quality
palpebral conjunctiva	UBERON:0001812	92.36	gold quality
pharyngeal mucosa	UBERON:0000355	92.34	gold quality
saphenous vein	UBERON:0007318	92.31	gold quality
pancreatic ductal cell	CL:0002079	92.07	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-111727	yes	453.97
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

85 targeting SUMF1, 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-5692A	100.00	74.40	6850
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488
HSA-MIR-548Y	99.94	71.28	3514

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 32)

• mutational analysis of SUMF1 in 20 Multiple sulfatase deficiency patients of different ethnic origin (PMID:15146462)
• characterization of the human Calpha-formylglycine-generating enzyme (PMID:15657036)
• FGE is a single-domain monomer with a surprising paucity of secondary structure and adopts a unique fold. The effect of all 18 missense mutations found in MSD patients is explained by the FGE structure, providing a molecular basis of MSD. (PMID:15907468)
• Sulphatase-modifying factor 1 interacts with SUMF2 to regulate sulphatase activities (PMID:15962010)
• co-delivery of SUMF1 may enhance the efficacy of gene therapy in several sulfatase deficiencies (PMID:17206939)
• study demonstrates that upon secretion, SUMF1 can be taken up from the medium by several cell lines; following its uptake, SUMF1 shuttles from the plasma membrane to the endoplasmic reticulum (PMID:17446859)
• Complete loss of SUMF1 function is likely to be lethal in humans. (PMID:17657823)
• Our data provide evidence that haploinsufficiency of ITPR1 alone, but not SUMF1, causes SCA16 and SCA15. (PMID:17932120)
• Molecular analysis of sulfatase modifying factor 1 mutations. (PMID:18157819)
• ERp44-mediated retention of FGE, indicating that noncovalent interactions between ERp44 and FGE are sufficient to mediate ER retention. (PMID:18178549)
• the non-catalytic N-terminal extension of formylglycine-generating enzyme is required for its biological activity and retention in the endoplasmic reticulum (PMID:18305113)
• Study shows that SUMF1 interacts with protein disulfide isomerase (PDI) and ERp44, two thioredoxin family members residing in the early secretory pathway, and with ERGIC-53, a lectin that shuttles between the ER and the Golgi. (PMID:18508857)
• This study present clinical findings of two consanguineous patients with multiple sulfatase deficiency. They were found to be homozygous for a novel missense mutation c.739G > C causing a p.G247R amino acid substitution in the SUMF1 protein. (PMID:18509892)
• We have identified a 414-kb deletion including the entire ITPR1 and exon 1 of SUMF1 in patients in a Japanese family with Spinocerebellar ataxia type 15. (PMID:18579805)
• This study identified genetic variation of SUMF1 in genes associated with in vivo glutamate measured using 1H magnetic resonance spectroscopic imaging in the grey matter of patients with multiple sclerosis. (PMID:20802204)
• Phenotypic outcome in Multiple Sulfatase Deficiency depends on both residual FGE activity as well as protein stability. (PMID:21224894)
• furin-mediated processing of FGE during secretion is a physiological means of higher eukaryotic cells to regulate FGE activity upon exit from the endoplasmic reticulum (PMID:23288839)
• A novel missense mutation & an insertional truncating mutation in SUMF1 gene causing nultiple sulphatase deficiency. (PMID:25222778)
• MSD presenting in the newborn period with hypotonia, apnoea, cyanosis and rolling eyes, hepato-splenomegaly and deafness. This patient was compound heterozygous for two so far undescribed SUMF1 mutations (c.191C > A; p.S64X and c.818A > G; p.D273G (PMID:25516103)
• This detailed clinical description and follow-up of a cohort of patients, together with the molecular characterisation of their underlying defects, contribute to improved knowledge of multiple sulfatase deficiency. (PMID:25885655)
• The complete kinetic parameters for both forms of FGE are described, along with a proposed mechanism for FGE catalysis that accounts for the copper-dependent activity. (PMID:25931126)
• SUMF1 catalyses a monooxygenase type of reaction. (PMID:26077311)
• We show that SUMF1 expression is affected in COPD patients compared to controls, and that SNPs in SUMF1 are associated with an increased risk of COPD. Certain COPD-associated SNPs have effects on either SUMF1 gene expression or on lung function. Collectively, this study shows that SUMF1 is associated with an increased risk of developing COPD. (PMID:28464818)
• Herein, in this report, it was aimed to depict two rare cases from two different families with similar gene mutations and clinical presentation, neuro-imaging, and laboratory result of MSD in Iran. (PMID:29479672)
• protein disulfide isomerase (PDI) plays a pivotal role in the recognition and quality control of Multiple sulfatase deficiency-causing FGE variants. (PMID:29972788)
• Multiple sulfatase deficiency is an autosomal recessive lysosomal storage disorder due to a deficiency in formylglycine-generating enzyme, which is encoded by the Sulfatase Modifying Factor 1 ( SUMF1) gene. (PMID:30124108)
• A homozygous missense variant of SUMF1 in the Bedouin population extends the clinical spectrum in ultrarare neonatal multiple sulfatase deficiency. (PMID:32048457)
• Multiple Sulfatase Deficiency: A Disease Comprising Mucopolysaccharidosis, Sphingolipidosis, and More Caused by a Defect in Posttranslational Modification. (PMID:32414121)
• A systematic review and meta-analysis of published cases reveals the natural disease history in multiple sulfatase deficiency. (PMID:32621519)
• Natural history of multiple sulfatase deficiency: Retrospective phenotyping and functional variant analysis to characterize an ultra-rare disease. (PMID:32749716)
• Association between SUMF1 polymorphisms and COVID-19 severity. (PMID:37344788)
• SUMF1 overexpression promotes tumorous cell growth and migration and is correlated with the immune status of patients with glioma. (PMID:38460946)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	sumf1	ENSDARG00000044203
mus_musculus	Sumf1	ENSMUSG00000030101
rattus_norvegicus	Sumf1	ENSRNOG00000006813
drosophila_melanogaster	CG7049	FBGN0035102

Paralogs (1): SUMF2 (ENSG00000129103)

Protein

Protein identifiers

Formylglycine-generating enzyme — Q8NBK3 (reviewed: Q8NBK3)

Alternative names: C-alpha-formylglycine-generating enzyme 1, Sulfatase-modifying factor 1

All UniProt accessions (3): Q8NBK3, E9PF05, F5GXA0

UniProt curated annotations — full annotation on UniProt →

Function. Oxidase that catalyzes the conversion of cysteine to 3-oxoalanine on target proteins, using molecular oxygen and an unidentified reducing agent. 3-oxoalanine modification, which is also named formylglycine (fGly), occurs in the maturation of arylsulfatases and some alkaline phosphatases that use the hydrated form of 3-oxoalanine as a catalytic nucleophile. Known substrates include GALNS, ARSA, STS and ARSE.

Subunit / interactions. Monomer, homodimer and heterodimer with SUMF2.

Subcellular location. Endoplasmic reticulum lumen.

Tissue specificity. Ubiquitous. Highly expressed in kidney, pancreas and liver. Detected at lower levels in leukocytes, lung, placenta, small intestine, skeletal muscle and heart.

Post-translational modifications. N-glycosylated. Contains high-mannose-type oligosaccharides.

Disease relevance. Multiple sulfatase deficiency (MSD) [MIM:272200] A clinically and biochemically heterogeneous disorder caused by the simultaneous impairment of all sulfatases, due to defective post-translational modification and activation. It combines features of individual sulfatase deficiencies such as metachromatic leukodystrophy, mucopolysaccharidosis, chondrodysplasia punctata, hydrocephalus, ichthyosis, neurologic deterioration and developmental delay. The disease is caused by variants affecting the gene represented in this entry. SUMF1 mutations result in defective post-translational modification of sulfatases.

Cofactor. The catalytic copper is required to activate oxygen and catalyze oxidative C-H activation.

Pathway. Protein modification; sulfatase oxidation.

Miscellaneous. The resulting 3-oxoalanine in the substrate protein is called C(alpha)-formylglycine by many authors. It should not be confused with N-formylglycine.

Similarity. Belongs to the sulfatase-modifying factor family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q8NBK3-1	1	yes
Q8NBK3-2	2
Q8NBK3-3	3
Q8NBK3-4	4
Q8NBK3-5	5

RefSeq proteins (3): NP_001158146, NP_001158147, NP_877437* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005532	SUMF_dom	Domain
IPR016187	CTDL_fold	Homologous_superfamily
IPR042095	SUMF_sf	Homologous_superfamily
IPR051043	Sulfatase_Mod_Factor_Kinase	Family

Pfam: PF03781

Enzyme classification (BRENDA):

• EC 1.8.3.7 — formylglycine-generating enzyme (BRENDA: 7 organisms, 18 substrates, 5 inhibitors, 11 Km, 14 kcat entries)

Substrate kinetics (BRENDA)

3 substrates with measured Km, best-characterized 3. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ABZ-SAL-3-OXO-L-ALA-SPTRA-NH2	0.1–0.55	5
ABZ-ATTPLCGPSRASILSGR	0.39–0.53	3
ABZ-SALCSPTRA-NH2	0.23–0.58	3

Catalyzed reactions (Rhea), 1 shown:

• L-cysteinyl-[sulfatase] + 2 a thiol + O2 = an organic disulfide + 3-oxo-L-alanyl-[sulfatase] + hydrogen sulfide + H2O + H(+) (RHEA:51152)

UniProt features (71 total): sequence variant 18, binding site 11, strand 11, helix 7, mutagenesis site 6, splice variant 4, sequence conflict 4, disulfide bond 3, region of interest 2, turn 2, signal peptide 1, chain 1, glycosylation site 1

Structure

Experimental structures (PDB)

18 structures.

PDB	Method	Resolution (Å)
5SSX	X-RAY DIFFRACTION	1.02
5SSZ	X-RAY DIFFRACTION	1.02
8ARU	X-RAY DIFFRACTION	1.08
1Z70	X-RAY DIFFRACTION	1.15
5SSY	X-RAY DIFFRACTION	1.29
2AFY	X-RAY DIFFRACTION	1.49
2AII	X-RAY DIFFRACTION	1.54
1Y1J	X-RAY DIFFRACTION	1.55
2AIJ	X-RAY DIFFRACTION	1.55
2HI8	X-RAY DIFFRACTION	1.64
2AFT	X-RAY DIFFRACTION	1.66
1Y1G	X-RAY DIFFRACTION	1.67
1Y1H	X-RAY DIFFRACTION	1.67
1Y1E	X-RAY DIFFRACTION	1.73
2AIK	X-RAY DIFFRACTION	1.73
1Y1F	X-RAY DIFFRACTION	1.8
2HIB	X-RAY DIFFRACTION	2
1Y1I	X-RAY DIFFRACTION	2.61

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NBK3-F1	85.39	0.75

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 (11): 296; 298; 300; 336; 341; 130; 259; 260; 273; 275; 293

Disulfide bonds (3): 50–52, 218–365, 235–346

Glycosylation sites (1): 141

Mutagenesis-validated functional residues (6):

Position	Phenotype
333	loss of activity.
333	reduces activity by 99%.
336	loss of activity.
337	reduces activity 5-fold.
340	no effect.
341	loss of activity.

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-1663150	The activation of arylsulfatases
R-HSA-9840310	Glycosphingolipid catabolism
R-HSA-1430728	Metabolism
R-HSA-163841	Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation
R-HSA-1660662	Glycosphingolipid metabolism
R-HSA-392499	Metabolism of proteins
R-HSA-428157	Sphingolipid metabolism
R-HSA-556833	Metabolism of lipids
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 287 (showing top): TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, KEGG_LYSOSOME, GOBP_MEMBRANE_LIPID_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GTGCCTT_MIR506, GOBP_GLYCOLIPID_CATABOLIC_PROCESS, GOBP_SPHINGOLIPID_METABOLIC_PROCESS, USF_01, TGTGTGA_MIR377, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_LIPID_METABOLIC_PROCESS, REACTOME_SPHINGOLIPID_METABOLISM, USF_02, GOBP_LIPOSACCHARIDE_METABOLIC_PROCESS

GO Biological Process (3): protein oxidation (GO:0018158), post-translational protein modification (GO:0043687), glycosphingolipid catabolic process (GO:0046479)

GO Molecular Function (6): oxidoreductase activity (GO:0016491), identical protein binding (GO:0042802), formylglycine-generating oxidase activity (GO:0120147), cupric ion binding (GO:1903135), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (3): endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1
Glycosphingolipid metabolism	1
Post-translational protein modification	1
Sphingolipid metabolism	1
Metabolism of lipids	1
Metabolism	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein modification process	2
glycosphingolipid metabolic process	1
glycolipid catabolic process	1
sphingolipid catabolic process	1
catalytic activity	1
protein binding	1
oxidoreductase activity, acting on a sulfur group of donors, oxygen as acceptor	1
copper ion binding	1
binding	1
cation binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
endoplasmic reticulum	1
intracellular organelle lumen	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1391 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SUMF1	GALNS	P34059	920
SUMF1	ARSB	P15848	857
SUMF1	ERP44	Q9BS26	837
SUMF1	ITPR1	Q14643	801
SUMF1	CNTN4	Q8IWV2	783
SUMF1	ARSA	P15289	781
SUMF1	SGSH	P51688	763
SUMF1	GLB1	P16278	614
SUMF1	IDS	P22304	614
SUMF1	SETMAR	Q53H47	602
SUMF1	NAGLU	P54802	586
SUMF1	DARS1	P14868	533
SUMF1	IDUA	P35475	525
SUMF1	LRRN1	Q6UXK5	501
SUMF1	ZNF385A	Q96PM9	497

IntAct

83 interactions, top by confidence:

A	B	Type	Score
SUMF1	SGSH	psi-mi:“MI:0914”(association)	0.710
SGSH	SUMF1	psi-mi:“MI:0915”(physical association)	0.710
B3GNT3	PGRMC1	psi-mi:“MI:0914”(association)	0.670
STIM2	PRKAB2	psi-mi:“MI:0914”(association)	0.640
SUMF1	SUMF2	psi-mi:“MI:0915”(physical association)	0.640
SUMF2	SUMF1	psi-mi:“MI:0915”(physical association)	0.640
SUMF1	SUMF2	psi-mi:“MI:0403”(colocalization)	0.640
CTRC	SUMF1	psi-mi:“MI:0915”(physical association)	0.590
ERP44	MEX3A	psi-mi:“MI:0914”(association)	0.530
IFNA21	IFIT3	psi-mi:“MI:0914”(association)	0.530
ARSA	ZBTB43	psi-mi:“MI:0914”(association)	0.530
GNS	CLPX	psi-mi:“MI:0914”(association)	0.530
PNLIP	LAMC1	psi-mi:“MI:0914”(association)	0.530
STS	GJA1	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
SUN2	POTEF	psi-mi:“MI:0914”(association)	0.530
GALNS	CLGN	psi-mi:“MI:0914”(association)	0.530
SGSH	FBXO21	psi-mi:“MI:0914”(association)	0.530

BioGRID (67): SUMF1 (Affinity Capture-MS), SUMF1 (Affinity Capture-MS), SUMF1 (Affinity Capture-MS), SUMF1 (Affinity Capture-MS), SUMF1 (Co-fractionation), SUMF1 (Affinity Capture-MS), SUMF1 (Affinity Capture-MS), SUMF1 (Affinity Capture-MS), SUMF1 (Affinity Capture-MS), SUMF1 (Affinity Capture-MS), SUMF1 (Affinity Capture-MS), SUMF1 (Affinity Capture-MS), SUMF1 (Affinity Capture-MS), SUMF1 (Affinity Capture-MS), SUMF1 (Affinity Capture-MS)

ESM2 similar proteins: A1A4K5, A2BGL3, D1A7C3, D4PHA7, I6Y8I5, O75808, P22413, P57110, P97812, Q09325, Q0P5L5, Q10979, Q13219, Q14DK5, Q16270, Q16549, Q2TBF2, Q3TCT4, Q505J3, Q5DTK1, Q5QQ49, Q5QQ50, Q5QQ51, Q5QQ56, Q5QQ57, Q5RCR5, Q61139, Q62849, Q64610, Q658N2, Q6P9A2, Q6UWX4, Q80XH4, Q811B1, Q86Y38, Q8BG58, Q8BPG6, Q8NBJ7, Q8NBK3, Q8R0F3

Diamond homologs: A0R5N0, G7CFI3, O69671, Q0P5L5, Q58CP2, Q5RCR5, Q7D513, Q8BPG6, Q8NBJ7, Q8NBK3, Q8R0F3, Q9F3C7, A0A0H3MBJ2, D1A7C3, I6Y8I5, P0DPS7, Q7AJA5, Q822R1, Q9PKP3, V9TSX0, O94632, O34722

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 83 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	6	42.3×	3e-07
Glycosphingolipid catabolism	7	34.2×	1e-07
Glycosphingolipid metabolism	6	30.1×	2e-06
Sphingolipid metabolism	6	16.8×	6e-05
Neutrophil degranulation	16	6.2×	3e-07
Metabolism of lipids	9	4.7×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	58
Likely pathogenic	51
Uncertain significance	204
Likely benign	311
Benign	38

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1067600	NM_182760.4(SUMF1):c.603-1G>C	Pathogenic
1070279	NC_000003.11:g.(?4403818)(4494743_?)del	Pathogenic
1070280	NC_000003.11:g.(?4403818)(4459826_?)del	Pathogenic
1072766	NM_182760.4(SUMF1):c.43G>T (p.Glu15Ter)	Pathogenic
1076822	NM_182760.4(SUMF1):c.451A>T (p.Lys151Ter)	Pathogenic
1323658	NM_182760.4(SUMF1):c.706C>T (p.Arg236Ter)	Pathogenic
1348585	NC_000003.11:g.(?4494540)(4494753_?)del	Pathogenic
1366344	NM_182760.4(SUMF1):c.323del (p.Ile108fs)	Pathogenic
1378318	NM_182760.4(SUMF1):c.603-2A>T	Pathogenic
1409518	NM_182760.4(SUMF1):c.903G>A (p.Trp301Ter)	Pathogenic
1422956	NM_182760.4(SUMF1):c.668del (p.Lys223fs)	Pathogenic
1431236	NM_182760.4(SUMF1):c.826C>T (p.Gln276Ter)	Pathogenic
1453143	NM_182760.4(SUMF1):c.539G>A (p.Trp180Ter)	Pathogenic
1456418	NM_182760.4(SUMF1):c.790G>T (p.Glu264Ter)	Pathogenic
1457189	NC_000003.11:g.(?4461738)(4461840_?)del	Pathogenic
1459688	NC_000003.11:g.(?4403818)(4461840_?)del	Pathogenic
1460004	NC_000003.11:g.(?4403818)(4508939_?)del	Pathogenic
1460108	NM_182760.4(SUMF1):c.632G>A (p.Trp211Ter)	Pathogenic
1460160	NM_182760.4(SUMF1):c.876C>G (p.Tyr292Ter)	Pathogenic
2022738	NM_182760.4(SUMF1):c.774del (p.Asn259fs)	Pathogenic
2029578	NM_182760.4(SUMF1):c.675dup (p.Pro226fs)	Pathogenic
2066505	NM_182760.4(SUMF1):c.572del (p.Pro191fs)	Pathogenic
2081614	NM_182760.4(SUMF1):c.552del (p.Gly185fs)	Pathogenic
2083297	NM_182760.4(SUMF1):c.1023T>A (p.Cys341Ter)	Pathogenic
2095730	NM_182760.4(SUMF1):c.908C>G (p.Ser303Ter)	Pathogenic
2203301	NM_182760.4(SUMF1):c.954+5G>T	Pathogenic
2427593	NC_000003.11:g.(?4490940)(4491034_?)del	Pathogenic
2663	NM_182760.4(SUMF1):c.519+5_519+8del	Pathogenic
2665	NM_182760.4(SUMF1):c.979C>T (p.Arg327Ter)	Pathogenic
2671	NM_182760.4(SUMF1):c.661del (p.Ala221fs)	Pathogenic

SpliceAI

435 predictions. Top by Δscore:

Variant	Effect	Δscore
3:3799917:GGG:G	donor_gain	0.9800
3:3799918:GG:G	donor_gain	0.9800
3:3799918:GGG:G	donor_gain	0.9800
3:3799919:GG:G	donor_gain	0.9800
3:3799917:GGGGT:G	donor_loss	0.9700
3:3799920:GT:G	donor_loss	0.9700
3:3799921:TAAG:T	donor_loss	0.9700
3:3801221:GC:G	donor_gain	0.9700
3:3799922:AA:A	donor_loss	0.9600
3:3844362:A:AG	acceptor_gain	0.9600
3:3844363:G:GG	acceptor_gain	0.9600
3:3844442:T:G	donor_gain	0.9600
3:3799920:G:GG	donor_gain	0.9500
3:3801244:GCC:G	donor_gain	0.9500
3:3843674:A:AG	acceptor_gain	0.9500
3:3844358:TTTCA:T	acceptor_loss	0.9500
3:3844359:TTCA:T	acceptor_loss	0.9500
3:3844360:TCA:T	acceptor_loss	0.9500
3:3844362:A:C	acceptor_loss	0.9500
3:3844363:G:GC	acceptor_loss	0.9500
3:3844363:GGCAC:G	acceptor_gain	0.9500
3:3801191:TTCTG:T	donor_gain	0.9400
3:3801242:CCGCC:C	donor_gain	0.9400
3:3801243:CGCC:C	donor_gain	0.9400
3:3801244:GCCG:G	donor_gain	0.9400
3:3801247:G:GG	donor_gain	0.9400
3:3801216:C:T	donor_gain	0.9300
3:3799483:C:T	donor_gain	0.9200
3:3799923:AG:A	donor_loss	0.9200
3:3801222:C:G	donor_gain	0.9200

AlphaMissense

2418 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:4362241:C:A	R343M	0.999
3:4410918:A:G	W301R	0.999
3:4410918:A:T	W301R	0.999
3:4410924:A:G	W299R	0.999
3:4410924:A:T	W299R	0.999
3:4417173:A:C	F265L	0.999
3:4417173:A:T	F265L	0.999
3:4417175:A:G	F265L	0.999
3:4420128:A:G	W180R	0.999
3:4420128:A:T	W180R	0.999
3:4362241:C:G	R343T	0.998
3:4410922:C:A	W299C	0.998
3:4410922:C:G	W299C	0.998
3:4417232:A:G	W246R	0.998
3:4417232:A:T	W246R	0.998
3:4420126:C:A	W180C	0.998
3:4420126:C:G	W180C	0.998
3:4420131:A:G	W179R	0.998
3:4420131:A:T	W179R	0.998
3:4362201:G:C	S356R	0.997
3:4362201:G:T	S356R	0.997
3:4362203:T:G	S356R	0.997
3:4362246:A:C	C341W	0.997
3:4362247:C:T	C341Y	0.997
3:4362248:A:G	C341R	0.997
3:4376336:G:C	C336W	0.997
3:4376337:C:T	C336Y	0.997
3:4376338:A:G	C336R	0.997
3:4410928:G:C	N297K	0.997
3:4410928:G:T	N297K	0.997

dbSNP variants (sampled 300 via entrez): RS1000003691 (3:4215238 C>G), RS1000004641 (3:4280496 A>G), RS1000007571 (3:4233230 G>A), RS1000017400 (3:4154691 C>A,G), RS1000018727 (3:4133576 T>C), RS1000026870 (3:4418562 T>C), RS1000031095 (3:4055858 T>C,G), RS1000034758 (3:4430929 C>A), RS1000036921 (3:4349941 A>C), RS1000037108 (3:4400010 A>G), RS1000040558 (3:4426764 C>A), RS1000042118 (3:4075841 A>T), RS1000042683 (3:4312736 G>A), RS1000043696 (3:4346656 G>A), RS1000044365 (3:4362908 T>C)

Disease associations

OMIM: gene MIM:607939 | disease phenotypes: MIM:272200, MIM:606658

GenCC curated gene-disease

Disease	Classification	Inheritance
mucosulfatidosis	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mucosulfatidosis	Definitive	AR

Mondo (3): mucosulfatidosis (MONDO:0010088), spinocerebellar ataxia type 15/16 (MONDO:0011694), neurodevelopmental disorder (MONDO:0700092)

Orphanet (3): Multiple sulfatase deficiency (Orphanet:585), Spinocerebellar ataxia type 15/16 (Orphanet:98769), Spinocerebellar ataxia type 16 (Orphanet:98770)

HPO phenotypes

50 total (30 of 50 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000280	Coarse facial features
HP:0000319	Smooth philtrum
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000463	Anteverted nares
HP:0000505	Visual impairment
HP:0000518	Cataract
HP:0000546	Retinal degeneration
HP:0000574	Thick eyebrow
HP:0000648	Optic atrophy
HP:0000943	Dysostosis multiplex
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001319	Neonatal hypotonia
HP:0001387	Joint stiffness
HP:0001744	Splenomegaly
HP:0002003	Large forehead
HP:0002059	Cerebral atrophy
HP:0002119	Ventriculomegaly
HP:0002208	Coarse hair
HP:0002240	Hepatomegaly
HP:0002376	Developmental regression

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST000783_4	Multiple sclerosis–Brain Glutamate Levels	6.000000e-07
GCST003488_15	Response to fenofibrate (triglyceride levels)	9.000000e-06
GCST004283_1	Midgestational circulating levels of PCBs	1.000000e-07
GCST004283_14	Midgestational circulating levels of PCBs	1.000000e-07
GCST004283_17	Midgestational circulating levels of PCBs	9.000000e-08
GCST004283_19	Midgestational circulating levels of PCBs	2.000000e-07
GCST004283_2	Midgestational circulating levels of PCBs	9.000000e-08
GCST007478_7	Non-word reading	3.000000e-06
GCST008161_117	Waist circumference adjusted for body mass index	8.000000e-06
GCST008959_2	Lipid traits	4.000000e-08
GCST010516_2	Fractures (paediatric)	1.000000e-07
GCST012277_9	Clostridioides difficle infection	2.000000e-06
GCST012490_14	Femur bone mineral density x serum urate levels interaction	3.000000e-13
GCST012490_451	Femur bone mineral density x serum urate levels interaction	3.000000e-10
GCST012616_17	Spondylosis	5.000000e-06

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0007681	triglyceride change measurement
EFO:0007042	polychlorinated biphenyls measurement
EFO:0007964	gestational serum measurement
EFO:0005299	non-word reading
EFO:0007789	BMI-adjusted waist circumference
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0009130	clostridium difficile infection
EFO:0004531	urate measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D052517	Multiple Sulfatase Deficiency Disease	C10.228.140.163.100.435.825.850.750; C16.320.565.189.435.825.850.750; C16.320.565.398.641.803.925.750; C16.320.565.595.554.825.850.750; C18.452.132.100.435.825.850.750; C18.452.584.563.641.803.925.750; C18.452.648.189.435.825.850.750; C18.452.648.398.641.803.925.750; C18.452.648.595.554.825.850.750
D065886	Neurodevelopmental Disorders	F03.625
C564685	Spinocerebellar Ataxia 15 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs793391	SUMF1		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	6
Benzo(a)pyrene	decreases expression, decreases methylation, increases expression	3
bisphenol A	affects cotreatment, increases expression, decreases methylation	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	affects cotreatment, increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	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
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	increases expression	1
jinfukang	increases expression	1
bisphenol AF	increases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Leflunomide	decreases expression	1
Cadmium	increases expression, increases abundance	1
Dexamethasone	affects cotreatment, increases expression	1
Estradiol	decreases expression	1
Formaldehyde	increases expression	1
Hydrogen Peroxide	increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Ozone	affects expression, increases abundance	1
Phenobarbital	affects expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01841983	Not specified	COMPLETED	Project A: Integrated Approaches to Improving the Health and Safety of Health Care Workers
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT03831737	Not specified	COMPLETED	Team-based Ergonomics Educational Model for Workplace WELLNESS Improvement: A Pilot Study
NCT06036693	Not specified	RECRUITING	MPS (RaDiCo Cohort) (RaDiCo-MPS)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers