GNS

Summary

GNS (glucosamine (N-acetyl)-6-sulfatase, HGNC:4422) is a protein-coding gene on chromosome 12q14.3, encoding N-acetylglucosamine-6-sulfatase (P15586). Hydrolyzes 6-sulfate groups in N-acetyl-d-glucosaminide units of heparin sulfate and keratan sulfate.

The product of this gene is a lysosomal enzyme found in all cells. It is involved in the catabolism of heparin, heparan sulphate, and keratan sulphate. Deficiency of this enzyme results in the accumulation of undegraded substrate and the lysosomal storage disorder mucopolysaccharidosis type IIID (Sanfilippo D syndrome). Mucopolysaccharidosis type IIID is the least common of the four subtypes of Sanfilippo syndrome.

Source: NCBI Gene 2799 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mucopolysaccharidosis type 3D (Definitive, ClinGen)
• Clinical variants (ClinVar): 852 total — 55 pathogenic, 24 likely-pathogenic
• Phenotypes (HPO): 73
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_002076

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4422
Approved symbol	GNS
Name	glucosamine (N-acetyl)-6-sulfatase
Location	12q14.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000135677
Ensembl biotype	protein_coding
OMIM	607664
Entrez	2799

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 17 protein_coding, 3 retained_intron

ENST00000258145, ENST00000418919, ENST00000537823, ENST00000540196, ENST00000540883, ENST00000541781, ENST00000542058, ENST00000543646, ENST00000545273, ENST00000905553, ENST00000905554, ENST00000905555, ENST00000905556, ENST00000967912, ENST00000967913, ENST00000967914, ENST00000967915, ENST00000967916, ENST00000967917, ENST00000967918

RefSeq mRNA: 1 — MANE Select: NM_002076 NM_002076

CCDS: CCDS8970

Canonical transcript exons

ENST00000258145 — 14 exons

Exon	Start	End
ENSE00000920633	64747712	64747918
ENSE00001157491	64745659	64745724
ENSE00001605982	64759085	64759406
ENSE00002271075	64713449	64716819
ENSE00003458409	64723006	64723113
ENSE00003489402	64740606	64740688
ENSE00003490960	64728956	64729057
ENSE00003570887	64720022	64720182
ENSE00003574682	64752698	64752757
ENSE00003580962	64743141	64743308
ENSE00003638405	64721595	64721705
ENSE00003640064	64739381	64739499
ENSE00003640739	64737004	64737107
ENSE00003649956	64744809	64744907

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 99.28.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 96.6899 / max 867.7586, expressed in 1824 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
131867	78.8504	1823
131866	15.2760	1671
131865	1.7795	501
131861	0.4973	21
131863	0.2436	21
131860	0.0268	4
131862	0.0162	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	99.28	gold quality
visceral pleura	UBERON:0002401	99.13	gold quality
nephron tubule	UBERON:0001231	98.95	gold quality
pigmented layer of retina	UBERON:0001782	98.83	gold quality
retina	UBERON:0000966	98.80	gold quality
right adrenal gland cortex	UBERON:0035827	98.74	gold quality
right adrenal gland	UBERON:0001233	98.73	gold quality
stromal cell of endometrium	CL:0002255	98.66	gold quality
metanephric glomerulus	UBERON:0004736	98.60	gold quality
pleura	UBERON:0000977	98.59	gold quality
kidney epithelium	UBERON:0004819	98.57	gold quality
renal glomerulus	UBERON:0000074	98.56	gold quality
renal medulla	UBERON:0000362	98.55	gold quality
left adrenal gland	UBERON:0001234	98.55	gold quality
adrenal gland	UBERON:0002369	98.52	gold quality
parietal pleura	UBERON:0002400	98.50	gold quality
adrenal cortex	UBERON:0001235	98.45	gold quality
periodontal ligament	UBERON:0008266	98.39	gold quality
left adrenal gland cortex	UBERON:0035825	98.31	gold quality
germinal epithelium of ovary	UBERON:0001304	98.29	gold quality
tibia	UBERON:0000979	98.20	gold quality
choroid plexus epithelium	UBERON:0003911	98.10	gold quality
monocyte	CL:0000576	98.07	gold quality
mononuclear cell	CL:0000842	97.69	gold quality
islet of Langerhans	UBERON:0000006	97.65	gold quality
leukocyte	CL:0000738	97.60	gold quality
secondary oocyte	CL:0000655	97.53	gold quality
lower lobe of lung	UBERON:0008949	97.41	gold quality
metanephros	UBERON:0000081	97.35	gold quality
mammary duct	UBERON:0001765	97.31	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	19.73
E-CURD-112	yes	15.67
E-MTAB-10137	no	592.04
E-GEOD-124858	no	392.52

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

170 targeting GNS, 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-513A-5P	100.00	69.77	2465
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3646	100.00	73.56	5283
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-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 6)

• The Sanfilippo syndrome type D patient was found to be homozygous for a single base pair deletion (c1169delA), which will cause a frameshift and premature termination of N-acetylglucosamine-6-sulphatase. (PMID:12624138)
• A large intragenic deletion of 8723 bp encompassing exons 2 and 3 has been identified, the first large intragenic deletion to be reported in any of the four Sanfilippo subtypes. Q272X has also been found. (PMID:16990043)
• Sanfilippo syndrome type D has 3 novel mutations in the GNS Gene. (PMID:17998446)
• We identified the novel homozygous single base pair insertion, c.1226GinsG, which leads to a frame-shift and a premature truncation of the GNS protein (p.R409Rfs21X). (PMID:19650410)
• 12 new patients and 15 novel mutations were identified in Mucopolysaccharidosis type IIID. (PMID:20232353)
• Mice deficient in GNS showed lysosomal storage pathology and a phenotype that closely resembled human MPSIIID. Moreover, treatment of the GNS-deficient animals with GNS-encoding adeno-associated viral (AAV) vectors of serotype 9 delivered to the cerebrospinal fluid completely corrected pathological storage, improved lysosomal functionality in the CNS and somatic tissues, resolved neuroinflammation (PMID:28334745)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	gnsa	ENSDARG00000023766
mus_musculus	Gns	ENSMUSG00000034707
rattus_norvegicus	Gns	ENSRNOG00000046159
drosophila_melanogaster	CG18278	FBGN0033836
drosophila_melanogaster	CG7408	FBGN0036765
drosophila_melanogaster	CG7402	FBGN0036768
drosophila_melanogaster	CG32191	FBGN0052191
drosophila_melanogaster	CG30059	FBGN0260475

Paralogs (16): ARSD (ENSG00000006756), IDS (ENSG00000010404), ARSF (ENSG00000062096), ARSA (ENSG00000100299), STS (ENSG00000101846), ARSB (ENSG00000113273), SULF1 (ENSG00000137573), GALNS (ENSG00000141012), ARSG (ENSG00000141337), ARSL (ENSG00000157399), ARSK (ENSG00000164291), ARSJ (ENSG00000180801), SGSH (ENSG00000181523), ARSI (ENSG00000183876), SULF2 (ENSG00000196562), ARSH (ENSG00000205667)

Protein

Protein identifiers

N-acetylglucosamine-6-sulfatase — P15586 (reviewed: P15586)

Alternative names: Glucosamine-6-sulfatase

All UniProt accessions (6): A0A024RBC5, P15586, F5H4C6, F6S8M0, H0YFA9, H7C3P4

UniProt curated annotations — full annotation on UniProt →

Function. Hydrolyzes 6-sulfate groups in N-acetyl-d-glucosaminide units of heparin sulfate and keratan sulfate.

Subcellular location. Lysosome.

Post-translational modifications. The form A (78 kDa) is processed by internal peptidase cleavage to a 32 kDa N-terminal species (form B) and a 48 kDa C-terminal species. The conversion to 3-oxoalanine (also known as C-formylglycine, FGly), of a serine or cysteine residue in prokaryotes and of a cysteine residue in eukaryotes, is critical for catalytic activity.

Disease relevance. Mucopolysaccharidosis 3D (MPS3D) [MIM:252940] A form of mucopolysaccharidosis type 3, an autosomal recessive lysosomal storage disease due to impaired degradation of heparan sulfate. MPS3 is characterized by severe central nervous system degeneration, but only mild somatic disease. Onset of clinical features usually occurs between 2 and 6 years; severe neurologic degeneration occurs in most patients between 6 and 10 years of age, and death occurs typically during the second or third decade of life. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 Ca(2+) ion per subunit.

Similarity. Belongs to the sulfatase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P15586-1	1	yes
P15586-2	2

RefSeq proteins (1): NP_002067* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000917	Sulfatase_N	Domain
IPR012251	GlcNAc_6-SO4ase	Family
IPR017850	Alkaline_phosphatase_core_sf	Homologous_superfamily
IPR024607	Sulfatase_CS	Conserved_site

Pfam: PF00884

Enzyme classification (BRENDA):

• EC 3.1.6.14 — N-acetylglucosamine-6-sulfatase (BRENDA: 8 organisms, 44 substrates, 17 inhibitors, 20 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

9 substrates with measured Km, best-characterized 9. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
O-(ALPHA-GLUCOSAMINE 6-SULFATE)-(1-3)-L-IDONIC A	0.0111–0.0482	4
O-(ALPHA-N-ACETYL GLUCOSAMINE 6-SULFATE)-(1-3)-L	0.0072–0.027	3
GLUCOSE 6-SULFATE	0.062–7.7	2
N-ACETYL-D-GLUCOSAMINE 6-SULFATE	4.2–13	2
N-ACETYLGLUCOSAMINE 6-SULFATE	0.0071–0.33	2
O-(ALPHA-GLUCOSAMINE 6-SULFATE)-(1-4)-L-O-(ALPHA	0.0035–0.028	2
4-METHYLUMBELLIFERYL SULFATE	5.8	1
O-(ALPHA-2-SULFAMINO GLUCOSAMINE 6-SULFATE)-(1-4	0.0108	1
TRISACCHARIDE WITH AN N-ACETYLGLUCOSAMINE 6-SULF	0.15	1

UniProt features (29 total): glycosylation site 13, binding site 5, sequence variant 4, modified residue 2, signal peptide 1, chain 1, active site 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P15586-F1	89.29	0.81

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): 91 (nucleophile)

Ligand- & substrate-binding residues (5): 55; 56; 91 (via 3-oxoalanine); 326; 327

Post-translational modifications (2): 91, 541

Glycosylation sites (13): 111, 117, 183, 198, 210, 279, 317, 362, 387, 405, 422, 449, 480

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-2022857	Keratan sulfate degradation
R-HSA-2206305	MPS IIID - Sanfilippo syndrome D
R-HSA-432720	Lysosome Vesicle Biogenesis
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 475 (showing top): SHEPARD_BMYB_MORPHOLINO_UP, REACTOME_INNATE_IMMUNE_SYSTEM, YAGI_AML_WITH_INV_16_TRANSLOCATION, SWEET_KRAS_ONCOGENIC_SIGNATURE, BROWNE_HCMV_INFECTION_8HR_UP, TGCACTT_MIR519C_MIR519B_MIR519A, GOCC_SECRETORY_GRANULE, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, MORI_IMMATURE_B_LYMPHOCYTE_UP, KEGG_LYSOSOME, MODULE_453, REACTOME_MEMBRANE_TRAFFICKING

GO Biological Process (4): glycosaminoglycan catabolic process (GO:0006027), heparan sulfate proteoglycan catabolic process (GO:0030200), keratan sulfate proteoglycan catabolic process (GO:0042340), glycosaminoglycan metabolic process (GO:0030203)

GO Molecular Function (7): glycosaminoglycan binding (GO:0005539), N-acetylglucosamine-6-sulfatase activity (GO:0008449), sulfuric ester hydrolase activity (GO:0008484), sulfate binding (GO:0043199), metal ion binding (GO:0046872), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (7): extracellular region (GO:0005576), azurophil granule lumen (GO:0035578), azurophil granule (GO:0042582), lysosomal lumen (GO:0043202), extracellular exosome (GO:0070062), ficolin-1-rich granule lumen (GO:1904813), lysosome (GO:0005764)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Keratan sulfate/keratin metabolism	1
Mucopolysaccharidoses	1
trans-Golgi Network Vesicle Budding	1
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
proteoglycan catabolic process	2
vacuolar lumen	2
aminoglycan catabolic process	1
glycosaminoglycan metabolic process	1
heparan sulfate proteoglycan metabolic process	1
keratan sulfate proteoglycan metabolic process	1
aminoglycan metabolic process	1
carbohydrate derivative binding	1
sulfuric ester hydrolase activity	1
hydrolase activity, acting on ester bonds	1
anion binding	1
sulfur compound binding	1
cation binding	1
binding	1
catalytic activity	1
cellular anatomical structure	1
secretory granule lumen	1
azurophil granule	1
primary lysosome	1
secretory granule	1
lysosome	1
extracellular vesicle	1
intracellular organelle lumen	1
ficolin-1-rich granule	1
lytic vacuole	1

Protein interactions and networks

STRING

1104 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GNS	NAGLU	P54802	958
GNS	HGSNAT	Q68CP4	757
GNS	IDUA	P35475	581
GNS	SGSH	P51688	507
GNS	GALNS	P34059	489
GNS	IDS	P22304	472
GNS	ATP6V0C	P27449	470
GNS	CD68	P34810	454
GNS	DNASE2B	Q8WZ79	427
GNS	AGXT2	Q9BYV1	418
GNS	AGMAT	Q9BSE5	418
GNS	ESCO2	Q56NI9	410
GNS	SHH	Q15465	407
GNS	SIMC1	Q8NDZ2	407
GNS	GLB1	P16278	406
GNS	SUMF1	Q8NBK3	406

IntAct

31 interactions, top by confidence:

A	B	Type	Score
GNS	CLPX	psi-mi:“MI:0914”(association)	0.530
ABL1	GNS	psi-mi:“MI:0915”(physical association)	0.400
SRC	GNS	psi-mi:“MI:0915”(physical association)	0.400
FYN	GNS	psi-mi:“MI:0915”(physical association)	0.400
GRB2	GNS	psi-mi:“MI:0915”(physical association)	0.400
GNS	NCK1	psi-mi:“MI:0915”(physical association)	0.400
PCNA	GNS	psi-mi:“MI:0915”(physical association)	0.370
Cep152	SH3PXD2B	psi-mi:“MI:0914”(association)	0.350
CEP43	CCHCR1	psi-mi:“MI:0914”(association)	0.350
PARD6B	PARD3	psi-mi:“MI:0914”(association)	0.350
Msn	ELOC	psi-mi:“MI:0914”(association)	0.350
KIF2A	GNS	psi-mi:“MI:0914”(association)	0.350
Prkaa1		psi-mi:“MI:0914”(association)	0.350
	ESYT2	psi-mi:“MI:0914”(association)	0.350
CUL1	NEFH	psi-mi:“MI:0914”(association)	0.350
G3BP1	AGPS	psi-mi:“MI:0914”(association)	0.350
	VPS37C	psi-mi:“MI:0914”(association)	0.350
POC5	PDHX	psi-mi:“MI:0914”(association)	0.350
SULF2	CCDC85C	psi-mi:“MI:0914”(association)	0.350
GNS	HSPD1	psi-mi:“MI:0914”(association)	0.350
IGF2R	MANBA	psi-mi:“MI:0914”(association)	0.350
GNS	IGF2R	psi-mi:“MI:0914”(association)	0.350
FECH	POTEF	psi-mi:“MI:0914”(association)	0.350
NRAS	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350
KRAS	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350
KCNJ2	ELAPOR2	psi-mi:“MI:2364”(proximity)	0.270
GNS		psi-mi:“MI:0915”(physical association)	0.000

BioGRID (147): GNS (Affinity Capture-MS), GNS (Affinity Capture-MS), GNS (Affinity Capture-MS), GNS (Affinity Capture-MS), GNS (Affinity Capture-MS), GNS (Affinity Capture-MS), GNS (Affinity Capture-MS), ENGASE (Affinity Capture-MS), SUMF1 (Affinity Capture-MS), FKBP14 (Affinity Capture-MS), SULF2 (Affinity Capture-MS), CLPX (Affinity Capture-MS), GNS (Affinity Capture-MS), CAPN2 (Affinity Capture-MS), GNS (Affinity Capture-RNA)

ESM2 similar proteins: A1A4K5, O14638, P06802, P08842, P15396, P15586, P15589, P15848, P22304, P22413, P33727, P50426, P50429, P51689, P51690, P54793, P97535, P97675, Q08890, Q08C93, Q13219, Q13822, Q1LZH9, Q32KH8, Q32KH9, Q32KJ9, Q3TYD4, Q5E9H0, Q5FYA8, Q5M900, Q5NDE3, Q5R5M5, Q5ZK90, Q60HH5, Q64610, Q66PG4, Q6DYE8, Q6NRQ1, Q6P9A2, Q6UWY0

Diamond homologs: P15586, P50426, Q1LZH9, Q21376, Q8BFR4, Q8CFG0, Q8IWU5, Q8IWU6, Q8K007, Q8VI60, Q90XB6, Q9VEX0, P08842, P14000, P15289, P15589, P34059, P50427, P50428, P50473, P51689, P51690, P54793, Q08DD1, Q32KH5, Q32KH8, Q32KH9, Q32KJ6, Q32KJ8, Q3TYD4, Q571E4, Q5FYA8, Q5FYB0, Q5FYB1, Q60HH5, Q8A2F6, Q8A2H2, Q8BM89, Q8WNQ7, T2KMG4

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
TFEB	“up-regulates quantity by expression”	GNS	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 37 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
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	5	103.8×	4e-07
Downstream signal transduction	5	76.1×	1e-06
NCAM signaling for neurite out-growth	5	54.4×	4e-06
Signaling by SCF-KIT	5	49.6×	4e-06
FCGR3A-mediated phagocytosis	5	37.4×	2e-05
RAF/MAP kinase cascade	5	12.2×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	55
Likely pathogenic	24
Uncertain significance	264
Likely benign	425
Benign	43

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1072342	NM_002076.4(GNS):c.506G>A (p.Trp169Ter)	Pathogenic
1073389	NM_002076.4(GNS):c.538A>T (p.Lys180Ter)	Pathogenic
1075562	NM_002076.4(GNS):c.887_888del (p.Leu296fs)	Pathogenic
1075633	NM_002076.4(GNS):c.1414C>T (p.Gln472Ter)	Pathogenic
1075873	NM_002076.4(GNS):c.638del (p.Leu213fs)	Pathogenic
1299282	NM_002076.4(GNS):c.875+2del	Pathogenic
1323028	NM_002076.4(GNS):c.459+1_459+2del	Pathogenic
1354681	NM_002076.4(GNS):c.386dup (p.Asn130fs)	Pathogenic
1358146	NM_002076.4(GNS):c.526G>T (p.Glu176Ter)	Pathogenic
1360836	NM_002076.4(GNS):c.1459C>T (p.Gln487Ter)	Pathogenic
1391029	NM_002076.4(GNS):c.1021_1022insTCTT (p.Arg341fs)	Pathogenic
1402148	NM_002076.4(GNS):c.379del (p.Gln127fs)	Pathogenic
1408205	NM_002076.4(GNS):c.118del (p.Val40fs)	Pathogenic
1413883	NM_002076.4(GNS):c.23del (p.Pro8fs)	Pathogenic
1418992	NM_002076.4(GNS):c.841_842insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNGACCTCGTGATCCGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCGACTAATTCTT (p.Ser280_Ser281insPhePhePhePhePhePhePheXaaXaaXaaXaaProArgAspProProAlaSerAlaSerGlnSerAlaGlyIleThrGlyValSerHisArgAlaArgProThrAsnSer)	Pathogenic
1452923	NM_002076.4(GNS):c.875+1G>A	Pathogenic
1453303	NM_002076.4(GNS):c.654C>A (p.Tyr218Ter)	Pathogenic
1455915	NM_002076.4(GNS):c.214_220del (p.Ala72fs)	Pathogenic
1459210	NM_002076.4(GNS):c.148dup (p.Val50fs)	Pathogenic
1460021	NM_002076.4(GNS):c.1420-2A>G	Pathogenic
1961741	NM_002076.4(GNS):c.255T>G (p.Tyr85Ter)	Pathogenic
1974056	NM_002076.4(GNS):c.1414dup (p.Gln472fs)	Pathogenic
1999386	NM_002076.4(GNS):c.286_287del (p.Ala96fs)	Pathogenic
2031201	NM_002076.4(GNS):c.974C>G (p.Ser325Ter)	Pathogenic
2033415	NM_002076.4(GNS):c.246del (p.Ser83fs)	Pathogenic
2135833	NM_002076.4(GNS):c.441del (p.Lys149fs)	Pathogenic
2137388	NM_002076.4(GNS):c.59_66del (p.Pro20fs)	Pathogenic
2425940	NC_000012.11:g.(?64849651)(65857102_?)del	Pathogenic
2501802	NM_002076.4(GNS):c.732C>A (p.Tyr244Ter)	Pathogenic
2696295	NM_002076.4(GNS):c.667G>T (p.Glu223Ter)	Pathogenic

SpliceAI

1922 predictions. Top by Δscore:

Variant	Effect	Δscore
12:64720016:ACTT:A	donor_loss	1.0000
12:64720017:CTTA:C	donor_loss	1.0000
12:64720018:TTAC:T	donor_loss	1.0000
12:64720019:TACCC:T	donor_loss	1.0000
12:64720020:A:AC	donor_gain	1.0000
12:64720020:A:AT	donor_loss	1.0000
12:64720020:AC:A	donor_gain	1.0000
12:64720021:C:CC	donor_gain	1.0000
12:64720021:C:CG	donor_loss	1.0000
12:64720021:CC:C	donor_gain	1.0000
12:64720180:CAC:C	acceptor_gain	1.0000
12:64720181:ACC:A	acceptor_loss	1.0000
12:64720183:C:A	acceptor_loss	1.0000
12:64720183:C:CC	acceptor_gain	1.0000
12:64720184:T:A	acceptor_loss	1.0000
12:64720192:A:C	acceptor_gain	1.0000
12:64723004:A:AC	donor_gain	1.0000
12:64723005:C:CC	donor_gain	1.0000
12:64723112:CT:C	acceptor_gain	1.0000
12:64728950:ACTT:A	donor_loss	1.0000
12:64728951:CT:C	donor_loss	1.0000
12:64728952:TT:T	donor_loss	1.0000
12:64728953:TACCA:T	donor_loss	1.0000
12:64728954:A:AC	donor_gain	1.0000
12:64728954:A:T	donor_loss	1.0000
12:64728955:C:CC	donor_gain	1.0000
12:64728955:C:G	donor_loss	1.0000
12:64729925:A:C	donor_gain	1.0000
12:64736998:ACCT:A	donor_loss	1.0000
12:64736999:CCTA:C	donor_loss	1.0000

AlphaMissense

3626 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:64721613:G:C	C467W	0.999
12:64721614:C:T	C467Y	0.999
12:64721652:A:C	C454W	0.999
12:64721653:C:T	C454Y	0.999
12:64721654:A:G	C454R	0.999
12:64721664:A:C	N450K	0.999
12:64721664:A:T	N450K	0.999
12:64721683:C:G	C444S	0.999
12:64721683:C:T	C444Y	0.999
12:64721684:A:T	C444S	0.999
12:64739398:T:A	D326V	0.999
12:64745679:A:G	W169R	0.999
12:64745679:A:T	W169R	0.999
12:64747802:C:A	W123C	0.999
12:64747802:C:G	W123C	0.999
12:64747880:A:C	S97R	0.999
12:64747880:A:T	S97R	0.999
12:64747882:T:G	S97R	0.999
12:64747889:G:C	S94R	0.999
12:64747889:G:T	S94R	0.999
12:64747891:T:G	S94R	0.999
12:64720048:A:C	C518W	0.998
12:64720049:C:T	C518Y	0.998
12:64720063:A:C	C513W	0.998
12:64720064:C:T	C513Y	0.998
12:64720085:C:G	R506P	0.998
12:64720132:G:C	N490K	0.998
12:64720132:G:T	N490K	0.998
12:64721608:A:C	F469C	0.998
12:64721615:A:G	C467R	0.998

dbSNP variants (sampled 300 via entrez): RS1000014569 (12:64716566 T>A,C), RS1000064275 (12:64721851 C>G,T), RS1000102400 (12:64741590 T>C), RS1000162560 (12:64734472 G>T), RS1000367534 (12:64727149 G>A), RS1000381159 (12:64720084 C>A,T), RS1000411804 (12:64741341 A>C,G), RS1000421322 (12:64742028 T>C), RS1000500130 (12:64735887 C>A,T), RS1000507776 (12:64726832 A>G), RS1000653829 (12:64728765 A>C), RS1000661252 (12:64733503 A>C,G), RS1000765455 (12:64721533 T>A), RS1000806004 (12:64721904 G>A), RS1000870086 (12:64739900 T>C,G)

Disease associations

OMIM: gene MIM:607664 | disease phenotypes: MIM:252940

GenCC curated gene-disease

Disease	Classification	Inheritance
mucopolysaccharidosis type 3D	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mucopolysaccharidosis type 3D	Definitive	AR

Mondo (2): mucopolysaccharidosis type 3D (MONDO:0009658), mucopolysaccharidosis type 3 (MONDO:0018937)

Orphanet (2): Mucopolysaccharidosis type 3 (Orphanet:581), Sanfilippo syndrome type D (Orphanet:79272)

HPO phenotypes

73 total (30 of 73 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000154	Wide mouth
HP:0000158	Macroglossia
HP:0000179	Thick lower lip vermilion
HP:0000187	Broad alveolar ridges
HP:0000256	Macrocephaly
HP:0000280	Coarse facial features
HP:0000316	Hypertelorism
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000403	Recurrent otitis media
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000490	Deeply set eye
HP:0000505	Visual impairment
HP:0000574	Thick eyebrow
HP:0000662	Nyctalopia
HP:0000664	Synophrys
HP:0000711	Restlessness
HP:0000713	Agitation
HP:0000718	Aggressive behavior
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0000900	Thickened ribs
HP:0000943	Dysostosis multiplex
HP:0001007	Hirsutism
HP:0001169	Broad palm
HP:0001249	Intellectual disability
HP:0001250	Seizure

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression	5
bisphenol A	decreases expression, increases expression	3
sodium arsenite	affects expression, increases expression	2
Benzo(a)pyrene	affects methylation, increases expression	2
Tretinoin	increases expression	2
bisphenol F	increases expression	1
TL8-506	affects cotreatment, increases expression	1
butyraldehyde	decreases expression	1
beta-methylcholine	affects expression	1
yessotoxin	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
ICG 001	increases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, increases expression	1
picoxystrobin	increases expression	1
PP242	increases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants, Occupational	decreases expression	1
Aminoglutethimide	decreases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Cadmium	increases expression	1
Carbamazepine	affects expression	1
Coumestrol	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ethyl Methanesulfonate	increases expression	1

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 finite cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_AB47	GM05093	Finite cell line	Male
CVCL_B1T5	Abcam HeLa GNS KO	Cancer cell line	Female
CVCL_D5ER	HeLa::TMEM192-3xHA GNS KO	Cancer cell line	Female
CVCL_E1Y6	HAP1 GNS (-) 1	Cancer cell line	Male
CVCL_E1Y7	HAP1 GNS (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04360265	PHASE3	ENROLLING_BY_INVITATION	Follow-up Study of AAV-Mediated Gene Transfer (UX111; Previously Known as ABO-102) for MPS Type IIIA
NCT00383448	PHASE2	COMPLETED	HSCT for High Risk Inherited Inborn Errors
NCT02060526	PHASE2	COMPLETED	Randomized, Controlled, Open-label, Multicenter, Safety and Efficacy Study of rhHNS Administration Via an IDDD in Pediatric Patients With Early Stage MPS IIIA Disease
NCT02350816	PHASE2	TERMINATED	An Extension Study to Determine Safety and Efficacy for Pediatric Patients With MPS Type IIIA Disease Who Participated in Study HGT-SAN-093.
NCT05648851	Not specified	COMPLETED	A Natural History Study of Sanfilippo Syndrome Type D
NCT02716246	PHASE2/PHASE3	RECRUITING	Phase I/II/III Gene Transfer Clinical Trial of scAAV9.U1a.hSGSH
NCT06333041	PHASE2/PHASE3	RECRUITING	Study of Cannabidiol in Sanfilippo Syndrome
NCT06614894	PHASE2/PHASE3	RECRUITING	An Open Label Dose Escalation Study to Assess the Safety, Tolerability, and Pharmacologic Properties of High Dose Ambroxol Hydrochloride in Adult (≥ 18 Years of Age) Subjects With MPS III
NCT01299727	PHASE1/PHASE2	TERMINATED	Extension of Study HGT-SAN-055 Evaluating Administration of rhHNS in Patients With Sanfilippo Syndrome Type A (MPS IIIA)
NCT01372228	PHASE1/PHASE2	TERMINATED	Phase I/II Pilot Study of Mixed Chimerism to Treat Inherited Metabolic Disorders
NCT04088734	PHASE1/PHASE2	TERMINATED	Gene Transfer Study of ABO-102 in Patients With Middle and Advanced Phases of MPS IIIA Disease
NCT01938014	Not specified	COMPLETED	Lysosomal Storage Disease: Health, Development, and Functional Outcome Surveillance in Preschool Children
NCT03161171	Not specified	COMPLETED	Parental Coping With Challenging Behavior in Mucopolysaccharidosis Type I-III
NCT05705674	Not specified	UNKNOWN	The Natural History Study of Patients With Sanfilippo Disease(s) (MPS3)