ST3GAL5

Summary

ST3GAL5 (ST3 beta-galactoside alpha-2,3-sialyltransferase 5, HGNC:10872) is a protein-coding gene on chromosome 2p11.2, encoding Lactosylceramide alpha-2,3-sialyltransferase (Q9UNP4). Transfers the sialyl group (N-acetyl-alpha-neuraminyl or NeuAc) from CMP-NeuAc to the non-reducing terminal galactose (Gal) of glycosphingolipids forming gangliosides (important molecules involved in the regulation of multiple cellular processes, including cell proliferation and….

Ganglioside GM3 is known to participate in the induction of cell differentiation, modulation of cell proliferation, maintenance of fibroblast morphology, signal transduction, and integrin-mediated cell adhesion. The protein encoded by this gene is a type II membrane protein which catalyzes the formation of GM3 using lactosylceramide as the substrate. The encoded protein is a member of glycosyltransferase family 29 and may be localized to the Golgi apparatus. Mutation in this gene has been associated with Amish infantile epilepsy syndrome. Transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 8869 — RefSeq curated summary.

At a glance

• Gene–disease (curated): GM3 synthase deficiency (Definitive, ClinGen)
• GWAS associations: 3
• Clinical variants (ClinVar): 426 total — 27 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 26
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_003896

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10872
Approved symbol	ST3GAL5
Name	ST3 beta-galactoside alpha-2,3-sialyltransferase 5
Location	2p11.2
Locus type	gene with protein product
Status	Approved
Aliases	ST3GalV, SIATGM3S
Ensembl gene	ENSG00000115525
Ensembl biotype	protein_coding
OMIM	604402
Entrez	8869

Gene structure

Transcript identifiers

Ensembl transcripts: 73 — 37 nonsense_mediated_decay, 20 protein_coding, 9 retained_intron, 7 protein_coding_CDS_not_defined

ENST00000306262, ENST00000377332, ENST00000393805, ENST00000393808, ENST00000433665, ENST00000455892, ENST00000461199, ENST00000461206, ENST00000461892, ENST00000473122, ENST00000484728, ENST00000487896, ENST00000490946, ENST00000638178, ENST00000638227, ENST00000638258, ENST00000638288, ENST00000638321, ENST00000638484, ENST00000638523, ENST00000638542, ENST00000638572, ENST00000638581, ENST00000638659, ENST00000638678, ENST00000638855, ENST00000638885, ENST00000638956, ENST00000638986, ENST00000639074, ENST00000639119, ENST00000639184, ENST00000639202, ENST00000639216, ENST00000639305, ENST00000639311, ENST00000639421, ENST00000639432, ENST00000639472, ENST00000639519, ENST00000639541, ENST00000639608, ENST00000639690, ENST00000639743, ENST00000639820, ENST00000639867, ENST00000639945, ENST00000639981, ENST00000640024, ENST00000640222, ENST00000640295, ENST00000640314, ENST00000640315, ENST00000640322, ENST00000640336, ENST00000640378, ENST00000640418, ENST00000640425, ENST00000640453, ENST00000640572, ENST00000640594, ENST00000640712, ENST00000640763, ENST00000640798, ENST00000640835, ENST00000640849, ENST00000640903, ENST00000640982, ENST00000640992, ENST00000928816, ENST00000928817, ENST00000971694, ENST00000971695

RefSeq mRNA: 13 — MANE Select: NM_003896 NM_001042437, NM_001354223, NM_001354224, NM_001354226, NM_001354227, NM_001354229, NM_001354233, NM_001354234, NM_001354238, NM_001354247, NM_001354248, NM_001363847, NM_003896

CCDS: CCDS1986, CCDS42705, CCDS86856, CCDS86857

Canonical transcript exons

ENST00000638572 — 7 exons

Exon	Start	End
ENSE00001135175	85847861	85848204
ENSE00003503511	85846377	85846563
ENSE00003532213	85844396	85844554
ENSE00003569961	85861181	85861292
ENSE00003582339	85863362	85863485
ENSE00003801687	85837120	85840392
ENSE00003807306	85888824	85888990

Expression profiles

Bgee: expression breadth ubiquitous, 267 present calls, max score 97.30.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.6770 / max 137.3933, expressed in 1648 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
29515	8.4247	1616
29514	2.4068	781
29513	0.8179	303
29512	0.0275	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland	UBERON:0001233	97.30	gold quality
right adrenal gland cortex	UBERON:0035827	97.02	gold quality
left adrenal gland	UBERON:0001234	96.62	gold quality
right lobe of thyroid gland	UBERON:0001119	96.60	gold quality
adrenal cortex	UBERON:0001235	96.50	gold quality
left lobe of thyroid gland	UBERON:0001120	96.37	gold quality
left adrenal gland cortex	UBERON:0035825	96.34	gold quality
thyroid gland	UBERON:0002046	96.18	gold quality
adrenal gland	UBERON:0002369	95.63	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.23	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.14	gold quality
decidua	UBERON:0002450	94.98	gold quality
spinal cord	UBERON:0002240	94.82	gold quality
middle temporal gyrus	UBERON:0002771	94.82	gold quality
putamen	UBERON:0001874	94.60	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.42	gold quality
prefrontal cortex	UBERON:0000451	94.39	gold quality
corpus callosum	UBERON:0002336	94.38	gold quality
primary visual cortex	UBERON:0002436	94.27	gold quality
nucleus accumbens	UBERON:0001882	94.18	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.10	gold quality
right frontal lobe	UBERON:0002810	94.05	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.97	gold quality
caudate nucleus	UBERON:0001873	93.95	gold quality
occipital lobe	UBERON:0002021	93.88	gold quality
cingulate cortex	UBERON:0003027	93.84	gold quality
anterior cingulate cortex	UBERON:0009835	93.77	gold quality
amygdala	UBERON:0001876	93.74	gold quality
frontal cortex	UBERON:0001870	93.49	gold quality
frontal lobe	UBERON:0016525	93.48	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-93593	yes	4.22
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF2, SP1, TFAP2A

miRNA regulators (miRDB)

76 targeting ST3GAL5, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 26)

• isolation and characterization of the promoter region (PMID:12393190)
• enhanced expression of GM3 synthase through protein kinase C /extracellular regulated kinases-dependent cAMP-responsive element binding protein activation by phorbol 12-myristate 13-acetate is associated with the differentiation of HL-60 cells (PMID:15385432)
• ). We sequenced genes in the region and identified a nonsense mutation in SIAT9, which is predicted to result in the premature termination of the GM3 synthase enzyme (also called lactosylceramide alpha-2,3 sialyltransferase). (PMID:15502825)
• These results are the first demonstration of the existence of a new isoform of human GM3 synthase, which could play an important role during HL60 cell differentiation. (PMID:16934889)
• GM3 synthase point mutation almost completely depletes human fibroblast cellular gangliosides, dampens membrane EGFR activation, and modulates related critical cell functions such as proliferation and migration (PMID:18480157)
• Ganglioside GM3 inhibits VEGF/VEGFR-2-mediated angiogenesis. Direct interaction of GM3 with VEGFR-2 is reported. (PMID:18974200)
• GM3 synthase mRNA levels were significantly higher in differentiated human monocyte-derived macrophages compared to monocytes and in atherosclerotic aorta compared to normal aorta (PMID:19415461)
• ST6Gal I and ST3Gal V were positively correlated with the high risk of pediatric acute leukemia. (PMID:19709745)
• GM3 synthase overexpression results in reduced cell motility and in caveolin-1 upregulation in human ovarian carcinoma cells (PMID:19759399)
• In vivo expression of the transcript gives rise to two human ST3Gal-V isoforms with distinct characteristics. (PMID:20219466)
• GM3 exhibits the potential to regulate the allosteric structural transition from inactive to a signaling EGFR dimer, by preventing the autophosphorylation of the intracellular kinase domain in response to ligand binding (PMID:21571640)
• Data demonstrate that valproic acid (VPA) transcriptionally regulates human GM3 synthase (hST3Gal V), which catalyzes ganglioside GM3 biosynthesis in ARPE-19 human retinal pigment epithelial cells. (PMID:21699754)
• GM3 synthase deficiency, responsible for early-onset epilepsy syndrome, leads to a secondary respiratory chain dysfunction. (PMID:22990144)
• Whole-exome sequencing of patients with salt and pepper syndrome shows a homozygous c.994G>A transition (p.E332K) in the ST3GAL5 gene. (PMID:24026681)
• this study indicated that sialylation involved in the development of MDR of AML cells probably through ST3GAL5 or ST8SIA4 regulating the activity of PI3K/Akt signaling and the expression of P-gp and MRP1. (PMID:24531716)
• Serum deprivation triggers upregulation of hST3Gal V gene expression through Runx2 activation by BMP signaling in MG-63 cells. (PMID:26729095)
• These cases broaden the phenotypic and genetic spectrum of GM3 synthase deficiency due to ST3GAL5 variants. Patients with intellectual disability or furthermore presenting with Rett-like phenotype should be suspected of GM3 synthase deficiency, a disorder of ganglioside biosynthesis. (PMID:27232954)
• Studied the miRNA expression in human hepatocellular carcinoma cell lines; 13 differentially expressed miRNAs were identified between MHCC97-H and MHCC97-L cells; and the same results were found in clinical samples. Found that ST3GAL5 was the direct target of miR-26a, miR-548l and miR-34a. (PMID:28218742)
• Data suggest that ganglioside glycosyltransferases ST3GAL5, ST8SIA1, and B4GALNT1 are S-acylated at conserved cysteine residues located close to cytoplasmic border of their transmembrane domains; ST3Gal-II is acylated at conserved cysteine residue in N-terminal cytoplasmic tail; for B4GALNT1 and ST3Gal-II, dimer formation controls their S-acylation status. (PMID:28698248)
• While no differences in clinical characteristics were detected in patients possessing the functional promoter haplotypes of ST3GAL5, exophthalmic values were significantly lower in patients with the ST8SIA1 haplotype, which showed a significant increase in promoter activity (PMID:29047240)
• Since the nineties, mice lacking genes for single glycosyltransferases involved in ganglioside biosynthesis, including ST3GAL5 and B4GALNT1, were created and studied. The resulting phenotypes were frequently mild or very mild, so double knock-out animals were created to effectively study the function of gangliosides (PMID:29983310)
• GM3 synthase deficiency is a neurodevelopmental disorder with consistent features of profound intellectual disability, choreoathetosis, and deafness. (PMID:30185102)
• HEK-293T clones permanently expressing HaloTag-ST3GAL5 carrying each of the five variants were assessed by quantitative PCR, flow cytometry, western blotting and confocal microscopy. Compared with the very mild phenotype of st3gal5 KO mouse models, the results suggest that unknown mechanisms, in addition to the lack of a-b-c-series gangliosides, contribute to the syndrome. (PMID:30576498)
• Identification of ST3GAL5 as a prognostic biomarker correlating with CD8(+) T cell exhaustion in clear cell renal cell carcinoma. (PMID:36172374)
• Neurological insights on two siblings with GM3 synthase deficiency due to novel compound heterozygous ST3GAL5 variants. (PMID:36690566)
• Neural-specific alterations in glycosphingolipid biosynthesis and cell signaling associated with two human ganglioside GM3 synthase deficiency variants. (PMID:37676252)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	st3gal5	ENSDARG00000037556
mus_musculus	St3gal5	ENSMUSG00000056091
rattus_norvegicus	St3gal5	ENSRNOG00000010284

Paralogs (14): ST3GAL1 (ENSG00000008513), ST3GAL6 (ENSG00000064225), ST6GALNAC1 (ENSG00000070526), ST6GALNAC2 (ENSG00000070731), ST6GAL1 (ENSG00000073849), ST3GAL4 (ENSG00000110080), ST6GALNAC5 (ENSG00000117069), C20orf173 (ENSG00000125975), ST3GAL3 (ENSG00000126091), ST6GALNAC4 (ENSG00000136840), ST6GAL2 (ENSG00000144057), ST3GAL2 (ENSG00000157350), ST6GALNAC6 (ENSG00000160408), ST6GALNAC3 (ENSG00000184005)

Protein

Protein identifiers

Lactosylceramide alpha-2,3-sialyltransferase — Q9UNP4 (reviewed: Q9UNP4)

Alternative names: CMP-NeuAc:lactosylceramide alpha-2,3-sialyltransferase, GM3 synthase, Ganglioside GM3 synthase, ST3Gal V, Sialyltransferase 9

All UniProt accessions (37): A0A0S2Z4Q7, A0A0S2Z4S6, Q9UNP4, A0A1W2PNR4, A0A1W2PNV2, A0A1W2PNZ0, A0A1W2PP52, A0A1W2PP82, A0A1W2PP90, A0A1W2PPB0, A0A1W2PPF6, A0A1W2PPG4, A0A1W2PPQ6, A0A1W2PPT1, A0A1W2PQ01, A0A1W2PQ08, A0A1W2PQ22, A0A1W2PQ40, A0A1W2PQB4, A0A1W2PQH5, A0A1W2PQM6, A0A1W2PQQ6, A0A1W2PQR0, A0A1W2PQT6, A0A1W2PR24, A0A1W2PR43, A0A1W2PR45, A0A1W2PR69, A0A1W2PRC6, A0A1W2PRD9, A0A1W2PRP8, A0A1W2PRT0, A0A1W2PRY1, A0A1X7SBT2, C9JYS9, E7EPY0, F8WEA8

UniProt curated annotations — full annotation on UniProt →

Function. Transfers the sialyl group (N-acetyl-alpha-neuraminyl or NeuAc) from CMP-NeuAc to the non-reducing terminal galactose (Gal) of glycosphingolipids forming gangliosides (important molecules involved in the regulation of multiple cellular processes, including cell proliferation and differentiation, apoptosis, embryogenesis, development, and oncogenesis). Mainly involved in the biosynthesis of ganglioside GM3 but can also use different glycolipids as substrate acceptors such as D-galactosylceramide (GalCer), asialo-GM2 (GA2) and asialo-GM1 (GA1), although less preferentially than beta-D-Gal-(1->4)-beta-D-Glc-(1<->1)-Cer (LacCer).

Subcellular location. Golgi apparatus membrane.

Tissue specificity. Ubiquitous. High expression in brain, skeletal muscle, placenta, and testis. mRNA widely distributed in human brain, but slightly elevated expression was observed in the cerebral cortex, temporal lobe, and putamen.

Post-translational modifications. N-glycosylated.

Disease relevance. Salt and pepper developmental regression syndrome (SPDRS) [MIM:609056] A rare autosomal recessive disorder characterized by infantile onset of severe, recurrent and refractory seizures, failure to thrive, psychomotor delay, developmental stagnation, and cortical blindness. Deafness is observed in some patients. Affected individuals have patches of skin hypo- or hyperpigmentation on the trunk, face, and extremities. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Glycolipid biosynthesis.

Similarity. Belongs to the glycosyltransferase 29 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9UNP4-1	1	yes
Q9UNP4-2	2
Q9UNP4-3	3

RefSeq proteins (12): NP_001035902, NP_001341152, NP_001341153, NP_001341155, NP_001341156, NP_001341158, NP_001341162, NP_001341163, NP_001341167, NP_001341177, NP_001350776, NP_003887* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001675	Glyco_trans_29	Family
IPR012163	Sialyl_trans	Family
IPR038578	GT29-like_sf	Homologous_superfamily
IPR051142	Glycosyltransferase_29	Family

Pfam: PF00777

Enzyme classification (BRENDA):

• EC 2.4.99.9 — lactosylceramide alpha-2,3-sialyltransferase (BRENDA: 0 organisms, 0 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 5 shown:

• a beta-D-Gal-(1->4)-beta-D-Glc-(1<->1)-Cer(d18:1(4E)) + CMP-N-acetyl-beta-neuraminate = a ganglioside GM3 (d18:1(4E)) + CMP + H(+) (RHEA:18417)
• ganglioside GA2 (d18:1(4E)/18:0) + CMP-N-acetyl-beta-neuraminate = ganglioside GM2 (d18:1(4E)/18:0) + CMP + H(+) (RHEA:41776)
• a beta-D-Gal-(1<->1’)-ceramide + CMP-N-acetyl-beta-neuraminate = N-acetyl-alpha-neuraminosyl-(2->3)-beta-D-galactosyl-(1<->1’)-ceramide + CMP + H(+) (RHEA:41780)
• ganglioside GA1 (d18:1(4E)/18:0) + CMP-N-acetyl-beta-neuraminate = ganglioside GM1 (d18:1(4E)/18:0) + CMP + H(+) (RHEA:41784)
• a beta-D-galactosyl-(1<->1’)-N-acylsphing-4-enine + CMP-N-acetyl-beta-neuraminate = a ganglioside GM4 (d18:1(4E)) + CMP + H(+) (RHEA:47600)

UniProt features (13 total): splice variant 3, glycosylation site 3, topological domain 2, chain 1, sequence variant 1, transmembrane region 1, region of interest 1, disulfide bond 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UNP4-F1	83.04	0.61

Functional residue map

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

Disulfide bonds (1): 195–353

Glycosylation sites (3): 86, 236, 390

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-4085001	Sialic acid metabolism
R-HSA-9840309	Glycosphingolipid biosynthesis
R-HSA-1430728	Metabolism
R-HSA-1660662	Glycosphingolipid metabolism
R-HSA-392499	Metabolism of proteins
R-HSA-428157	Sphingolipid metabolism
R-HSA-446193	Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein
R-HSA-446203	Asparagine N-linked glycosylation
R-HSA-446219	Synthesis of substrates in N-glycan biosythesis
R-HSA-556833	Metabolism of lipids
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 372 (showing top): CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, MYOGENIN_Q6, GOBP_GLYCOLIPID_BIOSYNTHETIC_PROCESS, GCANCTGNY_MYOD_Q6, MODULE_45, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, IVANOVA_HEMATOPOIESIS_MATURE_CELL, TGACCTY_ERR1_Q2, AP2_Q3, BOYLAN_MULTIPLE_MYELOMA_D_DN, WOTTON_RUNX_TARGETS_UP, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_CERAMIDE_BIOSYNTHETIC_PROCESS, MODULE_66, GALE_APL_WITH_FLT3_MUTATED_DN

GO Biological Process (4): ganglioside biosynthetic process (GO:0001574), glycosphingolipid biosynthetic process (GO:0006688), obsolete protein glycosylation (GO:0006486), lipid metabolic process (GO:0006629)

GO Molecular Function (5): beta-galactoside (CMP) alpha-2,3-sialyltransferase activity (GO:0003836), sialyltransferase activity (GO:0008373), lactosylceramide alpha-2,3-sialyltransferase activity (GO:0047291), transferase activity (GO:0016740), glycosyltransferase activity (GO:0016757)

GO Cellular Component (3): Golgi membrane (GO:0000139), membrane (GO:0016020), Golgi apparatus (GO:0005794)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Synthesis of substrates in N-glycan biosythesis	1
Glycosphingolipid metabolism	1
Sphingolipid metabolism	1
Metabolism of lipids	1
Asparagine N-linked glycosylation	1
Post-translational protein modification	1
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1
Metabolism	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
sialyltransferase activity	2
ganglioside metabolic process	1
glycosphingolipid biosynthetic process	1
ceramide biosynthetic process	1
glycosphingolipid metabolic process	1
glycolipid biosynthetic process	1
sphingolipid biosynthetic process	1
primary metabolic process	1
glycosyltransferase activity	1
catalytic activity	1
transferase activity	1
Golgi apparatus	1
bounding membrane of organelle	1
cellular anatomical structure	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

754 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ST3GAL5	ST8SIA1	Q92185	824
ST3GAL5	B4GALT6	Q9UBX8	766
ST3GAL5	ST8SIA5	O15466	684
ST3GAL5	UGCG	Q16739	658
ST3GAL5	B3GALT4	O96024	645
ST3GAL5	SLC35A1	P78382	623
ST3GAL5	B4GALT5	O43286	608
ST3GAL5	B4GALNT1	Q00973	590
ST3GAL5	B3GNT5	Q9BYG0	538
ST3GAL5	ST6GALNAC3	Q8NDV1	523
ST3GAL5	B3GALT5	Q9Y2C3	518
ST3GAL5	NANS	Q9NR45	512
ST3GAL5	CASD1	Q96PB1	509
ST3GAL5	A4GALT	Q9NPC4	507
ST3GAL5	SIAE	Q9HAT2	506

IntAct

4 interactions, top by confidence:

A	B	Type	Score
SLC39A5	FAM171A2	psi-mi:“MI:0914”(association)	0.640
ST3GAL5	RPSA2	psi-mi:“MI:0914”(association)	0.350
BIN1	ST3GAL5	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (20): TMEM259 (Affinity Capture-MS), NDUFAF7 (Affinity Capture-MS), HLA-DPB1 (Affinity Capture-MS), NDUFAF7 (Affinity Capture-MS), TMEM259 (Affinity Capture-MS), ST3GAL5 (Proximity Label-MS), GBF1 (Affinity Capture-MS), ATP1A3 (Affinity Capture-MS), PICALM (Affinity Capture-MS), NOMO1 (Affinity Capture-MS), PVRL2 (Affinity Capture-MS), TMEM259 (Affinity Capture-MS), PON2 (Affinity Capture-MS), RPSAP58 (Affinity Capture-MS), SP1 (Affinity Capture-MS)

ESM2 similar proteins: A0PJZ3, A2XFP3, A2XFT5, A2XFT6, B8AIZ4, C7J0P3, O04536, O48684, O88829, P08037, P15291, P15535, Q02527, Q09327, Q0V7R1, Q0WV13, Q10470, Q10MK2, Q10MQ0, Q16842, Q3UHH8, Q4G148, Q5CAZ6, Q5K027, Q5MJS3, Q5SP46, Q5ZKI6, Q68G12, Q6DE37, Q6GX83, Q6H765, Q6KB58, Q701R2, Q70D51, Q810K9, Q8CID3, Q8GWT1, Q8IXL6, Q8RXE1, Q92184

Diamond homologs: O88829, P61130, P61131, P61132, P61943, P97325, Q02734, Q08E15, Q11203, Q11206, Q5RE85, Q68G12, Q6H8M7, Q6KB54, Q6KB55, Q6ZH45, Q70D51, Q8NDV1, Q8RY00, Q8VIB3, Q91Y74, Q92182, Q9JM95, Q9R2B6, Q9UNP4, Q9Y274, A2ZI41, P54751, Q02745, Q11200, Q11201, Q11204, Q11205, Q16842, Q2QXM3, Q64686, Q6KB58, Q6KB59, Q9H4F1, Q9WUV2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ATF2	“up-regulates quantity by expression”	ST3GAL5	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	27
Likely pathogenic	9
Uncertain significance	167
Likely benign	166
Benign	20

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1047918	NM_003896.4(ST3GAL5):c.1030_1031del (p.Ile344fs)	Pathogenic
1073192	NM_003896.4(ST3GAL5):c.297T>G (p.Tyr99Ter)	Pathogenic
1075960	NM_003896.4(ST3GAL5):c.333T>G (p.Tyr111Ter)	Pathogenic
1456729	NM_003896.4(ST3GAL5):c.332dup (p.Tyr111Ter)	Pathogenic
1458990	NM_003896.4(ST3GAL5):c.567del (p.Lys190fs)	Pathogenic
2020623	NM_003896.4(ST3GAL5):c.694G>T (p.Glu232Ter)	Pathogenic
2048837	NM_003896.4(ST3GAL5):c.538G>T (p.Glu180Ter)	Pathogenic
2127063	NM_003896.4(ST3GAL5):c.289del (p.Met97fs)	Pathogenic
254246	NM_003896.4(ST3GAL5):c.601G>A (p.Gly201Arg)	Pathogenic
2714495	NM_003896.4(ST3GAL5):c.289dup (p.Met97fs)	Pathogenic
2732879	NM_003896.4(ST3GAL5):c.271G>T (p.Glu91Ter)	Pathogenic
2770576	NM_003896.4(ST3GAL5):c.359del (p.Cys120fs)	Pathogenic
2772718	NM_003896.4(ST3GAL5):c.374_381del (p.Ala125fs)	Pathogenic
2793672	NM_003896.4(ST3GAL5):c.422T>G (p.Leu141Ter)	Pathogenic
2799674	NM_003896.4(ST3GAL5):c.895dup (p.Ile299fs)	Pathogenic
2800048	NM_003896.4(ST3GAL5):c.1008+1G>A	Pathogenic
2847221	NM_003896.4(ST3GAL5):c.1001del (p.Arg334fs)	Pathogenic
2873426	NM_003896.4(ST3GAL5):c.1000del (p.Arg334fs)	Pathogenic
2887009	NM_003896.4(ST3GAL5):c.154C>T (p.Arg52Ter)	Pathogenic
3019854	NM_003896.4(ST3GAL5):c.337C>T (p.Gln113Ter)	Pathogenic
3247236	NC_000002.11:g.(?86088284)(86090628_?)del	Pathogenic
3247237	NC_000002.11:g.(?86073480)(86075347_?)del	Pathogenic
3389328	NM_003896.4(ST3GAL5):c.319-1G>C	Pathogenic
3726354	NM_003896.4(ST3GAL5):c.874del (p.Trp292fs)	Pathogenic
4291817	NM_003896.4(ST3GAL5):c.422dup (p.Leu141fs)	Pathogenic
5556	NM_003896.4(ST3GAL5):c.862C>T (p.Arg288Ter)	Pathogenic
969192	NM_003896.4(ST3GAL5):c.318+1del	Pathogenic
1065916	NM_003896.4(ST3GAL5):c.207-2A>C	Likely pathogenic
1325141	NM_003896.4(ST3GAL5):c.850-1G>A	Likely pathogenic
2444154	NM_003896.4(ST3GAL5):c.83-4119G>A	Likely pathogenic

SpliceAI

1996 predictions. Top by Δscore:

Variant	Effect	Δscore
2:85850751:A:AC	donor_gain	1.0000
2:85850752:C:CC	donor_gain	1.0000
2:85863484:TG:T	acceptor_gain	1.0000
2:85863484:TGC:T	acceptor_loss	1.0000
2:85863485:GCTG:G	acceptor_loss	1.0000
2:85863486:C:CC	acceptor_gain	1.0000
2:85863486:C:CG	acceptor_loss	1.0000
2:85863508:CAG:C	acceptor_gain	1.0000
2:85863509:A:T	acceptor_gain	1.0000
2:85863510:G:C	acceptor_gain	1.0000
2:85863510:G:GC	acceptor_gain	1.0000
2:85888819:CGTA:C	donor_loss	1.0000
2:85888820:GTA:G	donor_loss	1.0000
2:85888821:TA:T	donor_loss	1.0000
2:85888822:A:AG	donor_loss	1.0000
2:85888823:C:CG	donor_loss	1.0000
2:85840389:CGTT:C	acceptor_gain	0.9900
2:85840391:TTC:T	acceptor_loss	0.9900
2:85840392:TC:T	acceptor_loss	0.9900
2:85840393:C:CC	acceptor_gain	0.9900
2:85844400:T:C	donor_gain	0.9900
2:85847856:TGTA:T	donor_loss	0.9900
2:85847857:GTAC:G	donor_loss	0.9900
2:85847858:TAC:T	donor_loss	0.9900
2:85847859:ACCT:A	donor_loss	0.9900
2:85847860:CCTTA:C	donor_gain	0.9900
2:85847865:T:C	donor_gain	0.9900
2:85848036:C:T	acceptor_gain	0.9900
2:85853102:C:CT	acceptor_gain	0.9900
2:85853103:A:T	acceptor_gain	0.9900

AlphaMissense

2746 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:85840318:A:C	F361L	0.997
2:85840318:A:T	F361L	0.997
2:85840320:A:G	F361L	0.997
2:85844528:C:A	W292C	0.996
2:85844528:C:G	W292C	0.996
2:85846409:A:G	W273R	0.996
2:85846409:A:T	W273R	0.996
2:85847933:A:T	V197D	0.996
2:85846407:C:A	W273C	0.995
2:85846407:C:G	W273C	0.995
2:85846557:G:C	N223K	0.995
2:85846557:G:T	N223K	0.995
2:85840343:C:G	C353S	0.994
2:85840344:A:T	C353S	0.994
2:85840319:A:C	F361C	0.993
2:85840343:C:T	C353Y	0.993
2:85840344:A:G	C353R	0.993
2:85847864:A:T	I220K	0.993
2:85840385:G:T	P339H	0.992
2:85846417:T:A	D270V	0.992
2:85846425:C:A	K267N	0.992
2:85846425:C:G	K267N	0.992
2:85846428:A:C	F266L	0.992
2:85846428:A:T	F266L	0.992
2:85846430:A:G	F266L	0.992
2:85846441:A:T	V262D	0.992
2:85846522:C:A	G235V	0.992
2:85840342:G:C	C353W	0.991
2:85846426:T:A	K267M	0.991
2:85847940:A:G	C195R	0.991

dbSNP variants (sampled 300 via entrez): RS1000119931 (2:85837400 TAG>T), RS1000124560 (2:85848640 T>C), RS1000154929 (2:85873178 C>A), RS1000208593 (2:85859429 G>A,C,T), RS1000245009 (2:85867783 A>C,G), RS1000276746 (2:85867407 T>C), RS1000293412 (2:85853076 C>T), RS1000307828 (2:85867089 G>A,C), RS1000350563 (2:85861661 AAAGAAAAG>A), RS1000374 (2:85839050 G>A), RS1000486602 (2:85861368 A>G), RS1000585729 (2:85855950 G>A), RS1000694268 (2:85885723 G>A), RS1000906705 (2:85837008 C>T), RS1000907839 (2:85881070 C>G)

Disease associations

OMIM: gene MIM:604402 | disease phenotypes: MIM:609056

GenCC curated gene-disease

Disease	Classification	Inheritance
GM3 synthase deficiency	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
GM3 synthase deficiency	Definitive	AR

Mondo (2): GM3 synthase deficiency (MONDO:0018274), intellectual disability (MONDO:0001071)

Orphanet (4): Amish infantile epilepsy syndrome (Orphanet:171714), GM3 synthase deficiency (Orphanet:370933), Salt-and-pepper syndrome (Orphanet:370938), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000365	Hearing impairment
HP:0000572	Visual loss
HP:0000648	Optic atrophy
HP:0000737	Irritability
HP:0001034	Hypermelanotic macule
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis
HP:0001336	Myoclonus
HP:0001344	Absent speech
HP:0001508	Failure to thrive
HP:0002013	Vomiting
HP:0002069	Bilateral tonic-clonic seizure
HP:0002133	Status epilepticus
HP:0002283	Global brain atrophy
HP:0002376	Developmental regression
HP:0002395	Lower limb hyperreflexia
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0006834	Developmental stagnation at onset of seizures
HP:0008872	Feeding difficulties in infancy
HP:0010841	Multifocal epileptiform discharges
HP:0012391	Hyporeflexia of upper limbs
HP:0100704	Cerebral visual impairment

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004599_278	Mean platelet volume	4.000000e-09
GCST90002395_331	Mean platelet volume	2.000000e-17
GCST90002397_809	Mean spheric corpuscular volume	6.000000e-11

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	5
sodium arsenite	increases abundance, increases expression, decreases expression, affects cotreatment	4
Air Pollutants	affects cotreatment, decreases expression, increases abundance	3
Arsenic	increases abundance, affects methylation, affects cotreatment, decreases expression	3
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	2
Acetaminophen	increases expression, decreases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Tretinoin	increases expression	2
Cyclosporine	decreases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
propionaldehyde	increases expression	1
bisphenol A	decreases expression	1
trichostatin A	increases expression	1
arsenite	increases methylation	1
cobaltous chloride	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
ochratoxin A	increases acetylation, increases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
ICG 001	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	increases expression	1
Panobinostat	increases expression	1
Acrolein	affects cotreatment, decreases expression, increases abundance	1

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_D6IC	AOUMEYi002-A	Induced pluripotent stem cell	Female
CVCL_TQ52	HAP1 ST3GAL5 (-) 1	Cancer cell line	Male
CVCL_TQ53	HAP1 ST3GAL5 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT02234024	Not specified	UNKNOWN	Oral Supplementation of Gangliosides to Treat a Rare Metabolic Disorder
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability