GM3 synthase deficiency

Summary

GM3 synthase deficiency (MONDO:0018274) is a disease caused by ST3GAL5 (GenCC Definitive), with 4 cohort genes and 1 clinical trial.

At a glance

• Causal gene: ST3GAL5 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 457
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	GM3 synthase deficiency
Mondo ID	MONDO:0018274
OMIM	609056
Orphanet	171714, 370933, 370938
DOID	DOID:0060470
SNOMED CT	722762005
UMLS	C1836824
MedGen	323005
GARD	0012059
Is cancer (heuristic)	no

Also known as: Amish infantile epilepsy syndrome · disorder of lactosylceramide alpha-2,3-sialyltransferase activity · epilepsy syndrome, infantile-onset symptomatic · GM3 synthase deficiency · infantile-onset symptomatic epilepsy syndrome - developmental stagnation - blindness · infantile-onset symptomatic epilepsy syndrome-developmental stagnation-blindness syndrome · lactosylceramide alpha-2,3-sialyltransferase activity disease · salt & pepper syndrome · salt and pepper developmental regression syndrome · salt and pepper mental retardation syndrome · SPDRS · ST3GAL5-CDG

Data availability: 457 ClinVar variants · 3 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › GM3 synthase deficiency

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, hydrolethalus syndrome, 3-M syndrome, isolated hyperchlorhidrosis, dacryocystitis-osteopoikilosis syndrome, Hutchinson-Gilford progeria syndrome, achalasia microcephaly syndrome, acrorenal syndrome, autosomal recessive, beta-ketothiolase deficiency, autosomal recessive Alport syndrome, Alstrom syndrome, microphthalmia with limb anomalies, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Behr syndrome, bifid nose, autosomal recessive, Bloom syndrome, Bowen-Conradi syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, heart defects-limb shortening syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, COFS syndrome, craniometaphyseal dysplasia, autosomal recessive, Fraser syndrome, cystic fibrosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, persistent hyperplastic primary vitreous, autosomal recessive, Donnai-Barrow syndrome, Schöpf-Schulz-Passarge syndrome, cleft lip/palate-ectodermal dysplasia syndrome, Ellis-van Creveld syndrome, Wolcott-Rallison syndrome, autosomal recessive faciodigitogenital syndrome, acromesomelic dysplasia 2B, brittle cornea syndrome, triple-A syndrome, autosomal recessive humeroradial synostosis, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, Vici syndrome, Johanson-Blizzard syndrome, autosomal recessive Kenny-Caffey syndrome, Papillon-Lefevre disease, Haim-Munk syndrome, Laurence-Moon syndrome, Donohue syndrome, lipase deficiency, combined, autosomal recessive familial Mediterranean fever, thiamine-responsive megaloblastic anemia syndrome, cartilage-hair hypoplasia, Nijmegen breakage syndrome, pseudo-TORCH syndrome, Galloway-Mowat syndrome, mulibrey nanism, myotonia congenita, autosomal recessive, Schwartz-Jampel syndrome, proteosome-associated autoinflammatory syndrome, Netherton syndrome, Niemann-Pick disease type A, oculodentodigital dysplasia, autosomal recessive, odonto-onycho-dermal dysplasia, autosomal recessive omodysplasia, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, phenylketonuria, Bjornstad syndrome, Laron syndrome, autosomal recessive polycystic kidney disease, autosomal recessive inherited pseudoxanthoma elasticum, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, autosomal recessive Robinow syndrome, Sjogren-Larsson syndrome, scapuloperoneal spinal muscular atrophy, autosomal recessive, spondyloepiphyseal dysplasia tarda, autosomal recessive, inherited threoninemia, Pendred syndrome, autosomal recessive spondylocostal dysostosis, Werner syndrome, ABCD syndrome, Naxos disease, autosomal recessive amelia, human HOXA1 syndromes, sickle cell disease, autosomal recessive proximal renal tubular acidosis, hyper-IgM syndrome type 2, temtamy preaxial brachydactyly syndrome, TH-deficient dopa-responsive dystonia, craniosynostosis syndrome, autosomal recessive, Niemann-Pick disease type B, skin fragility-woolly hair-palmoplantar keratoderma syndrome, CoQ-responsive OXPHOS deficiency, familial adenomatous polyposis 2, Pierson syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, PHARC syndrome, Kahrizi syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, congenital prothrombin deficiency, immunodeficiency 31B, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, Nestor-Guillermo progeria syndrome, leukoencephalopathy with calcifications and cysts, mitochondrial pyruvate carrier deficiency, branched-chain keto acid dehydrogenase kinase deficiency, dyskeratosis congenita, autosomal recessive 5, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, alacrima, achalasia, and intellectual disability syndrome, hyperlipoproteinemia, type 1D, microcephaly and chorioretinopathy 2, congenital stationary night blindness 1G, combined oxidative phosphorylation deficiency 29, hypermanganesemia with dystonia 2, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, gnb5-related intellectual disability-cardiac arrhythmia syndrome, autosomal recessive spastic paraplegia type 78, autosomal recessive limb-girdle muscular dystrophy, Bardet-Biedl syndrome, autosomal recessive cerebellar ataxia, neuronopathy, distal hereditary motor, autosomal recessive, UV-sensitive syndrome, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Cockayne syndrome, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, leukoencephalopathy-palmoplantar keratoderma syndrome, autosomal recessive hypohidrotic ectodermal dysplasia, Warburg micro syndrome, autosomal recessive primary microcephaly, autosomal recessive progressive external ophthalmoplegia, Meier-Gorlin syndrome, autosomal recessive sideroblastic anemia, autosomal recessive intermediate Charcot-Marie-Tooth disease, Perrault syndrome, autosomal recessive hypophosphatemic rickets, de Barsy syndrome, leukocyte adhesion deficiency, Senior-Loken syndrome, autosomal recessive spastic ataxia, childhood-onset autosomal recessive myopathy with external ophthalmoplegia, autosomal recessive cerebral atrophy, autosomal recessive distal renal tubular acidosis, pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome, autosomal recessive brachyolmia, Aicardi-Goutieres syndrome, homocystinuria without methylmalonic aciduria, Niemann-Pick disease type C, nephronophthisis, autosomal recessive osteopetrosis, peroxisome biogenesis disorder, congenital non-bullous ichthyosiform erythroderma, Seckel syndrome, Usher syndrome, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, hearing loss, autosomal recessive, microcephaly, growth restriction, and increased sister chromatid exchange 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, congenital vertebral-cardiac-renal anomalies syndrome, hair defect with photosensitivity and intellectual disability syndrome, autosomal recessive severe congenital neutropenia, severe combined immunodeficiency due to CARMIL2 deficiency, extraoral halitosis due to methanethiol oxidase deficiency, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4, mismatch repair cancer syndrome, spondyloepimetaphyseal dysplasia with joint laxity, type 3, Kilquist syndrome, Duane anomaly-myopathy-scoliosis syndrome, autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, congenital myopathy with reduced type 2 muscle fibers, NAD(P)HX dehydratase deficiency, autosomal recessive ocular albinism, ichthyosis linearis circumflexa, eosinophil peroxidase deficiency, hyperphenylalaninemia due to DNAJC12 deficiency, autosomal recessive epidermolytic ichthyosis, Ehlers-Danlos syndrome, classic-like, 2, joint laxity, short stature, and myopia, HELIX syndrome, auditory neuropathy-optic atrophy syndrome, glycosylphosphatidylinositol biosynthesis defect 15, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, SCN4A-related myopathy, autosomal recessive, Uner Tan Syndrome, nephropathic cystinosis, Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2, permanent neonatal diabetes mellitus 1, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, Rajab interstitial lung disease with brain calcifications 1, Roberts-SC phocomelia syndrome, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, RPE65-related recessive retinopathy, GUCY2D-related recessive retinopathy, autosomal recessive titinopathy, intellectual disability, autosomal recessive, ALPL-related autosomal recessive hypophosphatasia, spastic paraplegia 18b, autosomal recessive, CEP164-related ciliopathy, RP1-related recessive retinopathy, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive, spastic paraplegia 30B, autosomal recessive, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, brain small vessel disease 2B, autosomal recessive, IMPG1-related recessive retinopathy, PROM1-related recessive retinopathy

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

457 retrieved; paginated sample, class counts are floors:

197 likely benign, 176 uncertain significance, 32 pathogenic, 22 conflicting classifications of pathogenicity, 9 benign, 9 pathogenic/likely pathogenic, 8 likely pathogenic, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1075293	NM_003896.4(ST3GAL5):c.32_39del (p.Arg11fs)	LOC129934236	Pathogenic	criteria provided, single submitter
2699279	NM_003896.4(ST3GAL5):c.10A>T (p.Lys4Ter)	LOC129934236	Pathogenic	criteria provided, single submitter
2765435	NM_003896.4(ST3GAL5):c.40dup (p.Leu14fs)	LOC129934236	Pathogenic	criteria provided, single submitter
2811489	NM_003896.4(ST3GAL5):c.47_62del (p.Pro16fs)	LOC129934236	Pathogenic	criteria provided, single submitter
2812534	NM_003896.4(ST3GAL5):c.64del (p.Ala22fs)	LOC129934236	Pathogenic	criteria provided, single submitter
959131	NM_003896.4(ST3GAL5):c.79C>T (p.Arg27Ter)	LOC129934236	Pathogenic	criteria provided, single submitter
1047918	NM_003896.4(ST3GAL5):c.1030_1031del (p.Ile344fs)	ST3GAL5	Pathogenic	no assertion criteria provided
1073192	NM_003896.4(ST3GAL5):c.297T>G (p.Tyr99Ter)	ST3GAL5	Pathogenic	criteria provided, multiple submitters, no conflicts
1075960	NM_003896.4(ST3GAL5):c.333T>G (p.Tyr111Ter)	ST3GAL5	Pathogenic	criteria provided, single submitter
1325142	NM_003896.4(ST3GAL5):c.282del (p.Met94fs)	ST3GAL5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456729	NM_003896.4(ST3GAL5):c.332dup (p.Tyr111Ter)	ST3GAL5	Pathogenic	criteria provided, single submitter
1457211	NM_003896.4(ST3GAL5):c.794del (p.Leu265fs)	ST3GAL5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458990	NM_003896.4(ST3GAL5):c.567del (p.Lys190fs)	ST3GAL5	Pathogenic	criteria provided, single submitter
2020623	NM_003896.4(ST3GAL5):c.694G>T (p.Glu232Ter)	ST3GAL5	Pathogenic	criteria provided, single submitter
2048837	NM_003896.4(ST3GAL5):c.538G>T (p.Glu180Ter)	ST3GAL5	Pathogenic	criteria provided, single submitter
2127063	NM_003896.4(ST3GAL5):c.289del (p.Met97fs)	ST3GAL5	Pathogenic	criteria provided, single submitter
2170400	NM_003896.4(ST3GAL5):c.1000C>T (p.Arg334Ter)	ST3GAL5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
254245	NM_003896.4(ST3GAL5):c.584G>C (p.Cys195Ser)	ST3GAL5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
254246	NM_003896.4(ST3GAL5):c.601G>A (p.Gly201Arg)	ST3GAL5	Pathogenic	criteria provided, single submitter
2714495	NM_003896.4(ST3GAL5):c.289dup (p.Met97fs)	ST3GAL5	Pathogenic	criteria provided, single submitter
2732879	NM_003896.4(ST3GAL5):c.271G>T (p.Glu91Ter)	ST3GAL5	Pathogenic	criteria provided, single submitter
2770576	NM_003896.4(ST3GAL5):c.359del (p.Cys120fs)	ST3GAL5	Pathogenic	criteria provided, single submitter
2772718	NM_003896.4(ST3GAL5):c.374_381del (p.Ala125fs)	ST3GAL5	Pathogenic	criteria provided, single submitter
2793672	NM_003896.4(ST3GAL5):c.422T>G (p.Leu141Ter)	ST3GAL5	Pathogenic	criteria provided, single submitter
2799674	NM_003896.4(ST3GAL5):c.895dup (p.Ile299fs)	ST3GAL5	Pathogenic	criteria provided, single submitter
2800048	NM_003896.4(ST3GAL5):c.1008+1G>A	ST3GAL5	Pathogenic	criteria provided, single submitter
2847221	NM_003896.4(ST3GAL5):c.1001del (p.Arg334fs)	ST3GAL5	Pathogenic	criteria provided, single submitter
2873426	NM_003896.4(ST3GAL5):c.1000del (p.Arg334fs)	ST3GAL5	Pathogenic	criteria provided, single submitter
2887009	NM_003896.4(ST3GAL5):c.154C>T (p.Arg52Ter)	ST3GAL5	Pathogenic	criteria provided, single submitter
3019854	NM_003896.4(ST3GAL5):c.337C>T (p.Gln113Ter)	ST3GAL5	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ST3GAL5	Definitive	Autosomal recessive	GM3 synthase deficiency	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ST3GAL5	Orphanet:370933	GM3 synthase deficiency
ATXN2	Orphanet:803	Amyotrophic lateral sclerosis
ATXN2	Orphanet:98756	Spinocerebellar ataxia type 2
POLR1A	Orphanet:1200	Burn-McKeown syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ST3GAL5	HGNC:10872	ENSG00000115525	Q9UNP4	Lactosylceramide alpha-2,3-sialyltransferase	gencc,clinvar
RORB	HGNC:10259	ENSG00000198963	Q92753	Nuclear receptor ROR-beta	clinvar
ATXN2	HGNC:10555	ENSG00000204842	Q99700	Ataxin-2	clinvar
POLR1A	HGNC:17264	ENSG00000068654	O95602	DNA-directed RNA polymerase I subunit RPA1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ST3GAL5	Lactosylceramide alpha-2,3-sialyltransferase	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 pro…
RORB	Nuclear receptor ROR-beta	Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5’-AGGTCA-3’ preceded by a short A-T-rich sequence.
ATXN2	Ataxin-2	Involved in EGFR trafficking, acting as negative regulator of endocytic EGFR internalization at the plasma membrane.
POLR1A	DNA-directed RNA polymerase I subunit RPA1	Catalytic core component of RNA polymerase I (Pol I), a DNA-dependent RNA polymerase which synthesizes ribosomal RNA precursors using the four ribonucleoside triphosphates as substrates.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Nuclear receptor	1	96.5×	0.031
Enzyme (other)	1	3.0×	0.441
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ST3GAL5	Enzyme (other)	yes	2.4.99.9	Glyco_trans_29, Sialyl_trans, GT29-like_sf
RORB	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
ATXN2	Other/Unknown	no		LsmAD_domain, PAM2_motif, LSM_dom_sf
POLR1A	Other/Unknown	no		RNA_pol_asu, RNA_pol_N, RNA_pol_Rpb1_3

Expression context

Cohort genes with no expression data: 0.

4 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	1
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1
buccal mucosa cell	1
colonic epithelium	1
olfactory bulb	1
stromal cell of endometrium	1
sural nerve	1
tibialis anterior	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ST3GAL5	267	ubiquitous	marker	right adrenal gland, right adrenal gland cortex, left adrenal gland
RORB	196	broad	marker	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus
ATXN2	286	ubiquitous	marker	buccal mucosa cell, colonic epithelium, olfactory bulb
POLR1A	198	ubiquitous	marker	sural nerve, tibialis anterior, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLR1A	4,620
ATXN2	3,360
RORB	1,432
ST3GAL5	778

Structural data

PDB: 2 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLR1A	O95602	7
ATXN2	Q99700	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ST3GAL5	Q9UNP4	83.04
RORB	Q92753	79.48

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 4 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glycosphingolipid biosynthesis	1	200.3×	0.027	ST3GAL5
Positive epigenetic regulation of rRNA expression	1	115.3×	0.027	POLR1A
Sialic acid metabolism	1	108.8×	0.027	ST3GAL5
RNA Polymerase I Transcription Termination	1	108.8×	0.027	POLR1A
Glycosphingolipid metabolism	1	100.2×	0.027	ST3GAL5
Synthesis of substrates in N-glycan biosythesis	1	97.6×	0.027	ST3GAL5
RNA Polymerase I Promoter Clearance	1	97.6×	0.027	POLR1A
Expression of BMAL (ARNTL), CLOCK, and NPAS2	1	97.6×	0.027	RORB
RNA Polymerase I Transcription	1	95.2×	0.027	POLR1A
Negative epigenetic regulation of rRNA expression	1	86.5×	0.027	POLR1A
Gene expression (Transcription)	2	11.9×	0.027	RORB, POLR1A
RNA Polymerase I Transcription Initiation	1	74.6×	0.028	POLR1A
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1	69.2×	0.028	ST3GAL5
Nuclear Receptor transcription pathway	1	66.8×	0.028	RORB
Sphingolipid metabolism	1	56.0×	0.031	ST3GAL5
B-WICH complex positively regulates rRNA expression	1	40.5×	0.037	POLR1A
RNA Polymerase I Promoter Escape	1	40.5×	0.037	POLR1A
NoRC negatively regulates rRNA expression	1	34.9×	0.041	POLR1A
Epigenetic regulation of gene expression	1	23.8×	0.057	POLR1A
Asparagine N-linked glycosylation	1	20.0×	0.064	ST3GAL5
Metabolism of lipids	1	10.5×	0.114	ST3GAL5
RNA Polymerase II Transcription	1	7.5×	0.151	RORB
Post-translational protein modification	1	6.4×	0.168	ST3GAL5
Generic Transcription Pathway	1	5.0×	0.201	RORB
Metabolism of proteins	1	4.1×	0.232	ST3GAL5
Metabolism	1	3.9×	0.237	ST3GAL5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of protein localization to nucleolus	1	1404.3×	0.009	POLR1A
nucleolar large rRNA transcription by RNA polymerase I	1	842.6×	0.009	POLR1A
RNA metabolic process	1	702.2×	0.009	ATXN2
retinal rod cell development	1	421.3×	0.009	RORB
amacrine cell differentiation	1	383.0×	0.009	RORB
RNA transport	1	383.0×	0.009	ATXN2
transcription by RNA polymerase I	1	351.1×	0.009	POLR1A
retinal cone cell development	1	351.1×	0.009	RORB
negative regulation of receptor internalization	1	300.9×	0.009	ATXN2
ganglioside biosynthetic process	1	280.9×	0.009	ST3GAL5
P-body assembly	1	263.3×	0.009	ATXN2
eye photoreceptor cell development	1	210.7×	0.010	RORB
glycosphingolipid biosynthetic process	1	150.5×	0.012	ST3GAL5
stress granule assembly	1	150.5×	0.012	ATXN2
negative regulation of osteoblast differentiation	1	73.9×	0.023	RORB
regulation of circadian rhythm	1	64.8×	0.023	RORB
retina development in camera-type eye	1	63.8×	0.023	RORB
rhythmic process	1	62.9×	0.023	RORB
cellular response to retinoic acid	1	58.5×	0.023	RORB
regulation of translation	1	54.7×	0.024	ATXN2
visual perception	1	19.9×	0.061	RORB
regulation of DNA-templated transcription	1	7.9×	0.137	RORB
negative regulation of DNA-templated transcription	1	7.9×	0.137	RORB
positive regulation of DNA-templated transcription	1	7.0×	0.147	RORB
positive regulation of transcription by RNA polymerase II	1	3.7×	0.253	RORB
regulation of transcription by RNA polymerase II	1	2.9×	0.302	RORB

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 2

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
RORB	TRETINOIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RORB	2	4
POLR1A	1	2
ST3GAL5	0	0
ATXN2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TRETINOIN	4	RORB
MOLIBRESIB	2	POLR1A
CINTIRORGON	1	RORB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
RORB	90	Binding:87, Functional:3
POLR1A	16	Binding:16
ATXN2	5	Binding:3, Functional:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ST3GAL5	2.4.99.9	lactosylceramide alpha-2,3-sialyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

3 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
TRETINOIN	4	RORB
MOLIBRESIB	2	POLR1A
CINTIRORGON	1	RORB

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	RORB
B	Phased (≥1) drug, not yet approved	1	POLR1A
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ST3GAL5
E	Difficult family or no structure, no drug	1	ATXN2

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ST3GAL5	0	—
ATXN2	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02234024	Not specified	UNKNOWN	Oral Supplementation of Gangliosides to Treat a Rare Metabolic Disorder