Niemann-Pick disease type B

Summary

Niemann-Pick disease type B (MONDO:0011871) is a disease caused by SMPD1 (GenCC Strong), with 2 cohort genes and 1 clinical trial. Top therapeutic interventions include cyclophosphamide anhydrous.

At a glance

• Prevalence: Unknown (Europe) [Orphanet-validated]
• Causal gene: SMPD1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 870
• Phenotypes (HPO): 47
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.4	Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

47 HPO clinical features (Orphanet curated; top 47 by frequency):

HPO ID	Term	Frequency
HP:0000823	Delayed puberty	Frequent (30-79%)
HP:0000938	Osteopenia	Frequent (30-79%)
HP:0000939	Osteoporosis	Frequent (30-79%)
HP:0001410	Decreased liver function	Frequent (30-79%)
HP:0001744	Splenomegaly	Frequent (30-79%)
HP:0001873	Thrombocytopenia	Frequent (30-79%)
HP:0001971	Hypersplenism	Frequent (30-79%)
HP:0002155	Hypertriglyceridemia	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0002750	Delayed skeletal maturation	Frequent (30-79%)
HP:0003077	Hyperlipidemia	Frequent (30-79%)
HP:0003119	Abnormal circulating lipid concentration	Frequent (30-79%)
HP:0003141	Increased LDL cholesterol concentration	Frequent (30-79%)
HP:0003233	Decreased HDL cholesterol concentration	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0006515	Interstitial pneumonitis	Frequent (30-79%)
HP:0006520	Progressive pulmonary function impairment	Frequent (30-79%)
HP:0006530	Abnormal pulmonary interstitial morphology	Frequent (30-79%)
HP:0010729	Cherry red spot of the macula	Frequent (30-79%)
HP:0012415	Abnormal blood gas level	Frequent (30-79%)
HP:0000707	Abnormality of the nervous system	Occasional (5-29%)
HP:0002194	Delayed gross motor development	Occasional (5-29%)
HP:0004887	Respiratory failure requiring assisted ventilation	Occasional (5-29%)
HP:0009830	Peripheral neuropathy	Occasional (5-29%)
HP:0030353	Decreased serum insulin-like growth factor 1	Occasional (5-29%)
HP:0000639	Nystagmus	Very rare (<1-4%)
HP:0000708	Atypical behavior	Very rare (<1-4%)
HP:0000716	Depression	Very rare (<1-4%)
HP:0001081	Cholelithiasis	Very rare (<1-4%)
HP:0001249	Intellectual disability	Very rare (<1-4%)
HP:0001251	Ataxia	Very rare (<1-4%)
HP:0001317	Abnormal cerebellum morphology	Very rare (<1-4%)
HP:0001328	Specific learning disability	Very rare (<1-4%)
HP:0001394	Cirrhosis	Very rare (<1-4%)
HP:0001399	Hepatic failure	Very rare (<1-4%)
HP:0001654	Abnormal heart valve morphology	Very rare (<1-4%)
HP:0001677	Coronaryartery atherosclerosis	Very rare (<1-4%)
HP:0001892	Abnormal bleeding	Very rare (<1-4%)
HP:0001973	Autoimmune thrombocytopenia	Very rare (<1-4%)
HP:0002121	Generalized non-motor (absence) seizure	Very rare (<1-4%)
HP:0002186	Apraxia	Very rare (<1-4%)
HP:0002725	Systemic lupus erythematosus	Very rare (<1-4%)
HP:0002756	Pathologic fracture	Very rare (<1-4%)
HP:0002896	Neoplasm of the liver	Very rare (<1-4%)
HP:0004836	Acute promyelocytic leukemia	Very rare (<1-4%)
HP:0007018	Attention deficit hyperactivity disorder	Very rare (<1-4%)
HP:0007302	Bipolar affective disorder	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Niemann-Pick disease type B
Mondo ID	MONDO:0011871
MeSH	D052537
OMIM	607616
Orphanet	77293
DOID	DOID:0070112
ICD-10-CM	E75.241
ICD-11	327269975
NCIT	C126866
SNOMED CT	39390005
UMLS	C0268243
MedGen	78651
GARD	0010729
Is cancer (heuristic)	no

Also known as: Niemann Pick disease type B · type B Niemann-Pick disease

Data availability: 870 ClinVar variants · 4 GenCC gene-disease records · 14 cell lines.

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 › Niemann-Pick disease type B

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, 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, GM3 synthase deficiency, 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

600 retrieved; paginated sample, class counts are floors:

316 likely benign, 63 pathogenic, 56 likely pathogenic, 54 conflicting classifications of pathogenicity, 52 uncertain significance, 38 pathogenic/likely pathogenic, 12 benign/likely benign, 9 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
198093	NM_000543.5(SMPD1):c.1826GCC[1] (p.Arg610del)	APBB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2980	NM_000543.5(SMPD1):c.1493G>T (p.Arg498Leu)	APBB1	Pathogenic	criteria provided, multiple submitters, no conflicts
2018848	NM_000543.5(SMPD1):c.69del (p.Thr24fs)	LOC130005193	Pathogenic	criteria provided, single submitter
2921607	NC_000011.10:g.6390221_6390884del	LOC130005193	Pathogenic	criteria provided, single submitter
100731	NM_000543.5(SMPD1):c.739G>A (p.Gly247Ser)	SMPD1	Pathogenic	criteria provided, multiple submitters, no conflicts
1073151	NM_000543.5(SMPD1):c.175del (p.Ala59fs)	SMPD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076908	NM_000543.5(SMPD1):c.839A>C (p.Asp280Ala)	SMPD1	Pathogenic	criteria provided, multiple submitters, no conflicts
1173968	NM_000543.5(SMPD1):c.668G>C (p.Cys223Ser)	SMPD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1173970	NM_000543.5(SMPD1):c.1088T>G (p.Leu363Arg)	SMPD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1173972	NM_000543.5(SMPD1):c.1148A>G (p.Asn383Ser)	SMPD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1173973	NM_000543.5(SMPD1):c.1171A>C (p.Asn391His)	SMPD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1173978	NM_000543.5(SMPD1):c.1598C>A (p.Pro533Gln)	SMPD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1353540	NM_000543.5(SMPD1):c.167G>A (p.Trp56Ter)	SMPD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1370114	NM_000543.5(SMPD1):c.1032T>G (p.Tyr344Ter)	SMPD1	Pathogenic	criteria provided, single submitter
1372840	NM_000543.5(SMPD1):c.1216C>T (p.Gln406Ter)	SMPD1	Pathogenic	criteria provided, single submitter
1386053	NM_000543.5(SMPD1):c.43del (p.Ser15fs)	SMPD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1399082	NM_000543.5(SMPD1):c.1576del (p.Ala526fs)	SMPD1	Pathogenic	criteria provided, single submitter
1420134	NM_000543.5(SMPD1):c.820del (p.Met274fs)	SMPD1	Pathogenic	criteria provided, single submitter
1427800	NM_000543.5(SMPD1):c.742G>T (p.Glu248Ter)	SMPD1	Pathogenic	criteria provided, multiple submitters, no conflicts
1430049	NM_000543.5(SMPD1):c.1643_1644insA (p.Asn549fs)	SMPD1	Pathogenic	criteria provided, single submitter
1451535	NM_000543.5(SMPD1):c.193dup (p.Ser65fs)	SMPD1	Pathogenic	criteria provided, single submitter
1452305	NM_000543.5(SMPD1):c.742G>C (p.Glu248Gln)	SMPD1	Pathogenic	criteria provided, single submitter
1452689	NM_000543.5(SMPD1):c.477_483dup (p.Leu162fs)	SMPD1	Pathogenic	criteria provided, single submitter
1453617	NM_000543.5(SMPD1):c.572del (p.Pro191fs)	SMPD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455924	NM_000543.5(SMPD1):c.1363C>T (p.Gln455Ter)	SMPD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456733	NM_000543.5(SMPD1):c.208_227del (p.Pro70fs)	SMPD1	Pathogenic	criteria provided, single submitter
1458477	NM_000543.5(SMPD1):c.148_151del (p.Ser50fs)	SMPD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459672	NM_000543.5(SMPD1):c.580_587dup (p.Gly197fs)	SMPD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1460100	NM_000543.5(SMPD1):c.39del (p.Arg14fs)	SMPD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1475471	NM_000543.5(SMPD1):c.1497_1498inv (p.Tyr500His)	SMPD1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 2 · 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
SMPD1	Definitive	Autosomal recessive	Niemann-Pick disease	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMPD1	Orphanet:77292	Infantile neurovisceral acid sphingomyelinase deficiency
SMPD1	Orphanet:77293	Chronic visceral acid sphingomyelinase deficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SMPD1	HGNC:11120	ENSG00000166311	P17405	Sphingomyelin phosphodiesterase	gencc,clinvar
APBB1	HGNC:581	ENSG00000166313	O00213	Amyloid beta precursor protein binding family B member 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMPD1	Sphingomyelin phosphodiesterase	Converts sphingomyelin to ceramide.
APBB1	Amyloid beta precursor protein binding family B member 1	Transcription coregulator that can have both coactivator and corepressor functions.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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
Scaffold/PPI	1	8.6×	0.160
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMPD1	Enzyme (other)	yes	3.1.4.12	Calcineurin-like_PHP, SaposinB_dom, Saposin-like
APBB1	Scaffold/PPI	no		WW_dom, PTB/PI_dom, PH-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
islet of Langerhans	1
stromal cell of endometrium	1
type B pancreatic cell	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMPD1	262	ubiquitous	marker	type B pancreatic cell, stromal cell of endometrium, islet of Langerhans
APBB1	242	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APBB1	2,826
SMPD1	1,729

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
APBB1	O00213	11
SMPD1	P17405	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
DNA Double Strand Break Response	1	237.9×	0.017	APBB1
Glycosphingolipid metabolism	1	150.3×	0.017	SMPD1
Glycosphingolipid catabolism	1	146.4×	0.017	SMPD1
DNA Double-Strand Break Repair	1	124.1×	0.017	APBB1
Regulation of clotting cascade	1	116.5×	0.017	SMPD1
Sphingolipid metabolism	1	84.0×	0.019	SMPD1
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	1	73.2×	0.019	APBB1
DNA Repair	1	49.2×	0.025	APBB1
Metabolism of lipids	1	15.8×	0.069	SMPD1
Metabolism	1	5.8×	0.165	SMPD1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
termination of signal transduction	1	2808.7×	0.005	SMPD1
sphingomyelin metabolic process	1	1685.2×	0.005	SMPD1
sphingomyelin catabolic process	1	1685.2×	0.005	SMPD1
positive regulation of apoptotic process	2	56.7×	0.005	SMPD1, APBB1
negative regulation of cell cycle G1/S phase transition	1	1203.7×	0.006	APBB1
response to type I interferon	1	936.2×	0.006	SMPD1
glycosphingolipid catabolic process	1	766.0×	0.007	SMPD1
positive regulation of viral entry into host cell	1	601.9×	0.007	SMPD1
smooth muscle contraction	1	401.2×	0.009	APBB1
positive regulation of endocytosis	1	401.2×	0.009	SMPD1
response to tumor necrosis factor	1	312.1×	0.009	SMPD1
plasma membrane repair	1	290.6×	0.009	SMPD1
response to cocaine	1	290.6×	0.009	SMPD1
response to interleukin-1	1	255.3×	0.009	SMPD1
signal transduction	2	16.1×	0.009	SMPD1, APBB1
ceramide biosynthetic process	1	210.7×	0.010	SMPD1
response to ionizing radiation	1	205.5×	0.010	SMPD1
symbiont entry into host cell	1	200.6×	0.010	SMPD1
positive regulation of protein secretion	1	172.0×	0.011	APBB1
negative regulation of MAPK cascade	1	150.5×	0.012	SMPD1
cellular response to UV	1	147.8×	0.012	SMPD1
wound healing	1	113.9×	0.014	SMPD1
cellular response to calcium ion	1	100.3×	0.015	SMPD1
cholesterol metabolic process	1	98.0×	0.015	SMPD1
axonogenesis	1	80.2×	0.018	APBB1
response to virus	1	72.0×	0.019	SMPD1
positive regulation of neuron projection development	1	68.5×	0.019	APBB1
chromatin organization	1	49.6×	0.026	APBB1
response to xenobiotic stimulus	1	34.5×	0.036	SMPD1
DNA damage response	1	26.8×	0.044	APBB1

Therapeutics

Drugs indicated or in trials for this disease

1 approved drug — disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Status
Olipudase Alfa	Approved (phase 4)

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
SMPD1	IMIPRAMINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SMPD1	3	4
APBB1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IMIPRAMINE	4	SMPD1
CHLORPROMAZINE	4	SMPD1
FENDILINE	2	SMPD1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
SMPD1	42	Binding:40, Functional:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SMPD1	3.1.4.12	sphingomyelin phosphodiesterase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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)
IMIPRAMINE	4	SMPD1
CHLORPROMAZINE	4	SMPD1
FENDILINE	2	SMPD1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SMPD1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	APBB1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
APBB1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00668564	PHASE2	TERMINATED	Hematopoietic Stem Cell Transplantation (HCT) for Inborn Errors of Metabolism

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CYCLOPHOSPHAMIDE ANHYDROUS	4	1