Beta-ketothiolase deficiency

Summary

Beta-ketothiolase deficiency (MONDO:0008760) is a disease caused by ACAT1 (GenCC Definitive), with 3 cohort genes and 3 clinical trials.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: ACAT1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 743
• Phenotypes (HPO): 42
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.72	Australia	Validated
Prevalence at birth	1-9 / 1 000 000	0.43	United States	Validated
Prevalence at birth	1-9 / 1 000 000	0.98	China	Validated
Prevalence at birth	1-9 / 1 000 000	0.53	Viet Nam	Validated

Signs & symptoms

Clinical features (HPO)

42 HPO clinical features (Orphanet curated; top 42 by frequency):

HPO ID	Term	Frequency
HP:0001941	Acidosis	Very frequent (80-99%)
HP:0001942	Metabolic acidosis	Very frequent (80-99%)
HP:0001945	Fever	Very frequent (80-99%)
HP:0002013	Vomiting	Very frequent (80-99%)
HP:0002149	Hyperuricemia	Very frequent (80-99%)
HP:0002789	Tachypnea	Very frequent (80-99%)
HP:0002919	Ketonuria	Very frequent (80-99%)
HP:0011446	Abnormality of higher mental function	Very frequent (80-99%)
HP:0000741	Apathy	Frequent (30-79%)
HP:0001259	Coma	Frequent (30-79%)
HP:0001262	Excessive daytime somnolence	Frequent (30-79%)
HP:0001894	Thrombocytosis	Frequent (30-79%)
HP:0001944	Dehydration	Frequent (30-79%)
HP:0001974	Leukocytosis	Frequent (30-79%)
HP:0001987	Hyperammonemia	Frequent (30-79%)
HP:0001993	Ketoacidosis	Frequent (30-79%)
HP:0002014	Diarrhea	Frequent (30-79%)
HP:0004372	Reduced consciousness/confusion	Frequent (30-79%)
HP:0012735	Cough	Frequent (30-79%)
HP:0000713	Agitation	Occasional (5-29%)
HP:0000822	Hypertension	Occasional (5-29%)
HP:0000969	Edema	Occasional (5-29%)
HP:0000980	Pallor	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0001265	Hyporeflexia	Occasional (5-29%)
HP:0001270	Motor delay	Occasional (5-29%)
HP:0001824	Weight loss	Occasional (5-29%)
HP:0001943	Hypoglycemia	Occasional (5-29%)
HP:0002039	Anorexia	Occasional (5-29%)
HP:0002151	Increased circulating lactate concentration	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0002615	Hypotension	Occasional (5-29%)
HP:0003074	Hyperglycemia	Occasional (5-29%)
HP:0007308	Extrapyramidal dyskinesia	Occasional (5-29%)
HP:0012523	Oral aversion	Occasional (5-29%)
HP:0012705	Abnormal metabolic brain imaging by MRS	Occasional (5-29%)
HP:0500001	Body odor	Occasional (5-29%)
HP:0001256	Intellectual disability, mild	Very rare (<1-4%)
HP:0010864	Intellectual disability, severe	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	beta-ketothiolase deficiency
Mondo ID	MONDO:0008760
MeSH	C535434
OMIM	203750
Orphanet	134
DOID	DOID:14723
NCIT	C98841
UMLS	C1536500
MedGen	280689
GARD	0000872
Is cancer (heuristic)	no

Also known as: 3-ketothiolase deficiency · 3-oxothiolase deficiency · Alpha methylacetoacetic aciduria · Alpha-methyl-acetoacetyl-CoA thiolase deficiency · Beta ketothiolase deficiency · beta-ketothiolase deficiency · BKT · mitochondrial acetoacetyl-CoA thiolase deficiency · mitochondrial acetoacetyl-coenzyme A thiolase deficiency · T2 deficiency

Data availability: 743 ClinVar variants · 6 GenCC gene-disease records · 2 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 › beta-ketothiolase 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, 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, 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:

300 likely benign, 99 uncertain significance, 63 pathogenic, 56 likely pathogenic, 35 pathogenic/likely pathogenic, 26 benign, 19 conflicting classifications of pathogenicity, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069705	NM_000019.4(ACAT1):c.749del (p.Val250fs)	ACAT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069757	NM_000019.4(ACAT1):c.1173dup (p.Ala392fs)	ACAT1	Pathogenic	criteria provided, single submitter
1072442	NM_000019.4(ACAT1):c.1163+1G>A	ACAT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073055	NM_000019.4(ACAT1):c.233del (p.Lys78fs)	ACAT1	Pathogenic	criteria provided, single submitter
1074319	NM_000019.4(ACAT1):c.571del (p.Ile191fs)	ACAT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074893	NM_000019.4(ACAT1):c.261dup (p.Glu88fs)	ACAT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076202	NM_000019.4(ACAT1):c.1100T>A (p.Leu367Ter)	ACAT1	Pathogenic	criteria provided, single submitter
1076974	NC_000011.9:g.(?107992324)(107992415_?)del	ACAT1	Pathogenic	criteria provided, single submitter
1172774	NM_000019.4(ACAT1):c.252del (p.Glu85fs)	ACAT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1172775	NM_000019.4(ACAT1):c.1117A>T (p.Lys373Ter)	ACAT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1332697	NM_000019.4(ACAT1):c.238+2T>A	ACAT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1332739	NM_000019.4(ACAT1):c.731-2A>G	ACAT1	Pathogenic	criteria provided, single submitter
1358108	NM_000019.4(ACAT1):c.537del (p.Ile179fs)	ACAT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1367924	NC_000011.9:g.(?108005849)(108005989_?)del	ACAT1	Pathogenic	criteria provided, single submitter
1374250	NM_000019.4(ACAT1):c.316C>T (p.Gln106Ter)	ACAT1	Pathogenic	criteria provided, single submitter
1384281	NM_000019.4(ACAT1):c.846dup (p.Ala283fs)	ACAT1	Pathogenic	criteria provided, single submitter
1397530	NM_000019.4(ACAT1):c.378_379del (p.Ala127fs)	ACAT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1408987	NM_000019.4(ACAT1):c.824del (p.Asn275fs)	ACAT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1416775	NM_000019.4(ACAT1):c.30del (p.Ser10fs)	ACAT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1426396	NM_000019.4(ACAT1):c.1189C>A (p.His397Asn)	ACAT1	Pathogenic	criteria provided, single submitter
1438212	NM_000019.4(ACAT1):c.1128_1131dup (p.Gly378fs)	ACAT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1439830	NM_000019.4(ACAT1):c.1114C>T (p.Gln372Ter)	ACAT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1449779	NM_000019.4(ACAT1):c.826+2T>C	ACAT1	Pathogenic	criteria provided, single submitter
1452347	NM_000019.4(ACAT1):c.655_656insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNGATGGTCTCGATCTCCTGACCTCATGATCCACCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCGCTATTAATTCTT (p.Tyr219delinsPhePhePhePhePhePhePheXaaXaaXaaXaaTrpSerArgSerProAspLeuMetIleHisProProArgProProLysValLeuGlyLeuGlnAlaTer)	ACAT1	Pathogenic	criteria provided, single submitter
1454055	NM_000019.4(ACAT1):c.763G>T (p.Glu255Ter)	ACAT1	Pathogenic	criteria provided, single submitter
1454343	NM_000019.4(ACAT1):c.787A>T (p.Lys263Ter)	ACAT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456767	NM_000019.4(ACAT1):c.491_495del (p.Asn164fs)	ACAT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457479	NM_000019.4(ACAT1):c.134dup (p.Ser46fs)	ACAT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459346	NC_000011.9:g.(?108010782)(108012437_?)del	ACAT1	Pathogenic	criteria provided, single submitter
1459493	NM_000019.4(ACAT1):c.733C>T (p.Gln245Ter)	ACAT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 1 · 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
ACAT1	Definitive	Autosomal recessive	beta-ketothiolase deficiency	6
SOAT1	Definitive	Autosomal recessive	beta-ketothiolase deficiency	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACAT1	Orphanet:134	Beta-ketothiolase deficiency

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SOAT1	HGNC:11177	ENSG00000057252	P35610	Sterol O-acyltransferase 1	gencc,clinvar
ACAT1	HGNC:93	ENSG00000075239	P24752	Acetyl-CoA acetyltransferase, mitochondrial	gencc,clinvar
ACAT2	HGNC:94	ENSG00000120437	Q9BWD1	Acetyl-CoA acetyltransferase, cytosolic	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SOAT1	Sterol O-acyltransferase 1	Catalyzes the formation of fatty acid-cholesterol esters, which are less soluble in membranes than cholesterol.
ACAT1	Acetyl-CoA acetyltransferase, mitochondrial	This is one of the enzymes that catalyzes the last step of the mitochondrial beta-oxidation pathway, an aerobic process breaking down fatty acids into acetyl-CoA.
ACAT2	Acetyl-CoA acetyltransferase, cytosolic	Involved in the biosynthetic pathway of cholesterol.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
Enzyme (other)	2	8.0×	0.039
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SOAT1	Enzyme (other)	yes	2.3.1.26	MBOAT_fam, Oat_ACAT_DAG_ARE, Sterol_acyltranf_meta
ACAT1	Other/Unknown	no		Thiolase, Thiolase-like, Thiolase_AS
ACAT2	Enzyme (other)	yes	2.3.1.9	Thiolase, Thiolase-like, Thiolase_AS

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	2
right adrenal gland	1
right adrenal gland cortex	1
nephron tubule	1
renal medulla	1
skeletal muscle tissue of rectus abdominis	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SOAT1	266	ubiquitous	marker	adrenal tissue, right adrenal gland cortex, right adrenal gland
ACAT1	294	ubiquitous	marker	nephron tubule, skeletal muscle tissue of rectus abdominis, renal medulla
ACAT2	283	ubiquitous	marker	ventricular zone, ganglionic eminence, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACAT1	2,836
SOAT1	2,327
ACAT2	2,250

Intra-cohort edges

A	B	Sources
ACAT1	ACAT2	biogrid_interaction, intact

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACAT1	P24752	7
SOAT1	P35610	5
ACAT2	Q9BWD1	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. Enrichment computed across 3 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
Beta-ketothiolase deficiency	1	3806.7×	0.006	ACAT1
Utilization of Ketone Bodies	1	951.7×	0.009	ACAT1
Ketone body metabolism	1	634.4×	0.009	ACAT1
Diseases of branched-chain amino acid catabolism	1	634.4×	0.009	ACAT1
Synthesis of Ketone Bodies	1	475.8×	0.010	ACAT1
Cholesterol biosynthesis	1	380.7×	0.010	ACAT2
Metabolism of lipids	2	21.0×	0.010	ACAT1, ACAT2
Lanosterol biosynthesis	1	253.8×	0.011	ACAT2
Maturation of TCA enzymes and regulation of TCA cycle	1	190.3×	0.012	ACAT1
LDL clearance	1	181.3×	0.012	SOAT1
Branched-chain amino acid catabolism	1	158.6×	0.012	ACAT1
Plasma lipoprotein clearance	1	158.6×	0.012	SOAT1
Citric acid cycle (TCA cycle)	1	141.0×	0.013	ACAT1
Plasma lipoprotein assembly, remodeling, and clearance	1	76.1×	0.021	SOAT1
Metabolism of steroids	1	45.9×	0.031	ACAT2
Metabolism	2	7.7×	0.031	ACAT1, ACAT2
Mitochondrial protein degradation	1	38.1×	0.035	ACAT1
Aerobic respiration and respiratory electron transport	1	29.5×	0.043	ACAT1
Diseases of metabolism	1	26.8×	0.045	ACAT1
Metabolism of amino acids and derivatives	1	22.5×	0.050	ACAT1
Transport of small molecules	1	8.4×	0.126	SOAT1
Disease	1	4.4×	0.222	ACAT1
Metabolism of proteins	1	4.1×	0.223	ACAT1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
metanephric proximal convoluted tubule development	1	5617.3×	0.002	ACAT1
propionyl-CoA biosynthetic process	1	5617.3×	0.002	ACAT1
farnesyl diphosphate biosynthetic process, mevalonate pathway	1	1872.4×	0.003	ACAT2
obsolete ketone body metabolic process	1	1872.4×	0.003	ACAT1
acetyl-CoA catabolic process	1	1404.3×	0.003	ACAT1
ketone body catabolic process	1	1404.3×	0.003	ACAT1
coenzyme A metabolic process	1	1123.5×	0.003	ACAT1
positive regulation of amyloid precursor protein biosynthetic process	1	1123.5×	0.003	SOAT1
L-isoleucine catabolic process	1	936.2×	0.003	ACAT1
acetyl-CoA biosynthetic process	1	802.5×	0.003	ACAT1
macrophage derived foam cell differentiation	1	802.5×	0.003	SOAT1
cholesterol storage	1	802.5×	0.003	SOAT1
coenzyme A biosynthetic process	1	510.7×	0.004	ACAT1
very-low-density lipoprotein particle assembly	1	401.2×	0.004	SOAT1
low-density lipoprotein particle clearance	1	330.4×	0.005	SOAT1
cholesterol efflux	1	175.5×	0.009	SOAT1
response to starvation	1	156.0×	0.009	ACAT1
response to hormone	1	144.0×	0.010	ACAT1
adipose tissue development	1	133.8×	0.010	ACAT1
fatty acid beta-oxidation	1	124.8×	0.010	ACAT1
liver development	1	73.9×	0.016	ACAT1
cholesterol metabolic process	1	65.3×	0.017	SOAT1
fatty acid metabolic process	1	64.6×	0.017	ACAT2
cholesterol homeostasis	1	52.0×	0.020	SOAT1
lipid metabolic process	1	30.5×	0.032	ACAT2

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 evidence-associated genes (100%) 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
SOAT1	PROGESTERONE
ACAT1	MITOTANE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SOAT1	6	4
ACAT1	5	4
ACAT2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PROGESTERONE	4	SOAT1
MITOTANE	4	ACAT1
AVASIMIBE	2	SOAT1
EFLUCIMIBE	2	ACAT1, SOAT1
NEVANIMIBE	2	ACAT1, SOAT1
PACTIMIBE	2	SOAT1
ELDACIMIBE	2	ACAT1
LECIMIBIDE	2	ACAT1
AZD-7687	1	SOAT1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
SOAT1	136	Binding:127, Functional:8, ADMET:1
ACAT1	12	Binding:12
ACAT2	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SOAT1	2.3.1.26	sterol O-acyltransferase
ACAT2	2.3.1.9	acetyl-CoA C-acetyltransferase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
SOAT1	136

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

9 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)
PROGESTERONE	4	SOAT1
MITOTANE	4	ACAT1
AVASIMIBE	2	SOAT1
EFLUCIMIBE	2	ACAT1, SOAT1
NEVANIMIBE	2	ACAT1, SOAT1
PACTIMIBE	2	SOAT1
ELDACIMIBE	2	ACAT1
LECIMIBIDE	2	ACAT1
AZD-7687	1	SOAT1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	SOAT1, ACAT1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ACAT2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
ACAT2	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan