Sitosterolemia 1

Summary

Sitosterolemia 1 (MONDO:0020747) is a disease caused by variants in ABCG5 and ABCG8, with 3 cohort genes.

At a glance

• Causal genes: ABCG5 (GenCC Definitive), ABCG8 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 295

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	sitosterolemia 1
Mondo ID	MONDO:0020747
OMIM	210250
DOID	DOID:0070634
UMLS	C2749759
MedGen	440869
GARD	0025235
Is cancer (heuristic)	no

Also known as: sitosterolemia 1 · STSL1

Data availability: 295 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic dyslipidemia › sitosterolemia › sitosterolemia 1

Related subtypes (1): sitosterolemia 2

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

295 retrieved; paginated sample, class counts are floors:

146 uncertain significance, 80 conflicting classifications of pathogenicity, 20 benign, 18 benign/likely benign, 12 pathogenic, 9 pathogenic/likely pathogenic, 8 likely pathogenic, 1 likely benign, 1 benign/likely benign; association

ClinVar	Variant (HGVS)	Gene	Classification	Review
30485	NM_022436.3(ABCG5):c.1336C>T (p.Arg446Ter)	ABCG5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
817282	NM_022436.3(ABCG5):c.575del (p.Gly192fs)	ABCG5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1698995	NM_022437.3(ABCG8):c.1752G>A (p.Trp584Ter)	ABCG8	Pathogenic	criteria provided, multiple submitters, no conflicts
2076036	NM_022437.3(ABCG8):c.490C>T (p.Arg164Ter)	ABCG8	Pathogenic	criteria provided, multiple submitters, no conflicts
2150526	NM_022437.3(ABCG8):c.408del (p.Gln137fs)	ABCG8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2439032	NM_022437.3(ABCG8):c.1756+2T>A	ABCG8	Pathogenic	criteria provided, single submitter
39520	NM_022437.3(ABCG8):c.320C>G (p.Ser107Ter)	ABCG8	Pathogenic	criteria provided, multiple submitters, no conflicts
4848608	NC_000002.11:g.(?44066109)(44110128_?)del	ABCG8	Pathogenic	criteria provided, single submitter
4967	NM_022437.3(ABCG8):c.1083G>A (p.Trp361Ter)	ABCG8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4968	NM_022437.3(ABCG8):c.1720G>A (p.Gly574Arg)	ABCG8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4971	NM_022437.3(ABCG8):c.547del (p.Gln183fs)	ABCG8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4972	NM_022437.3(ABCG8):c.1234C>T (p.Arg412Ter)	ABCG8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4973	NM_022437.3(ABCG8):c.1787T>G (p.Leu596Arg)	ABCG8	Pathogenic	no assertion criteria provided
4974	NM_022437.3(ABCG8):c.691C>A (p.Pro231Thr)	ABCG8	Pathogenic	no assertion criteria provided
499930	NM_022437.3(ABCG8):c.1608G>A (p.Trp536Ter)	ABCG8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
499942	NM_022437.3(ABCG8):c.64-2A>G	ABCG8	Pathogenic	criteria provided, multiple submitters, no conflicts
500779	NM_022437.3(ABCG8):c.120C>A (p.Tyr40Ter)	ABCG8	Pathogenic	criteria provided, multiple submitters, no conflicts
501952	NM_022437.3(ABCG8):c.647_657dup (p.Arg220fs)	ABCG8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
546173	NM_022437.3(ABCG8):c.965-1G>C	ABCG8	Pathogenic	criteria provided, multiple submitters, no conflicts
960091	NM_022437.3(ABCG8):c.1444del (p.Leu482fs)	ABCG8	Pathogenic	criteria provided, multiple submitters, no conflicts
972743	NM_022437.3(ABCG8):c.904C>T (p.Gln302Ter)	ABCG8	Pathogenic	no assertion criteria provided
1684427	NM_022437.3(ABCG8):c.881T>G (p.Leu294Ter)	ABCG8	Likely pathogenic	criteria provided, single submitter
1698806	NM_022437.3(ABCG8):c.562-1G>A	ABCG8	Likely pathogenic	criteria provided, single submitter
2438989	NM_022437.3(ABCG8):c.641del (p.Ser214fs)	ABCG8	Likely pathogenic	criteria provided, single submitter
4081083	NM_022437.3(ABCG8):c.250_280dup (p.Lys94delinsMetTer)	ABCG8	Likely pathogenic	criteria provided, single submitter
4086217	NM_022437.3(ABCG8):c.1437C>G (p.Tyr479Ter)	ABCG8	Likely pathogenic	criteria provided, single submitter
4277396	NM_022437.3(ABCG8):c.382A>T (p.Lys128Ter)	ABCG8	Likely pathogenic	criteria provided, single submitter
4526866	NM_022437.3(ABCG8):c.1751G>A (p.Trp584Ter)	ABCG8	Likely pathogenic	criteria provided, single submitter
4845754	NM_022437.3(ABCG8):c.1906del (p.Asp636fs)	ABCG8	Likely pathogenic	criteria provided, single submitter
1677567	NM_022437.3(ABCG8):c.2T>C (p.Met1Thr)	ABCG5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 6 · 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
ABCG5	Definitive	Autosomal recessive	sitosterolemia 1	5
ABCG8	Definitive	Autosomal recessive	sitosterolemia	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ABCG5	Orphanet:2882	Sitosterolemia
ABCG5	Orphanet:391665	Homozygous familial hypercholesterolemia
ABCG8	Orphanet:2882	Sitosterolemia
ABCG8	Orphanet:391665	Homozygous familial hypercholesterolemia
DYNC2LI1	Orphanet:289	Ellis Van Creveld syndrome
DYNC2LI1	Orphanet:474	Jeune syndrome

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
ABCG5	HGNC:13886	ENSG00000138075	Q9H222	ATP-binding cassette sub-family G member 5	gencc,clinvar
ABCG8	HGNC:13887	ENSG00000143921	Q9H221	ATP-binding cassette sub-family G member 8	gencc,clinvar
DYNC2LI1	HGNC:24595	ENSG00000138036	Q8TCX1	Cytoplasmic dynein 2 light intermediate chain 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ABCG5	ATP-binding cassette sub-family G member 5	ABCG5 and ABCG8 form an obligate heterodimer that mediates Mg(2+)- and ATP-dependent sterol transport across the cell membrane.
ABCG8	ATP-binding cassette sub-family G member 8	ABCG5 and ABCG8 form an obligate heterodimer that mediates Mg(2+)- and ATP-dependent sterol transport across the cell membrane.
DYNC2LI1	Cytoplasmic dynein 2 light intermediate chain 1	Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 2 complex (dynein-2 complex), a motor protein complex that drives the movement of cargos along microtubules within cilia and flagella in concert with the i…

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
Transporter	2	51.9×	1e-03
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ABCG5	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM
ABCG8	Transporter	yes		ABC_transporter-like_ATP-bd, ABC2_TM, ABC_transporter-like_CS
DYNC2LI1	Other/Unknown	no		Dynein_light_int_chain, P-loop_NTPase, DYNC2LI1

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
jejunal mucosa	2
right lobe of liver	2
duodenum	1
liver	1
bronchial epithelial cell	1
mucosa of paranasal sinus	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ABCG5	61	tissue_specific	marker	jejunal mucosa, right lobe of liver, duodenum
ABCG8	66	tissue_specific	marker	right lobe of liver, liver, jejunal mucosa
DYNC2LI1	293	ubiquitous	marker	right uterine tube, bronchial epithelial cell, mucosa of paranasal sinus

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABCG5	1,996
ABCG8	1,920
DYNC2LI1	852

Intra-cohort edges

A	B	Sources
ABCG5	ABCG8	biogrid_interaction, intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCG5	Q9H222	8
ABCG8	Q9H221	8
DYNC2LI1	Q8TCX1	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
Defective ABCG8 causes GBD4 and sitosterolemia	2	3806.7×	3e-07	ABCG5, ABCG8
Defective ABCG5 causes sitosterolemia	2	3806.7×	3e-07	ABCG5, ABCG8
ABC transporters in lipid homeostasis	2	400.7×	3e-05	ABCG5, ABCG8
ABC transporter disorders	2	292.8×	5e-05	ABCG5, ABCG8
NR1H2 and NR1H3-mediated signaling	2	262.5×	5e-05	ABCG5, ABCG8
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	2	205.8×	7e-05	ABCG5, ABCG8
Disorders of transmembrane transporters	2	92.8×	3e-04	ABCG5, ABCG8
ABC-family protein mediated transport	2	81.0×	3e-04	ABCG5, ABCG8
Signaling by Nuclear Receptors	2	68.0×	4e-04	ABCG5, ABCG8
Transport of small molecules	2	16.8×	0.006	ABCG5, ABCG8
Intraflagellar transport	1	66.8×	0.018	DYNC2LI1
Disease	2	8.7×	0.018	ABCG5, ABCG8
Signal Transduction	2	6.8×	0.027	ABCG5, ABCG8

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
negative regulation of intestinal phytosterol absorption	2	5617.3×	2e-07	ABCG5, ABCG8
negative regulation of intestinal cholesterol absorption	2	5617.3×	2e-07	ABCG5, ABCG8
sterol transport	2	1872.4×	2e-06	ABCG5, ABCG8
intestinal cholesterol absorption	2	936.2×	6e-06	ABCG5, ABCG8
response to muscle activity	2	387.4×	3e-05	ABCG5, ABCG8
cholesterol efflux	2	351.1×	3e-05	ABCG5, ABCG8
triglyceride homeostasis	2	321.0×	3e-05	ABCG5, ABCG8
response to nutrient	2	197.1×	7e-05	ABCG5, ABCG8
transmembrane transport	2	112.3×	2e-04	ABCG5, ABCG8
cholesterol homeostasis	2	104.0×	2e-04	ABCG5, ABCG8
response to xenobiotic stimulus	2	46.0×	1e-03	ABCG5, ABCG8
intraciliary transport involved in cilium assembly	1	802.5×	0.002	DYNC2LI1
intraciliary retrograde transport	1	374.5×	0.003	DYNC2LI1
phospholipid transport	1	234.1×	0.005	ABCG8
regulation of cilium assembly	1	200.6×	0.006	DYNC2LI1
response to ionizing radiation	1	137.0×	0.008	ABCG5
determination of left/right symmetry	1	85.1×	0.012	DYNC2LI1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ABCG5	0	0
ABCG8	0	0
DYNC2LI1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	ABCG5, ABCG8
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	DYNC2LI1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ABCG5	0	—
ABCG8	0	—
DYNC2LI1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.