Sitosterolemia 2

Summary

Sitosterolemia 2 (MONDO:0020748) is a disease caused by ABCG5 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: ABCG5 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 124

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	sitosterolemia 2
Mondo ID	MONDO:0020748
OMIM	618666
DOID	DOID:0060983
UMLS	C5231453
MedGen	1684715
GARD	0016372
Is cancer (heuristic)	no

Also known as: STSL2

Data availability: 124 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic dyslipidemia › sitosterolemia › sitosterolemia 2

Related subtypes (1): sitosterolemia 1

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

124 retrieved; paginated sample, class counts are floors:

78 uncertain significance, 24 conflicting classifications of pathogenicity, 7 pathogenic, 7 pathogenic/likely pathogenic, 6 likely pathogenic, 1 benign/likely benign, 1 benign/likely benign; association

ClinVar	Variant (HGVS)	Gene	Classification	Review
1120119	NM_022436.3(ABCG5):c.751C>T (p.Gln251Ter)	ABCG5	Pathogenic	criteria provided, multiple submitters, no conflicts
2426862	NM_022436.3(ABCG5):c.547C>T (p.Arg183Ter)	ABCG5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2537289	NM_022436.3(ABCG5):c.1762+1G>A	ABCG5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30484	NM_022436.3(ABCG5):c.46C>T (p.Gln16Ter)	ABCG5	Pathogenic	no assertion criteria provided
30485	NM_022436.3(ABCG5):c.1336C>T (p.Arg446Ter)	ABCG5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3392533	NM_022436.3(ABCG5):c.1464-1G>C	ABCG5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4077824	NM_022436.3(ABCG5):c.1375C>T (p.Gln459Ter)	ABCG5	Pathogenic	criteria provided, single submitter
4976	NM_022436.3(ABCG5):c.1222C>T (p.Arg408Ter)	ABCG5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4977	NM_022436.3(ABCG5):c.727C>T (p.Arg243Ter)	ABCG5	Pathogenic	criteria provided, multiple submitters, no conflicts
4978	NM_022436.3(ABCG5):c.1256G>A (p.Arg419His)	ABCG5	Pathogenic	criteria provided, multiple submitters, no conflicts
4979	NM_022436.3(ABCG5):c.1256G>C (p.Arg419Pro)	ABCG5	Pathogenic	no assertion criteria provided
4980	NM_022436.3(ABCG5):c.1166G>A (p.Arg389His)	ABCG5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4981	NM_022436.3(ABCG5):c.229G>T (p.Glu77Ter)	ABCG5	Pathogenic	no assertion criteria provided
808732	NM_022436.3(ABCG5):c.1374C>G (p.Tyr458Ter)	ABCG5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2584572	NM_022436.3(ABCG5):c.576del (p.Ile193fs)	ABCG5	Likely pathogenic	criteria provided, single submitter
3061912	NM_022436.3(ABCG5):c.351_354dup (p.Ala119fs)	ABCG5	Likely pathogenic	criteria provided, single submitter
4081082	NM_022436.3(ABCG5):c.1464-2A>G	ABCG5	Likely pathogenic	criteria provided, single submitter
4086127	NM_022436.3(ABCG5):c.1378_1379insT (p.Lys460fs)	ABCG5	Likely pathogenic	criteria provided, single submitter
4293362	NM_022436.3(ABCG5):c.575dup (p.Ile193fs)	ABCG5	Likely pathogenic	criteria provided, single submitter
4819397	NM_022436.3(ABCG5):c.191G>A (p.Trp64Ter)	ABCG5	Likely pathogenic	criteria provided, single submitter
1321322	NM_022436.3(ABCG5):c.-76C>T	ABCG5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1492861	NM_022436.3(ABCG5):c.1228A>G (p.Asn410Asp)	ABCG5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1684420	NM_022436.3(ABCG5):c.1890del (p.Phe630fs)	ABCG5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1699077	NM_022436.3(ABCG5):c.1649+2dup	ABCG5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1753674	NM_022436.3(ABCG5):c.1223G>A (p.Arg408Gln)	ABCG5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2060432	NM_022436.3(ABCG5):c.805G>A (p.Gly269Arg)	ABCG5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2079540	NM_022436.3(ABCG5):c.697G>A (p.Val233Ile)	ABCG5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2199424	NM_022436.3(ABCG5):c.1886C>G (p.Ser629Ter)	ABCG5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2438774	NM_022436.3(ABCG5):c.1217G>A (p.Arg406Gln)	ABCG5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2461783	NM_022436.3(ABCG5):c.833C>T (p.Ala278Val)	ABCG5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
ABCG5	Definitive	Autosomal recessive	sitosterolemia 1	5

Orphanet rare-disease linkage (cohort genes)

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

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
ABCG5	HGNC:13886	ENSG00000138075	Q9H222	ATP-binding cassette sub-family G member 5	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.
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: 1 · Difficult: 0 · Unknown: 1 · 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
Transporter	1	38.9×	0.051
Other/Unknown	1	0.9×	0.805

Per-gene assignment

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

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
duodenum	1
jejunal mucosa	1
right lobe of 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
DYNC2LI1	293	ubiquitous	marker	right uterine tube, bronchial epithelial cell, mucosa of paranasal sinus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABCG5	1,996
DYNC2LI1	852

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCG5	Q9H222	8
DYNC2LI1	Q8TCX1	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
Defective ABCG8 causes GBD4 and sitosterolemia	1	2855.0×	0.002	ABCG5
Defective ABCG5 causes sitosterolemia	1	2855.0×	0.002	ABCG5
ABC transporters in lipid homeostasis	1	300.5×	0.013	ABCG5
ABC transporter disorders	1	219.6×	0.013	ABCG5
NR1H2 and NR1H3-mediated signaling	1	196.9×	0.013	ABCG5
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	1	154.3×	0.014	ABCG5
Intraflagellar transport	1	100.2×	0.018	DYNC2LI1
Disorders of transmembrane transporters	1	69.6×	0.023	ABCG5
ABC-family protein mediated transport	1	60.7×	0.024	ABCG5
Signaling by Nuclear Receptors	1	51.0×	0.025	ABCG5
Transport of small molecules	1	12.6×	0.092	ABCG5
Disease	1	6.5×	0.159	ABCG5
Signal Transduction	1	5.1×	0.187	ABCG5

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
negative regulation of intestinal phytosterol absorption	1	4213.0×	0.002	ABCG5
negative regulation of intestinal cholesterol absorption	1	4213.0×	0.002	ABCG5
sterol transport	1	1404.3×	0.003	ABCG5
intraciliary transport involved in cilium assembly	1	1203.7×	0.003	DYNC2LI1
intestinal cholesterol absorption	1	702.2×	0.005	ABCG5
intraciliary retrograde transport	1	561.7×	0.005	DYNC2LI1
regulation of cilium assembly	1	300.9×	0.007	DYNC2LI1
response to muscle activity	1	290.6×	0.007	ABCG5
cholesterol efflux	1	263.3×	0.007	ABCG5
triglyceride homeostasis	1	240.7×	0.007	ABCG5
response to ionizing radiation	1	205.5×	0.007	ABCG5
response to nutrient	1	147.8×	0.009	ABCG5
determination of left/right symmetry	1	127.7×	0.010	DYNC2LI1
transmembrane transport	1	84.3×	0.014	ABCG5
cholesterol homeostasis	1	78.0×	0.014	ABCG5
response to xenobiotic stimulus	1	34.5×	0.029	ABCG5

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
DYNC2LI1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	1	ABCG5
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	DYNC2LI1

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)
ABCG5	0	—
DYNC2LI1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.