Alagille syndrome due to a NOTCH2 point mutation

Summary

Alagille syndrome due to a NOTCH2 point mutation (MONDO:0012439) is a disease caused by NOTCH2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: NOTCH2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 356

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Alagille syndrome due to a NOTCH2 point mutation
Mondo ID	MONDO:0012439
OMIM	610205
Orphanet	261629
UMLS	C1857761
MedGen	341844
GARD	0017252
Is cancer (heuristic)	no

Also known as: Alagille syndrome 2 · Alagille syndrome due to a NOTCH2 point mutation · Alagille syndrome type 2 · Alagille syndrome-NOTCH2 · Alagille-Watson syndrome due to a NOTCH2 point mutation · ALGS2 · Arteriohepatic dysplasia due to a NOTCH2 point mutation · syndromic bile duct paucity due to a NOTCH2 point mutation

Data availability: 356 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Alagille syndrome › Alagille syndrome due to a NOTCH2 point mutation

Related subtypes (2): Alagille syndrome due to 20p12 microdeletion, Alagille syndrome due to a JAG1 point mutation

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

356 retrieved; paginated sample, class counts are floors:

244 uncertain significance, 47 conflicting classifications of pathogenicity, 19 benign/likely benign, 18 likely benign, 17 likely pathogenic, 8 pathogenic, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1012187	NM_024408.4(NOTCH2):c.6125T>C (p.Met2042Thr)	NOTCH2	Pathogenic	criteria provided, single submitter
1703257	NM_024408.4(NOTCH2):c.5930-2A>G	NOTCH2	Pathogenic	no assertion criteria provided
1805691	NM_024408.4(NOTCH2):c.4593dup (p.Leu1532fs)	NOTCH2	Pathogenic	criteria provided, single submitter
4531884	NM_024408.4(NOTCH2):c.1176del (p.Asn393fs)	NOTCH2	Pathogenic	criteria provided, single submitter
518450	NM_024408.4(NOTCH2):c.7198C>T (p.Arg2400Ter)	NOTCH2	Pathogenic	criteria provided, multiple submitters, no conflicts
684619	NM_024408.4(NOTCH2):c.5644C>T (p.His1882Tyr)	NOTCH2	Pathogenic	no assertion criteria provided
9229	NM_024408.4(NOTCH2):c.5930-1G>A	NOTCH2	Pathogenic	no assertion criteria provided
9230	NM_024408.4(NOTCH2):c.1331G>A (p.Cys444Tyr)	NOTCH2	Pathogenic	no assertion criteria provided
1034042	NM_024408.4(NOTCH2):c.2587C>T (p.Pro863Ser)	NOTCH2	Likely pathogenic	criteria provided, single submitter
1329467	NM_024408.4(NOTCH2):c.6586C>T (p.Gln2196Ter)	NOTCH2	Likely pathogenic	criteria provided, single submitter
1690994	NM_024408.4(NOTCH2):c.6450del (p.Val2151fs)	NOTCH2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2581163	NM_024408.4(NOTCH2):c.6028-5T>A	NOTCH2	Likely pathogenic	criteria provided, single submitter
2582390	NM_024408.4(NOTCH2):c.1492T>C (p.Cys498Arg)	NOTCH2	Likely pathogenic	criteria provided, single submitter
3062308	NM_024408.4(NOTCH2):c.6139del (p.Arg2047fs)	NOTCH2	Likely pathogenic	criteria provided, single submitter
3256880	NM_024408.4(NOTCH2):c.4756del (p.Glu1586fs)	NOTCH2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3581868	NM_024408.4(NOTCH2):c.6640del (p.Ala2214fs)	NOTCH2	Likely pathogenic	criteria provided, single submitter
3587878	NM_024408.4(NOTCH2):c.2626G>T (p.Glu876Ter)	NOTCH2	Likely pathogenic	criteria provided, single submitter
3587981	NM_024408.4(NOTCH2):c.2569dup (p.Tyr857fs)	NOTCH2	Likely pathogenic	criteria provided, single submitter
3589944	NM_024408.4(NOTCH2):c.905dup (p.Cys302fs)	NOTCH2	Likely pathogenic	criteria provided, single submitter
3590518	NM_024408.4(NOTCH2):c.416-2A>G	NOTCH2	Likely pathogenic	criteria provided, single submitter
3600341	NM_024408.4(NOTCH2):c.1310A>C (p.Asp437Ala)	NOTCH2	Likely pathogenic	criteria provided, single submitter
3900023	NM_024408.4(NOTCH2):c.3338-2A>G	NOTCH2	Likely pathogenic	no assertion criteria provided
4528331	NM_024408.4(NOTCH2):c.1235G>T (p.Cys412Phe)	NOTCH2	Likely pathogenic	criteria provided, single submitter
599225	NM_024408.4(NOTCH2):c.5431C>T (p.Gln1811Ter)	NOTCH2	Likely pathogenic	no assertion criteria provided
635423	NM_024408.4(NOTCH2):c.6460del (p.Ser2153_Leu2154insTer)	NOTCH2	Likely pathogenic	no assertion criteria provided
1017215	NM_024408.4(NOTCH2):c.2785G>A (p.Gly929Arg)	NOTCH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1310937	NM_024408.4(NOTCH2):c.5624G>A (p.Arg1875Gln)	NOTCH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
134965	NM_024408.4(NOTCH2):c.3206G>A (p.Arg1069Gln)	NOTCH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
134982	NM_024408.4(NOTCH2):c.6979A>G (p.Thr2327Ala)	NOTCH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1359168	NM_024408.4(NOTCH2):c.5423C>T (p.Thr1808Ile)	NOTCH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · 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
NOTCH2	Strong	Autosomal dominant	Alagille syndrome due to a NOTCH2 point mutation	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NOTCH2	Orphanet:261629	Alagille syndrome due to a NOTCH2 point mutation
NOTCH2	Orphanet:955	Hajdu-Cheney syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NOTCH2	HGNC:7882	ENSG00000134250	Q04721	Neurogenic locus notch homolog protein 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NOTCH2	Neurogenic locus notch homolog protein 2	Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

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	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NOTCH2	Scaffold/PPI	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
pigmented layer of retina	1
retina	1
skin of hip	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NOTCH2	294	ubiquitous	marker	pigmented layer of retina, retina, skin of hip

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NOTCH2	5,266

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NOTCH2	Q04721	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective LFNG causes SCDO3	1	2284.0×	0.002	NOTCH2
Pre-NOTCH Processing in the Endoplasmic Reticulum	1	1903.3×	0.002	NOTCH2
NOTCH2 intracellular domain regulates transcription	1	951.7×	0.003	NOTCH2
Pre-NOTCH Processing in Golgi	1	634.4×	0.003	NOTCH2
NOTCH4 Intracellular Domain Regulates Transcription	1	571.0×	0.003	NOTCH2
NOTCH2 Activation and Transmission of Signal to the Nucleus	1	439.2×	0.003	NOTCH2
Notch-HLH transcription pathway	1	407.9×	0.003	NOTCH2
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	1	146.4×	0.008	NOTCH2
Pre-NOTCH Transcription and Translation	1	122.8×	0.008	NOTCH2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cholangiocyte proliferation	1	8426.0×	0.002	NOTCH2
regulation of osteoclast development	1	8426.0×	0.002	NOTCH2
intrahepatic bile duct development	1	5617.3×	0.002	NOTCH2
glomerular capillary formation	1	5617.3×	0.002	NOTCH2
ciliary body morphogenesis	1	4213.0×	0.002	NOTCH2
cellular response to tumor cell	1	4213.0×	0.002	NOTCH2
proximal tubule development	1	3370.4×	0.002	NOTCH2
atrioventricular node development	1	2808.7×	0.002	NOTCH2
hepatocyte proliferation	1	2106.5×	0.002	NOTCH2
marginal zone B cell differentiation	1	1872.4×	0.002	NOTCH2
positive regulation of smooth muscle cell differentiation	1	1872.4×	0.002	NOTCH2
morphogenesis of an epithelial sheet	1	1685.2×	0.002	NOTCH2
podocyte development	1	1532.0×	0.002	NOTCH2
placenta blood vessel development	1	1404.3×	0.002	NOTCH2
atrial septum morphogenesis	1	1296.3×	0.002	NOTCH2
left/right axis specification	1	1203.7×	0.002	NOTCH2
positive regulation of keratinocyte proliferation	1	991.3×	0.002	NOTCH2
cell fate determination	1	936.2×	0.002	NOTCH2
inflammatory response to antigenic stimulus	1	936.2×	0.002	NOTCH2
pulmonary valve morphogenesis	1	936.2×	0.002	NOTCH2
myeloid dendritic cell differentiation	1	936.2×	0.002	NOTCH2
bone remodeling	1	936.2×	0.002	NOTCH2
positive regulation of Ras protein signal transduction	1	887.0×	0.002	NOTCH2
positive regulation of osteoclast differentiation	1	581.1×	0.003	NOTCH2
positive regulation of BMP signaling pathway	1	455.5×	0.004	NOTCH2
embryonic limb morphogenesis	1	401.2×	0.005	NOTCH2
positive regulation of miRNA transcription	1	290.6×	0.006	NOTCH2
humoral immune response	1	280.9×	0.006	NOTCH2
heart looping	1	267.5×	0.006	NOTCH2
hemopoiesis	1	267.5×	0.006	NOTCH2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NOTCH2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NOTCH2	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NOTCH2

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)
NOTCH2	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.