Muscular dystrophy, limb-girdle, autosomal recessive 27

Summary

Muscular dystrophy, limb-girdle, autosomal recessive 27 (MONDO:0030456) is a disease caused by JAG2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: JAG2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 27

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	muscular dystrophy, limb-girdle, autosomal recessive 27
Mondo ID	MONDO:0030456
OMIM	619566
DOID	DOID:0061133
UMLS	C5562002
MedGen	1794212
GARD	0025567
Is cancer (heuristic)	no

Also known as: LGMDR27

Data availability: 27 ClinVar variants · 3 GenCC gene-disease records.

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 › autosomal recessive limb-girdle muscular dystrophy › muscular dystrophy, limb-girdle, autosomal recessive 27

Related subtypes (31): epidermolysis bullosa simplex 5B, with muscular dystrophy, autosomal recessive limb-girdle muscular dystrophy type 2A, autosomal recessive limb-girdle muscular dystrophy type 2B, autosomal recessive limb-girdle muscular dystrophy type 2C, autosomal recessive limb-girdle muscular dystrophy type 2H, autosomal recessive limb-girdle muscular dystrophy type 2F, autosomal recessive limb-girdle muscular dystrophy type 2G, autosomal recessive limb-girdle muscular dystrophy type 2E, autosomal recessive limb-girdle muscular dystrophy type 2I, autosomal recessive limb-girdle muscular dystrophy type 2D, autosomal recessive limb-girdle muscular dystrophy type 2J, autosomal recessive limb-girdle muscular dystrophy type 2K, autosomal recessive limb-girdle muscular dystrophy type 2L, autosomal recessive limb-girdle muscular dystrophy type 2M, autosomal recessive limb-girdle muscular dystrophy type 2O, autosomal recessive limb-girdle muscular dystrophy type 2N, autosomal recessive limb-girdle muscular dystrophy type 2Q, autosomal recessive limb-girdle muscular dystrophy type 2P, autosomal recessive limb-girdle muscular dystrophy type 2T, autosomal recessive limb-girdle muscular dystrophy type R18, autosomal recessive limb-girdle muscular dystrophy type 2U, limb-girdle muscular dystrophy due to POMK deficiency, autosomal recessive limb-girdle muscular dystrophy type 2X, autosomal recessive limb-girdle muscular dystrophy type 2W, autosomal recessive limb-girdle muscular dystrophy type 2Y, autosomal recessive limb-girdle muscular dystrophy type 2R1, muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 8, muscular dystrophy, limb-girdle, autosomal recessive 23, muscular dystrophy, limb-girdle, autosomal recessive 26, muscular dystrophy, limb-girdle, autosomal recessive 28, muscular dystrophy, limb-girdle, autosomal recessive 29

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

27 retrieved; paginated sample, class counts are floors:

20 uncertain significance, 4 likely pathogenic, 2 conflicting classifications of pathogenicity, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1527878	NM_002226.5(JAG2):c.1219_1225del (p.Phe407fs)	JAG2	Pathogenic	criteria provided, single submitter
1300192	NM_002226.5(JAG2):c.2515G>A (p.Gly839Arg)	JAG2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1527879	NM_002226.5(JAG2):c.841G>T (p.Gly281Cys)	JAG2	Likely pathogenic	criteria provided, single submitter
1677287	NM_002226.5(JAG2):c.493C>T (p.Arg165Ter)	JAG2	Likely pathogenic	criteria provided, single submitter
3064851	NM_002226.5(JAG2):c.312C>A (p.Tyr104Ter)	JAG2	Likely pathogenic	criteria provided, single submitter
1300193	NM_002226.5(JAG2):c.221G>C (p.Cys74Ser)	JAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1677289	NM_002226.5(JAG2):c.2134C>T (p.Arg712Cys)	JAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1300190	NM_002226.5(JAG2):c.728C>A (p.Ala243Asp)	JAG2	Uncertain significance	criteria provided, single submitter
1300191	NM_002226.5(JAG2):c.490G>A (p.Glu164Lys)	JAG2	Uncertain significance	criteria provided, single submitter
1300194	NM_002226.5(JAG2):c.2044C>T (p.Pro682Ser)	JAG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1677284	NM_002226.5(JAG2):c.2473C>T (p.Arg825Cys)	JAG2	Uncertain significance	criteria provided, single submitter
1677285	NM_002226.5(JAG2):c.2930T>C (p.Phe977Ser)	JAG2	Uncertain significance	criteria provided, single submitter
1677286	NM_002226.5(JAG2):c.283A>G (p.Thr95Ala)	JAG2	Uncertain significance	criteria provided, single submitter
1677288	NM_002226.5(JAG2):c.1073A>T (p.Asn358Ile)	JAG2	Uncertain significance	criteria provided, single submitter
1803192	NM_002226.5(JAG2):c.2308G>A (p.Gly770Arg)	JAG2	Uncertain significance	criteria provided, single submitter
3068242	NM_002226.5(JAG2):c.2434C>T (p.Arg812Cys)	JAG2	Uncertain significance	criteria provided, single submitter
3235094	NM_002226.5(JAG2):c.1021G>T (p.Gly341Cys)	JAG2	Uncertain significance	criteria provided, single submitter
3235095	NM_002226.5(JAG2):c.703T>C (p.Trp235Arg)	JAG2	Uncertain significance	criteria provided, single submitter
3235096	NM_002226.5(JAG2):c.2350C>T (p.Arg784Cys)	JAG2	Uncertain significance	criteria provided, single submitter
3359217	NM_002226.5(JAG2):c.2561_2569del (p.Pro854_Gly856del)	JAG2	Uncertain significance	no assertion criteria provided
3359218	NM_002226.5(JAG2):c.860G>A (p.Cys287Tyr)	JAG2	Uncertain significance	no assertion criteria provided
3367028	NM_002226.5(JAG2):c.2369C>G (p.Thr790Ser)	JAG2	Uncertain significance	criteria provided, single submitter
3773806	NM_002226.5(JAG2):c.3269_3314dup (p.Trp1105fs)	JAG2	Uncertain significance	criteria provided, single submitter
3896886	NM_002226.5(JAG2):c.2419G>A (p.Gly807Ser)	JAG2	Uncertain significance	criteria provided, single submitter
3896887	NM_002226.5(JAG2):c.2318T>C (p.Phe773Ser)	JAG2	Uncertain significance	criteria provided, single submitter
3896888	NM_002226.5(JAG2):c.1135G>A (p.Gly379Arg)	JAG2	Uncertain significance	criteria provided, single submitter
4277568	NM_002226.5(JAG2):c.2203C>T (p.Arg735Cys)	JAG2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 0 · 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
JAG2	Strong	Autosomal recessive	muscular dystrophy, limb-girdle, autosomal recessive 27	3

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
JAG2	HGNC:6189	ENSG00000184916	Q9Y219	Protein jagged-2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
JAG2	Protein jagged-2	Putative Notch ligand involved in the mediation of Notch signaling.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
JAG2	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, VWF_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
apex of heart	1
nipple	1
pituitary gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
JAG2	281	broad	marker	nipple, apex of heart, pituitary gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
JAG2	3,546

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
JAG2	Q9Y219	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. 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
Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	2855.0×	0.004	JAG2
Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	1631.4×	0.004	JAG2
Signaling by NOTCH1 HD Domain Mutants in Cancer	1	1268.9×	0.004	JAG2
Constitutive Signaling by NOTCH1 HD Domain Mutants	1	761.3×	0.004	JAG2
Signaling by NOTCH2	1	713.8×	0.004	JAG2
Signaling by NOTCH3	1	519.1×	0.004	JAG2
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	475.8×	0.004	JAG2
NOTCH2 Activation and Transmission of Signal to the Nucleus	1	439.2×	0.004	JAG2
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1	407.9×	0.004	JAG2
Signaling by NOTCH1 in Cancer	1	407.9×	0.004	JAG2
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1	407.9×	0.004	JAG2
Signaling by NOTCH1	1	356.9×	0.004	JAG2
Activated NOTCH1 Transmits Signal to the Nucleus	1	356.9×	0.004	JAG2
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	196.9×	0.006	JAG2
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	196.9×	0.006	JAG2
Signaling by NOTCH	1	175.7×	0.007	JAG2
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.020	JAG2
Disease	1	13.1×	0.081	JAG2
Signal Transduction	1	10.2×	0.098	JAG2

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
epithelial cell apoptotic process involved in palatal shelf morphogenesis	1	16852.0×	9e-04	JAG2
auditory receptor cell fate commitment	1	5617.3×	9e-04	JAG2
thymic T cell selection	1	5617.3×	9e-04	JAG2
gamma-delta T cell differentiation	1	2106.5×	0.002	JAG2
morphogenesis of embryonic epithelium	1	1532.0×	0.002	JAG2
respiratory system process	1	936.2×	0.003	JAG2
T cell differentiation	1	383.0×	0.005	JAG2
positive regulation of Notch signaling pathway	1	351.1×	0.005	JAG2
regulation of cell adhesion	1	306.4×	0.005	JAG2
odontogenesis of dentin-containing tooth	1	300.9×	0.005	JAG2
Notch signaling pathway	1	141.6×	0.010	JAG2
skeletal system development	1	125.8×	0.011	JAG2
regulation of cell population proliferation	1	115.4×	0.011	JAG2
in utero embryonic development	1	72.0×	0.016	JAG2
spermatogenesis	1	35.2×	0.030	JAG2
cell differentiation	1	29.1×	0.034	JAG2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
JAG2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	JAG2

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)
JAG2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.