autosomal recessive limb-girdle muscular dystrophy type 2P

Summary

autosomal recessive limb-girdle muscular dystrophy type 2P (MONDO:0013440) is a disease caused by DAG1 (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DAG1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 590
• Phenotypes (HPO): 15
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		1	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

15 HPO clinical features (Orphanet curated; top 15 by frequency):

HPO ID	Term	Frequency
HP:0003236	Elevated circulating creatine kinase concentration	Very frequent (80-99%)
HP:0006785	Limb-girdle muscular dystrophy	Very frequent (80-99%)
HP:0030099	Reduced muscle fiber alpha dystroglycan	Very frequent (80-99%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0002317	Unsteady gait	Frequent (30-79%)
HP:0002515	Waddling gait	Frequent (30-79%)
HP:0003551	Difficulty climbing stairs	Frequent (30-79%)
HP:0008981	Calf muscle hypertrophy	Frequent (30-79%)
HP:0010864	Intellectual disability, severe	Frequent (30-79%)
HP:0001256	Intellectual disability, mild	Occasional (5-29%)
HP:0002465	Poor speech	Occasional (5-29%)
HP:0002938	Lumbar hyperlordosis	Occasional (5-29%)
HP:0003391	Gowers sign	Occasional (5-29%)
HP:0003707	Calf muscle pseudohypertrophy	Occasional (5-29%)
HP:0006466	Ankle flexion contracture	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive limb-girdle muscular dystrophy type 2P
Mondo ID	MONDO:0013440
OMIM	613818
Orphanet	280333
DOID	DOID:0110293
UMLS	C4511963
MedGen	1386785
GARD	0012541
Is cancer (heuristic)	no

Also known as: autosomal recessive limb-girdle muscular dystrophy caused by mutation in DAG1 · DAG1 autosomal recessive limb-girdle muscular dystrophy · LGMD2P · limb-girdle muscular dystrophy type 2P · MDDGC9 · muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 9

Data availability: 590 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › congenital muscular dystrophy › muscular dystrophy-dystroglycanopathy › muscular dystrophy-dystroglycanopathy, type C › autosomal recessive limb-girdle muscular dystrophy type 2P

Related subtypes (8): autosomal recessive limb-girdle muscular dystrophy type 2K, 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 2T, autosomal recessive limb-girdle muscular dystrophy type 2U, limb-girdle muscular dystrophy due to POMK deficiency, muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 8

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

590 retrieved; paginated sample, class counts are floors:

326 uncertain significance, 179 likely benign, 56 conflicting classifications of pathogenicity, 10 benign, 9 pathogenic, 6 benign/likely benign, 4 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3246864	NC_000003.11:g.(?48895920)(49570632_?)del	AMT	Pathogenic	criteria provided, single submitter
1073860	NM_004393.6(DAG1):c.41C>A (p.Ser14Ter)	DAG1	Pathogenic	criteria provided, single submitter
3246914	NC_000003.11:g.(?49568210)(49570632_?)del	DAG1	Pathogenic	criteria provided, single submitter
4785636	NM_004393.6(DAG1):c.1056_1057del (p.Glu352fs)	DAG1	Pathogenic	criteria provided, single submitter
4786300	NM_004393.6(DAG1):c.616del (p.Gln206fs)	DAG1	Pathogenic	criteria provided, single submitter
539125	NM_004393.6(DAG1):c.440del (p.Gln147fs)	DAG1	Pathogenic	criteria provided, single submitter
654870	NM_004393.6(DAG1):c.235C>T (p.Arg79Ter)	DAG1	Pathogenic	criteria provided, single submitter
842859	NM_004393.6(DAG1):c.285+1G>A	DAG1	Pathogenic	criteria provided, single submitter
958922	NM_004393.6(DAG1):c.330G>A (p.Trp110Ter)	DAG1	Pathogenic	criteria provided, single submitter
1709072	NM_004393.6(DAG1):c.721_722del (p.Phe241fs)	DAG1	Likely pathogenic	criteria provided, single submitter
3233447	NM_004393.6(DAG1):c.112del (p.Ala38fs)	DAG1	Likely pathogenic	no assertion criteria provided
3338231	NM_004393.6(DAG1):c.255_258delinsCC (p.Leu86fs)	DAG1	Likely pathogenic	no assertion criteria provided
471776	NM_004393.6(DAG1):c.454_467del (p.Phe152fs)	DAG1	Likely pathogenic	criteria provided, single submitter
1054355	NM_004393.6(DAG1):c.2215_2216del (p.Arg739fs)	DAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1079508	NM_004393.6(DAG1):c.1251T>C (p.Ala417=)	DAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1176024	NM_004393.6(DAG1):c.15G>A (p.Val5=)	DAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
195220	NM_004393.6(DAG1):c.258G>C (p.Leu86Phe)	DAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
195221	NM_004393.6(DAG1):c.183T>C (p.Val61=)	DAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
196385	NM_004393.6(DAG1):c.498G>A (p.Ser166=)	DAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
196386	NM_004393.6(DAG1):c.2196G>A (p.Pro732=)	DAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
196387	NM_004393.6(DAG1):c.735G>A (p.Pro245=)	DAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
208542	NM_004393.6(DAG1):c.2006G>T (p.Cys669Phe)	DAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
257585	NM_004393.6(DAG1):c.1308G>A (p.Thr436=)	DAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
281825	NM_004393.6(DAG1):c.278T>C (p.Ile93Thr)	DAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
282414	NM_004393.6(DAG1):c.1905C>T (p.Phe635=)	DAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
282535	NM_004393.6(DAG1):c.717G>A (p.Ser239=)	DAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
282862	NM_004393.6(DAG1):c.2561G>A (p.Arg854Gln)	DAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
283113	NM_004393.6(DAG1):c.2192C>T (p.Ala731Val)	DAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
283248	NM_004393.6(DAG1):c.1690C>A (p.Leu564Ile)	DAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
283316	NM_004393.6(DAG1):c.1022C>T (p.Thr341Ile)	DAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 7 · 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
DAG1	Definitive	Autosomal recessive	autosomal recessive limb-girdle muscular dystrophy type 2P	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DAG1	Orphanet:206599	Isolated asymptomatic elevation of creatine phosphokinase
DAG1	Orphanet:280333	Alpha-dystroglycan-related limb-girdle muscular dystrophy R16
DAG1	Orphanet:370997	Muscle-eye-brain disease with bilateral multicystic leucodystrophy
DAG1	Orphanet:899	Walker-Warburg syndrome
AMT	Orphanet:289857	Neonatal glycine encephalopathy
AMT	Orphanet:289860	Infantile glycine encephalopathy
AMT	Orphanet:289863	Atypical glycine encephalopathy

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
DAG1	HGNC:2666	ENSG00000173402	Q14118	Dystroglycan 1	gencc,clinvar
AMT	HGNC:473	ENSG00000145020	P48728	Aminomethyltransferase, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DAG1	Dystroglycan 1	The dystroglycan complex is involved in a number of signaling events and processes including laminin deposition and extracellular matrix assembly, acetylcholine receptor clustering, sarcolemmal stability, cell survival, peripheral nerve my…
AMT	Aminomethyltransferase, mitochondrial	The glycine cleavage system catalyzes the degradation of glycine.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Antibody/Immunoglobulin	1	14.6×	0.135
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DAG1	Antibody/Immunoglobulin	yes		Cadg, DAG1_C, Ig-like_fold
AMT	Enzyme (other)	yes	1.4.1.27	GCVT_N, GcvT, GcvT_C

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
dorsal root ganglion	1
olfactory bulb	1
trigeminal ganglion	1
liver	1
right lobe of liver	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DAG1	299	ubiquitous	marker	olfactory bulb, trigeminal ganglion, dorsal root ganglion
AMT	140	broad	yes	right lobe of liver, liver, right uterine tube

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DAG1	2,301
AMT	1,716

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DAG1	Q14118	8
AMT	P48728	2

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 POMGNT1 causes MDDGA3, MDDGB3 and MDDGC3	1	2855.0×	0.002	DAG1
Defective POMT2 causes MDDGA2, MDDGB2 and MDDGC2	1	1903.3×	0.002	DAG1
Defective POMT1 causes MDDGA1, MDDGB1 and MDDGC1	1	1903.3×	0.002	DAG1
DAG1 core M1 glycosylations	1	1427.5×	0.002	DAG1
DAG1 core M2 glycosylations	1	1142.0×	0.002	DAG1
DAG1 core M3 glycosylations	1	951.7×	0.002	DAG1
Glycine degradation	1	815.7×	0.002	AMT
Matriglycan biosynthesis on DAG1	1	407.9×	0.004	DAG1
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	184.2×	0.008	DAG1
Formation of the dystrophin-glycoprotein complex (DGC)	1	154.3×	0.008	DAG1
Non-integrin membrane-ECM interactions	1	77.2×	0.014	DAG1
ECM proteoglycans	1	75.1×	0.014	DAG1
Regulation of expression of SLITs and ROBOs	1	34.6×	0.029	DAG1

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
muscle attachment	1	8426.0×	0.002	DAG1
nerve maturation	1	8426.0×	0.002	DAG1
glycine catabolic process	1	4213.0×	0.002	AMT
calcium-dependent cell-matrix adhesion	1	4213.0×	0.002	DAG1
glycine decarboxylation via glycine cleavage system	1	2808.7×	0.002	AMT
retrograde trans-synaptic signaling by trans-synaptic protein complex	1	2808.7×	0.002	DAG1
response to denervation involved in regulation of muscle adaptation	1	1203.7×	0.005	DAG1
morphogenesis of an epithelial sheet	1	842.6×	0.005	DAG1
angiogenesis involved in wound healing	1	842.6×	0.005	DAG1
branching involved in salivary gland morphogenesis	1	702.2×	0.005	DAG1
microtubule anchoring	1	648.1×	0.005	DAG1
axon regeneration	1	561.7×	0.005	DAG1
commissural neuron axon guidance	1	495.6×	0.005	DAG1
nerve development	1	468.1×	0.005	DAG1
myelination in peripheral nervous system	1	443.5×	0.005	DAG1
skeletal muscle tissue regeneration	1	443.5×	0.005	DAG1
regulation of neurotransmitter receptor localization to postsynaptic specialization membrane	1	443.5×	0.005	DAG1
epithelial tube branching involved in lung morphogenesis	1	421.3×	0.005	DAG1
cellular response to cholesterol	1	421.3×	0.005	DAG1
positive regulation of myelination	1	383.0×	0.005	DAG1
positive regulation of cell-matrix adhesion	1	337.0×	0.005	DAG1
positive regulation of oligodendrocyte differentiation	1	337.0×	0.005	DAG1
membrane protein ectodomain proteolysis	1	324.1×	0.005	DAG1
positive regulation of Rac protein signal transduction	1	324.1×	0.005	DAG1
regulation of synapse organization	1	324.1×	0.005	DAG1
inhibitory synapse assembly	1	312.1×	0.005	DAG1
response to muscle activity	1	290.6×	0.005	DAG1
basement membrane organization	1	255.3×	0.005	DAG1
response to peptide hormone	1	195.9×	0.007	DAG1
heart morphogenesis	1	187.2×	0.007	DAG1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DAG1	0	0
AMT	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
DAG1	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AMT	1.4.1.27, 2.1.2.10	glycine cleavage system, aminomethyltransferase

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	2	DAG1, AMT
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
DAG1	4	—
AMT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05989620	Not specified	RECRUITING	Long-Term Development of Muscular Dystrophy Outcome Assessments