Myopathy, distal, 5

Summary

Myopathy, distal, 5 (MONDO:0014877) is a disease caused by ADSS1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ADSS1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 38
• Phenotypes (HPO): 37

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		19	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

37 HPO clinical features (Orphanet curated; top 37 by frequency):

HPO ID	Term	Frequency
HP:0002317	Unsteady gait	Very frequent (80-99%)
HP:0003236	Elevated circulating creatine kinase concentration	Very frequent (80-99%)
HP:0003458	EMG: myopathic abnormalities	Very frequent (80-99%)
HP:0001315	Reduced tendon reflexes	Frequent (30-79%)
HP:0002091	Restrictive ventilatory defect	Frequent (30-79%)
HP:0003551	Difficulty climbing stairs	Frequent (30-79%)
HP:0003700	Generalized amyotrophy	Frequent (30-79%)
HP:0003731	Quadriceps muscle weakness	Frequent (30-79%)
HP:0003805	Rimmed vacuoles	Frequent (30-79%)
HP:0007210	Lower limb amyotrophy	Frequent (30-79%)
HP:0008944	Distal lower limb amyotrophy	Frequent (30-79%)
HP:0008959	Distal upper limb muscle weakness	Frequent (30-79%)
HP:0008994	Proximal muscle weakness in lower limbs	Frequent (30-79%)
HP:0009027	Foot dorsiflexor weakness	Frequent (30-79%)
HP:0009046	Difficulty running	Frequent (30-79%)
HP:0009050	Quadriceps muscle atrophy	Frequent (30-79%)
HP:0009053	Distal lower limb muscle weakness	Frequent (30-79%)
HP:0009129	Upper limb amyotrophy	Frequent (30-79%)
HP:0030051	Tip-toe gait	Frequent (30-79%)
HP:0030193	Fatigable weakness of chewing muscles	Frequent (30-79%)
HP:0030319	Weakness of facial musculature	Frequent (30-79%)
HP:0031108	Triceps weakness	Frequent (30-79%)
HP:0031237	Internally nucleated skeletal muscle fibers	Frequent (30-79%)
HP:0032341	Reduced forced vital capacity	Frequent (30-79%)
HP:0034391	Elbow contracture	Frequent (30-79%)
HP:0034677	Ankle contracture	Frequent (30-79%)
HP:0000218	High palate	Occasional (5-29%)
HP:0001639	Hypertrophic cardiomyopathy	Occasional (5-29%)
HP:0002359	Frequent falls	Occasional (5-29%)
HP:0002540	Inability to walk	Occasional (5-29%)
HP:0003376	Steppage gait	Occasional (5-29%)
HP:0003798	Nemaline bodies	Occasional (5-29%)
HP:0009072	Decreased Achilles reflex	Occasional (5-29%)
HP:0012548	Fatty replacement of skeletal muscle	Occasional (5-29%)
HP:0003474	Somatic sensory dysfunction	Excluded (0%)
HP:0002200	Pseudobulbar signs	Very rare (<1-4%)
HP:0005216	Impaired mastication	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	myopathy, distal, 5
Mondo ID	MONDO:0014877
OMIM	617030
Orphanet	482601
UMLS	C5567521
MedGen	1798944
GARD	0017878
Is cancer (heuristic)	no

Also known as: adenylosuccinate synthetase-like 1-related distal myopathy · ADSSL1 distal myopathy · ADSSL1-related distal myopathy · distal myopathy caused by mutation in ADSSL1 · MPD5 · myopathy, distal, 5; MPD5 · myopathy, distal, type 5

Data availability: 38 ClinVar variants · 2 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › muscular dystrophy › distal myopathy › myopathy, distal, 5

Related subtypes (10): myopathy, distal, infantile-onset, MYH7-related skeletal myopathy, Miyoshi myopathy, distal myopathy with anterior tibial onset, myopathy, distal, with rimmed vacuoles, autosomal dominant distal myopathy, nebulin-related early-onset distal myopathy, myopathy, distal, 7, adult-onset, X-linked, oculopharyngodistal myopathy, asymptomatic hyperckemia-myalgia-rhabdomyolysis syndrome

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

38 retrieved; paginated sample, class counts are floors:

20 uncertain significance, 5 benign, 4 pathogenic/likely pathogenic, 3 conflicting classifications of pathogenicity, 3 likely pathogenic, 3 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1681960	NM_152328.5(ADSS1):c.741dup (p.Lys248fs)	ADSS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1681965	NM_152328.5(ADSS1):c.746_755del (p.Lys249fs)	ADSS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1681988	NM_152328.5(ADSS1):c.967C>T (p.Gln323Ter)	ADSS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
243025	NM_152328.5(ADSS1):c.781G>A (p.Asp261Asn)	ADSS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
243026	NM_152328.5(ADSS1):c.919del (p.Ile307fs)	ADSS1	Pathogenic	criteria provided, multiple submitters, no conflicts
692295	NM_152328.5(ADSS1):c.741del (p.Lys248fs)	ADSS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
983553	NM_152328.5(ADSS1):c.1091T>C (p.Leu364Pro)	ADSS1	Pathogenic	no assertion criteria provided
1068337	NM_152328.5(ADSS1):c.193-2del	ADSS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2440052	NM_152328.5(ADSS1):c.193-5103del	ADSS1	Likely pathogenic	criteria provided, single submitter
2725585	NM_152328.5(ADSS1):c.949-2A>G	ADSS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068137	NM_152328.5(ADSS1):c.794-2A>G	ADSS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1681918	NM_152328.5(ADSS1):c.372G>C (p.Trp124Cys)	ADSS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
983554	NM_152328.5(ADSS1):c.769G>A (p.Ala257Thr)	ADSS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029191	NM_152328.5(ADSS1):c.750C>G (p.Ile250Met)	ADSS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1681882	NM_152328.5(ADSS1):c.193-4988T>A	ADSS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1681956	NM_152328.5(ADSS1):c.683T>C (p.Ile228Thr)	ADSS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1681958	NM_152328.5(ADSS1):c.709T>C (p.Tyr237His)	ADSS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1681979	NM_152328.5(ADSS1):c.880G>A (p.Val294Met)	ADSS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1681980	NM_152328.5(ADSS1):c.911G>A (p.Arg304His)	ADSS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1682029	NM_152328.5(ADSS1):c.1291C>T (p.Arg431Cys)	ADSS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1988439	NM_152328.5(ADSS1):c.193-5037G>T	ADSS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2438891	NM_152328.5(ADSS1):c.1265T>A (p.Leu422Gln)	ADSS1	Uncertain significance	criteria provided, single submitter
2438892	NM_152328.5(ADSS1):c.193-4994A>C	ADSS1	Uncertain significance	criteria provided, single submitter
2438894	NM_152328.5(ADSS1):c.823T>G (p.Cys275Gly)	ADSS1	Uncertain significance	criteria provided, single submitter
2438895	NM_152328.5(ADSS1):c.1223G>A (p.Gly408Glu)	ADSS1	Uncertain significance	criteria provided, single submitter
2438896	NM_152328.5(ADSS1):c.548G>T (p.Cys183Phe)	ADSS1	Uncertain significance	criteria provided, single submitter
2438897	NM_152328.5(ADSS1):c.409G>C (p.Val137Leu)	ADSS1	Uncertain significance	criteria provided, single submitter
2438899	NM_152328.5(ADSS1):c.201C>G (p.Asn67Lys)	ADSS1	Uncertain significance	criteria provided, single submitter
2438900	NM_152328.5(ADSS1):c.1364A>T (p.Gln455Leu)	ADSS1	Uncertain significance	criteria provided, single submitter
3064999	NM_152328.5(ADSS1):c.1073_1073+1insT	ADSS1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 1 · 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
ADSS1	Strong	Autosomal recessive	myopathy, distal, 5	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ADSS1	Orphanet:482601	Adenylosuccinate synthetase-like 1-related distal myopathy

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
ADSS1	HGNC:20093	ENSG00000185100	Q8N142	Adenylosuccinate synthetase isozyme 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ADSS1	Adenylosuccinate synthetase isozyme 1	Component of the purine nucleotide cycle (PNC), which interconverts IMP and AMP to regulate the nucleotide levels in various tissues, and which contributes to glycolysis and ammoniagenesis.

Protein-family classification

Druggable: 1 · 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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ADSS1	Enzyme (other)	yes	6.3.4.4	Adenylosuccinate_synthetase, Adenylosuccin_syn_GTP-bd, P-loop_NTPase

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
quadriceps femoris	1
skeletal muscle tissue of rectus abdominis	1
vastus lateralis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ADSS1	242	ubiquitous	marker	quadriceps femoris, vastus lateralis, skeletal muscle tissue of rectus abdominis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ADSS1	2,407

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ADSS1	Q8N142	93.10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Purine ribonucleoside monophosphate biosynthesis	1	1038.2×	1e-03	ADSS1

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
AMP biosynthetic process	1	4213.0×	0.001	ADSS1
IMP metabolic process	1	4213.0×	0.001	ADSS1
AMP salvage	1	2808.7×	0.001	ADSS1
aspartate metabolic process	1	2106.5×	0.001	ADSS1
‘de novo’ AMP biosynthetic process	1	2106.5×	0.001	ADSS1
L-glutamine metabolic process	1	1296.3×	0.001	ADSS1
cellular response to electrical stimulus	1	1296.3×	0.001	ADSS1
response to muscle activity	1	581.1×	0.002	ADSS1
response to starvation	1	468.1×	0.003	ADSS1
immune system process	1	391.9×	0.003	ADSS1
cellular response to xenobiotic stimulus	1	240.7×	0.004	ADSS1

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
ADSS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ADSS1	6.3.4.4	adenylosuccinate synthase

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	1	ADSS1
E	Difficult family or no structure, no drug	0

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)
ADSS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.