Ullrich congenital muscular dystrophy

Summary

Ullrich congenital muscular dystrophy (MONDO:0000355) is a disease with 4 cohort genes and 3 clinical trials. The dominant Reactome pathway is Collagen chain trimerization (4 cohort genes).

At a glance

• Prevalence: 1-9 / 1 000 000 (United Kingdom) [Orphanet-validated]
• Cohort genes: 4
• ClinVar variants: 7
• Phenotypes (HPO): 31
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.13	United Kingdom	Validated
Point prevalence	1-9 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

31 HPO clinical features (Orphanet curated; top 31 by frequency):

HPO ID	Term	Frequency
HP:0000174	Abnormal palate morphology	Very frequent (80-99%)
HP:0001371	Flexion contracture	Very frequent (80-99%)
HP:0002808	Kyphosis	Very frequent (80-99%)
HP:0003236	Elevated circulating creatine kinase concentration	Very frequent (80-99%)
HP:0003306	Spinal rigidity	Very frequent (80-99%)
HP:0003324	Generalized muscle weakness	Very frequent (80-99%)
HP:0003458	EMG: myopathic abnormalities	Very frequent (80-99%)
HP:0003557	Increased variability in muscle fiber diameter	Very frequent (80-99%)
HP:0004303	Abnormal muscle fiber morphology	Very frequent (80-99%)
HP:0005072	Hyperextensibility at wrists	Very frequent (80-99%)
HP:0006149	Increased laxity of fingers	Very frequent (80-99%)
HP:0100297	Increased endomysial connective tissue	Very frequent (80-99%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0000347	Micrognathia	Frequent (30-79%)
HP:0000470	Short neck	Frequent (30-79%)
HP:0000473	Torticollis	Frequent (30-79%)
HP:0000565	Esotropia	Frequent (30-79%)
HP:0001181	Adducted thumb	Frequent (30-79%)
HP:0001238	Slender finger	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0001558	Decreased fetal movement	Frequent (30-79%)
HP:0002359	Frequent falls	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002827	Hip dislocation	Frequent (30-79%)
HP:0002878	Respiratory failure	Frequent (30-79%)
HP:0002987	Elbow flexion contracture	Frequent (30-79%)
HP:0003700	Generalized amyotrophy	Frequent (30-79%)
HP:0006380	Knee flexion contracture	Frequent (30-79%)
HP:0008081	Pes valgus	Frequent (30-79%)
HP:0009113	Diaphragmatic weakness	Frequent (30-79%)
HP:0010511	Long toe	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Ullrich congenital muscular dystrophy
Mondo ID	MONDO:0000355
MeSH	C537521
OMIM	254090
Orphanet	75840
DOID	DOID:0050558
ICD-11	1011547453
NCIT	C123438
SNOMED CT	240062007
UMLS	C4551860
MedGen	1642667
GARD	0004769
Is cancer (heuristic)	no

Also known as: late onset scleroatonic familial myopathy (subtype) · scleroatonic muscular dystrophy · scleroatonic Ullrich disease · UCMD · Ullrich disease · Ullrich scleroatonic muscular dystrophy

Data availability: 7 ClinVar variants · 4 GenCC gene-disease records · 34 cell lines.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › congenital muscular dystrophy › Ullrich congenital muscular dystrophy

Related subtypes (22): Bethlem myopathy, arthrogryposis due to muscular dystrophy, congenital muscular dystrophy-infantile cataract-hypogonadism syndrome, muscular dystrophy, congenital, with rapid progression, congenital myasthenic syndrome 10, megaconial type congenital muscular dystrophy, congenital muscular dystrophy 1B, congenital merosin-deficient muscular dystrophy 1A, congenital muscular dystrophy due to integrin alpha-7 deficiency, congenital muscular dystrophy due to LMNA mutation, congenital muscular dystrophy-respiratory failure-skin abnormalities-joint hyperlaxity syndrome, congenital myopathy, Paradas type, autosomal recessive myogenic arthrogryposis multiplex congenita, muscular dystrophy-dystroglycanopathy, congenital muscular dystrophy with hyperlaxity, muscle-eye-brain disease, rigid spine syndrome, congenital muscular dystrophy with cataracts and intellectual disability, SNUPN-related muscular dystrophy with or without multi-system involvement, congenital muscular dystrophy caused by variation in POMGNT2, collagen 6-related congenital muscular dystrophy, congenital muscular dystrophy without intellectual disability

Subtypes (4): Ullrich congenital muscular dystrophy 1A, Ullrich congenital muscular dystrophy 2, Ullrich congenital muscular dystrophy 1B, Ullrich congenital muscular dystrophy 1C

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

7 retrieved; paginated sample, class counts are floors:

6 conflicting classifications of pathogenicity, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
522655	NM_004370.6(COL12A1):c.5288A>G (p.Asn1763Ser)	COL12A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
522739	NM_004370.6(COL12A1):c.1760T>C (p.Ile587Thr)	COL12A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
542500	NM_004370.6(COL12A1):c.7690C>T (p.Pro2564Ser)	COL12A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
548487	NM_004370.6(COL12A1):c.2108C>T (p.Ala703Val)	COL12A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
582140	NM_004370.6(COL12A1):c.2968G>T (p.Asp990Tyr)	COL12A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
838940	NM_004370.6(COL12A1):c.4616C>T (p.Thr1539Met)	COL12A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
638444	NM_004370.6(COL12A1):c.793C>T (p.Arg265Cys)	COL12A1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 43 · Orphanet: 14 · 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
COL6A2	Definitive	Autosomal dominant	Ullrich congenital muscular dystrophy 1B	11
COL6A3	Definitive	Autosomal recessive	Ullrich congenital muscular dystrophy 1C	15
COL12A1	Strong	Autosomal recessive	Ullrich congenital muscular dystrophy 2	8
COL6A1	Strong	Autosomal dominant	Ullrich congenital muscular dystrophy 1A	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COL12A1	Orphanet:536516	Myopathic Ehlers-Danlos syndrome
COL12A1	Orphanet:610	Bethlem muscular dystrophy
COL12A1	Orphanet:75840	Ullrich congenital muscular dystrophy
COL6A1	Orphanet:610	Bethlem muscular dystrophy
COL6A1	Orphanet:646113	Intermediate collagen VI-related muscular dystrophy
COL6A1	Orphanet:75840	Ullrich congenital muscular dystrophy
COL6A2	Orphanet:289380	Myosclerosis
COL6A2	Orphanet:610	Bethlem muscular dystrophy
COL6A2	Orphanet:646113	Intermediate collagen VI-related muscular dystrophy
COL6A2	Orphanet:75840	Ullrich congenital muscular dystrophy
COL6A3	Orphanet:464440	Primary dystonia, DYT27 type
COL6A3	Orphanet:610	Bethlem muscular dystrophy
COL6A3	Orphanet:646113	Intermediate collagen VI-related muscular dystrophy
COL6A3	Orphanet:75840	Ullrich congenital muscular dystrophy

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
COL12A1	HGNC:2188	ENSG00000111799	Q99715	Collagen alpha-1(XII) chain	gencc,clinvar
COL6A1	HGNC:2211	ENSG00000142156	P12109	Collagen alpha-1(VI) chain	gencc
COL6A2	HGNC:2212	ENSG00000142173	P12110	Collagen alpha-2(VI) chain	gencc
COL6A3	HGNC:2213	ENSG00000163359	P12111	Collagen alpha-3(VI) chain	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL12A1	Collagen alpha-1(XII) chain	Type XII collagen interacts with type I collagen-containing fibrils, the COL1 domain could be associated with the surface of the fibrils, and the COL2 and NC3 domains may be localized in the perifibrillar matrix.
COL6A1	Collagen alpha-1(VI) chain	Collagen VI acts as a cell-binding protein.
COL6A2	Collagen alpha-2(VI) chain	Collagen VI acts as a cell-binding protein.
COL6A3	Collagen alpha-3(VI) chain	Collagen VI acts as a cell-binding protein.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · 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
Antibody/Immunoglobulin	2	14.6×	0.013
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL12A1	Antibody/Immunoglobulin	yes		VWF_A, FN3_dom, Collagen
COL6A1	Other/Unknown	no		VWF_A, Collagen, vWFA_dom_sf
COL6A2	Other/Unknown	no		VWF_A, Collagen, vWFA_dom_sf
COL6A3	Antibody/Immunoglobulin	yes		VWF_A, Kunitz_BPTI, FN3_dom

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
stromal cell of endometrium	3
calcaneal tendon	1
cartilage tissue	1
tibia	1
lower esophagus muscularis layer	1
tendon of biceps brachii	1
descending thoracic aorta	1
right coronary artery	1
skin of hip	1
visceral pleura	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL12A1	240	ubiquitous	marker	tibia, calcaneal tendon, cartilage tissue
COL6A1	291	ubiquitous	marker	stromal cell of endometrium, tendon of biceps brachii, lower esophagus muscularis layer
COL6A2	263	ubiquitous	marker	stromal cell of endometrium, right coronary artery, descending thoracic aorta
COL6A3	264	broad	marker	stromal cell of endometrium, visceral pleura, skin of hip

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL6A1	3,049
COL6A2	2,786
COL6A3	2,267
COL12A1	2,219

Intra-cohort edges

A	B	Sources
COL12A1	COL6A1	string_interaction
COL12A1	COL6A3	string_interaction
COL6A1	COL6A2	string_interaction
COL6A1	COL6A3	string_interaction
COL6A2	COL6A3	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL6A3	P12111	6
COL12A1	Q99715	1
COL6A1	P12109	1
COL6A2	P12110	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Collagen chain trimerization	4	259.6×	2e-09	COL12A1, COL6A1, COL6A2, COL6A3
Assembly of collagen fibrils and other multimeric structures	4	200.3×	2e-09	COL12A1, COL6A1, COL6A2, COL6A3
Collagen degradation	4	175.7×	2e-09	COL12A1, COL6A1, COL6A2, COL6A3
Collagen biosynthesis and modifying enzymes	4	170.4×	2e-09	COL12A1, COL6A1, COL6A2, COL6A3
Signaling by PDGF	3	190.3×	3e-07	COL6A1, COL6A2, COL6A3
NCAM1 interactions	3	186.2×	3e-07	COL6A1, COL6A2, COL6A3
ECM proteoglycans	3	112.7×	1e-06	COL6A1, COL6A2, COL6A3
Integrin cell surface interactions	3	100.8×	2e-06	COL6A1, COL6A2, COL6A3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to UV	3	274.8×	6e-06	COL6A1, COL6A2, COL6A3
phosphatidylinositol 3-kinase/protein kinase B signal transduction	3	158.0×	1e-05	COL6A1, COL6A2, COL6A3
neuron apoptotic process	3	138.9×	1e-05	COL6A1, COL6A2, COL6A3
cell adhesion	4	37.5×	1e-05	COL12A1, COL6A1, COL6A2, COL6A3
endodermal cell differentiation	2	247.8×	3e-04	COL12A1, COL6A1
response to glucose	2	127.7×	0.001	COL6A2, COL6A3
collagen fibril organization	2	112.3×	0.001	COL12A1, COL6A1
response to polyamine macromolecule	1	4213.0×	0.002	COL6A1
muscle cell apoptotic process	1	2106.5×	0.003	COL6A1
response to decreased oxygen levels	1	2106.5×	0.003	COL6A1
limb joint morphogenesis	1	1404.3×	0.004	COL6A1
fat cell proliferation	1	1404.3×	0.004	COL6A1
multicellular organismal locomotion	1	1404.3×	0.004	COL6A1
regulation of collagen fibril organization	1	1404.3×	0.004	COL6A1
muscle system process	1	1053.2×	0.004	COL6A1
sensory perception of mechanical stimulus	1	1053.2×	0.004	COL6A1
response to bleomycin	1	842.6×	0.005	COL6A1
apoptotic nuclear changes	1	702.2×	0.005	COL6A1
skeletal muscle tissue growth	1	702.2×	0.005	COL6A1
mitochondrial depolarization	1	601.9×	0.006	COL6A1
caveola assembly	1	526.6×	0.007	COL6A1
lung epithelial cell differentiation	1	468.1×	0.007	COL6A1
reduction of food intake in response to dietary excess	1	421.3×	0.007	COL6A1
skeletal muscle fiber differentiation	1	421.3×	0.007	COL6A1
mitochondrial transmembrane transport	1	421.3×	0.007	COL6A1
tissue remodeling	1	324.1×	0.009	COL6A1
response to peptide	1	280.9×	0.009	COL6A1
response to reactive oxygen species	1	263.3×	0.009	COL6A1
energy reserve metabolic process	1	263.3×	0.009	COL6A1
collagen metabolic process	1	263.3×	0.009	COL6A1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COL12A1	0	0
COL6A1	0	0
COL6A2	0	0
COL6A3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	COL12A1, COL6A3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	COL6A1, COL6A2

Undrugged target profiles

4 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
COL12A1	0	—
COL6A1	0	—
COL6A2	0	—
COL6A3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01438788	PHASE2	COMPLETED	Low Protein Diet in Patients With Collagen VI Related Myopathies
NCT03693898	Not specified	UNKNOWN	MR in Patients With Collagen VI Related Myopathies
NCT04020159	Not specified	UNKNOWN	Global Registry for COL6-related Dystrophies