Myofibrillar myopathy 2

Summary

Myofibrillar myopathy 2 (MONDO:0012130) is a disease caused by CRYAB (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CRYAB (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 33
• Phenotypes (HPO): 21

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		17	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0001618	Dysphonia	Very frequent (80-99%)
HP:0002015	Dysphagia	Very frequent (80-99%)
HP:0009063	Progressive distal muscle weakness	Very frequent (80-99%)
HP:0000467	Neck muscle weakness	Frequent (30-79%)
HP:0001265	Hyporeflexia	Frequent (30-79%)
HP:0003325	Limb-girdle muscle weakness	Frequent (30-79%)
HP:0003327	Axial muscle weakness	Frequent (30-79%)
HP:0003458	EMG: myopathic abnormalities	Frequent (30-79%)
HP:0003557	Increased variability in muscle fiber diameter	Frequent (30-79%)
HP:0003736	Autophagic vacuoles	Frequent (30-79%)
HP:0009027	Foot dorsiflexor weakness	Frequent (30-79%)
HP:0030225	Accumulation of muscle fiber desmin	Frequent (30-79%)
HP:0040081	Abnormal circulating creatine kinase concentration	Frequent (30-79%)
HP:0100020	Posterior capsular cataract	Frequent (30-79%)
HP:0100299	Muscle fiber inclusion bodies	Frequent (30-79%)
HP:0001288	Gait disturbance	Occasional (5-29%)
HP:0001349	Facial diplegia	Occasional (5-29%)
HP:0001638	Cardiomyopathy	Occasional (5-29%)
HP:0002747	Respiratory insufficiency due to muscle weakness	Occasional (5-29%)
HP:0003552	Muscle stiffness	Occasional (5-29%)
HP:0009073	Progressive proximal muscle weakness	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	myofibrillar myopathy 2
Mondo ID	MONDO:0012130
MeSH	C563848
OMIM	608810
Orphanet	399058
DOID	DOID:0080093
UMLS	C1837317
MedGen	324735
GARD	0017651
Is cancer (heuristic)	no

Also known as: alpha-B crystallinopathy · autosomal dominant distal myopathy caused by mutation in CRYAB · CRYAB autosomal dominant distal myopathy · CRYAB-related myofibrillar myopathy · late-onset distal crystallinopathy · MFM2 · myofibrillar myopathy type 2 · myopathy, myofibrillar, 2 · myopathy, myofibrillar, type 2

Data availability: 33 ClinVar variants · 3 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant distal myopathy › myofibrillar myopathy 2

Related subtypes (14): tibial muscular dystrophy, myopathy, myofibrillar, 9, with early respiratory failure, distal myopathy, Welander type, myofibrillar myopathy 3, myofibrillar myopathy 4, Finnish upper limb-onset distal myopathy, distal myopathy with posterior leg and anterior hand involvement, distal myopathy, Tateyama type, adult-onset distal myopathy due to VCP mutation, KLHL9-related early-onset distal myopathy, distal myopathy with vocal cord weakness, TARDBP-related predominantly upper-limb distal myopathy, asymetric thumb-handgrip weakness-distal myopathy, calf-predominant weakness-gastrocnemius medialis atrophy-distal myopathy

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

33 retrieved; paginated sample, class counts are floors:

20 uncertain significance, 6 conflicting classifications of pathogenicity, 4 pathogenic, 2 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
16953	NM_001289808.2(CRYAB):c.358A>G (p.Arg120Gly)	CRYAB	Pathogenic	no assertion criteria provided
29669	NM_001289808.2(CRYAB):c.60del (p.Ser21fs)	CRYAB	Pathogenic	criteria provided, single submitter
41930	NM_001289808.2(CRYAB):c.325G>C (p.Asp109His)	CRYAB	Pathogenic	no assertion criteria provided
804222	NM_001289808.2(CRYAB):c.514del (p.Ala172fs)	CRYAB	Pathogenic	criteria provided, single submitter
1032782	NM_001289808.2(CRYAB):c.519del (p.Lys174fs)	CRYAB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
178013	NM_001289808.2(CRYAB):c.116C>T (p.Pro39Leu)	CRYAB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
302430	NM_001289808.2(CRYAB):c.*38G>C	CRYAB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
38963	NM_001289808.2(CRYAB):c.343del (p.Ser115fs)	CRYAB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
41929	NM_001289808.2(CRYAB):c.166C>T (p.Arg56Trp)	CRYAB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
44232	NM_001289808.2(CRYAB):c.152C>T (p.Pro51Leu)	CRYAB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1044759	NM_001289808.2(CRYAB):c.37C>A (p.Pro13Thr)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1390439	NM_001289808.2(CRYAB):c.41T>C (p.Phe14Ser)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1410499	NM_001289808.2(CRYAB):c.319C>T (p.Arg107Cys)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1506812	NM_001289808.2(CRYAB):c.503C>G (p.Ala168Gly)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1507716	NM_001289808.2(CRYAB):c.362A>G (p.Lys121Arg)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
16955	NM_001289808.2(CRYAB):c.464_465del (p.Pro155fs)	CRYAB	Uncertain significance	criteria provided, single submitter
16956	NM_001289808.2(CRYAB):c.451C>T (p.Gln151Ter)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
201688	NM_001289808.2(CRYAB):c.16C>T (p.His6Tyr)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
302432	NM_001289808.2(CRYAB):c.102G>T (p.Glu34Asp)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
393088	NM_001289808.2(CRYAB):c.367C>T (p.Arg123Trp)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
41925	NM_001289808.2(CRYAB):c.470G>A (p.Arg157His)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
569482	NM_001289808.2(CRYAB):c.65G>A (p.Arg22His)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
571646	NM_001289808.2(CRYAB):c.115C>G (p.Pro39Ala)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
643345	NM_001289808.2(CRYAB):c.275A>G (p.Lys92Arg)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
657190	NM_001289808.2(CRYAB):c.115C>T (p.Pro39Ser)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
657757	NM_001289808.2(CRYAB):c.119C>T (p.Thr40Met)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
810752	NM_001289808.2(CRYAB):c.482T>C (p.Ile161Thr)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
877466	NM_001289808.2(CRYAB):c.*60G>A	CRYAB	Uncertain significance	criteria provided, single submitter
879070	NM_001289808.2(CRYAB):c.176G>A (p.Ser59Asn)	CRYAB	Uncertain significance	criteria provided, single submitter
964348	NM_001289808.2(CRYAB):c.31C>G (p.Arg11Gly)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 6 · 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
CRYAB	Definitive	Autosomal dominant	myofibrillar myopathy 2	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CRYAB	Orphanet:154	Familial isolated dilated cardiomyopathy
CRYAB	Orphanet:280553	Fatal infantile hypertonic myofibrillar myopathy
CRYAB	Orphanet:399058	Alpha-B crystallin-related late-onset myopathy
CRYAB	Orphanet:441452	Early-onset lamellar cataract
CRYAB	Orphanet:98991	Early-onset nuclear cataract
CRYAB	Orphanet:98993	Early-onset posterior polar cataract

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
CRYAB	HGNC:2389	ENSG00000109846	P02511	Alpha-crystallin B chain	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CRYAB	Alpha-crystallin B chain	May contribute to the transparency and refractive index of the lens.

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)
CRYAB	Other/Unknown	no		Alpha-crystallin/sHSP_animal, A-crystallin/Hsp20_dom, Alpha-crystallin_N

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
cardiac ventricle	1
left ventricle myocardium	1
middle frontal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CRYAB	289	ubiquitous	marker	middle frontal gyrus, left ventricle myocardium, cardiac ventricle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CRYAB	3,368

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CRYAB	P02511	21

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
HSF1-dependent transactivation	1	317.2×	0.003	CRYAB

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
microtubule polymerization or depolymerization	1	16852.0×	0.001	CRYAB
negative regulation of intracellular transport	1	5617.3×	0.002	CRYAB
regulation of programmed cell death	1	2808.7×	0.002	CRYAB
apoptotic process involved in morphogenesis	1	2808.7×	0.002	CRYAB
tubulin complex assembly	1	1685.2×	0.003	CRYAB
negative regulation of amyloid fibril formation	1	1296.3×	0.003	CRYAB
negative regulation of reactive oxygen species metabolic process	1	936.2×	0.004	CRYAB
stress-activated MAPK cascade	1	702.2×	0.004	CRYAB
protein refolding	1	624.1×	0.004	CRYAB
cellular response to gamma radiation	1	601.9×	0.004	CRYAB
response to hydrogen peroxide	1	468.1×	0.005	CRYAB
negative regulation of protein-containing complex assembly	1	455.5×	0.005	CRYAB
response to heat	1	421.3×	0.005	CRYAB
lens development in camera-type eye	1	374.5×	0.005	CRYAB
glutathione metabolic process	1	351.1×	0.005	CRYAB
muscle contraction	1	208.1×	0.007	CRYAB
response to estradiol	1	198.3×	0.007	CRYAB
muscle organ development	1	166.8×	0.008	CRYAB
negative regulation of cell growth	1	144.0×	0.009	CRYAB
protein folding	1	103.4×	0.012	CRYAB
response to hypoxia	1	95.8×	0.012	CRYAB
negative regulation of gene expression	1	69.1×	0.016	CRYAB
protein stabilization	1	66.9×	0.016	CRYAB
negative regulation of apoptotic process	1	34.8×	0.030	CRYAB
negative regulation of DNA-templated transcription	1	31.6×	0.032	CRYAB

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
CRYAB	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
CRYAB	13	Binding:13

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	CRYAB

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)
CRYAB	13	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.