Distal myopathy

Summary

Distal myopathy (MONDO:0018949) is a disease (an umbrella term covering 11 Mondo subtypes) caused by DNAJB4 (GenCC Strong), with 19 cohort genes and 1 clinical trial.

At a glance

• Prevalence: 1-9 / 1 000 000 (United Kingdom) [Orphanet-validated]
• Causal gene: DNAJB4 (GenCC Strong)
• Umbrella term: 11 Mondo subtypes
• Cohort genes: 19
• ClinVar variants: 26
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.33	United Kingdom	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	distal myopathy
Mondo ID	MONDO:0018949
OMIM	160500
Orphanet	599
DOID	DOID:11720
ICD-11	596283352
NCIT	C84675
SNOMED CT	58795000
UMLS	C0751336
MedGen	155541
GARD	0018699
Is cancer (heuristic)	no

Also known as: distal muscular dystrophy · distal myopathy · Miyoshi muscular dystrophy

Data availability: 26 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 11 Mondo subtypes.

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

Related subtypes (10): muscular dystrophy, Barnes type, muscular dystrophy, cardiac type, muscular dystrophy, Hemizygous lethal type, muscular dystrophy, Mabry type, muscular dystrophy, progressive Pectorodorsal, progressive muscular dystrophy, congenital muscular dystrophy, Fukuda-Miyanomae-Nakata syndrome, LAMA2-related muscular dystrophy, DMD-related muscular dystrophy

Subtypes (11): myopathy, distal, infantile-onset, MYH7-related skeletal myopathy, Miyoshi myopathy, distal myopathy with anterior tibial onset, myopathy, distal, 5, 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

26 retrieved; paginated sample, class counts are floors:

12 conflicting classifications of pathogenicity, 9 uncertain significance, 3 likely pathogenic, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
55857	NM_001003800.2(BICD2):c.320C>T (p.Ser107Leu)	BICD2	Pathogenic	criteria provided, multiple submitters, no conflicts
5836	NM_006790.3(MYOT):c.179C>G (p.Ser60Cys)	PKD2L2-DT	Pathogenic	criteria provided, multiple submitters, no conflicts
2683801	NM_031157.4(HNRNPA1):c.1113_*2delinsTAA (p.Arg371_Ter373delinsSerXaa)	HNRNPA1	Likely pathogenic	criteria provided, single submitter
584450	NM_014365.3(HSPB8):c.520_533del (p.Tyr174fs)	HSPB8	Likely pathogenic	criteria provided, single submitter
1180795	NM_007289.4(MME):c.499T>A (p.Trp167Arg)	MME	Likely pathogenic	criteria provided, multiple submitters, no conflicts
965865	NM_000080.4(CHRNE):c.671G>A (p.Gly224Asp)	C17orf107	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
665144	NM_001376.5(DYNC1H1):c.8343+5G>A	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
309949	NM_004984.4(KIF5A):c.2881G>A (p.Ala961Thr)	KIF5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
418382	NM_001164508.2(NEB):c.22370G>C (p.Ser7457Thr)	NEB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
655388	NM_001164508.2(NEB):c.17518G>A (p.Ala5840Thr)	NEB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
92125	NM_182961.4(SYNE1):c.11675T>C (p.Leu3892Ser)	SYNE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
246488	NM_021625.5(TRPV4):c.2513C>T (p.Pro838Leu)	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
177972	NM_001267550.2(TTN):c.26494A>G (p.Ile8832Val)	TTN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
282240	NM_001267550.2(TTN):c.14746A>G (p.Lys4916Glu)	TTN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
46671	NM_001267550.2(TTN):c.20341G>A (p.Glu6781Lys)	TTN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
506427	NM_001267550.2(TTN):c.71903A>C (p.Asn23968Thr)	TTN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
47513	NM_001267550.2(TTN):c.91621G>A (p.Gly30541Arg)	TTN-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4072174	NM_001376.5(DYNC1H1):c.1067C>T (p.Ala356Val)	DYNC1H1	Uncertain significance	criteria provided, single submitter
4075088	NM_001458.5(FLNC):c.6365G>A (p.Ser2122Asn)	FLNC	Uncertain significance	criteria provided, single submitter
3109864	NM_016532.4(INPP5K):c.86C>G (p.Pro29Arg)	INPP5K	Uncertain significance	criteria provided, multiple submitters, no conflicts
3536863	NM_000426.4(LAMA2):c.5079T>A (p.Asn1693Lys)	LAMA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
581411	NM_000426.4(LAMA2):c.8444C>G (p.Thr2815Arg)	LAMA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
224402	NM_000540.3(RYR1):c.12553G>A (p.Ala4185Thr)	RYR1	Uncertain significance	reviewed by expert panel
566092	NM_182961.4(SYNE1):c.4562G>A (p.Arg1521Gln)	SYNE1	Uncertain significance	criteria provided, multiple submitters, no conflicts
4075212	NM_001267550.2(TTN):c.11311+2266A>T	TTN	Uncertain significance	criteria provided, single submitter
1732748	NM_001267550.2(TTN):c.62867T>C (p.Ile20956Thr)	TTN-AS1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 68 · 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
DNAJB4	Strong	Autosomal recessive	congenital myopathy 21 with early respiratory failure	6
KLHL9	Moderate	Autosomal dominant	distal myopathy	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DNAJB4	Orphanet:700170	DNAJB4-related distal myopathy
KLHL9	Orphanet:399081	KLHL9-related early-onset distal myopathy
RYR1	Orphanet:169186	Autosomal recessive centronuclear myopathy
RYR1	Orphanet:169189	Autosomal dominant centronuclear myopathy
RYR1	Orphanet:178145	Moderate multiminicore disease with hand involvement
RYR1	Orphanet:324581	Benign Samaritan congenital myopathy
RYR1	Orphanet:33108	Lethal multiple pterygium syndrome
RYR1	Orphanet:423	Malignant hyperthermia of anesthesia
RYR1	Orphanet:424107	Congenital myopathy with myasthenic-like onset
RYR1	Orphanet:466650	Exercise-induced malignant hyperthermia
RYR1	Orphanet:597	Central core disease
RYR1	Orphanet:700188	Calf-predominant weakness-gastrocnemius medialis atrophy-distal myopathy
RYR1	Orphanet:98905	Congenital multicore myopathy with external ophthalmoplegia
RYR1	Orphanet:99741	King-Denborough syndrome
TTN	Orphanet:140922	Titin-related limb-girdle muscular dystrophy R10
TTN	Orphanet:154	Familial isolated dilated cardiomyopathy
TTN	Orphanet:169186	Autosomal recessive centronuclear myopathy
TTN	Orphanet:178464	Hereditary myopathy with early respiratory failure
TTN	Orphanet:289377	Early-onset myopathy with fatal cardiomyopathy
TTN	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
TTN	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
TTN	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
TTN	Orphanet:324604	Classic multiminicore myopathy
TTN	Orphanet:334	Hereditary atrial fibrillation
TTN	Orphanet:466921	Childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome
TTN	Orphanet:609	Tibial muscular dystrophy
TTN	Orphanet:707983	Early-onset autosomal recessive TTN-related distal myopathy
SYNE1	Orphanet:319332	Autosomal recessive myogenic arthrogryposis multiplex congenita
SYNE1	Orphanet:88644	Autosomal recessive ataxia, Beauce type
SYNE1	Orphanet:98853	Autosomal dominant Emery-Dreifuss muscular dystrophy
BICD2	Orphanet:363454	BICD2-related autosomal dominant childhood-onset proximal spinal muscular atrophy
TRPV4	Orphanet:1216	Autosomal dominant congenital benign spinal muscular atrophy
TRPV4	Orphanet:263482	Spondyloepimetaphyseal dysplasia, Maroteaux type
TRPV4	Orphanet:2635	Metatropic dysplasia
TRPV4	Orphanet:431255	Scapuloperoneal spinal muscular atrophy
TRPV4	Orphanet:85169	Familial digital arthropathy-brachydactyly
TRPV4	Orphanet:86820	Familial avascular necrosis of femoral head
TRPV4	Orphanet:93304	Autosomal dominant brachyolmia
TRPV4	Orphanet:93314	Spondylometaphyseal dysplasia, Kozlowski type
TRPV4	Orphanet:99937	Autosomal dominant Charcot-Marie-Tooth disease type 2C
DYNC1H1	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
DYNC1H1	Orphanet:209341	DYNC1H1-related autosomal dominant childhood-onset proximal spinal muscular atrophy
DYNC1H1	Orphanet:284232	Autosomal dominant Charcot-Marie-Tooth disease type 2O
HSPB8	Orphanet:139525	Distal hereditary motor neuropathy type 2
HSPB8	Orphanet:476093	HSPB8-related autosomal dominant distal axonal motor neuropathy-myofibrillar myopathy syndrome
HSPB8	Orphanet:99945	Autosomal dominant Charcot-Marie-Tooth disease type 2L
INPP5K	Orphanet:662184	Congenital muscular dystrophy-cataract-intellectual disability syndrome
FLNC	Orphanet:171445	Muscle filaminopathy
FLNC	Orphanet:63273	FLNC-related handgrip and calf weakness-distal myopathy
FLNC	Orphanet:75249	Familial isolated restrictive cardiomyopathy

Cohort genes → proteins

19 cohort genes, 17 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	19

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DNAJB4	HGNC:14886	ENSG00000162616	Q9UDY4	DnaJ homolog subfamily B member 4	gencc
KLHL9	HGNC:18732	ENSG00000198642	Q9P2J3	Kelch-like protein 9	gencc
RYR1	HGNC:10483	ENSG00000196218	P21817	Ryanodine receptor 1	clinvar
TTN	HGNC:12403	ENSG00000155657	Q8WZ42	Titin	clinvar
SYNE1	HGNC:17089	ENSG00000131018	Q8NF91	Nesprin-1	clinvar
BICD2	HGNC:17208	ENSG00000185963	Q8TD16	Protein bicaudal D homolog 2	clinvar
TRPV4	HGNC:18083	ENSG00000111199	Q9HBA0	Transient receptor potential cation channel subfamily V member 4	clinvar
DYNC1H1	HGNC:2961	ENSG00000197102	Q14204	Cytoplasmic dynein 1 heavy chain 1	clinvar
HSPB8	HGNC:30171	ENSG00000152137	Q9UJY1	Heat shock protein beta-8	clinvar
INPP5K	HGNC:33882	ENSG00000132376	Q9BT40	Inositol polyphosphate 5-phosphatase K	clinvar
C17orf107	HGNC:37238	ENSG00000205710	Q6ZR85	Uncharacterized protein C17orf107	clinvar
FLNC	HGNC:3756	ENSG00000128591	Q14315	Filamin-C	clinvar
TTN-AS1	HGNC:44124	ENSG00000237298		TTN antisense RNA 1	clinvar
HNRNPA1	HGNC:5031	ENSG00000135486	P09651	Heterogeneous nuclear ribonucleoprotein A1	clinvar
PKD2L2-DT	HGNC:55557	ENSG00000250159		PKD2L2 divergent transcript	clinvar
KIF5A	HGNC:6323	ENSG00000155980	Q12840	Kinesin heavy chain isoform 5A	clinvar
LAMA2	HGNC:6482	ENSG00000196569	P24043	Laminin subunit alpha-2	clinvar
MME	HGNC:7154	ENSG00000196549	P08473	Neprilysin	clinvar
NEB	HGNC:7720	ENSG00000183091	P20929	Nebulin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DNAJB4	DnaJ homolog subfamily B member 4	Probable chaperone.
KLHL9	Kelch-like protein 9	Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex required for mitotic progression and cytokinesis.
RYR1	Ryanodine receptor 1	Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytosol and thereby plays a key role in triggering muscle contraction following depolarization of T-tubules.
TTN	Titin	Key component in the assembly and functioning of vertebrate striated muscles.
SYNE1	Nesprin-1	Multi-isomeric modular protein which forms a linking network between organelles and the actin cytoskeleton to maintain the subcellular spatial organization.
BICD2	Protein bicaudal D homolog 2	Acts as an adapter protein linking the dynein motor complex to various cargos and converts dynein from a non-processive to a highly processive motor in the presence of dynactin.
TRPV4	Transient receptor potential cation channel subfamily V member 4	Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity.
DYNC1H1	Cytoplasmic dynein 1 heavy chain 1	Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules.
HSPB8	Heat shock protein beta-8	Involved in the chaperone-assisted selective autophagy (CASA), a crucial process for protein quality control, particularly in mechanical strained cells and tissues such as muscle.
INPP5K	Inositol polyphosphate 5-phosphatase K	Inositol 5-phosphatase which acts on inositol 1,4,5-trisphosphate, inositol 1,3,4,5-tetrakisphosphate, phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate.
FLNC	Filamin-C	Muscle-specific filamin, which plays a central role in sarcomere assembly and organization.
HNRNPA1	Heterogeneous nuclear ribonucleoprotein A1	Involved in the packaging of pre-mRNA into hnRNP particles, transport of poly(A) mRNA from the nucleus to the cytoplasm and modulation of splice site selection.
KIF5A	Kinesin heavy chain isoform 5A	Microtubule-dependent motor required for slow axonal transport of neurofilament proteins (NFH, NFM and NFL).
LAMA2	Laminin subunit alpha-2	Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.
MME	Neprilysin	Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids.
NEB	Nebulin	This giant muscle protein may be involved in maintaining the structural integrity of sarcomeres and the membrane system associated with the myofibrils.

Protein-family classification

Druggable: 6 · Difficult: 1 · Unknown: 12 · Druggable fraction: 0.32

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
Ion channel	2	11.7×	0.087
Protease	1	1.9×	0.704
Antibody/Immunoglobulin	1	1.5×	0.704
Kinase	1	1.5×	0.704
Other/Unknown	12	1.1×	0.704
Scaffold/PPI	1	0.9×	0.791
Enzyme (other)	1	0.6×	0.809

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DNAJB4	Other/Unknown	no		DnaJ_domain, DnaJ_C, HSP40/DnaJ_pept-bd
KLHL9	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf
RYR1	Ion channel	yes		RIH_dom, B30.2/SPRY, Ryanodine_rcpt
TTN	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ig_sub2, Ig_sub
SYNE1	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat
BICD2	Other/Unknown	no		BICD
TRPV4	Ion channel	yes		Ankyrin_rpt, Ion_trans_dom, TrpV1-4
DYNC1H1	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
HSPB8	Other/Unknown	no		Alpha-crystallin/sHSP_animal, A-crystallin/Hsp20_dom, HSP20-like_chaperone
INPP5K	Enzyme (other)	yes	3.1.3.56	IPPc, Endo/exonu/phosph_ase_sf, SKICH
C17orf107	Other/Unknown	no		C17orf107
FLNC	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom
TTN-AS1	Other/Unknown	no
HNRNPA1	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, HnRNPA1/A2_C
PKD2L2-DT	Other/Unknown	no
KIF5A	Other/Unknown	no		Kinesin_motor_dom, Kinesin_motor_CS, P-loop_NTPase
LAMA2	Other/Unknown	no		Laminin_IV, EGF, Laminin_G
MME	Protease	yes	3.4.24.11	Peptidase_M13, Peptidase_M13_N, Peptidase_M13_C
NEB	Scaffold/PPI	no		Nebulin_repeat, SH3_domain, Nebulin-like

Expression context

Cohort genes with no expression data: 0.

17 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)	19
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	4
hindlimb stylopod muscle	4
calcaneal tendon	3
gluteal muscle	3
skeletal muscle tissue of biceps brachii	2
skeletal muscle tissue of rectus abdominis	2
biceps brachii	2
cerebellar hemisphere	2
right hemisphere of cerebellum	2
ganglionic eminence	2
ventricular zone	2
mucosa of stomach	2
right atrium auricular region	2
tibialis anterior	2
choroid plexus epithelium	1
corpus epididymis	1
mucosa of paranasal sinus	1
gingiva	1
gingival epithelium	1
hair follicle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DNAJB4	290	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, calcaneal tendon, skeletal muscle tissue of biceps brachii
KLHL9	294	ubiquitous	marker	corpus epididymis, mucosa of paranasal sinus, choroid plexus epithelium
RYR1	214	broad	marker	gluteal muscle, gastrocnemius, hindlimb stylopod muscle
TTN	223	broad	marker	biceps brachii, gluteal muscle, skeletal muscle tissue of biceps brachii
SYNE1	275	ubiquitous	marker	cerebellar hemisphere, right hemisphere of cerebellum, calcaneal tendon
BICD2	290	ubiquitous	marker	gingival epithelium, gingiva, hair follicle
TRPV4	171	ubiquitous	marker	cartilage tissue, lower esophagus mucosa, olfactory segment of nasal mucosa
DYNC1H1	290	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone
HSPB8	284	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, mucosa of stomach, gastrocnemius
INPP5K	283	ubiquitous	marker	pigmented layer of retina, right lung, right lobe of thyroid gland
C17orf107	131	broad	yes	adenohypophysis, pituitary gland, right atrium auricular region
FLNC	255	ubiquitous	marker	gastrocnemius, hindlimb stylopod muscle, tibialis anterior
TTN-AS1	174	ubiquitous	marker	hindlimb stylopod muscle, gastrocnemius, right atrium auricular region
HNRNPA1	295	ubiquitous	marker	ganglionic eminence, ventricular zone, embryo
PKD2L2-DT	135		yes	skeletal muscle tissue, hindlimb stylopod muscle, male germ line stem cell (sensu Vertebrata) in testis
KIF5A	198	broad	marker	right frontal lobe, right hemisphere of cerebellum, cerebellar hemisphere
LAMA2	272	ubiquitous	marker	mucosa of stomach, calcaneal tendon, right ovary
MME	212	ubiquitous	marker	jejunal mucosa, renal glomerulus, metanephric glomerulus
NEB	204	tissue_specific	marker	gluteal muscle, tibialis anterior, biceps brachii

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HNRNPA1	6,616
TTN	4,237
DYNC1H1	4,215
KIF5A	3,241
FLNC	3,174
SYNE1	2,886
DNAJB4	2,877
LAMA2	2,688
MME	2,648
BICD2	2,275

Intra-cohort edges

A	B	Sources
BICD2	DYNC1H1	string_interaction
HSPB8	TTN	intact
NEB	TTN	intact, string_interaction
RYR1	TTN	intact
SYNE1	TTN	string_interaction

Structural data

PDB: 14 · AlphaFold-only: 3 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DYNC1H1	Q14204	97
HNRNPA1	P09651	73
TTN	Q8WZ42	64
TRPV4	Q9HBA0	19
MME	P08473	16
FLNC	Q14315	14
KIF5A	Q12840	4
SYNE1	Q8NF91	3
NEB	P20929	3
RYR1	P21817	2
BICD2	Q8TD16	2
LAMA2	P24043	2
HSPB8	Q9UJY1	1
INPP5K	Q9BT40	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KLHL9	Q9P2J3	92.00
DNAJB4	Q9UDY4	83.43
C17orf107	Q6ZR85	58.75

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 97. Enrichment computed across 19 evidence-associated genes (15 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 15 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Striated Muscle Contraction	2	41.1×	0.043	TTN, NEB
Peptide hormone metabolism	2	36.2×	0.043	KIF5A, MME
Muscle contraction	3	15.4×	0.043	RYR1, MME, NEB
COPI-independent Golgi-to-ER retrograde traffic	2	27.7×	0.056	BICD2, DYNC1H1
Golgi-to-ER retrograde transport	2	17.7×	0.107	BICD2, KIF5A
Cardiac conduction	2	14.5×	0.121	RYR1, MME
Intra-Golgi and retrograde Golgi-to-ER traffic	2	14.0×	0.121	BICD2, KIF5A
MHC class II antigen presentation	2	11.9×	0.144	DYNC1H1, KIF5A
RHO GTPases activate KTN1	1	69.2×	0.155	KIF5A
Cell-extracellular matrix interactions	1	44.8×	0.159	FLNC
Physiological factors	1	44.8×	0.159	MME
Metabolism of Angiotensinogen to Angiotensins	1	42.3×	0.159	MME
MET promotes cell motility	1	40.1×	0.159	LAMA2
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	36.2×	0.159	MME
Attachment of bacteria to epithelial cells	1	33.1×	0.159	LAMA2
Insulin processing	1	30.4×	0.159	KIF5A
FGFR2 alternative splicing	1	28.2×	0.159	HNRNPA1
TRP channels	1	27.2×	0.159	TRPV4
Signaling by FGFR2	1	27.2×	0.159	HNRNPA1
Laminin interactions	1	25.4×	0.159	LAMA2
MET activates PTK2 signaling	1	25.4×	0.159	LAMA2
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	24.6×	0.159	LAMA2
PI Metabolism	1	23.8×	0.159	INPP5K
Signaling by FGFR	1	23.1×	0.159	HNRNPA1
HSF1-dependent transactivation	1	21.1×	0.159	HSPB8
Signaling by MET	1	21.1×	0.159	LAMA2
SARS-CoV-1 modulates host translation machinery	1	20.6×	0.159	HNRNPA1
Formation of the dystrophin-glycoprotein complex (DGC)	1	20.6×	0.159	LAMA2
Signaling by Receptor Tyrosine Kinases	2	6.9×	0.159	HNRNPA1, LAMA2
Meiosis	1	19.0×	0.166	SYNE1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 16 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
hyperosmotic salinity response	1	1053.2×	0.025	TRPV4
neuropeptide processing	1	1053.2×	0.025	MME
blood vessel endothelial cell delamination	1	1053.2×	0.025	TRPV4
positive regulation of renal water transport	1	1053.2×	0.025	INPP5K
vasopressin secretion	1	526.6×	0.025	TRPV4
positive regulation of striated muscle contraction	1	526.6×	0.025	TRPV4
creatinine metabolic process	1	526.6×	0.025	MME
regulation of response to osmotic stress	1	526.6×	0.025	TRPV4
microtubule anchoring at microtubule organizing center	1	526.6×	0.025	BICD2
calcium ion import into cytosol	1	526.6×	0.025	TRPV4
substance P catabolic process	1	351.1×	0.025	MME
skeletal muscle myosin thick filament assembly	1	351.1×	0.025	TTN
sarcomerogenesis	1	351.1×	0.025	TTN
cellular hypotonic salinity response	1	351.1×	0.025	TRPV4
positive regulation of macrophage inflammatory protein 1 alpha production	1	351.1×	0.025	TRPV4
cardiac muscle thin filament assembly	1	351.1×	0.025	NEB
nuclear matrix anchoring at nuclear membrane	1	351.1×	0.025	SYNE1
somatic muscle development	1	263.3×	0.025	NEB
regulation of actin filament length	1	263.3×	0.025	NEB
negative regulation of dephosphorylation	1	263.3×	0.025	INPP5K
minus-end-directed organelle transport along microtubule	1	263.3×	0.025	BICD2
negative regulation of D-glucose transmembrane transport	1	210.7×	0.025	INPP5K
positive regulation of microtubule depolymerization	1	210.7×	0.025	TRPV4
positive regulation of synaptic transmission, cholinergic	1	210.7×	0.025	LAMA2
regulation of metaphase plate congression	1	210.7×	0.025	DYNC1H1
cellular response to sodium arsenite	1	210.7×	0.025	HNRNPA1
retrograde neuronal dense core vesicle transport	1	210.7×	0.025	KIF5A
amygdala development	1	175.5×	0.025	MME
skeletal muscle thin filament assembly	1	175.5×	0.025	TTN
hormone catabolic process	1	175.5×	0.025	MME

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 3 · Undrugged: 16

Druggability breadth: 8 of 19 evidence-associated genes (42%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TRPV4	6	3
MME	4	2
DYNC1H1	1	2
DNAJB4	0	0
KLHL9	0	0
RYR1	0	0
TTN	0	0
SYNE1	0	0
BICD2	0	0
HSPB8	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CANNABINOL	3	TRPV4
TETRAHYDROCANNABIVARIN	2	TRPV4
CANNABIDIVARIN	2	TRPV4
GSK2798745	2	TRPV4
CANNABIGEROL	2	TRPV4
MOLIBRESIB	2	DYNC1H1
CYCLOVALONE	2	MME
OMAPATRILAT	2	MME
SAMPATRILAT	2	MME
CANDOXATRILAT	2	MME
ABT-102	1	TRPV4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
MME	125	Binding:110, ADMET:15
TRPV4	99	Binding:94, Functional:5
RYR1	16	Binding:13, Functional:3
KIF5A	8	Binding:8
DYNC1H1	7	Binding:7
HNRNPA1	7	Binding:7
TTN	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TTN	2.7.11.1	non-specific serine/threonine protein kinase
INPP5K	3.1.3.56	inositol-polyphosphate 5-phosphatase
MME	3.4.24.11	neprilysin

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
MME	125

Pharmacogenomics

Cohort genes with a PharmGKB record: 17; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
RYR1	1

Chemical tractability of cohort targets

11 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.

Compound	Max phase	Cohort target (bioactivity)
CANNABINOL	3	TRPV4
TETRAHYDROCANNABIVARIN	2	TRPV4
CANNABIDIVARIN	2	TRPV4
GSK2798745	2	TRPV4
CANNABIGEROL	2	TRPV4
MOLIBRESIB	2	DYNC1H1
CYCLOVALONE	2	MME
OMAPATRILAT	2	MME
SAMPATRILAT	2	MME
CANDOXATRILAT	2	MME
ABT-102	1	TRPV4

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	3	TRPV4, DYNC1H1, MME
C	Druggable family + PDB, no drug	4	RYR1, TTN, INPP5K, FLNC
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	12	DNAJB4, KLHL9, SYNE1, BICD2, HSPB8, C17orf107, TTN-AS1, HNRNPA1, PKD2L2-DT, KIF5A (+2 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DNAJB4	0	—
KLHL9	0	—
RYR1	16	—
TTN	1	—
SYNE1	0	—
BICD2	0	—
HSPB8	0	—
INPP5K	0	—
C17orf107	0	—
FLNC	0	—
TTN-AS1	0	—
HNRNPA1	7	—
PKD2L2-DT	0	—
KIF5A	8	—
LAMA2	0	—
NEB	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
NCT07502989	Not specified	RECRUITING	Muscle Health Measurements Using Electrical Impedance Myography