Typical nemaline myopathy

Summary

Typical nemaline myopathy (MONDO:0015737) is a disease (an umbrella term covering 6 Mondo subtypes) with 6 cohort genes. The dominant Reactome pathway is Striated Muscle Contraction (3 cohort genes).

At a glance

• Prevalence: 1-9 / 100 000 (Europe)
• Umbrella term: 6 Mondo subtypes
• Cohort genes: 6
• Phenotypes (HPO): 39

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

39 HPO clinical features (Orphanet curated; top 39 by frequency):

HPO ID	Term	Frequency
HP:0000218	High palate	Frequent (30-79%)
HP:0001265	Hyporeflexia	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001319	Neonatal hypotonia	Frequent (30-79%)
HP:0002093	Respiratory insufficiency	Frequent (30-79%)
HP:0003325	Limb-girdle muscle weakness	Frequent (30-79%)
HP:0003327	Axial muscle weakness	Frequent (30-79%)
HP:0003557	Increased variability in muscle fiber diameter	Frequent (30-79%)
HP:0003722	Neck flexor weakness	Frequent (30-79%)
HP:0003803	Type 1 muscle fiber predominance	Frequent (30-79%)
HP:0009027	Foot dorsiflexor weakness	Frequent (30-79%)
HP:0010628	Facial palsy	Frequent (30-79%)
HP:0030198	Fatigable weakness of distal limb muscles	Frequent (30-79%)
HP:0000275	Narrow face	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000470	Short neck	Occasional (5-29%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0000767	Pectus excavatum	Occasional (5-29%)
HP:0000774	Narrow chest	Occasional (5-29%)
HP:0001349	Facial diplegia	Occasional (5-29%)
HP:0001371	Flexion contracture	Occasional (5-29%)
HP:0001561	Polyhydramnios	Occasional (5-29%)
HP:0002375	Hypokinesia	Occasional (5-29%)
HP:0002515	Waddling gait	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002804	Arthrogryposis multiplex congenita	Occasional (5-29%)
HP:0002827	Hip dislocation	Occasional (5-29%)
HP:0002857	Genu valgum	Occasional (5-29%)
HP:0002877	Nocturnal hypoventilation	Occasional (5-29%)
HP:0002970	Genu varum	Occasional (5-29%)
HP:0003198	Myopathy	Occasional (5-29%)
HP:0003236	Elevated circulating creatine kinase concentration	Occasional (5-29%)
HP:0003306	Spinal rigidity	Occasional (5-29%)
HP:0003307	Hyperlordosis	Occasional (5-29%)
HP:0003798	Nemaline bodies	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)
HP:0030196	Fatigable weakness of respiratory muscles	Occasional (5-29%)
HP:0030200	Fatiguable weakness of proximal limb muscles	Occasional (5-29%)
HP:0002808	Kyphosis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	typical nemaline myopathy
Mondo ID	MONDO:0015737
Orphanet	171436
ICD-11	1105111633
UMLS	C5680453
MedGen	1806265
GARD	0012822
Is cancer (heuristic)	no

Also known as: typical congenital nemaline myopathy

Data availability: 6 GenCC gene-disease records · 51 cell lines.

Disease family

An umbrella term covering 6 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › typical nemaline myopathy

Related subtypes (216): polymicrogyria, congenital myasthenic syndrome with tubular aggregates, prenatal-onset spinal muscular atrophy with congenital bone fractures, anencephaly, cerebral cavernous malformation, meningocele, progressive external ophthalmoplegia, congenital nystagmus, congenital toxoplasmosis, congenital contractural arachnodactyly, congenital trigeminal anesthesia, familial congenital palsy of trochlear nerve, Myhre syndrome, Aase-Smith syndrome, KBG syndrome, autosomal dominant primary microcephaly, Mobius syndrome, MYH7-related skeletal myopathy, congenital stationary night blindness autosomal dominant 2, Prader-Willi syndrome, congenital myopathy 7A, myosin storage, autosomal dominant, Smith-Magenis syndrome, spina bifida, Freeman-Sheldon syndrome, isolated cerebellar hypoplasia/agenesis, Chediak-Higashi syndrome, Cohen syndrome, multiple pterygium-malignant hyperthermia syndrome, corpus callosum, agenesis of, congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, diastematomyelia, EEM syndrome, Mowat-Wilson syndrome, Johanson-Blizzard syndrome, intellectual disability, Buenos-Aires type, myasthenia, congenital, refractory to acetylcholinesterase inhibitors, congenital myasthenic syndrome 6, Bailey-Bloch congenital myopathy, congenital stationary night blindness 1B, radioulnar synostosis-developmental delay-hypotonia syndrome, Schinzel-Giedion syndrome, schizencephaly, intellectual disability, Wolff type, X-linked intellectual disability-plagiocephaly syndrome, X-linked adrenal hypoplasia congenita, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, syndromic X-linked intellectual disability Claes-Jensen type, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, blepharophimosis - intellectual disability syndrome, MKB type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, infantile-onset X-linked spinal muscular atrophy, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, X-linked intellectual disability with marfanoid habitus, Wieacker-Wolff syndrome, MERRF syndrome, macrocephaly-spastic paraplegia-dysmorphism syndrome, intellectual disability-sparse hair-brachydactyly syndrome, myofibrillar myopathy 1, isolated hereditary congenital facial paralysis, fibrosis of extraocular muscles, congenital, 2, Pierpont syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, Bohring-Opitz syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, developmental malformations-deafness-dystonia syndrome, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, AICA-ribosiduria, myofibrillar myopathy 3, fibrosis of extraocular muscles, congenital, 3c, myofibrillar myopathy 4, myofibrillar myopathy 5, cone-rod synaptic disorder, congenital nonprogressive, congenital stationary night blindness autosomal dominant 3, congenital stationary night blindness autosomal dominant 1, intellectual disability, autosomal recessive 12, progressive myoclonic epilepsy type 3, chromosome 15q13.3 microdeletion syndrome, combined pituitary hormone deficiencies, genetic form, congenital stationary night blindness 1D, DYRK1A-related intellectual disability syndrome, Pitt-Hopkins-like syndrome 2, developmental and epileptic encephalopathy, 15, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, hypotonia, infantile, with psychomotor retardation and characteristic facies, developmental and epileptic encephalopathy, 18, CTCF-related neurodevelopmental disorder, autism spectrum disorder due to AUTS2 deficiency, developmental and epileptic encephalopathy, 23, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, Bardet-Biedl syndrome 11, cerebellar-facial-dental syndrome, fibrosis of extraocular muscles, congenital, 5, congenital myasthenic syndrome 15, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, congenital myasthenic syndrome 18, autosomal recessive spinocerebellar ataxia 20, Houge-Janssens syndrome 1, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, congenital stationary night blindness 1G, hypomyelinating leukodystrophy 10, developmental and epileptic encephalopathy, 50, congenital insensitivity to pain-hypohidrosis syndrome, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, SLC39A8-CDG, spastic paraplegia-severe developmental delay-epilepsy syndrome, cardiac anomalies - developmental delay - facial dysmorphism syndrome, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, intellectual disability, autosomal recessive 53, TELO2-related intellectual disability-neurodevelopmental disorder, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, autosomal recessive limb-girdle muscular dystrophy type 2Y, myofibrillar myopathy 7, short stature-brachydactyly-obesity-global developmental delay syndrome, autosomal recessive limb-girdle muscular dystrophy type 2R1, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, congenital laryngeal palsy, congenital or early infantile CACH syndrome, congenital epulis, severe congenital nemaline myopathy, intermediate nemaline myopathy, childhood-onset nemaline myopathy, adult-onset nemaline myopathy, qualitative or quantitative defects of protein involved in O-glycosylation of alpha-dystroglycan, holoprosencephaly, congenital insensitivity to pain with hyperhidrosis, congenital hydrocephalus, familial congenital mirror movements, macrocephaly-short stature-paraplegia syndrome, cephalocele, mitochondrial neurogastrointestinal encephalomyopathy, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, 7p22.1 microduplication syndrome, congenital achiasma, congenital retinal arteriovenous communication, 3q27.3 microdeletion syndrome, Prader-Willi-like syndrome, 9q31.1q31.3 microdeletion syndrome, congenital oculomotor nerve palsy, congenital abducens nerve palsy, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, congenital insensitivity to pain with severe intellectual disability, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, lissencephaly spectrum disorders, hyaline body myopathy, 22q11.2 deletion syndrome, craniorachischisis, Leber congenital amaurosis, Ritscher-Schinzel syndrome, Rubinstein-Taybi syndrome, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, congenital muscular dystrophy, congenital vitreoretinal dysplasia, periventricular nodular heterotopia, postsynaptic congenital myasthenic syndrome, subcortical band heterotopia, congenital fibrosis of extraocular muscles type 1, Al Gazali Khidr Prem Chandran syndrome, distal arthrogryposis Moore weaver type, congenital myotonic dystrophy, myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive, intellectual disability, autosomal dominant 47, intellectual disability, autosomal dominant 48, spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis, myasthenic syndrome, congenital, 23, presynaptic, myasthenic syndrome, congenital, 24, presynaptic, myasthenic syndrome, congenital, 25, presynaptic, developmental and epileptic encephalopathy, 77, night blindness, congenital stationary, type1i, neuropathy, congenital hypomelinating, congenital axonal neuropathy with encephalopathy, developmental and epileptic encephalopathy, 73, PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, isolated exencephaly, myasthenic syndrome, congenital, 22, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, 9q33.3q34.11 microdeletion syndrome, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, SIN3A-related intellectual disability syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, X-linked congenital stationary night blindness, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, FOXG1 disorder, alpha-actinopathy, TPM3-related myopathy, X-linked recessive mitochondrial myopathy, RYR1-related myopathy, TTN-related myopathy, TPM2-related myopathy, myopathy caused by variation in POMGNT1, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, segmental spinal dysgenesis, myopathy, myofibrillar, 13, with rimmed vacuoles, congenital neuronal ceroid lipofuscinosis 10

Subtypes (6): congenital myopathy 2a, typical, autosomal dominant, nemaline myopathy 2, congenital myopathy 23, nemaline myopathy 7, nemaline myopathy 9, nemaline myopathy 10

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 54 · Orphanet: 29 · 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
ACTA1	Definitive	Semidominant	congenital myopathy 2a, typical, autosomal dominant	15
CFL2	Definitive	Autosomal recessive	nemaline myopathy 7	5
LMOD3	Definitive	Autosomal recessive	nemaline myopathy 10	5
NEB	Definitive	Autosomal recessive	nemaline myopathy 2	10
KLHL41	Strong	Autosomal recessive	nemaline myopathy 9	7
TPM2	Strong	Autosomal dominant	congenital myopathy 23	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TPM2	Orphanet:1146	Distal arthrogryposis type 1
TPM2	Orphanet:1147	Sheldon-Hall syndrome
TPM2	Orphanet:171436	Typical nemaline myopathy
TPM2	Orphanet:171439	Childhood-onset nemaline myopathy
TPM2	Orphanet:171881	Cap myopathy
TPM2	Orphanet:2020	Congenital fiber-type disproportion myopathy
ACTA1	Orphanet:171430	Severe congenital nemaline myopathy
ACTA1	Orphanet:171433	Intermediate nemaline myopathy
ACTA1	Orphanet:171436	Typical nemaline myopathy
ACTA1	Orphanet:171439	Childhood-onset nemaline myopathy
ACTA1	Orphanet:2020	Congenital fiber-type disproportion myopathy
ACTA1	Orphanet:447977	Progressive scapulohumeroperoneal distal myopathy
ACTA1	Orphanet:97240	Zebra body myopathy
ACTA1	Orphanet:97244	Rigid spine syndrome
ACTA1	Orphanet:98904	Congenital myopathy with excess of thin filaments
KLHL41	Orphanet:171430	Severe congenital nemaline myopathy
KLHL41	Orphanet:171433	Intermediate nemaline myopathy
KLHL41	Orphanet:171436	Typical nemaline myopathy
KLHL41	Orphanet:171439	Childhood-onset nemaline myopathy
CFL2	Orphanet:171436	Typical nemaline myopathy
LMOD3	Orphanet:171430	Severe congenital nemaline myopathy
LMOD3	Orphanet:171436	Typical nemaline myopathy
NEB	Orphanet:171430	Severe congenital nemaline myopathy
NEB	Orphanet:171433	Intermediate nemaline myopathy
NEB	Orphanet:171436	Typical nemaline myopathy
NEB	Orphanet:171439	Childhood-onset nemaline myopathy
NEB	Orphanet:33108	Lethal multiple pterygium syndrome
NEB	Orphanet:399103	Autosomal recessive distal nebulin myopathy
NEB	Orphanet:708123	Autosomal dominant distal nebulin myopathy

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TPM2	HGNC:12011	ENSG00000198467	P07951	Tropomyosin beta chain	gencc
ACTA1	HGNC:129	ENSG00000143632	P68133	Actin, alpha skeletal muscle	gencc
KLHL41	HGNC:16905	ENSG00000239474	O60662	Kelch-like protein 41	gencc
CFL2	HGNC:1875	ENSG00000165410	Q9Y281	Cofilin-2	gencc
LMOD3	HGNC:6649	ENSG00000163380	Q0VAK6	Leiomodin-3	gencc
NEB	HGNC:7720	ENSG00000183091	P20929	Nebulin	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TPM2	Tropomyosin beta chain	Binds to actin filaments in muscle and non-muscle cells.
ACTA1	Actin, alpha skeletal muscle	Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.
KLHL41	Kelch-like protein 41	Involved in skeletal muscle development and differentiation.
CFL2	Cofilin-2	Controls reversibly actin polymerization and depolymerization in a pH-sensitive manner.
LMOD3	Leiomodin-3	Essential for the organization of sarcomeric actin thin filaments in skeletal muscle.
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: 0 · Difficult: 1 · Unknown: 5 · 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
Scaffold/PPI	1	2.9×	0.301
Other/Unknown	5	1.5×	0.301

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TPM2	Other/Unknown	no		Tropomyosin
ACTA1	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS
KLHL41	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf
CFL2	Other/Unknown	no		ADF-H, ADF/Cofilin, ADF-H/Gelsolin-like_dom_sf
LMOD3	Other/Unknown	no		TMOD, LRR_dom_sf
NEB	Scaffold/PPI	no		Nebulin_repeat, SH3_domain, Nebulin-like

Expression context

Cohort genes with no expression data: 0.

6 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
tibialis anterior	3
gluteal muscle	2
biceps brachii	2
blood vessel layer	1
popliteal artery	1
saphenous vein	1
diaphragm	1
skeletal muscle tissue of biceps brachii	1
gastrocnemius	1
hindlimb stylopod muscle	1
cardiac muscle of right atrium	1
left ventricle myocardium	1
quadriceps femoris	1
vastus lateralis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TPM2	283	ubiquitous	marker	saphenous vein, popliteal artery, blood vessel layer
ACTA1	203	broad	marker	gluteal muscle, skeletal muscle tissue of biceps brachii, diaphragm
KLHL41	184	broad	marker	tibialis anterior, gastrocnemius, hindlimb stylopod muscle
CFL2	261	ubiquitous	marker	cardiac muscle of right atrium, left ventricle myocardium, tibialis anterior
LMOD3	170	tissue_specific	marker	biceps brachii, vastus lateralis, quadriceps femoris
NEB	204	tissue_specific	marker	gluteal muscle, tibialis anterior, biceps brachii

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CFL2	4,226
NEB	1,402
KLHL41	1,144
LMOD3	838
ACTA1	523
TPM2	357

Intra-cohort edges

A	B	Sources
CFL2	KLHL41	string_interaction
CFL2	LMOD3	string_interaction
KLHL41	LMOD3	string_interaction
KLHL41	NEB	biogrid_interaction, intact, string_interaction
LMOD3	NEB	string_interaction
NEB	TPM2	biogrid_interaction

Structural data

PDB: 3 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CFL2	Q9Y281	11
ACTA1	P68133	5
NEB	P20929	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KLHL41	O60662	93.48
TPM2	P07951	91.51
LMOD3	Q0VAK6	67.79

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 6 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
Striated Muscle Contraction	3	231.5×	2e-06	TPM2, ACTA1, NEB
Muscle contraction	2	38.6×	0.007	ACTA1, NEB
Regulation of CDH1 Function	1	237.9×	0.021	ACTA1
Formation of the dystrophin-glycoprotein complex (DGC)	1	77.2×	0.045	ACTA1
Smooth Muscle Contraction	1	66.4×	0.045	TPM2
Activation of STAT3 by cadherin engagement	1	40.8×	0.055	ACTA1
Non-integrin membrane-ECM interactions	1	38.6×	0.055	ACTA1
Class I MHC mediated antigen processing & presentation	1	17.5×	0.103	KLHL41
Extracellular matrix organization	1	15.8×	0.103	ACTA1
Neddylation	1	11.8×	0.123	KLHL41
Antigen processing: Ubiquitination & Proteasome degradation	1	9.3×	0.141	KLHL41
Adaptive Immune System	1	7.5×	0.159	KLHL41
Post-translational protein modification	1	4.8×	0.222	KLHL41
Immune System	1	3.2×	0.286	KLHL41
Metabolism of proteins	1	3.1×	0.286	KLHL41

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
skeletal muscle thin filament assembly	2	936.2×	3e-05	ACTA1, LMOD3
muscle contraction	3	104.0×	3e-05	TPM2, ACTA1, LMOD3
myofibril assembly	2	374.5×	1e-04	KLHL41, LMOD3
striated muscle contraction	2	280.9×	1e-04	KLHL41, LMOD3
skeletal muscle fiber development	2	181.2×	3e-04	ACTA1, LMOD3
regulation of ATP-dependent activity	1	1404.3×	0.003	TPM2
regulation of myoblast proliferation	1	1404.3×	0.003	KLHL41
cardiac muscle thin filament assembly	1	936.2×	0.003	NEB
somatic muscle development	1	702.2×	0.003	NEB
actin filament fragmentation	1	702.2×	0.003	CFL2
regulation of actin filament length	1	702.2×	0.003	NEB
actin filament organization	2	39.6×	0.003	TPM2, LMOD3
mesenchyme migration	1	561.7×	0.004	ACTA1
regulation of skeletal muscle cell differentiation	1	468.1×	0.004	KLHL41
regulation of myoblast differentiation	1	401.2×	0.005	KLHL41
pointed-end actin filament capping	1	401.2×	0.005	LMOD3
positive regulation of skeletal muscle fiber development	1	351.1×	0.005	LMOD3
positive regulation of actin filament depolymerization	1	312.1×	0.005	CFL2
actin nucleation	1	312.1×	0.005	LMOD3
actin filament depolymerization	1	216.1×	0.007	CFL2
actin filament severing	1	200.6×	0.007	CFL2
muscle cell cellular homeostasis	1	108.0×	0.012	CFL2
sarcomere organization	1	63.8×	0.020	CFL2
skeletal muscle cell differentiation	1	57.3×	0.021	KLHL41
skeletal muscle tissue development	1	48.4×	0.024	CFL2
muscle organ development	1	27.8×	0.040	NEB
proteasome-mediated ubiquitin-dependent protein catabolic process	1	8.7×	0.118	KLHL41
protein ubiquitination	1	6.9×	0.141	KLHL41
positive regulation of gene expression	1	6.5×	0.145	ACTA1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 6

Druggability breadth: 1 of 6 evidence-associated genes (17%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TPM2	0	0
ACTA1	0	0
KLHL41	0	0
CFL2	0	0
LMOD3	0	0
NEB	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
KLHL41	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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	6	TPM2, ACTA1, KLHL41, CFL2, LMOD3, NEB

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TPM2	0	—
ACTA1	0	—
KLHL41	1	—
CFL2	0	—
LMOD3	0	—
NEB	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.