Nemaline myopathy

Summary

Nemaline myopathy (MONDO:0018958) is a disease (an umbrella term covering 8 Mondo subtypes) with 12 cohort genes and 11 clinical trials. The dominant Reactome pathway is Striated Muscle Contraction (6 cohort genes). Top therapeutic interventions include tyrosine.

At a glance

• Prevalence: 1-9 / 1 000 000 (United Kingdom) [Orphanet-validated]
• Umbrella term: 8 Mondo subtypes
• Cohort genes: 12
• ClinVar variants: 350
• Clinical trials: 11

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	2	Europe	Validated
Point prevalence	1-9 / 1 000 000	0.2	United Kingdom	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	nemaline myopathy
Mondo ID	MONDO:0018958
MeSH	D017696
OMIM	256030
Orphanet	607
DOID	DOID:3191
ICD-10-CM	G71.21
ICD-11	1996502540
SNOMED CT	75072002
UMLS	C0206157
MedGen	61528
GARD	0012033
Is cancer (heuristic)	no

Also known as: congenital rod disease · NEM · nemaline body disease · nemaline myopathy · nemaline rod disease · nemaline rod myopathy · NM · Rod body disease · rod myopathy · Rod-body myopathy

Data availability: 350 ClinVar variants · 17 ClinGen variant curations · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 8 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › congenital myopathy › congenital structural myopathy › nemaline myopathy

Related subtypes (5): autosomal dominant centronuclear myopathy, inborn mitochondrial myopathy, congenital fiber-type disproportion myopathy, myofibrillar myopathy, autosomal dominant nebulin-related myopathy

Subtypes (8): nemaline myopathy 5, MYPN-related myopathy, severe congenital nemaline myopathy, typical nemaline myopathy, childhood-onset nemaline myopathy, adult-onset nemaline myopathy, nemaline myopathy 5B, autosomal recessive, childhood-onset, nemaline myopathy 5C, autosomal dominant

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

350 retrieved; paginated sample, class counts are floors:

141 pathogenic/likely pathogenic, 72 likely pathogenic, 64 pathogenic, 41 conflicting classifications of pathogenicity, 25 uncertain significance, 4 likely benign, 2 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2582806	NM_001100.4(ACTA1):c.868G>A (p.Asp290Asn)	ACTA1	Pathogenic	criteria provided, single submitter
2635623	NM_001100.4(ACTA1):c.686T>C (p.Met229Thr)	ACTA1	Pathogenic	criteria provided, multiple submitters, no conflicts
3233251	NM_001100.4(ACTA1):c.466G>C (p.Asp156His)	ACTA1	Pathogenic	criteria provided, single submitter
3233255	NM_001100.4(ACTA1):c.203C>A (p.Thr68Asn)	ACTA1	Pathogenic	criteria provided, single submitter
183243	NM_006063.3(KLHL41):c.641del (p.Asn214fs)	KLHL41	Pathogenic/Likely pathogenic	no assertion criteria provided
2503969	NM_001164508.2(NEB):c.19519A>T (p.Lys6507Ter)	LOC126806373	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224413	NM_032608.7(MYO18B):c.6496G>T (p.Glu2166Ter)	MYO18B	Pathogenic	criteria provided, single submitter
3233263	NM_032578.4(MYPN):c.3158+1G>A	MYPN	Pathogenic	criteria provided, single submitter
1066812	NM_001164508.2(NEB):c.1570-2del	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068470	NM_001164508.2(NEB):c.24003_24006dup (p.Glu8003fs)	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071068	NM_001164508.2(NEB):c.19156G>T (p.Glu6386Ter)	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071473	NM_001164508.2(NEB):c.175C>T (p.Gln59Ter)	NEB	Pathogenic	criteria provided, multiple submitters, no conflicts
1071773	NM_001164508.2(NEB):c.9840C>G (p.Tyr3280Ter)	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072759	NM_001164508.2(NEB):c.133_146del (p.Ser45fs)	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073497	NM_001164508.2(NEB):c.23998_24002dup (p.Gln8002fs)	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073581	NM_001164508.2(NEB):c.24176_24179dup (p.Lys8061fs)	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073671	NM_001164508.2(NEB):c.6562del (p.Glu2188fs)	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074607	NM_001164508.2(NEB):c.8803C>T (p.Gln2935Ter)	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075153	NM_001164508.2(NEB):c.20995A>T (p.Lys6999Ter)	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075448	NM_001164508.2(NEB):c.4843A>T (p.Lys1615Ter)	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075629	NM_001164508.2(NEB):c.22905+1del	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076082	NM_001164508.2(NEB):c.3601A>T (p.Lys1201Ter)	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076427	NM_001164508.2(NEB):c.11024dup (p.Asp3676fs)	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323339	NM_001164508.2(NEB):c.21829C>T (p.Gln7277Ter)	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339664	NM_001164508.2(NEB):c.20975_20976del (p.Lys6992fs)	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339685	NM_001164508.2(NEB):c.23628_23631del (p.Gln7876fs)	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1356561	NM_001164508.2(NEB):c.25129C>T (p.Arg8377Ter)	NEB	Pathogenic	criteria provided, multiple submitters, no conflicts
1365254	NM_001164508.2(NEB):c.9580C>T (p.Gln3194Ter)	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1382666	NM_001164507.2(NEB):c.21406C>T (p.Gln7136Ter)	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1385740	NM_001164508.2(NEB):c.23998_24001del (p.Leu8000fs)	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 43 · 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
TNNT1	Strong	Autosomal recessive	nemaline myopathy 5	7
TNNT3	Strong	Autosomal recessive	congenital myopathy	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TNNT3	Orphanet:1146	Distal arthrogryposis type 1
TNNT3	Orphanet:1147	Sheldon-Hall syndrome
TNNT1	Orphanet:98902	Amish nemaline myopathy
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
TPM3	Orphanet:171433	Intermediate nemaline myopathy
TPM3	Orphanet:171439	Childhood-onset nemaline myopathy
TPM3	Orphanet:171881	Cap myopathy
TPM3	Orphanet:178342	Inflammatory myofibroblastic tumor
TPM3	Orphanet:2020	Congenital fiber-type disproportion myopathy
TPM3	Orphanet:476406	Congenital generalized hypercontractile muscle stiffness syndrome
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
MYO18B	Orphanet:447974	Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome
MYPN	Orphanet:154	Familial isolated dilated cardiomyopathy
MYPN	Orphanet:171439	Childhood-onset nemaline myopathy
MYPN	Orphanet:171881	Cap myopathy
MYPN	Orphanet:75249	Familial isolated restrictive cardiomyopathy
FLNC	Orphanet:171445	Muscle filaminopathy
FLNC	Orphanet:63273	FLNC-related handgrip and calf weakness-distal myopathy
FLNC	Orphanet:75249	Familial isolated restrictive cardiomyopathy
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

12 cohort genes, 12 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	12

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TNNT3	HGNC:11950	ENSG00000130595	P45378	Troponin T, fast skeletal muscle	gencc,clinvar
TNNT1	HGNC:11948	ENSG00000105048	P13805	Troponin T, slow skeletal muscle	gencc
TPM2	HGNC:12011	ENSG00000198467	P07951	Tropomyosin beta chain	clinvar
TPM3	HGNC:12012	ENSG00000143549	P06753	Tropomyosin alpha-3 chain	clinvar
ACTA1	HGNC:129	ENSG00000143632	P68133	Actin, alpha skeletal muscle	clinvar
KLHL41	HGNC:16905	ENSG00000239474	O60662	Kelch-like protein 41	clinvar
MYO18B	HGNC:18150	ENSG00000133454	Q8IUG5	Unconventional myosin-XVIIIb	clinvar
RIF1	HGNC:23207	ENSG00000080345	Q5UIP0	Telomere-associated protein RIF1	clinvar
MYPN	HGNC:23246	ENSG00000138347	Q86TC9	Myopalladin	clinvar
LRIF1	HGNC:30299	ENSG00000121931	Q5T3J3	Ligand-dependent nuclear receptor-interacting factor 1	clinvar
FLNC	HGNC:3756	ENSG00000128591	Q14315	Filamin-C	clinvar
NEB	HGNC:7720	ENSG00000183091	P20929	Nebulin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TNNT3	Troponin T, fast skeletal muscle	Troponin T is the tropomyosin-binding subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.
TNNT1	Troponin T, slow skeletal muscle	Troponin T is the tropomyosin-binding subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.
TPM2	Tropomyosin beta chain	Binds to actin filaments in muscle and non-muscle cells.
TPM3	Tropomyosin alpha-3 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.
MYO18B	Unconventional myosin-XVIIIb	May be involved in intracellular trafficking of the muscle cell when in the cytoplasm, whereas entering the nucleus, may be involved in the regulation of muscle specific genes.
RIF1	Telomere-associated protein RIF1	Key regulator of TP53BP1 that plays a key role in the repair of double-strand DNA breaks (DSBs) in response to DNA damage: acts by promoting non-homologous end joining (NHEJ)-mediated repair of DSBs.
MYPN	Myopalladin	Component of the sarcomere that tethers together nebulin (skeletal muscle) and nebulette (cardiac muscle) to alpha-actinin, at the Z lines.
LRIF1	Ligand-dependent nuclear receptor-interacting factor 1	Together with SMCHD1, involved in chromosome X inactivation in females by promoting the compaction of heterochromatin.
FLNC	Filamin-C	Muscle-specific filamin, which plays a central role in sarcomere assembly and organization.
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: 2 · Difficult: 1 · Unknown: 9 · Druggable fraction: 0.17

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	4.9×	0.185
Other/Unknown	9	1.3×	0.221
Scaffold/PPI	1	1.4×	0.511

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TNNT3	Other/Unknown	no		Troponin, TNNT, Troponin_sf
TNNT1	Other/Unknown	no		Troponin, TNNT, Troponin_sf
TPM2	Other/Unknown	no		Tropomyosin
TPM3	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
MYO18B	Other/Unknown	no		Myosin_head_motor_dom-like, P-loop_NTPase, MYSc_Myo18
RIF1	Other/Unknown	no		ARM-like, ARM-type_fold, Rif1_N
MYPN	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
LRIF1	Other/Unknown	no		LRIF1
FLNC	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom
NEB	Scaffold/PPI	no		Nebulin_repeat, SH3_domain, Nebulin-like

Expression context

Cohort genes with no expression data: 0.

12 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)	12
unknown	0

Top tissues across cohort

Tissue	Cohort genes
hindlimb stylopod muscle	7
gastrocnemius	6
diaphragm	3
gluteal muscle	3
tibialis anterior	3
skeletal muscle tissue of biceps brachii	2
skeletal muscle tissue	1
blood vessel layer	1
popliteal artery	1
saphenous vein	1
skeletal muscle tissue of rectus abdominis	1
apex of heart	1
buccal mucosa cell	1
vastus lateralis	1
calcaneal tendon	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TNNT3	135	broad	marker	hindlimb stylopod muscle, skeletal muscle tissue, gastrocnemius
TNNT1	192	ubiquitous	marker	gluteal muscle, skeletal muscle tissue of biceps brachii, diaphragm
TPM2	283	ubiquitous	marker	saphenous vein, popliteal artery, blood vessel layer
TPM3	243	ubiquitous	marker	diaphragm, hindlimb stylopod muscle, skeletal muscle tissue of rectus abdominis
ACTA1	203	broad	marker	gluteal muscle, skeletal muscle tissue of biceps brachii, diaphragm
KLHL41	184	broad	marker	tibialis anterior, gastrocnemius, hindlimb stylopod muscle
MYO18B	148	broad	marker	apex of heart, gastrocnemius, hindlimb stylopod muscle
RIF1	279	ubiquitous	marker	buccal mucosa cell, gastrocnemius, hindlimb stylopod muscle
MYPN	116	broad	marker	hindlimb stylopod muscle, gastrocnemius, vastus lateralis
LRIF1	271	ubiquitous	marker	calcaneal tendon, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
FLNC	255	ubiquitous	marker	gastrocnemius, hindlimb stylopod muscle, tibialis anterior
NEB	204	tissue_specific	marker	gluteal muscle, tibialis anterior, biceps brachii

Protein interactions among cohort

Intra-cohort edges: 12.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TPM3	4,099
FLNC	3,174
RIF1	2,384
MYO18B	1,775
MYPN	1,764
TNNT1	1,426
NEB	1,402
LRIF1	1,295
TNNT3	1,197
KLHL41	1,144

Intra-cohort edges

A	B	Sources
KLHL41	MYO18B	string_interaction
KLHL41	MYPN	string_interaction
KLHL41	NEB	biogrid_interaction, intact, string_interaction
KLHL41	TNNT1	string_interaction
KLHL41	TNNT3	string_interaction
KLHL41	TPM3	string_interaction
MYO18B	MYPN	string_interaction
MYO18B	TNNT1	string_interaction
MYPN	NEB	biogrid_interaction, string_interaction
NEB	TNNT1	string_interaction
NEB	TPM2	biogrid_interaction
TNNT1	TPM3	biogrid_interaction, intact, string_interaction

Structural data

PDB: 5 · AlphaFold-only: 7 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FLNC	Q14315	14
ACTA1	P68133	5
NEB	P20929	3
TPM3	P06753	1
RIF1	Q5UIP0	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KLHL41	O60662	93.48
TPM2	P07951	91.51
TNNT3	P45378	77.99
TNNT1	P13805	74.89
MYO18B	Q8IUG5	60.66
MYPN	Q86TC9	52.71
LRIF1	Q5T3J3	48.88

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. Enrichment computed across 12 evidence-associated genes (9 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 9 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	6	205.8×	1e-12	TNNT3, TNNT1, TPM2, TPM3, ACTA1, NEB
Smooth Muscle Contraction	2	59.0×	0.005	TPM2, TPM3
Muscle contraction	2	17.1×	0.036	ACTA1, NEB
Regulation of CDH1 Function	1	105.7×	0.045	ACTA1
Cell-extracellular matrix interactions	1	74.6×	0.051	FLNC
Formation of the dystrophin-glycoprotein complex (DGC)	1	34.3×	0.084	ACTA1
RHOV GTPase cycle	1	31.7×	0.084	TPM3
Nonhomologous End-Joining (NHEJ)	1	18.7×	0.101	RIF1
Activation of STAT3 by cadherin engagement	1	18.1×	0.101	ACTA1
Non-integrin membrane-ECM interactions	1	17.1×	0.101	ACTA1
Signaling by ALK fusions and activated point mutants	1	16.7×	0.101	TPM3
Class I MHC mediated antigen processing & presentation	1	7.8×	0.192	KLHL41
Extracellular matrix organization	1	7.0×	0.196	ACTA1
Neddylation	1	5.3×	0.237	KLHL41
Antigen processing: Ubiquitination & Proteasome degradation	1	4.1×	0.276	KLHL41
Adaptive Immune System	1	3.3×	0.314	KLHL41
Post-translational protein modification	1	2.1×	0.427	KLHL41
Immune System	1	1.4×	0.532	KLHL41
Metabolism of proteins	1	1.4×	0.532	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 12 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sarcomere organization	4	127.7×	9e-07	TNNT3, TNNT1, MYPN, FLNC
regulation of ATP-dependent activity	2	1404.3×	1e-05	TNNT3, TPM2
muscle contraction	3	52.0×	3e-04	TPM2, TPM3, ACTA1
skeletal muscle contraction	2	85.1×	0.003	TNNT3, TNNT1
slow-twitch skeletal muscle fiber contraction	1	1404.3×	0.005	TNNT1
negative regulation of muscle contraction	1	1404.3×	0.005	TNNT1
positive regulation of calcium-dependent ATPase activity	1	1404.3×	0.005	TNNT3
regulation of myoblast proliferation	1	702.2×	0.008	KLHL41
cardiac muscle thin filament assembly	1	468.1×	0.011	NEB
somatic muscle development	1	351.1×	0.012	NEB
regulation of actin filament length	1	351.1×	0.012	NEB
mesenchyme migration	1	280.9×	0.013	ACTA1
skeletal muscle thin filament assembly	1	234.1×	0.013	ACTA1
regulation of skeletal muscle cell differentiation	1	234.1×	0.013	KLHL41
transition between fast and slow fiber	1	200.6×	0.013	TNNT1
regulation of myoblast differentiation	1	200.6×	0.013	KLHL41
actin filament organization	2	19.8×	0.013	TPM2, TPM3
regulation of striated muscle contraction	1	175.5×	0.015	TNNT3
telomere maintenance in response to DNA damage	1	156.0×	0.015	RIF1
dosage compensation by inactivation of X chromosome	1	127.7×	0.017	LRIF1
subtelomeric heterochromatin formation	1	127.7×	0.017	RIF1
positive regulation of isotype switching	1	108.0×	0.019	RIF1
myofibril assembly	1	93.6×	0.021	KLHL41
dendrite self-avoidance	1	87.8×	0.022	MYPN
positive regulation of double-strand break repair via nonhomologous end joining	1	82.6×	0.022	RIF1
striated muscle contraction	1	70.2×	0.025	KLHL41
cardiac muscle cell development	1	52.0×	0.031	MYO18B
negative regulation of double-strand break repair via homologous recombination	1	52.0×	0.031	RIF1
skeletal muscle fiber development	1	45.3×	0.035	ACTA1
negative regulation of gene expression, epigenetic	1	33.4×	0.045	RIF1

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Tyrosine.

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 11

Druggability breadth: 4 of 12 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RIF1	1	2
TNNT3	0	0
TNNT1	0	0
TPM2	0	0
TPM3	0	0
ACTA1	0	0
KLHL41	0	0
MYO18B	0	0
MYPN	0	0
LRIF1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	RIF1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TPM3	18	Binding:18
RIF1	7	Binding:7
KLHL41	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 12; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 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)
MOLIBRESIB	2	RIF1

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	1	RIF1
C	Druggable family + PDB, no drug	1	FLNC
D	Druggable family + AlphaFold only, no drug	1	MYPN
E	Difficult family or no structure, no drug	9	TNNT3, TNNT1, TPM2, TPM3, ACTA1, KLHL41, MYO18B, LRIF1, NEB

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TNNT3	0	—
TNNT1	0	—
TPM2	0	—
TPM3	18	—
ACTA1	0	—
KLHL41	1	—
MYO18B	0	—
MYPN	0	—
LRIF1	0	—
FLNC	0	—
NEB	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 11.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	10
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02035501	PHASE2	UNKNOWN	Treatment of TNNT1-Myopathy With L-Tyrosine.
NCT00272883	Not specified	RECRUITING	Molecular and Genetic Studies of Congenital Myopathies
NCT06157268	Not specified	RECRUITING	The Natural History and Muscle Fatigability of Patients With Congenital Myopathies.
NCT06670378	Not specified	ACTIVE_NOT_RECRUITING	Natural History Study for Patients With Nemaline Myopathy in the UK
NCT06774703	Not specified	NOT_YET_RECRUITING	Nemaline Myopathy Clinical Research Network (NM-CTRN)
NCT06791369	Not specified	NOT_YET_RECRUITING	The Prevalence of RYR1-related Disease
NCT07201636	Not specified	NOT_YET_RECRUITING	Natural History Study for Patients With Nemaline Myopathy in Belgium
NCT07478172	Not specified	RECRUITING	Effects of Whole-body Electrical Muscle Stimulation Exercise on Adults With Neuromuscular Disease
NCT07488806	Not specified	RECRUITING	Natural History Study for Patients With Nemaline Myopathy in Spain
NCT03728803	Not specified	COMPLETED	Inspiratory Muscle Training in Nemaline Myopathy
NCT05099107	Not specified	COMPLETED	Changes of Motor Function Tests in Congenital Myopathy Subjects Treated With Oral Salbutamol as Compared to no Treatment

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TYROSINE	4	1