Nemaline myopathy 9

Summary

Nemaline myopathy 9 (MONDO:0014326) is a disease caused by KLHL41 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: KLHL41 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 288

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	nemaline myopathy 9
Mondo ID	MONDO:0014326
OMIM	615731
DOID	DOID:0110929
UMLS	C3810384
MedGen	816714
GARD	0016007
Is cancer (heuristic)	no

Also known as: KLHL41 nemaline myopathy · NEM9 · nemaline myopathy 9 · nemaline myopathy caused by mutation in KLHL41 · nemaline myopathy type 9

Data availability: 288 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › severe congenital nemaline myopathy › nemaline myopathy 9

Related subtypes (4): congenital myopathy 2a, typical, autosomal dominant, nemaline myopathy 2, nemaline myopathy 8, 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

ClinVar germline variants

288 retrieved; paginated sample, class counts are floors:

133 uncertain significance, 106 likely benign, 24 pathogenic, 9 benign/likely benign, 7 benign, 3 pathogenic/likely pathogenic, 3 likely pathogenic, 3 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1071146	NM_006063.3(KLHL41):c.1566G>A (p.Trp522Ter)	KLHL41	Pathogenic	criteria provided, single submitter
1073199	NM_006063.3(KLHL41):c.1027C>T (p.Gln343Ter)	KLHL41	Pathogenic	criteria provided, multiple submitters, no conflicts
1074897	NM_006063.3(KLHL41):c.1307_1308del (p.Lys436fs)	KLHL41	Pathogenic	criteria provided, single submitter
1324627	NM_006063.3(KLHL41):c.215del (p.Lys72fs)	KLHL41	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324628	NM_006063.3(KLHL41):c.1416dup (p.Gly473fs)	KLHL41	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459768	NM_006063.3(KLHL41):c.1690G>T (p.Glu564Ter)	KLHL41	Pathogenic	criteria provided, single submitter
183241	NM_006063.3(KLHL41):c.459delinsACTC (p.Ser153_Ala154insLeu)	KLHL41	Pathogenic	no assertion criteria provided
183242	NM_006063.3(KLHL41):c.1748_1755del (p.Lys583fs)	KLHL41	Pathogenic	no assertion criteria provided
183243	NM_006063.3(KLHL41):c.641del (p.Asn214fs)	KLHL41	Pathogenic/Likely pathogenic	no assertion criteria provided
183244	NM_006063.3(KLHL41):c.575AAG[2] (p.Glu194del)	KLHL41	Pathogenic	no assertion criteria provided
183245	NM_006063.3(KLHL41):c.1238C>T (p.Ser413Leu)	KLHL41	Pathogenic	no assertion criteria provided
1982923	NM_006063.3(KLHL41):c.155_159del (p.Ser52fs)	KLHL41	Pathogenic	criteria provided, single submitter
2022391	NM_006063.3(KLHL41):c.1044T>G (p.Tyr348Ter)	KLHL41	Pathogenic	criteria provided, single submitter
2030088	NM_006063.3(KLHL41):c.1632_1633del (p.Tyr545fs)	KLHL41	Pathogenic	criteria provided, single submitter
2065093	NM_006063.3(KLHL41):c.468dup (p.Phe157fs)	KLHL41	Pathogenic	criteria provided, single submitter
2118516	NM_006063.3(KLHL41):c.756_757insT (p.Lys253Ter)	KLHL41	Pathogenic	criteria provided, single submitter
2815530	NM_006063.3(KLHL41):c.1425G>A (p.Trp475Ter)	KLHL41	Pathogenic	criteria provided, single submitter
3624557	NM_006063.3(KLHL41):c.613C>T (p.Arg205Ter)	KLHL41	Pathogenic	criteria provided, single submitter
3724021	NM_006063.3(KLHL41):c.624_628del (p.Glu209fs)	KLHL41	Pathogenic	criteria provided, single submitter
3730222	NM_006063.3(KLHL41):c.1093C>T (p.Gln365Ter)	KLHL41	Pathogenic	criteria provided, single submitter
4712589	NM_006063.3(KLHL41):c.1615del (p.Ser539fs)	KLHL41	Pathogenic	criteria provided, single submitter
4713743	NM_006063.3(KLHL41):c.446_447insT (p.Arg149fs)	KLHL41	Pathogenic	criteria provided, single submitter
4725975	NM_006063.3(KLHL41):c.678del (p.Leu226_Met227insTer)	KLHL41	Pathogenic	criteria provided, single submitter
566091	NM_006063.3(KLHL41):c.215dup (p.Glu73fs)	KLHL41	Pathogenic	criteria provided, single submitter
581470	NM_006063.3(KLHL41):c.168_175del (p.Pro56_Tyr57insTer)	KLHL41	Pathogenic	criteria provided, single submitter
645750	NM_006063.3(KLHL41):c.930_939del (p.Asn310fs)	KLHL41	Pathogenic	criteria provided, single submitter
646196	NM_006063.3(KLHL41):c.1296del (p.Lys432fs)	KLHL41	Pathogenic	criteria provided, single submitter
1465145	NM_006063.3(KLHL41):c.667C>T (p.Arg223Cys)	KLHL41	Likely pathogenic	criteria provided, single submitter
2445984	NM_006063.3(KLHL41):c.881_890del (p.Asp294fs)	KLHL41	Likely pathogenic	criteria provided, single submitter
2873424	NM_006063.3(KLHL41):c.1561_1562+2del	KLHL41	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 4 · 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
KLHL41	Strong	Autosomal recessive	nemaline myopathy 9	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

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
KLHL41	HGNC:16905	ENSG00000239474	O60662	Kelch-like protein 41	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KLHL41	Kelch-like protein 41	Involved in skeletal muscle development and differentiation.

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)
KLHL41	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf

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
gastrocnemius	1
hindlimb stylopod muscle	1
tibialis anterior	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KLHL41	184	broad	marker	tibialis anterior, gastrocnemius, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KLHL41	1,144

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KLHL41	O60662	93.48

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Class I MHC mediated antigen processing & presentation	1	70.1×	0.059	KLHL41
Neddylation	1	47.4×	0.059	KLHL41
Antigen processing: Ubiquitination & Proteasome degradation	1	37.2×	0.059	KLHL41
Adaptive Immune System	1	29.8×	0.059	KLHL41
Post-translational protein modification	1	19.2×	0.073	KLHL41
Immune System	1	13.0×	0.081	KLHL41
Metabolism of proteins	1	12.4×	0.081	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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of myoblast proliferation	1	8426.0×	9e-04	KLHL41
regulation of skeletal muscle cell differentiation	1	2808.7×	0.001	KLHL41
regulation of myoblast differentiation	1	2407.4×	0.001	KLHL41
myofibril assembly	1	1123.5×	0.002	KLHL41
striated muscle contraction	1	842.6×	0.002	KLHL41
skeletal muscle cell differentiation	1	343.9×	0.004	KLHL41
proteasome-mediated ubiquitin-dependent protein catabolic process	1	52.2×	0.022	KLHL41
protein ubiquitination	1	41.4×	0.024	KLHL41

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
KLHL41	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: 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	KLHL41

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)
KLHL41	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.