KLHL41

Summary

KLHL41 (kelch like family member 41, HGNC:16905) is a protein-coding gene on chromosome 2q31.1, encoding Kelch-like protein 41 (O60662). Involved in skeletal muscle development and differentiation.

This gene is a member of the kelch-like family. The encoded protein contains a BACK domain, a BTB/POZ domain, and 5 Kelch repeats. This protein is thought to function in skeletal muscle development and maintenance. Mutations in this gene have been associated with nemaline myopathy (NM), a rare congenital muscle disorder.

Source: NCBI Gene 10324 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nemaline myopathy 9 (Strong, GenCC) — +4 more curated relationships
• Clinical variants (ClinVar): 363 total — 25 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 101
• Druggable target: yes
• MANE Select transcript: NM_006063

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16905
Approved symbol	KLHL41
Name	kelch like family member 41
Location	2q31.1
Locus type	gene with protein product
Status	Approved
Aliases	SARCOSIN, Krp1
Ensembl gene	ENSG00000239474
Ensembl biotype	protein_coding
OMIM	607701
Entrez	10324

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000284669, ENST00000463400, ENST00000480330, ENST00000946624, ENST00000946625, ENST00000946626, ENST00000946627

RefSeq mRNA: 1 — MANE Select: NM_006063 NM_006063

CCDS: CCDS2234

Canonical transcript exons

ENST00000284669 — 6 exons

Exon	Start	End
ENSE00001016120	169525585	169526258
ENSE00001016123	169509702	169510888
ENSE00003468653	169520861	169521007
ENSE00003596093	169514854	169514961
ENSE00003602250	169514574	169514731
ENSE00003645040	169518190	169518375

Expression profiles

Bgee: expression breadth ubiquitous, 184 present calls, max score 99.98.

FANTOM5 (CAGE): breadth broad, TPM avg 27.6402 / max 10311.9666, expressed in 331 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
23546	27.1575	329
202463	0.3818	73
23547	0.0524	16
23548	0.0336	14
23549	0.0148	9

Top tissues by expression

254 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
tibialis anterior	UBERON:0001385	99.98	gold quality
gastrocnemius	UBERON:0001388	99.89	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.85	gold quality
biceps brachii	UBERON:0001507	99.81	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.77	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.74	gold quality
skeletal muscle tissue	UBERON:0001134	99.65	gold quality
quadriceps femoris	UBERON:0001377	99.36	gold quality
body of tongue	UBERON:0011876	99.33	gold quality
vastus lateralis	UBERON:0001379	99.29	gold quality
muscle organ	UBERON:0001630	98.80	gold quality
skeletal muscle organ	UBERON:0014892	98.80	gold quality
deltoid	UBERON:0001476	98.68	gold quality
muscle of leg	UBERON:0001383	98.61	gold quality
heart right ventricle	UBERON:0002080	96.09	gold quality
heart left ventricle	UBERON:0002084	95.69	gold quality
muscle tissue	UBERON:0002385	95.22	gold quality
cardiac ventricle	UBERON:0002082	95.19	gold quality
left ventricle myocardium	UBERON:0006566	94.26	gold quality
right atrium auricular region	UBERON:0006631	94.06	gold quality
apex of heart	UBERON:0002098	93.64	gold quality
myocardium	UBERON:0002349	93.38	gold quality
cardiac atrium	UBERON:0002081	93.37	gold quality
tongue	UBERON:0001723	92.80	gold quality
cardiac muscle of right atrium	UBERON:0003379	92.38	gold quality
islet of Langerhans	UBERON:0000006	91.89	gold quality
heart	UBERON:0000948	91.10	gold quality
mucosa of stomach	UBERON:0001199	86.67	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.64	gold quality
superior surface of tongue	UBERON:0007371	83.02	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-124472	yes	2099.76
E-HCAD-56	yes	1242.52
E-ANND-3	yes	11.67
E-ENAD-27	yes	7.47
E-CURD-112	no	403.79

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

21 targeting KLHL41, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-122B-5P	99.46	70.81	1457
HSA-MIR-208A-5P	99.42	70.83	1913
HSA-MIR-208B-5P	99.42	70.83	1952
HSA-MIR-372-5P	99.41	69.11	2299
HSA-MIR-302A-5P	99.39	68.21	1913
HSA-MIR-2054	99.20	68.89	1699
HSA-MIR-10B-3P	99.04	66.98	988
HSA-MIR-4699-5P	98.99	67.50	1210
HSA-MIR-4709-3P	98.88	68.04	1594
HSA-MIR-1322	97.98	68.96	625
HSA-MIR-6857-3P	96.70	65.43	915
HSA-MIR-4280	96.44	67.69	473
HSA-MIR-549A-5P	96.35	68.08	587
HSA-MIR-151A-5P	95.79	68.73	162
HSA-MIR-151B	95.79	68.73	162
HSA-MIR-4323	93.93	63.89	656

Literature-anchored findings (GeneRIF, showing 1)

• Mutations in KLHL41 showed phenotype-genotype correlation: Frameshift mutations resulted in severe phenotypes with neonatal death, whereas missense changes resulted in impaired motor function with survival into late childhood and/or early adulthood. (PMID:24268659)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	klhl41b	ENSDARG00000006757
danio_rerio	klhl41a	ENSDARG00000068888
mus_musculus	Klhl41	ENSMUSG00000075307
rattus_norvegicus	Bbs5	ENSRNOG00000007127

Paralogs (54): KLHL13 (ENSG00000003096), KLHL20 (ENSG00000076321), KEAP1 (ENSG00000079999), KLHL42 (ENSG00000087448), KLHL22 (ENSG00000099910), KLHL4 (ENSG00000102271), KLHL2 (ENSG00000109466), KLHL5 (ENSG00000109790), BACH2 (ENSG00000112182), KLHL18 (ENSG00000114648), KLHL24 (ENSG00000114796), IVNS1ABP (ENSG00000116679), KLHL12 (ENSG00000117153), KLHL29 (ENSG00000119771), KBTBD7 (ENSG00000120696), KLHL7 (ENSG00000122550), KLHL31 (ENSG00000124743), KLHDC7B (ENSG00000130487), KLHL36 (ENSG00000135686), KLHL8 (ENSG00000145332), KLHL3 (ENSG00000146021), KLHL35 (ENSG00000149243), KLHL1 (ENSG00000150361), BACH1 (ENSG00000156273), KLHL40 (ENSG00000157119), KLHL10 (ENSG00000161594), KLHL21 (ENSG00000162413), KLHDC8A (ENSG00000162873), KBTBD8 (ENSG00000163376), KBTBD6 (ENSG00000165572), KLHL26 (ENSG00000167487), KLHL30 (ENSG00000168427), KBTBD2 (ENSG00000170852), KLHL6 (ENSG00000172578), KLHL15 (ENSG00000174010), KLHL38 (ENSG00000175946), KBTBD11 (ENSG00000176595), KLHDC7A (ENSG00000179023), KLHL28 (ENSG00000179454), KBTBD3 (ENSG00000182359)

Protein

Protein identifiers

Kelch-like protein 41 — O60662 (reviewed: O60662)

Alternative names: Kel-like protein 23, Kelch repeat and BTB domain-containing protein 10, Kelch-related protein 1, Sarcosin

All UniProt accessions (1): O60662

UniProt curated annotations — full annotation on UniProt →

Function. Involved in skeletal muscle development and differentiation. Regulates proliferation and differentiation of myoblasts and plays a role in myofibril assembly by promoting lateral fusion of adjacent thin fibrils into mature, wide myofibrils. Required for pseudopod elongation in transformed cells.

Subunit / interactions. Interacts with NRAP. Interacts with LASP1. Part of a complex that contains CUL3, RBX1 and KLHL41.

Subcellular location. Cytoplasm. Cytoskeleton. Cell projection. Pseudopodium. Ruffle. Myofibril. Sarcomere. M line. Sarcoplasmic reticulum membrane. Endoplasmic reticulum membrane.

Tissue specificity. Sarcomeric muscle.

Post-translational modifications. Ubiquitinated by E3 ubiquitin ligase complex formed by CUL3 and RBX1 and probably targeted for proteasome-independent degradation. Quinone-induced oxidative stress increases its ubiquitination.

Disease relevance. Nemaline myopathy 9 (NEM9) [MIM:615731] An autosomal recessive form of nemaline myopathy. Nemaline myopathies are muscular disorders characterized by muscle weakness of varying severity and onset, and abnormal thread-like or rod-shaped structures in muscle fibers on histologic examination. NEM9 phenotype is highly variable, ranging from death in infancy due to lack of antigravity movements, to slowly progressive distal muscle weakness with preserved ambulation later in childhood. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
O60662-1	Long	yes
O60662-2	Short

RefSeq proteins (1): NP_006054* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR006652	Kelch_1	Repeat
IPR011333	SKP1/BTB/POZ_sf	Homologous_superfamily
IPR011705	BACK	Domain
IPR015915	Kelch-typ_b-propeller	Homologous_superfamily
IPR017096	BTB-kelch_protein	Family
IPR030571	KLHL41_KL41B_BTB_POZ_dom	Domain

Pfam: PF00651, PF07707, PF24681

UniProt features (17 total): repeat 5, sequence variant 4, sequence conflict 3, domain 2, chain 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60662-F1	93.48	0.91

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 3

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-8951664	Neddylation
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 365 (showing top): GOBP_MUSCLE_TISSUE_DEVELOPMENT, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, MODULE_255, GOBP_REGULATION_OF_SKELETAL_MUSCLE_CELL_DIFFERENTIATION, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GCANCTGNY_MYOD_Q6, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, MODULE_317, TGACCTY_ERR1_Q2, MEF2_02, GOCC_RUFFLE, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, CAGCTG_AP4_Q5

GO Biological Process (8): striated muscle contraction (GO:0006941), protein ubiquitination (GO:0016567), myofibril assembly (GO:0030239), skeletal muscle cell differentiation (GO:0035914), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), regulation of myoblast differentiation (GO:0045661), regulation of myoblast proliferation (GO:2000291), regulation of skeletal muscle cell differentiation (GO:2001014)

GO Molecular Function (2): ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (15): ruffle (GO:0001726), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), pseudopodium (GO:0031143), M band (GO:0031430), Cul3-RING ubiquitin ligase complex (GO:0031463), sarcoplasmic reticulum membrane (GO:0033017), endoplasmic reticulum (GO:0005783), membrane (GO:0016020), sarcoplasmic reticulum (GO:0016529), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Post-translational protein modification	1
Class I MHC mediated antigen processing & presentation	1
Immune System	1
Metabolism of proteins	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
regulation of cell differentiation	2
plasma membrane bounded cell projection	2
cytoplasm	2
muscle contraction	1
protein modification by small protein conjugation	1
cellular component assembly involved in morphogenesis	1
actomyosin structure organization	1
striated muscle cell development	1
supramolecular fiber organization	1
membraneless organelle assembly	1
skeletal muscle tissue development	1
cell differentiation	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
myoblast differentiation	1
regulation of cell population proliferation	1
myoblast proliferation	1
skeletal muscle cell differentiation	1
enzyme-substrate adaptor activity	1
binding	1
cell leading edge	1
nuclear lumen	1
intracellular anatomical structure	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
intracellular membraneless organelle	1
membrane	1
cell periphery	1
A band	1
cullin-RING ubiquitin ligase complex	1
endoplasmic reticulum membrane	1
sarcoplasmic reticulum	1
bounding membrane of organelle	1
endomembrane system	1
intracellular membrane-bounded organelle	1
endoplasmic reticulum	1
sarcoplasm	1

Protein interactions and networks

STRING

1062 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLHL41	NEB	P20929	784
KLHL41	LASP1	Q14847	784
KLHL41	LMOD3	Q0VAK6	775
KLHL41	CUL3	Q13618	704
KLHL41	TNNT1	P13805	681
KLHL41	TPM2	P06468	644
KLHL41	MYPN	Q86TC9	599
KLHL41	ACTA1	P02568	574
KLHL41	MYO18B	Q8IUG5	572
KLHL41	TPM3	P06753	571
KLHL41	NEBL	O76041	557
KLHL41	TNNT3	P45378	526
KLHL41	CFL2	Q9Y281	512
KLHL41	RBX1	P62877	488
KLHL41	NRAP	Q86VF7	475
KLHL41	KLHDC1	Q8N7A1	475

IntAct

47 interactions, top by confidence:

A	B	Type	Score
RCHY1	KLHL41	psi-mi:“MI:0915”(physical association)	0.720
KLHL41	RCHY1	psi-mi:“MI:0915”(physical association)	0.720
KLHL41	NRAP	psi-mi:“MI:0915”(physical association)	0.690
KLHL41	NRAP	psi-mi:“MI:0407”(direct interaction)	0.690
KLHL41	NEB	psi-mi:“MI:0407”(direct interaction)	0.590
KLHL41	SPMIP2	psi-mi:“MI:0915”(physical association)	0.560
VHL	KLHL41	psi-mi:“MI:0915”(physical association)	0.560
KLHL40	CBX4	psi-mi:“MI:0914”(association)	0.530
KLHL41	NEB	psi-mi:“MI:0915”(physical association)	0.520
KLHL41	NEB	psi-mi:“MI:2364”(proximity)	0.520
NEB	KLHL41	psi-mi:“MI:2364”(proximity)	0.520
KLHL41	HNRNPAB	psi-mi:“MI:0915”(physical association)	0.400
PCNA	KLHL41	psi-mi:“MI:0915”(physical association)	0.370
KLHL41	RBM4	psi-mi:“MI:0915”(physical association)	0.370
KLHL41	IFRD1	psi-mi:“MI:0915”(physical association)	0.370
FOXF2	VWA8	psi-mi:“MI:0914”(association)	0.350
TRIM10	POLRMT	psi-mi:“MI:0914”(association)	0.350
ELAPOR1	KLHL41	psi-mi:“MI:0914”(association)	0.350
UTP11	KLHL41	psi-mi:“MI:0914”(association)	0.350
BEX4	KLHL41	psi-mi:“MI:0914”(association)	0.350
MRPS23	MYH7B	psi-mi:“MI:0914”(association)	0.350
ESR2	PSMD11	psi-mi:“MI:0914”(association)	0.350
KLHL41	SPMIP2	psi-mi:“MI:0915”(physical association)	0.000
KLHL41	RCHY1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (35): RCHY1 (Two-hybrid), KLHL41 (Biochemical Activity), KLHL41 (Affinity Capture-MS), KLHL41 (Affinity Capture-MS), KLHL41 (Affinity Capture-MS), KLHL41 (Affinity Capture-MS), KLHL41 (Affinity Capture-MS), NEB (FRET), NRAP (FRET), NEB (Two-hybrid), NRAP (Two-hybrid), IFRD1 (Two-hybrid), RBM4 (Two-hybrid), KLHL41 (Affinity Capture-Western), KLHL41 (Two-hybrid)

ESM2 similar proteins: A2AAX3, A2AUC9, B3DIV9, D2HEW7, D3ZA50, D3ZZC3, E9QJ30, G3X9X1, O14682, O35709, O60662, Q08BL9, Q0D2A9, Q1LYM6, Q2TBA0, Q2WGJ6, Q3B7M1, Q4KLM4, Q53GT1, Q56A24, Q5EB39, Q5RCQ9, Q5RDY3, Q5RGB8, Q5U504, Q5U575, Q5ZJU2, Q66HD2, Q6DEL7, Q6DFF7, Q6GQU2, Q6NYM1, Q6Q7X9, Q6TFL4, Q6V595, Q8BRG6, Q8BWA5, Q8CA72, Q8IY47, Q8N4N3

Diamond homologs: A2AUC9, B0WWP2, B1WBS3, B2RXF5, B3DIV9, B3M9V8, B3NDN0, B4GRJ2, B4HIK1, B4J045, B4L0G9, B4LIG6, B4MXW3, B4PD06, B4QLQ2, D3Z8N4, E0CZ16, E7F6F9, E9Q4F2, E9QIN8, E9QJ30, F1LZ52, F1LZF0, F1MBP6, F1QEG2, O60662, O94889, O95198, P59280, Q01295, Q08DK3, Q13105, Q16RL8, Q1LYM6, Q24206, Q2M0J9, Q2TBA0, Q54D84, Q5EB39, Q5R7B8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

363 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	25
Likely pathogenic	5
Uncertain significance	180
Likely benign	120
Benign	14

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1071146	NM_006063.3(KLHL41):c.1566G>A (p.Trp522Ter)	Pathogenic
1073199	NM_006063.3(KLHL41):c.1027C>T (p.Gln343Ter)	Pathogenic
1074897	NM_006063.3(KLHL41):c.1307_1308del (p.Lys436fs)	Pathogenic
1458428	NC_000002.11:g.(?170218811)(170382206_?)del	Pathogenic
1459768	NM_006063.3(KLHL41):c.1690G>T (p.Glu564Ter)	Pathogenic
183241	NM_006063.3(KLHL41):c.459delinsACTC (p.Ser153_Ala154insLeu)	Pathogenic
183242	NM_006063.3(KLHL41):c.1748_1755del (p.Lys583fs)	Pathogenic
183244	NM_006063.3(KLHL41):c.575AAG[2] (p.Glu194del)	Pathogenic
183245	NM_006063.3(KLHL41):c.1238C>T (p.Ser413Leu)	Pathogenic
1982923	NM_006063.3(KLHL41):c.155_159del (p.Ser52fs)	Pathogenic
2022391	NM_006063.3(KLHL41):c.1044T>G (p.Tyr348Ter)	Pathogenic
2030088	NM_006063.3(KLHL41):c.1632_1633del (p.Tyr545fs)	Pathogenic
2065093	NM_006063.3(KLHL41):c.468dup (p.Phe157fs)	Pathogenic
2118516	NM_006063.3(KLHL41):c.756_757insT (p.Lys253Ter)	Pathogenic
2815530	NM_006063.3(KLHL41):c.1425G>A (p.Trp475Ter)	Pathogenic
3624557	NM_006063.3(KLHL41):c.613C>T (p.Arg205Ter)	Pathogenic
3724021	NM_006063.3(KLHL41):c.624_628del (p.Glu209fs)	Pathogenic
3730222	NM_006063.3(KLHL41):c.1093C>T (p.Gln365Ter)	Pathogenic
4712589	NM_006063.3(KLHL41):c.1615del (p.Ser539fs)	Pathogenic
4713743	NM_006063.3(KLHL41):c.446_447insT (p.Arg149fs)	Pathogenic
4725975	NM_006063.3(KLHL41):c.678del (p.Leu226_Met227insTer)	Pathogenic
566091	NM_006063.3(KLHL41):c.215dup (p.Glu73fs)	Pathogenic
581470	NM_006063.3(KLHL41):c.168_175del (p.Pro56_Tyr57insTer)	Pathogenic
645750	NM_006063.3(KLHL41):c.930_939del (p.Asn310fs)	Pathogenic
646196	NM_006063.3(KLHL41):c.1296del (p.Lys432fs)	Pathogenic
1465145	NM_006063.3(KLHL41):c.667C>T (p.Arg223Cys)	Likely pathogenic
2445984	NM_006063.3(KLHL41):c.881_890del (p.Asp294fs)	Likely pathogenic
2873424	NM_006063.3(KLHL41):c.1561_1562+2del	Likely pathogenic
429539	NM_006063.3(KLHL41):c.1707G>A (p.Trp569Ter)	Likely pathogenic
817308	NM_006063.3(KLHL41):c.83_107delinsTGTCA (p.Asp28fs)	Likely pathogenic

SpliceAI

717 predictions. Top by Δscore:

Variant	Effect	Δscore
2:169510885:CCAGG:C	donor_loss	1.0000
2:169510886:CAGGT:C	donor_loss	1.0000
2:169510889:G:GA	donor_loss	1.0000
2:169514730:GT:G	donor_gain	1.0000
2:169514962:G:GG	donor_gain	1.0000
2:169518181:T:TA	acceptor_gain	1.0000
2:169518187:C:G	acceptor_gain	1.0000
2:169518188:A:AG	acceptor_gain	1.0000
2:169518189:G:GA	acceptor_gain	1.0000
2:169518189:GA:G	acceptor_gain	1.0000
2:169518189:GAA:G	acceptor_gain	1.0000
2:169518189:GAAA:G	acceptor_gain	1.0000
2:169518189:GAAAA:G	acceptor_gain	1.0000
2:169518315:G:GT	donor_gain	1.0000
2:169518371:AATAA:A	donor_gain	1.0000
2:169518372:A:AG	donor_gain	1.0000
2:169518372:A:G	donor_gain	1.0000
2:169518372:ATAA:A	donor_gain	1.0000
2:169518373:TAA:T	donor_gain	1.0000
2:169518374:AA:A	donor_gain	1.0000
2:169518374:AAG:A	donor_loss	1.0000
2:169518375:AGT:A	donor_loss	1.0000
2:169518376:G:GG	donor_gain	1.0000
2:169518376:GTGA:G	donor_gain	1.0000
2:169520859:A:AG	acceptor_gain	1.0000
2:169520859:AGATG:A	acceptor_gain	1.0000
2:169520860:G:GG	acceptor_gain	1.0000
2:169520860:GATGG:G	acceptor_gain	1.0000
2:169521004:GGAA:G	donor_gain	1.0000
2:169521005:GAA:G	donor_gain	1.0000

AlphaMissense

4002 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:169509941:A:C	S55R	1.000
2:169509943:T:A	S55R	1.000
2:169509943:T:G	S55R	1.000
2:169510144:C:G	C122W	1.000
2:169514595:T:A	W378R	1.000
2:169514595:T:C	W378R	1.000
2:169525607:T:A	W578R	1.000
2:169525607:T:C	W578R	1.000
2:169509834:T:A	L19H	0.999
2:169509834:T:C	L19P	0.999
2:169509846:T:C	L23P	0.999
2:169509855:T:C	L26P	0.999
2:169509916:C:G	C46W	0.999
2:169509936:C:A	A53D	0.999
2:169509951:T:C	F58S	0.999
2:169510106:G:C	A110P	0.999
2:169510107:C:A	A110D	0.999
2:169510142:T:C	C122R	0.999
2:169510143:G:A	C122Y	0.999
2:169510155:T:C	L126P	0.999
2:169510202:G:A	G142R	0.999
2:169510202:G:C	G142R	0.999
2:169510203:G:A	G142E	0.999
2:169510239:C:A	A154D	0.999
2:169510385:T:A	W203R	0.999
2:169510385:T:C	W203R	0.999
2:169510485:T:A	V236D	0.999
2:169510668:G:C	R297T	0.999
2:169510668:G:T	R297M	0.999
2:169510669:G:C	R297S	0.999

dbSNP variants (sampled 300 via entrez): RS1000077434 (2:169525704 G>A,T), RS1000305360 (2:169518988 T>C), RS1000363648 (2:169511199 A>G), RS1000414679 (2:169509566 A>G), RS1000593443 (2:169518600 T>C), RS1000595227 (2:169512884 C>T), RS1000717987 (2:169511036 C>A,G,T), RS1000787458 (2:169509147 C>A), RS1001213110 (2:169507730 A>T), RS1002032876 (2:169513016 G>A,T), RS1002717301 (2:169513904 TGGTG>T), RS1002796941 (2:169512523 A>T), RS1002924983 (2:169507817 A>G), RS1003046718 (2:169523551 A>G,T), RS1003288320 (2:169508921 C>T)

Disease associations

OMIM: gene MIM:607701 | disease phenotypes: MIM:615731, MIM:256030

GenCC curated gene-disease

Disease	Classification	Inheritance
nemaline myopathy 9	Strong	Autosomal recessive
severe congenital nemaline myopathy	Supportive	Autosomal recessive
intermediate nemaline myopathy	Supportive	Autosomal dominant
typical nemaline myopathy	Supportive	Autosomal dominant
childhood-onset nemaline myopathy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
nemaline myopathy 9	Moderate	AR

Mondo (6): nemaline myopathy 9 (MONDO:0014326), nemaline myopathy (MONDO:0018958), severe congenital nemaline myopathy (MONDO:0015735), intermediate nemaline myopathy (MONDO:0015736), typical nemaline myopathy (MONDO:0015737), childhood-onset nemaline myopathy (MONDO:0015738)

Orphanet (1): Nemaline myopathy (Orphanet:607)

HPO phenotypes

101 total (30 of 101 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000175	Cleft palate
HP:0000218	High palate
HP:0000239	Large fontanelles
HP:0000275	Narrow face
HP:0000276	Long face
HP:0000316	Hypertelorism
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000467	Neck muscle weakness
HP:0000470	Short neck
HP:0000508	Ptosis
HP:0000602	Ophthalmoplegia
HP:0000765	Abnormal thorax morphology
HP:0000767	Pectus excavatum
HP:0000774	Narrow chest
HP:0000775	Abnormality of the diaphragm
HP:0000883	Thin ribs
HP:0001181	Adducted thumb
HP:0001265	Hyporeflexia
HP:0001270	Motor delay
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001319	Neonatal hypotonia
HP:0001324	Muscle weakness
HP:0001337	Tremor

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D017696	Myopathies, Nemaline	C05.651.575.290; C10.668.491.550.290

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6196058 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects cotreatment, increases expression	4
methylmercuric chloride	decreases expression	2
Vorinostat	affects cotreatment, increases expression	2
trichostatin A	increases expression	1
vanadyl sulfate	increases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
incobotulinumtoxinA	decreases expression	1
Sunitinib	decreases expression	1
Leflunomide	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Benztropine	affects cotreatment, decreases expression	1
Cuprizone	affects cotreatment, decreases expression	1
Cytarabine	decreases expression	1
Dimethyl Sulfoxide	affects expression	1
Doxorubicin	decreases expression	1
Thimerosal	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Triclosan	decreases expression	1
Urethane	decreases expression	1
Okadaic Acid	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL6094274	Binding	Binding affinity to KBTBD10 (unknown origin) at 10 uM by thermal shift assay	Structure-Guided Conformational Restriction Leading to High-Affinity, Selective, and Cell-Active Tetrahydroisoquinoline-Based Noncovalent Keap1-Nrf2 Inhibitors. — J Med Chem

Clinical trials (associated diseases)

11 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02035501	PHASE2	UNKNOWN	Treatment of TNNT1-Myopathy With L-Tyrosine.
NCT00272883	Not specified	RECRUITING	Molecular and Genetic Studies of Congenital Myopathies
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
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