CFL2

Summary

CFL2 (cofilin 2, HGNC:1875) is a protein-coding gene on chromosome 14q13.1, encoding Cofilin-2 (Q9Y281). Controls reversibly actin polymerization and depolymerization in a pH-sensitive manner.

This gene encodes an intracellular protein that is involved in the regulation of actin-filament dynamics. This protein is a major component of intranuclear and cytoplasmic actin rods. It can bind G- and F-actin in a 1:1 ratio of cofilin to actin, and it reversibly controls actin polymerization and depolymerization in a pH-dependent manner. Mutations in this gene cause nemaline myopathy type 7, a form of congenital myopathy. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 1073 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nemaline myopathy 7 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 10
• Clinical variants (ClinVar): 162 total — 7 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 71
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_138638

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1875
Approved symbol	CFL2
Name	cofilin 2
Location	14q13.1
Locus type	gene with protein product
Status	Approved
Aliases	NEM7
Ensembl gene	ENSG00000165410
Ensembl biotype	protein_coding
OMIM	601443
Entrez	1073

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 2 nonsense_mediated_decay

ENST00000298159, ENST00000341223, ENST00000422678, ENST00000554470, ENST00000555765, ENST00000556161, ENST00000672163, ENST00000672517, ENST00000673315

RefSeq mRNA: 3 — MANE Select: NM_138638 NM_001243645, NM_021914, NM_138638

CCDS: CCDS58311, CCDS9649, CCDS9650

Canonical transcript exons

ENST00000298159 — 4 exons

Exon	Start	End
ENSE00001349971	34714538	34714593
ENSE00003520764	34713254	34713561
ENSE00003658631	34713060	34713136
ENSE00003749396	34709113	34712977

Expression profiles

Bgee: expression breadth ubiquitous, 261 present calls, max score 99.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 78.6754 / max 4299.0004, expressed in 1789 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
142806	51.8063	1726
142807	12.3266	1684
142808	4.1315	1459
142805	3.9002	1067
142804	1.8350	601
142809	1.5285	947
142811	1.2266	619
142803	0.9853	367
142801	0.3258	111
142802	0.2278	81

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cardiac muscle of right atrium	UBERON:0003379	99.81	gold quality
left ventricle myocardium	UBERON:0006566	99.81	gold quality
tibialis anterior	UBERON:0001385	99.76	gold quality
deltoid	UBERON:0001476	99.76	gold quality
myocardium	UBERON:0002349	99.69	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.68	gold quality
quadriceps femoris	UBERON:0001377	99.66	gold quality
vastus lateralis	UBERON:0001379	99.65	gold quality
biceps brachii	UBERON:0001507	99.62	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.54	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.45	gold quality
skeletal muscle tissue	UBERON:0001134	99.44	gold quality
heart right ventricle	UBERON:0002080	99.39	gold quality
muscle organ	UBERON:0001630	99.37	gold quality
skeletal muscle organ	UBERON:0014892	99.37	gold quality
gastrocnemius	UBERON:0001388	99.33	gold quality
corpus callosum	UBERON:0002336	99.32	gold quality
muscle of leg	UBERON:0001383	99.31	gold quality
body of tongue	UBERON:0011876	99.17	gold quality
muscle tissue	UBERON:0002385	98.95	gold quality
saphenous vein	UBERON:0007318	98.77	gold quality
smooth muscle tissue	UBERON:0001135	98.72	gold quality
pons	UBERON:0000988	98.61	gold quality
inferior vagus X ganglion	UBERON:0005363	98.61	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.49	gold quality
cardiac atrium	UBERON:0002081	98.45	gold quality
cardiac ventricle	UBERON:0002082	98.45	gold quality
heart left ventricle	UBERON:0002084	98.44	gold quality
right atrium auricular region	UBERON:0006631	98.37	gold quality
spinal cord	UBERON:0002240	98.36	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	11.84
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

268 targeting CFL2, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-126-5P	100.00	72.71	3180
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-499A-5P	99.98	70.79	1323

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 29)

• actin depolymerizing factor/cofilins play an active role in establishing new interprotomer interfaces in F-actin that substitute for disrupted or weakened (as in ADP-actin) longitudinal contacts in filaments (PMID:16530787)
• CFL2, encoding the actin-binding protein muscle cofilin-2, is mutated in two siblings with congenital myopathy. (PMID:17160903)
• Resting T cells from infected patients carry significantly higher levels of active cofilin. (PMID:18928553)
• MLP binds directly to CFL2 in human cardiac and skeletal muscles. (PMID:19752190)
• FXa-mediated sustained cofilin inactivation leads to stabilization of actin filaments incompatible with migration (PMID:20347121)
• PHD2 affects cell migration and F-actin formation via RhoA/rho-associated kinase-dependent cofilin phosphorylation (PMID:20801873)
• Differential expression of up-regulated cofilin-1 and down-regulated cofilin-2 characteristic of pancreatic cancer tissues (PMID:21894436)
• the cofilin-induced change in the filament twist is due to a unique conformation of the actin molecule unrelated to any previously observed state (PMID:22158895)
• cofilins 1 and 2 only weakly interact with 14-3-3 and therefore cannot directly compete with phosphorylated small heat shock protein HspB6 for its binding to 14-3-3 zeta (PMID:22450169)
• A novel homozygous missense mutation in exon 2 (c.19G>A, p.Val7Met) of CFL2 was identified in two siblings with congenital myopathy. (PMID:22560515)
• Studies indicate that cofilin binds actin stoichiometrically - one cofilin molecule per actin filament subunit. (PMID:23395798)
• study investigated the comparison of the levels of cofilin-1 and cofilin-2 in regressive QR-32 and progressive QRsP-11cells by western blotting (PMID:24023293)
• patients with severe nemaline myopathy should be screened for mutations in CFL2. (PMID:24610938)
• In primary tumours, both desmin and CFL2 expression predicted improved overall survival in multivariate analyses (PMID:24889065)
• The serum lever of Alzheimer’s disease were increase and the expression of clf2 strongly correlated with the Mini-Mental State Examination scores of the AD patients (PMID:25502766)
• Cofilin 2 phosphorylation and genetic overexpression plays a role in the pathogenesis of idiopathic dilated cardiomyopthay. (PMID:25814227)
• analysis of human Cof1, Cof2, and ADF effects on actin filament severing and turnover (PMID:26996939)
• The greatest levels of circulating miR-297 and miR-19b-3p with its common target CFL2 are associated with metastatic prostate cancer. (PMID:28091918)
• Here we report atomic-level characterization by magic angle spinning (MAS) NMR of the muscle isoform of human cofilin 2 (CFL2) bound to F-actin. We demonstrate that resonance assignments for the majority of atoms are readily accomplished and we derive the intermolecular interface between CFL2 and F-actin. (PMID:28303963)
• miR-3189-3p mimics enhanced the effects of the S100A4 siRNA on the inhibition of gastric cancer cell proliferation and migration by targeting CFL2. (PMID:29342841)
• severe Congenital myopathies related to novel homozygous or compound heterozygous loss-of-function mutations in CFL2, are reported. (PMID:29457652)
• The secreted levels of the cofilin-2 protein in radioresistant NPC patients were significantly higher than those of radiosensitive cases. (PMID:29664897)
• These results identify cofilin as a key molecule that may be therapeutically targeted to restore T cell motility necessary for T cell tissue repopulation, immune reconstitution, and immune control of viremia. (PMID:30662943)
• LncRNA SOX2 overlapping transcript (SOX2-OT) expression was conspicuously elevated in prostate cancer (PC) tissues and cells. Silenced SOX2-OT could repress PC cell proliferation and migration. SOX2-OT bound with miR-369-3p and negatively correlated with miR-369-3p in PC. Cofilin 2 (CFL2) was found to be a downstream target gene of miR-369-3p. (PMID:31623830)
• Knockin mouse model of the human CFL2 p.A35T mutation results in a unique splicing defect and severe myopathy phenotype. (PMID:32160286)
• Phosphorylated cofilin-2 is more prone to oxidative modifications on Cys39 and favors amyloid fibril formation. (PMID:32863228)
• Circ_0008673 regulates breast cancer malignancy by miR-153-3p/CFL2 axis. (PMID:34324029)
• Magic angle spinning NMR structure of human cofilin-2 assembled on actin filaments reveals isoform-specific conformation and binding mode. (PMID:35440100)
• Troponin and a Myopathy-Linked Mutation in TPM3 Inhibit Cofilin-2-Induced Thin Filament Depolymerization. (PMID:38003645)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	cfl2	ENSDARG00000014106
mus_musculus	Cfl2	ENSMUSG00000062929
rattus_norvegicus	Cfl2	ENSRNOG00000045892
drosophila_melanogaster	tsr	FBGN0011726
drosophila_melanogaster	CG6873	FBGN0030951
caenorhabditis_elegans		WBGENE00006794
caenorhabditis_elegans		WBGENE00302980

Paralogs (2): DSTN (ENSG00000125868), CFL1 (ENSG00000172757)

Protein

Protein identifiers

Cofilin-2 — Q9Y281 (reviewed: Q9Y281)

Alternative names: Cofilin, muscle isoform

All UniProt accessions (4): F8WDN3, G3V2U0, Q549N0, Q9Y281

UniProt curated annotations — full annotation on UniProt →

Function. Controls reversibly actin polymerization and depolymerization in a pH-sensitive manner. Its F-actin depolymerization activity is regulated by association with CSPR3. It has the ability to bind G- and F-actin in a 1:1 ratio of cofilin to actin. It is the major component of intranuclear and cytoplasmic actin rods. Required for muscle maintenance. May play a role during the exchange of alpha-actin forms during the early postnatal remodeling of the sarcomere.

Subunit / interactions. Interacts with CSRP3; possibly two molecules of CFL2 can interact with one molecule if CSRP3.

Subcellular location. Nucleus matrix. Cytoplasm. Cytoskeleton.

Tissue specificity. Isoform CFL2b is expressed predominantly in skeletal muscle and heart. Isoform CFL2a is expressed in various tissues.

Post-translational modifications. The phosphorylation of Ser-24 may prevent recognition of the nuclear localization signal.

Disease relevance. Nemaline myopathy 7 (NEM7) [MIM:610687] A 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. Nemaline myopathy type 7 presents at birth with hypotonia and generalized weakness. Major motor milestones are delayed, but independent ambulation is achieved. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the actin-binding proteins ADF family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9Y281-1	CFL2b	yes
Q9Y281-2	CFL2a
Q9Y281-3	3

RefSeq proteins (3): NP_001230574, NP_068733, NP_619579* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002108	ADF-H	Domain
IPR017904	ADF/Cofilin	Family
IPR029006	ADF-H/Gelsolin-like_dom_sf	Homologous_superfamily

Pfam: PF00241

UniProt features (31 total): helix 8, strand 7, modified residue 4, sequence variant 3, turn 2, region of interest 2, initiator methionine 1, chain 1, domain 1, short sequence motif 1, splice variant 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
9Y9P	ELECTRON MICROSCOPY	2.06
9Y9L	ELECTRON MICROSCOPY	3.06
9Y9M	ELECTRON MICROSCOPY	3.06
9Q7K	ELECTRON MICROSCOPY	3.13
9Y52	ELECTRON MICROSCOPY	3.46
9Q7N	ELECTRON MICROSCOPY	3.48
9Q7M	ELECTRON MICROSCOPY	3.5
9Y9J	ELECTRON MICROSCOPY	3.58
9Q7L	ELECTRON MICROSCOPY	3.68
7M0G	SOLID-STATE NMR
7U8K	SOLID-STATE NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y281-F1	88.78	0.51

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 (4): 1, 2, 3, 6

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 514 (showing top): WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, GOBP_MUSCLE_TISSUE_DEVELOPMENT, WWTAAGGC_UNKNOWN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, XU_GH1_AUTOCRINE_TARGETS_UP, NKX25_02, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_DISASSEMBLY, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, KONG_E2F1_TARGETS, GOBP_SARCOMERE_ORGANIZATION, CHANDRAN_METASTASIS_DN, CEBPB_01, LINDGREN_BLADDER_CANCER_CLUSTER_2A_DN

GO Biological Process (9): skeletal muscle tissue development (GO:0007519), actin filament depolymerization (GO:0030042), actin filament fragmentation (GO:0030043), positive regulation of actin filament depolymerization (GO:0030836), sarcomere organization (GO:0045214), muscle cell cellular homeostasis (GO:0046716), actin filament severing (GO:0051014), actin filament organization (GO:0007015), actin polymerization or depolymerization (GO:0008154)

GO Molecular Function (3): actin filament binding (GO:0051015), actin binding (GO:0003779), protein binding (GO:0005515)

GO Cellular Component (9): obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), actin cytoskeleton (GO:0015629), nuclear matrix (GO:0016363), Z disc (GO:0030018), I band (GO:0031674), extracellular exosome (GO:0070062), nucleus (GO:0005634), cytoskeleton (GO:0005856)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
actin filament depolymerization	2
striated muscle tissue development	1
skeletal muscle organ development	1
actin polymerization or depolymerization	1
protein depolymerization	1
regulation of actin filament depolymerization	1
positive regulation of cytoskeleton organization	1
positive regulation of protein depolymerization	1
positive regulation of supramolecular fiber organization	1
myofibril assembly	1
actomyosin structure organization	1
cellular homeostasis	1
actin filament-based process	1
actin cytoskeleton organization	1
supramolecular fiber organization	1
actin filament organization	1
actin binding	1
protein-containing complex binding	1
cytoskeletal protein binding	1
binding	1
intracellular anatomical structure	1
cytoskeleton	1
nuclear lumen	1
I band	1
sarcomere	1
extracellular vesicle	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

3948 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CFL2	WASL	O00401	997
CFL2	HCLS1	P14317	995
CFL2	CTTN	Q14247	995
CFL2	WDR1	O75083	985
CFL2	LIMK1	P53667	983
CFL2	PFN1	P07737	959
CFL2	PFN4	Q8NHR9	958
CFL2	PFN3	P60673	948
CFL2	SSH1	Q8WYL5	948
CFL2	CDC42	P21181	920
CFL2	ACTR2	P61160	917
CFL2	RHOA	P06749	902
CFL2	LIMK2	P53671	901
CFL2	ACTN1	P12814	897
CFL2	PDXP	Q96GD0	893

IntAct

109 interactions, top by confidence:

A	B	Type	Score
ACTB	CFL2	psi-mi:“MI:0915”(physical association)	0.910
CFL2	ACTB	psi-mi:“MI:0915”(physical association)	0.910
ACTG1	CFL2	psi-mi:“MI:0915”(physical association)	0.850
CFL2	ACTG1	psi-mi:“MI:0915”(physical association)	0.850
CFL1	CAP2	psi-mi:“MI:0914”(association)	0.640
TAE1	CFL2	psi-mi:“MI:0915”(physical association)	0.560
CFL2	AIP1	psi-mi:“MI:0915”(physical association)	0.560
AIP1	CFL2	psi-mi:“MI:0915”(physical association)	0.560
CFL2	TAE1	psi-mi:“MI:0915”(physical association)	0.560
EHHADH	CFL2	psi-mi:“MI:0915”(physical association)	0.560
DSTN	CFL2	psi-mi:“MI:0915”(physical association)	0.560
TRIM7	CFL2	psi-mi:“MI:0915”(physical association)	0.560
RAB2A	CFL2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (169): CFL2 (Two-hybrid), CFL2 (Two-hybrid), CFL2 (Two-hybrid), CFL2 (Two-hybrid), CAP2 (Two-hybrid), DSTN (Two-hybrid), POT1 (Two-hybrid), CFL2 (Affinity Capture-MS), CFL2 (Two-hybrid), CFL2 (Two-hybrid), ABAT (Co-fractionation), AKR1B1 (Co-fractionation), ALDH4A1 (Co-fractionation), CAT (Co-fractionation), CFL2 (Co-fractionation)

ESM2 similar proteins: A0PJN4, A1L167, A2VDL8, B0BNA5, F1LMZ8, O00231, O88544, O88761, O94973, P17427, P18484, P21566, P22234, P38024, P45591, P48444, P51583, P61201, P61202, P61203, P79101, P97834, Q01405, Q0VCK5, Q14019, Q148F1, Q15436, Q2HJ57, Q2KI42, Q2TBL9, Q3SZA0, Q3TXS7, Q5F418, Q5G6V9, Q5R5S4, Q5R9J9, Q5R9P3, Q5RA77, Q5RB59, Q6IQT4

Diamond homologs: O15902, O49606, P0CM06, P0CM07, P0DJ26, P0DJ27, P10668, P18359, P18760, P21566, P23528, P30174, P30175, P37167, P45591, P45592, P45593, P45594, P45695, P46251, P60981, P60982, P78929, P86292, P86293, Q03048, Q07749, Q07750, Q0D744, Q0DLA3, Q10P87, Q148F1, Q2QLT8, Q337A5, Q39250, Q39251, Q41764, Q43694, Q4I963, Q4P6E9

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
TESK2	“down-regulates activity”	CFL2	phosphorylation
TESK1	“down-regulates activity”	CFL2	phosphorylation
CFL2	“down-regulates quantity”	F-actin_assembly	binding
LIMK1	“down-regulates activity”	CFL2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 79 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Sensory processing of sound	6	34.3×	1e-05
Regulation of actin dynamics for phagocytic cup formation	6	20.5×	1e-04
Sensory processing of sound by inner hair cells of the cochlea	6	18.1×	2e-04
FCGR3A-mediated phagocytosis	5	17.3×	1e-03
Signaling by ALK fusions and activated point mutants	5	13.9×	2e-03
Sensory Perception	6	10.6×	1e-03
Diseases of signal transduction by growth factor receptors and second messengers	7	7.4×	2e-03
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	8	5.0×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
actin filament organization	6	10.9×	2e-03
actin cytoskeleton organization	8	9.7×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	1
Uncertain significance	81
Likely benign	46
Benign	21

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
1395680	NM_138638.5(CFL2):c.100_103del (p.Lys34fs)	Pathogenic
2000758	NM_138638.5(CFL2):c.154_157del (p.Ala52fs)	Pathogenic
2073433	NM_138638.5(CFL2):c.4-115A>C	Pathogenic
2722427	NM_138638.5(CFL2):c.4-115A>G	Pathogenic
657372	NC_000014.9:g.(?34710372)(34713686_?)del	Pathogenic
800930	NM_138638.5(CFL2):c.338del (p.Ser113fs)	Pathogenic
8160	NM_138638.5(CFL2):c.103G>A (p.Ala35Thr)	Pathogenic
432127	NM_138638.5(CFL2):c.119T>A (p.Leu40Ter)	Likely pathogenic

SpliceAI

635 predictions. Top by Δscore:

Variant	Effect	Δscore
14:34712815:G:C	donor_gain	1.0000
14:34712837:AAGAT:A	donor_gain	1.0000
14:34712894:C:CT	donor_gain	1.0000
14:34712895:T:TT	donor_gain	1.0000
14:34712901:G:A	donor_gain	1.0000
14:34713250:ACACC:A	donor_loss	1.0000
14:34713251:CACCA:C	donor_loss	1.0000
14:34713253:C:A	donor_loss	1.0000
14:34713275:T:TA	donor_gain	1.0000
14:34713279:T:A	donor_gain	1.0000
14:34713283:AGACT:A	donor_gain	1.0000
14:34713413:T:TA	donor_gain	1.0000
14:34713557:GAAGC:G	acceptor_gain	1.0000
14:34713558:AAGC:A	acceptor_gain	1.0000
14:34713560:GC:G	acceptor_gain	1.0000
14:34713560:GCCT:G	acceptor_loss	1.0000
14:34713561:CC:C	acceptor_gain	1.0000
14:34713561:CCTGA:C	acceptor_loss	1.0000
14:34713562:C:A	acceptor_loss	1.0000
14:34713562:C:CC	acceptor_gain	1.0000
14:34713563:T:A	acceptor_loss	1.0000
14:34713568:A:AC	acceptor_gain	1.0000
14:34713568:A:C	acceptor_gain	1.0000
14:34712854:TG:T	donor_gain	0.9900
14:34712877:T:TA	donor_gain	0.9900
14:34712891:C:CT	donor_gain	0.9900
14:34712892:T:TT	donor_gain	0.9900
14:34712892:TAC:T	donor_gain	0.9900
14:34713054:TTGTA:T	donor_loss	0.9900
14:34713055:TGTA:T	donor_loss	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000499953 (14:34713892 C>G), RS1000893755 (14:34714415 C>A,T), RS1001020172 (14:34714253 G>A,C), RS1001681235 (14:34708815 T>A,C,G), RS1001908174 (14:34714893 C>A), RS1002241476 (14:34714853 T>C), RS1002622253 (14:34716204 T>G), RS1003146525 (14:34715930 G>A), RS1003448827 (14:34711346 A>C), RS1003788941 (14:34712222 A>AT), RS1004476717 (14:34714070 C>A,G,T), RS1004680147 (14:34713492 T>C), RS1004797977 (14:34713823 A>G), RS1005687804 (14:34714728 G>A,T), RS1005697121 (14:34715276 T>C)

Disease associations

OMIM: gene MIM:601443 | disease phenotypes: MIM:610687, MIM:160150

GenCC curated gene-disease

Disease	Classification	Inheritance
nemaline myopathy 7	Definitive	Autosomal recessive
typical nemaline myopathy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
nemaline myopathy 7	Definitive	AR

Mondo (3): nemaline myopathy 7 (MONDO:0012538), centronuclear myopathy (MONDO:0018947), typical nemaline myopathy (MONDO:0015737)

Orphanet (2): Typical nemaline myopathy (Orphanet:171436), Centronuclear myopathy (Orphanet:595)

HPO phenotypes

71 total (30 of 71 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000275	Narrow face
HP:0000347	Micrognathia
HP:0000467	Neck muscle weakness
HP:0000470	Short neck
HP:0000508	Ptosis
HP:0000767	Pectus excavatum
HP:0000774	Narrow chest
HP:0001252	Hypotonia
HP:0001265	Hyporeflexia
HP:0001270	Motor delay
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001319	Neonatal hypotonia
HP:0001324	Muscle weakness
HP:0001349	Facial diplegia
HP:0001371	Flexion contracture
HP:0001561	Polyhydramnios
HP:0001623	Breech presentation
HP:0001763	Pes planus
HP:0002093	Respiratory insufficiency
HP:0002194	Delayed gross motor development
HP:0002359	Frequent falls
HP:0002375	Hypokinesia
HP:0002515	Waddling gait
HP:0002650	Scoliosis
HP:0002747	Respiratory insufficiency due to muscle weakness
HP:0002751	Kyphoscoliosis
HP:0002804	Arthrogryposis multiplex congenita

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST006061_210	Atrial fibrillation	9.000000e-13
GCST006061_58	Atrial fibrillation	1.000000e-13
GCST006414_21	Atrial fibrillation	3.000000e-15
GCST008156_133	Hip circumference adjusted for BMI	8.000000e-06
GCST011939_24	Takayasu arteritis	3.000000e-09
GCST90011898_23	Alanine aminotransferase levels	9.000000e-13
GCST90011899_13	Aspartate aminotransferase levels	1.000000e-10
GCST90013405_27	Liver enzyme levels (alanine transaminase)	1.000000e-18
GCST90013663_74	Alanine aminotransferase levels	1.000000e-14
GCST90013664_70	Aspartate aminotransferase levels	5.000000e-13

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008039	BMI-adjusted hip circumference
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C565198	Nemaline Myopathy 7 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

56 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects expression, increases abundance, decreases expression	3
bisphenol A	increases expression, affects cotreatment	2
trichostatin A	affects cotreatment, decreases expression	2
Smoke	decreases expression, increases abundance	2
Valproic Acid	affects expression, decreases methylation	2
aristolochic acid I	decreases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
methylmercuric chloride	decreases expression	1
sodium arsenate	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression	1
perfluorooctanoic acid	decreases expression	1
coumarin	decreases phosphorylation	1
1,4-phenylenebis(methylene)selenocyanate	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
fenpyroximate	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
quinocetone	decreases expression, increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
gardiquimod	increases expression, decreases reaction	1
picoxystrobin	decreases expression	1
bisphenol AF	increases expression	1
Vorinostat	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants, Occupational	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04033159	PHASE1/PHASE2	TERMINATED	Early Phase Human Drug Trial to Investigate Dynamin 101 (DYN101) in Patients ≥ 16 Years With Centronuclear Myopathies
NCT04743557	PHASE1/PHASE2	WITHDRAWN	Early Phase Human Drug Trial to Investigate DYN101 in Participants 2 to 17 Years With Centronuclear Myopathies
NCT00272883	Not specified	RECRUITING	Molecular and Genetic Studies of Congenital Myopathies
NCT03351270	Not specified	COMPLETED	Prospective Natural History Study of Patients With Myotubular Myopathy and Other CentroNuclear Myopathies
NCT04064307	Not specified	RECRUITING	Myotubular and Centronuclear Myopathy Patient Registry
NCT04977648	Not specified	WITHDRAWN	Natural History Study of Patients With Centronuclear Myopathies
NCT05099107	Not specified	COMPLETED	Changes of Motor Function Tests in Congenital Myopathy Subjects Treated With Oral Salbutamol as Compared to no Treatment
NCT05982119	Not specified	RECRUITING	Assessments in Patients With Muscular Pathology and in Control Subjects : The ActiLiège Next Study
NCT06157268	Not specified	RECRUITING	The Natural History and Muscle Fatigability of Patients With Congenital Myopathies.
NCT06791369	Not specified	NOT_YET_RECRUITING	The Prevalence of RYR1-related Disease
NCT07021820	Not specified	RECRUITING	Multispectral Optoacoustic Tomography for Advanced Imaging of Centronuclear Myopathy
NCT07478172	Not specified	RECRUITING	Effects of Whole-body Electrical Muscle Stimulation Exercise on Adults With Neuromuscular Disease