PYROXD1

Summary

PYROXD1 (pyridine nucleotide-disulphide oxidoreductase domain 1, HGNC:26162) is a protein-coding gene on chromosome 12p12.1, encoding tRNA ligase complex-associated NAD(P)H dehydrogenase PYROXD1 (Q8WU10). Flavoprotein whose role is to protect RTCB, the catalytic subunit of the tRNA ligase complex (tRNA-LC) involved in tRNA splicing and unfolded protein response, from oxidative inactivation. It is a selective cancer dependency (DepMap: 78.5% of cell lines).

This gene encodes a nuclear-cytoplasmic pyridine nucleotide-disulphide reductase (PNDR). PNDRs are flavoproteins that catalyze the pyridine nucleotide-dependent reduction of thiol residues in other proteins. The encoded protein belongs to the class I pyridine nucleotide-disulphide oxidoreductase family but lacks the C-terminal dimerization domain found in other family members and instead has a C-terminal nitrile reductase domain. It localizes to the nucleus and to striated sarcomeric compartments. Naturally occurring mutations in this gene cause early-onset myopathy with internalized nuclei and myofibrillar disorganization. A pseudogene of this gene has been defined on chromosome 11.

Source: NCBI Gene 79912 — RefSeq curated summary.

At a glance

• Gene–disease (curated): myofibrillar myopathy 8 (Definitive, ClinGen)
• Clinical variants (ClinVar): 721 total — 15 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 48
• Cancer dependency (DepMap): dependent in 78.5% of screened cell lines
• MANE Select transcript: NM_024854

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26162
Approved symbol	PYROXD1
Name	pyridine nucleotide-disulphide oxidoreductase domain 1
Location	12p12.1
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp762G094, FLJ22028
Ensembl gene	ENSG00000121350
Ensembl biotype	protein_coding
OMIM	617220
Entrez	79912

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 8 protein_coding, 4 nonsense_mediated_decay, 3 retained_intron

ENST00000240651, ENST00000375266, ENST00000536851, ENST00000538072, ENST00000538582, ENST00000538615, ENST00000543476, ENST00000544187, ENST00000544970, ENST00000887642, ENST00000887643, ENST00000887644, ENST00000964888, ENST00000964889, ENST00000964890

RefSeq mRNA: 3 — MANE Select: NM_024854 NM_001350912, NM_001350913, NM_024854

CCDS: CCDS31755, CCDS86287

Canonical transcript exons

ENST00000240651 — 12 exons

Exon	Start	End
ENSE00002211137	21468506	21471250
ENSE00002216927	21437655	21437814
ENSE00003469298	21449563	21449691
ENSE00003502817	21452081	21452154
ENSE00003537461	21467481	21467618
ENSE00003549313	21462008	21462120
ENSE00003555658	21440368	21440448
ENSE00003571892	21455995	21456095
ENSE00003615719	21461025	21461154
ENSE00003689310	21462740	21462862
ENSE00003690821	21455132	21455292
ENSE00003691346	21445347	21445466

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 95.90.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.6556 / max 132.9588, expressed in 1587 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
124664	5.5872	1513
124665	1.0099	652
206645	0.0586	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	95.90	gold quality
mucosa of sigmoid colon	UBERON:0004993	93.61	gold quality
colonic mucosa	UBERON:0000317	93.41	gold quality
jejunal mucosa	UBERON:0000399	93.26	gold quality
nephron tubule	UBERON:0001231	93.16	gold quality
choroid plexus epithelium	UBERON:0003911	93.05	gold quality
endothelial cell	CL:0000115	92.85	gold quality
calcaneal tendon	UBERON:0003701	92.74	gold quality
biceps brachii	UBERON:0001507	90.41	gold quality
bronchial epithelial cell	CL:0002328	90.01	gold quality
body of pancreas	UBERON:0001150	89.79	gold quality
kidney epithelium	UBERON:0004819	89.79	gold quality
monocyte	CL:0000576	89.74	gold quality
mononuclear cell	CL:0000842	89.60	gold quality
renal glomerulus	UBERON:0000074	89.60	gold quality
rectum	UBERON:0001052	89.37	gold quality
ileal mucosa	UBERON:0000331	89.35	gold quality
cauda epididymis	UBERON:0004360	89.30	gold quality
leukocyte	CL:0000738	89.24	gold quality
deltoid	UBERON:0001476	89.19	gold quality
metanephric glomerulus	UBERON:0004736	88.93	gold quality
corpus epididymis	UBERON:0004359	88.91	gold quality
tibialis anterior	UBERON:0001385	88.80	gold quality
jejunum	UBERON:0002115	88.77	gold quality
heart right ventricle	UBERON:0002080	88.69	gold quality
pancreatic ductal cell	CL:0002079	88.66	gold quality
pancreas	UBERON:0001264	88.49	gold quality
epithelium of nasopharynx	UBERON:0001951	88.42	gold quality
nasopharynx	UBERON:0001728	88.40	gold quality
germinal epithelium of ovary	UBERON:0001304	88.35	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.43

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

120 targeting PYROXD1, 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-190A-3P	100.00	80.35	5520
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 78.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 8)

• We characterize variants in the oxidoreductase PYROXD1 as a cause of early-onset myopathy with distinctive histopathology and introduce altered redox regulation as a primary cause of congenital muscle disease. (PMID:27745833)
• Pyroxd1 pathogenic mutations in the limb-girdle muscular dystrophy patients from Saudi Arabia and Sudan. (PMID:30345904)
• PYROXD1 variants can cause an adult-onset slowly progressive limb-girdle muscular dystrophy-type phenotype. (PMID:30515627)
• A siRNA-based method for efficient silencing of PYROXD1 gene expression in the colon cancer cell line HCT116. (PMID:31502705)
• Myopathy associated with homozygous PYROXD1 pathogenic variants detected by genome sequencing. (PMID:32037607)
• Clinical and genetic characterization of PYROXD1-related myopathy patients from Turkey. (PMID:33694278)
• The oxidoreductase PYROXD1 uses NAD(P)(+) as an antioxidant to sustain tRNA ligase activity in pre-tRNA splicing and unfolded protein response. (PMID:33930333)
• Connective tissue presentation in two families expands the phenotypic spectrum of PYROXD1 disorders. (PMID:36920481)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pyroxd1	ENSDARG00000104817
mus_musculus	Pyroxd1	ENSMUSG00000041671
rattus_norvegicus	Pyroxd1	ENSRNOG00000012472
drosophila_melanogaster	Pyroxd1	FBGN0032846
caenorhabditis_elegans		WBGENE00007744

Paralogs (7): DLD (ENSG00000091140), GSR (ENSG00000104687), AIFM1 (ENSG00000156709), AIFM3 (ENSG00000183773), TXNRD2 (ENSG00000184470), TXNRD3 (ENSG00000197763), TXNRD1 (ENSG00000198431)

Protein

Protein identifiers

tRNA ligase complex-associated NAD(P)H dehydrogenase PYROXD1 — Q8WU10 (reviewed: Q8WU10)

Alternative names: Pyridine nucleotide-disulfide oxidoreductase domain-containing protein 1

All UniProt accessions (4): B4DEW4, B5MDP1, Q8WU10, H0YGU0

UniProt curated annotations — full annotation on UniProt →

Function. Flavoprotein whose role is to protect RTCB, the catalytic subunit of the tRNA ligase complex (tRNA-LC) involved in tRNA splicing and unfolded protein response, from oxidative inactivation. It directly binds and shields the catalytic center of RTCB, prior to guanylylation, when it is inactive and its active site is vulnerable to oxidation under aerobic conditions. The interaction of PYROXD1 with RTCB is allosterically regulated by NAD(P)H binding and reduction of its FAD cofactor, while reoxidation of PYROXD1 thanks to its NADPH dehydrogenase activity triggers the timed release of RTCB, enabling its subsequent activation. Thereby, this protective mechanism may also function as a molecular timer, regulating RTCB activation through controlled release.

Subunit / interactions. Monomeric. Interacts with RTCB; NAD(P)H binding to PYROXD1 promotes its direct interaction with RTCB while the reoxidation of PYROXD1, triggers the release of RTCB. The interaction with RTCB also depends on divalent cations.

Subcellular location. Nucleus. Cytoplasm. Cytosol. Myofibril. Sarcomere.

Disease relevance. Myopathy, myofibrillar, 8 (MFM8) [MIM:617258] A form of myofibrillar myopathy, a group of chronic neuromuscular disorders characterized at ultrastructural level by disintegration of the sarcomeric Z disk and myofibrils, and replacement of the normal myofibrillar markings by small dense granules, or larger hyaline masses, or amorphous material. MFM8 is an autosomal recessive form, clinically characterized by slowly progressive symmetrical weakness affecting both proximal and distal muscles, with normal to moderately elevated creatine kinase. Mild facial weakness, a high palate, nasal speech, and swallowing difficulties are typical features, mild restrictive lung disease is common, and late-onset cardiac involvement may be present. The disease is caused by variants affecting the gene represented in this entry. A mutation in PYROXD1 is the cause of autosomal recessive limb-girdle muscular dystrophy. The affected individual with a homozygous recessive PYROXD1 mutation showed progressive muscle weakness with an onset at the age of 9 years. Initial symptoms included excessive falling while running, with slowly progressive weakness. Difficulty navigating stairs by the age if 18, and loss of ambulation at the age of 37 years. Neurological examination showed proximal symmetrical muscle weakness and wasting, along with calf muscle pseudohypertrophy.

Cofactor. Binds 1 FAD per subunit.

Domain organisation. The C-terminal domain mediates the interaction with RTCB, physically occluding its catalytic center and thereby shielding ‘Cys-122’. This prevents oxidative inactivation of RTCB by protecting ‘Cys-122’ from oxidation.

Similarity. Belongs to the class-I pyridine nucleotide-disulfide oxidoreductase family. PYROXD1 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8WU10-1	1	yes
Q8WU10-2	2

RefSeq proteins (3): NP_001337841, NP_001337842, NP_079130* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR016156	FAD/NAD-linked_Rdtase_dimer_sf	Homologous_superfamily
IPR023753	FAD/NAD-binding_dom	Domain
IPR036188	FAD/NAD-bd_sf	Homologous_superfamily
IPR041575	Rubredoxin_C	Domain
IPR050260	FAD-bd_OxRdtase	Family

Pfam: PF07992, PF18267

Catalyzed reactions (Rhea), 4 shown:

• NADPH + O2 + H(+) = H2O2 + NADP(+) (RHEA:11260)
• NADH + O2 + H(+) = H2O2 + NAD(+) (RHEA:11264)
• A + NADH + H(+) = AH2 + NAD(+) (RHEA:11356)
• A + NADPH + H(+) = AH2 + NADP(+) (RHEA:13149)

UniProt features (67 total): strand 25, binding site 13, helix 12, mutagenesis site 6, turn 3, region of interest 2, sequence variant 2, chain 1, modified residue 1, splice variant 1, compositionally biased region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6ZK7	X-RAY DIFFRACTION	3.2
8ORJ	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WU10-F1	88.64	0.76

Functional residue map

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

Ligand- & substrate-binding residues (13): 157; 158; 233; 239; 374; 410; 412; 18; 21; 42; 43; 87 …

Post-translational modifications (1): 1

Mutagenesis-validated functional residues (6):

Position	Phenotype
239	changed nadph dehydrogenase activity and loss of interaction.
376	increased nadph dehydrogenase activity.
410	loss of nadph dehydrogenase activity.
498	decreased interaction with rtcb and decreased ability to preserve rtcb activity in oxidative conditions.
499	decreased interaction with rtcb and decreased ability to preserve rtcb activity in oxidative conditions.
500	decreased interaction with rtcb and decreased ability to preserve rtcb activity in oxidative conditions.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 232 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_TRNA_METABOLIC_PROCESS, GOBP_RNA_SPLICING_VIA_ENDONUCLEOLYTIC_CLEAVAGE_AND_LIGATION, MODULE_480, GOBP_RNA_SPLICING, NRF2_01, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_NAD_P_H, SPIELMAN_LYMPHOBLAST_EUROPEAN_VS_ASIAN_DN, CETS1P54_01, GOBP_TRNA_PROCESSING, MODULE_427, CHEN_HOXA5_TARGETS_9HR_UP, SCGGAAGY_ELK1_02, MGGAAGTG_GABP_B

GO Biological Process (2): tRNA exon ligation (GO:0000968), cellular response to oxidative stress (GO:0034599)

GO Molecular Function (4): NAD(P)H oxidase H2O2-forming activity (GO:0016174), molecular sensor activity (GO:0140299), protein binding (GO:0005515), oxidoreductase activity (GO:0016491)

GO Cellular Component (3): nucleus (GO:0005634), sarcomere (GO:0030017), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
RNA exon ligation	1
tRNA splicing, via endonucleolytic cleavage and ligation	1
response to oxidative stress	1
cellular response to chemical stress	1
oxidoreductase activity, acting on NAD(P)H, oxygen as acceptor	1
molecular function regulator activity	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
myofibril	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1800 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PYROXD1	FADS6	Q8N9I5	562
PYROXD1	RECQL	P46063	530
PYROXD1	C14orf119	Q9NWQ9	520
PYROXD1	MYOT	Q9UBF9	492
PYROXD1	GOLT1B	Q9Y3E0	469
PYROXD1	DNAJB6	O75190	448
PYROXD1	MCTP1	Q6DN14	447
PYROXD1	PLAC9	Q5JTB6	434
PYROXD1	SRP14	P37108	425
PYROXD1	OR2L13	Q8N349	420
PYROXD1	ICA1L	Q8NDH6	418
PYROXD1	PDXK	O00764	416
PYROXD1	LDB3	O75112	400
PYROXD1	JAKMIP3	Q5VZ66	397
PYROXD1	LMAN1	P49257	396

IntAct

13 interactions, top by confidence:

A	B	Type	Score
PYROXD1	UPRT	psi-mi:“MI:0915”(physical association)	0.830
UPRT	PYROXD1	psi-mi:“MI:0915”(physical association)	0.830
PYROXD1	NIPSNAP2	psi-mi:“MI:0915”(physical association)	0.400
CFTR	PYROXD1	psi-mi:“MI:0915”(physical association)	0.370
UPRT	PYROXD1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (20): UPRT (Two-hybrid), UPRT (Two-hybrid), FDXR (Co-fractionation), PYROXD1 (Two-hybrid), PYROXD1 (Two-hybrid), PYROXD1 (Proximity Label-MS), PYROXD1 (Negative Genetic), PYROXD1 (Negative Genetic), PYROXD1 (Negative Genetic), PYROXD1 (Affinity Capture-MS), PYROXD1 (PCA), PYROXD1 (Proximity Label-MS), PYROXD1 (Proximity Label-MS), PYROXD1 (Cross-Linking-MS (XL-MS)), APP (Reconstituted Complex)

ESM2 similar proteins: A0PJE2, A5PJM4, A7YVH9, B4F6I3, B5FXE5, D3ZDM7, D4A2H2, O15269, O35296, O35469, O35704, O54695, O64489, O88736, P09367, P11172, P13439, P20132, P24815, P26439, P31228, P31754, P56937, Q2KIJ5, Q3TMV7, Q3TY86, Q5R514, Q5R9T5, Q5REJ2, Q60555, Q60HD1, Q62904, Q64421, Q68FS6, Q6GLW8, Q6IQS6, Q6PBT5, Q80SY6, Q8BUE4, Q8CCT7

Diamond homologs: A2RIB7, A7YVH9, P37061, P37062, Q3TMV7, Q40977, Q42711, Q54H36, Q5REJ2, Q68FS6, Q6PBT5, Q7N4V5, Q8WU10, Q9VIP2, G2ITT5, P48639, Q58065, X5CY81, Q8U1M0, Q9UYU5, O05940

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	12
Uncertain significance	352
Likely benign	216
Benign	91

Top pathogenic / likely-pathogenic (27)

Variant ID	HGVS	Classification
1460467	NC_000012.11:g.(?21590665)(21615816_?)del	Pathogenic
2498274	NM_024854.5(PYROXD1):c.1061A>G (p.Tyr354Cys)	Pathogenic
2498275	NM_024854.5(PYROXD1):c.334_337del (p.Leu112fs)	Pathogenic
2766974	NM_024854.5(PYROXD1):c.1194dup (p.Ile399fs)	Pathogenic
2794865	NM_024854.5(PYROXD1):c.649+1_649+2del	Pathogenic
2804827	NM_024854.5(PYROXD1):c.199G>T (p.Glu67Ter)	Pathogenic
2805653	NM_024854.5(PYROXD1):c.1168_1169del (p.Met390fs)	Pathogenic
2880801	NM_024854.5(PYROXD1):c.736_739del (p.Lys246fs)	Pathogenic
3680772	NM_024854.5(PYROXD1):c.519G>A (p.Trp173Ter)	Pathogenic
3702107	NM_024854.5(PYROXD1):c.332_333del (p.Cys111fs)	Pathogenic
372279	NM_024854.5(PYROXD1):c.1116G>C (p.Gln372His)	Pathogenic
372280	NM_024854.5(PYROXD1):c.464A>G (p.Asn155Ser)	Pathogenic
372281	NM_024854.5(PYROXD1):c.414+1G>A	Pathogenic
372282	NM_024854.5(PYROXD1):c.1160_1163dup (p.Lys388fs)	Pathogenic
4730468	NM_024854.5(PYROXD1):c.213del (p.Met72fs)	Pathogenic
1220425	NM_024854.5(PYROXD1):c.1254+1del	Likely pathogenic
1707879	NC_000012.12:g.21468736AGA[1]	Likely pathogenic
1946629	NM_024854.5(PYROXD1):c.1117-2A>G	Likely pathogenic
2100984	NM_024854.5(PYROXD1):c.488+1G>T	Likely pathogenic
2574704	NM_024854.5(PYROXD1):c.740G>A (p.Gly247Glu)	Likely pathogenic
3621859	NM_024854.5(PYROXD1):c.166-2A>G	Likely pathogenic
3644180	NM_024854.5(PYROXD1):c.649+2T>G	Likely pathogenic
3676886	NM_024854.5(PYROXD1):c.84+2T>C	Likely pathogenic
3678442	NM_024854.5(PYROXD1):c.750+1G>T	Likely pathogenic
3701999	NM_024854.5(PYROXD1):c.750+1G>A	Likely pathogenic
4767732	NM_024854.5(PYROXD1):c.881-2A>T	Likely pathogenic
987046	NM_024854.5(PYROXD1):c.1247_1250del (p.Asn416fs)	Likely pathogenic

SpliceAI

2033 predictions. Top by Δscore:

Variant	Effect	Δscore
12:21437763:G:T	donor_gain	1.0000
12:21437811:GCAG:G	donor_gain	1.0000
12:21437813:AGGTA:A	donor_loss	1.0000
12:21437814:GGT:G	donor_loss	1.0000
12:21437816:T:A	donor_loss	1.0000
12:21440359:A:AG	acceptor_gain	1.0000
12:21440360:A:G	acceptor_gain	1.0000
12:21440361:A:AG	acceptor_gain	1.0000
12:21440362:A:AG	acceptor_gain	1.0000
12:21440364:TAAGT:T	acceptor_loss	1.0000
12:21440365:A:AG	acceptor_gain	1.0000
12:21440365:AAGTT:A	acceptor_gain	1.0000
12:21440366:A:G	acceptor_gain	1.0000
12:21440366:AGTT:A	acceptor_gain	1.0000
12:21440367:G:GG	acceptor_gain	1.0000
12:21440367:GTT:G	acceptor_gain	1.0000
12:21440367:GTTG:G	acceptor_gain	1.0000
12:21440445:GCAG:G	donor_gain	1.0000
12:21440446:CAGGT:C	donor_loss	1.0000
12:21440447:AGGTA:A	donor_loss	1.0000
12:21440448:GGTA:G	donor_loss	1.0000
12:21440449:GTAAG:G	donor_loss	1.0000
12:21440450:T:A	donor_loss	1.0000
12:21445334:T:A	acceptor_gain	1.0000
12:21445335:G:A	acceptor_gain	1.0000
12:21445342:TACAG:T	acceptor_loss	1.0000
12:21445343:ACAGA:A	acceptor_loss	1.0000
12:21445344:CA:C	acceptor_loss	1.0000
12:21445345:AG:A	acceptor_loss	1.0000
12:21445467:G:GG	donor_gain	1.0000

AlphaMissense

3315 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:21467490:T:A	W376R	0.999
12:21467490:T:C	W376R	0.999
12:21449616:T:G	C113W	0.998
12:21455160:T:A	W173R	0.998
12:21455160:T:C	W173R	0.998
12:21467492:G:C	W376C	0.998
12:21467492:G:T	W376C	0.998
12:21468672:T:C	L474P	0.998
12:21449672:G:C	R132P	0.997
12:21456060:T:A	W239R	0.997
12:21456060:T:C	W239R	0.997
12:21462068:T:A	V314D	0.997
12:21462818:G:C	D358H	0.996
12:21462819:A:C	D358A	0.996
12:21462819:A:T	D358V	0.996
12:21449608:T:C	C111R	0.995
12:21449615:G:A	C113Y	0.995
12:21462070:A:C	S315R	0.995
12:21462072:T:A	S315R	0.995
12:21462072:T:G	S315R	0.995
12:21462074:C:A	A316D	0.995
12:21462810:C:A	A355D	0.995
12:21462813:C:A	A356D	0.995
12:21462819:A:G	D358G	0.995
12:21462826:T:G	C360W	0.995
12:21468626:G:C	A459P	0.995
12:21437795:G:A	G22D	0.994
12:21449614:T:C	C113R	0.994
12:21449671:C:A	R132S	0.994
12:21452142:C:A	A159E	0.994

dbSNP variants (sampled 300 via entrez): RS1000092505 (12:21450285 A>G), RS1000171841 (12:21467254 A>G), RS1000227813 (12:21459931 C>T), RS1000286434 (12:21467013 A>T), RS1000535567 (12:21448810 TAAAG>T), RS1000601224 (12:21454622 T>G), RS1000673435 (12:21454332 C>G), RS1000757313 (12:21443410 ATAAT>A), RS1000758548 (12:21437645 A>C,G,T), RS1000923969 (12:21443326 G>T), RS1001066838 (12:21443051 T>C), RS1001208861 (12:21451467 T>A), RS1001262921 (12:21451767 A>G), RS1001295883 (12:21437802 T>C), RS1001424470 (12:21446311 C>G)

Disease associations

OMIM: gene MIM:617220 | disease phenotypes: MIM:620370, MIM:617258

GenCC curated gene-disease

Disease	Classification	Inheritance
myofibrillar myopathy 8	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
myofibrillar myopathy 8	Definitive	AR

Mondo (5): RECON progeroid syndrome (MONDO:0957266), myofibrillar myopathy 8 (MONDO:0014993), familial ovarian cancer (MONDO:0016248), hereditary neoplastic syndrome (MONDO:0015356), hereditary breast ovarian cancer syndrome (MONDO:0003582)

Orphanet (3): Inherited cancer-predisposing syndrome (Orphanet:140162), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145), OBSOLETE: Familial ovarian cancer (Orphanet:213517)

HPO phenotypes

48 total (30 of 48 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000098	Tall stature
HP:0000218	High palate
HP:0000276	Long face
HP:0000347	Micrognathia
HP:0000467	Neck muscle weakness
HP:0000508	Ptosis
HP:0000577	Exotropia
HP:0000689	Dental malocclusion
HP:0000767	Pectus excavatum
HP:0001265	Hyporeflexia
HP:0001284	Areflexia
HP:0001319	Neonatal hypotonia
HP:0001324	Muscle weakness
HP:0001382	Joint hypermobility
HP:0001611	Hypernasal speech
HP:0001653	Mitral regurgitation
HP:0001761	Pes cavus
HP:0001763	Pes planus
HP:0001771	Achilles tendon contracture
HP:0002015	Dysphagia
HP:0002058	Myopathic facies
HP:0002091	Restrictive ventilatory defect
HP:0002359	Frequent falls
HP:0002650	Scoliosis
HP:0002783	Recurrent lower respiratory tract infections
HP:0002792	Reduced vital capacity
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003306	Spinal rigidity
HP:0003388	Easy fatigability

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Air Pollutants	increases oxidation, increases expression, decreases expression, affects cotreatment, increases abundance	3
Valproic Acid	increases expression, affects expression, decreases methylation	3
perfluorooctane sulfonic acid	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Cyclosporine	increases expression	2
Particulate Matter	increases abundance, increases expression, decreases expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
cobaltous chloride	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
perfluoro-n-nonanoic acid	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
jinfukang	decreases expression	1
Decitabine	affects expression	1
Sunitinib	increases expression	1
Leflunomide	increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	affects expression	1
Coumestrol	affects cotreatment, decreases expression	1
Estradiol	increases expression	1
Ivermectin	decreases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02562170	PHASE4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
NCT00673335	PHASE3	COMPLETED	Letrozole in Preventing Breast Cancer in Postmenopausal Women With a BRCA1 or BRCA2 Mutation
NCT00685256	PHASE3	COMPLETED	Standard Genetic Counseling With or Without a Decision Guide in Improving Communication Between Mothers Undergoing BRCA1/2 Testing and Their Minor-Age Children
NCT03162276	PHASE3	UNKNOWN	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00253539	PHASE2	COMPLETED	Arzoxifene or Tamoxifen in Preventing Breast Cancer in Premenopausal Women at High Risk for Breast Cancer
NCT00305695	PHASE2	COMPLETED	Zoledronate or Observation in Maintaining Bone Mineral Density in Patients Who Are Undergoing Surgery to Remove Both Ovaries
NCT00321633	PHASE2	COMPLETED	Carboplatin or Docetaxel in Treating Women With Metastatic Genetic Breast Cancer
NCT01333748	PHASE2	COMPLETED	Search Allelic Imbalance of Expression of BRCA Genes in Hereditary Risk of Breast and/or Ovarian Cancer
NCT01367639	PHASE2	COMPLETED	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00535119	PHASE1	COMPLETED	Veliparib, Carboplatin, and Paclitaxel in Treating Patients With Advanced Solid Cancer
NCT00892736	PHASE1	COMPLETED	Veliparib in Treating Patients With Malignant Solid Tumors That Do Not Respond to Previous Therapy
NCT00040222	Not specified	COMPLETED	Clinical, Genetic, Behavioral, Laboratory and Epidemiologic Characterization of Individuals and Families at High Risk of Breast/Ovarian Cancer
NCT00001496	Not specified	COMPLETED	Establishment of Normal Breast Epithelial Cell Lines From Patients at High Risk for Breast Cancer
NCT00001898	Not specified	COMPLETED	Microarray Analysis for Human Genetic Disease
NCT00026884	Not specified	RECRUITING	Collection of Serum and Tissue Samples From Patients With Biopsy-Proved or Suspected Malignant Disease
NCT02289326	Not specified	COMPLETED	Biomarker Monitoring in TP53 Mutation Carriers
NCT02958462	Not specified	RECRUITING	Pre-myeloid Cancer and Bone Marrow Failure Clinic Study
NCT03160274	Not specified	RECRUITING	Genetic Analysis of Pheochromocytomas, Paragangliomas and Associated Conditions
NCT03426878	Not specified	COMPLETED	Cancer Health Assessments Reaching Many
NCT03857594	Not specified	ACTIVE_NOT_RECRUITING	Integrative Sequencing In Germline and Hereditary Tumours
NCT03973450	Not specified	UNKNOWN	Epidemiology of Pituitary Tumours: Prevalence of Associated Neoplasia
NCT03979612	Not specified	UNKNOWN	Evaluation of the Adhesion to the GENEPY Network
NCT04261972	Not specified	ACTIVE_NOT_RECRUITING	Cell-free DNA in Hereditary And High-Risk Malignancies 1
NCT04494945	Not specified	RECRUITING	Identifying and Caring for Individuals With Inherited Cancer Syndrome
NCT04541654	Not specified	RECRUITING	Li-Fraumeni & TP53 (LiFT UP): Understanding and Progress
NCT04763915	Not specified	ACTIVE_NOT_RECRUITING	Improving Care After Inherited Cancer Testing
NCT05562778	Not specified	RECRUITING	Chatbot to Maximize Hereditary Cancer Genetic Risk Assessment
NCT05664867	Not specified	RECRUITING	Implementation of Population Cancer Genetic Services in Federally Qualified Health Centers (FQHC)
NCT05721326	Not specified	COMPLETED	Sequential EHR Based Interventions to Increase Genetic Testing for Breast and Ovarian Cancer Predisposition
NCT06096688	Not specified	RECRUITING	Discovering New Targets for Colorectal and Endometrial Cancer Risk Reduction
NCT06654466	Not specified	RECRUITING	Closing the GAPS: Guideline Adherence, Prevention and Surveillance in Hereditary Cancer
NCT06708429	Not specified	RECRUITING	Lynch Syndrome X-Talk of Enteral Mucosa With Immune System
NCT06726642	Not specified	RECRUITING	CfDNA in Hereditary And High-risk Malignancies 2
NCT06914726	Not specified	ENROLLING_BY_INVITATION	Patient Centered Clinical Decision Support for Hereditary Cancer Syndromes
NCT06927947	Not specified	RECRUITING	Navigation Interventions to Improve Cascade Genetic Testing Among Relatives of Patients With Hereditary Cancer Syndromes
NCT06999954	Not specified	RECRUITING	Shwachman-Diamond Syndrome Global Patient Survey and Partnering Platform
NCT07052266	Not specified	RECRUITING	Trial of Combined Obstetric Carrier Screening and Hereditary Cancer Screening
NCT07195071	Not specified	RECRUITING	Feasibility Trial of Combination of Obstetrical Carrier Screening and Hereditary Cancer Screening
NCT07378423	Not specified	RECRUITING	Questionnaire on Congenital Cancer Signs Through Self-Assessment
NCT07381985	Not specified	ENROLLING_BY_INVITATION	Strategy for Management of Patients With Hereditary Cancer Syndromes (HCS) in a Rural Environment