ADSS1

Summary

ADSS1 (adenylosuccinate synthase 1, HGNC:20093) is a protein-coding gene on chromosome 14q32.33, encoding Adenylosuccinate synthetase isozyme 1 (Q8N142). Component of the purine nucleotide cycle (PNC), which interconverts IMP and AMP to regulate the nucleotide levels in various tissues, and which contributes to glycolysis and ammoniagenesis.

This gene encodes a member of the adenylosuccinate synthase family of proteins. The encoded muscle-specific enzyme plays a role in the purine nucleotide cycle by catalyzing the first step in the conversion of inosine monophosphate (IMP) to adenosine monophosphate (AMP). Mutations in this gene may cause adolescent onset distal myopathy. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 122622 — RefSeq curated summary.

At a glance

• Gene–disease (curated): myopathy, distal, 5 (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 553 total — 51 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 45
• MANE Select transcript: NM_152328

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20093
Approved symbol	ADSS1
Name	adenylosuccinate synthase 1
Location	14q32.33
Locus type	gene with protein product
Status	Approved
Aliases	FLJ38602
Ensembl gene	ENSG00000185100
Ensembl biotype	protein_coding
OMIM	612498
Entrez	122622

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 6 protein_coding, 5 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000330877, ENST00000332972, ENST00000553540, ENST00000553580, ENST00000554281, ENST00000554657, ENST00000555486, ENST00000555674, ENST00000555884, ENST00000556623, ENST00000557271, ENST00000557582, ENST00000710323, ENST00000852145

RefSeq mRNA: 3 — MANE Select: NM_152328 NM_001320424, NM_152328, NM_199165

CCDS: CCDS9990, CCDS9991

Canonical transcript exons

ENST00000330877 — 13 exons

Exon	Start	End
ENSE00001310704	104739750	104739816
ENSE00002488717	104746951	104747310
ENSE00003478481	104740839	104740920
ENSE00003486124	104741117	104741243
ENSE00003515794	104740601	104740708
ENSE00003519555	104743067	104743191
ENSE00003531898	104746236	104746385
ENSE00003596912	104738376	104738438
ENSE00003630275	104735020	104735122
ENSE00003641060	104741848	104742002
ENSE00003647734	104739328	104739378
ENSE00003658900	104744812	104744909
ENSE00004011464	104724229	104724462

Expression profiles

Bgee: expression breadth ubiquitous, 242 present calls, max score 99.74.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.3352 / max 1267.6571, expressed in 1180 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
141837	6.1916	741
141836	1.5397	707
141835	0.5785	338
141839	0.0163	4
141838	0.0092	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
quadriceps femoris	UBERON:0001377	99.74	gold quality
vastus lateralis	UBERON:0001379	99.74	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.61	gold quality
tibialis anterior	UBERON:0001385	99.53	gold quality
skeletal muscle tissue	UBERON:0001134	99.52	gold quality
biceps brachii	UBERON:0001507	99.45	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.43	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.39	gold quality
deltoid	UBERON:0001476	99.38	gold quality
gastrocnemius	UBERON:0001388	99.29	gold quality
body of tongue	UBERON:0011876	99.17	gold quality
left ventricle myocardium	UBERON:0006566	99.15	gold quality
apex of heart	UBERON:0002098	98.96	gold quality
cardiac muscle of right atrium	UBERON:0003379	98.43	gold quality
muscle of leg	UBERON:0001383	98.25	gold quality
heart left ventricle	UBERON:0002084	97.61	gold quality
cardiac ventricle	UBERON:0002082	97.58	gold quality
cardiac atrium	UBERON:0002081	97.44	gold quality
right atrium auricular region	UBERON:0006631	97.40	gold quality
muscle tissue	UBERON:0002385	97.13	gold quality
myocardium	UBERON:0002349	96.74	gold quality
popliteal artery	UBERON:0002250	96.28	gold quality
tibial artery	UBERON:0007610	96.27	gold quality
heart	UBERON:0000948	96.09	gold quality
heart right ventricle	UBERON:0002080	95.96	gold quality
left testis	UBERON:0004533	95.39	gold quality
aorta	UBERON:0000947	95.17	gold quality
right testis	UBERON:0004534	94.85	gold quality
tongue	UBERON:0001723	94.14	gold quality
ascending aorta	UBERON:0001496	93.99	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.63

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MEF2C, NFATC4

miRNA regulators (miRDB)

15 targeting ADSS1, 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-9-5P	100.00	72.28	2361
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-548AV-5P	99.60	70.84	2107
HSA-MIR-548K	99.60	70.84	2107
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-8054	99.48	70.81	2084
HSA-MIR-4284	99.36	65.25	1293
HSA-MIR-5693	99.24	66.67	1106
HSA-MIR-3117-5P	99.04	67.93	618
HSA-MIR-4801	98.96	69.42	2096
HSA-MIR-3074-5P	98.82	66.56	1414
HSA-MIR-1270	96.94	66.65	931
HSA-MIR-620	96.94	66.79	888
HSA-MIR-592	96.59	67.59	817

Literature-anchored findings (GeneRIF, showing 4)

• A novel muscle isozyme of adenylosuccinate synthetase, human AdSSL1, is identified from human bone marrow stromal cells. (PMID:15786719)
• Mutations in ADSSL1 are the novel genetic cause of autosomal recessive adolescent onset distal myopathy. (PMID:26506222)
• Study investigated the clinical manifestation in Korean patients with ADSSL1 mutations. Patients with ADSSL1 mutations demonstrated distal muscle weakness in adolescence, followed by quadriceps muscle weakness in the early 30s. All patients had mild facial weakness and two patients complained of easy fatigue while eating and chewing. Muscle biopsies and whole body muscle MR imaging findings are discussed. (PMID:28268051)
• ADSSL1 myopathy is the most common nemaline myopathy in Japan with variable clinical features. (PMID:32646962)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	adss1	ENSDARG00000099517
mus_musculus	Adss1	ENSMUSG00000011148
rattus_norvegicus	Adss1	ENSRNOG00000046763
drosophila_melanogaster	Adss	FBGN0027493
caenorhabditis_elegans		WBGENE00016509

Paralogs (1): ADSS2 (ENSG00000035687)

Protein

Protein identifiers

Adenylosuccinate synthetase isozyme 1 — Q8N142 (reviewed: Q8N142)

Alternative names: Adenylosuccinate synthetase, basic isozyme, Adenylosuccinate synthetase, muscle isozyme, Adenylosuccinate synthetase-like 1, IMP–aspartate ligase 1

All UniProt accessions (4): Q8N142, G3V232, G3V2N1, G3V5D8

UniProt curated annotations — full annotation on UniProt →

Function. Component of the purine nucleotide cycle (PNC), which interconverts IMP and AMP to regulate the nucleotide levels in various tissues, and which contributes to glycolysis and ammoniagenesis. Catalyzes the first committed step in the biosynthesis of AMP from IMP.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm.

Tissue specificity. Predominantly expressed in skeletal muscle and heart, as well as in several hematopoietic cell lines and solid tumors.

Disease relevance. Myopathy, distal, 5 (MPD5) [MIM:617030] A form of distal myopathy, a group of muscular disorders characterized by progressive muscular weakness and muscle atrophy beginning in the hands, the legs or the feet. MPD5 is an autosomal recessive form, predominantly affecting the lower limbs. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 Mg(2+) ion per subunit.

Pathway. Purine metabolism; AMP biosynthesis via de novo pathway; AMP from IMP: step 1/2.

Similarity. Belongs to the adenylosuccinate synthetase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8N142-1	1	yes
Q8N142-2	2

RefSeq proteins (3): NP_001307353, NP_689541, NP_954634 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001114	Adenylosuccinate_synthetase	Family
IPR018220	Adenylosuccin_syn_GTP-bd	Binding_site
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR027509	AdSS_1_vert	Family
IPR033128	Adenylosuccin_syn_Lys_AS	Active_site
IPR042109	Adenylosuccinate_synth_dom1	Homologous_superfamily
IPR042110	Adenylosuccinate_synth_dom2	Homologous_superfamily
IPR042111	Adenylosuccinate_synth_dom3	Homologous_superfamily

Pfam: PF00709

Enzyme classification (BRENDA):

• EC 6.3.4.4 — adenylosuccinate synthase (BRENDA: 39 organisms, 46 substrates, 147 inhibitors, 309 Km, 69 kcat entries)

Substrate kinetics (BRENDA)

15 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GTP	0.0044–1.7	98
IMP	0.009–3.8	85
ASP	0.03–5.4	37
L-ASPARTATE	0.01–9	20
L-ASP	0.004–3.3	17
ASPARTATE	0.17–2.6	11
HYDROXYLAMINE	91–255	5
ITP	1.07–17.3	4
UTP	1.27–4.38	4
2’-DIMP	0.041–0.48	3
XTP	0.0286–0.388	3
ALLOPURINOL RIBONUCLEOTIDE	0.34	2
ARABINOSYLIMP	0.26	2
8-AZAIMP	0.05	1
BETA-D-ARABINOSYLIMP	0.85	1

Catalyzed reactions (Rhea), 1 shown:

• IMP + L-aspartate + GTP = N(6)-(1,2-dicarboxyethyl)-AMP + GDP + phosphate + 2 H(+) (RHEA:15753)

UniProt features (22 total): binding site 16, active site 2, chain 1, region of interest 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N142-F1	93.10	0.85

Functional residue map

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

Catalytic / active sites (2): 43 (proton acceptor); 71 (proton donor)

Ligand- & substrate-binding residues (16): 70; 163 (in other chain); 177; 256 (in other chain); 271 (in other chain); 331–337; 335 (in other chain); 337; 363–365; 445–448; 42–48; 43–46 (in other chain) …

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-73817	Purine ribonucleoside monophosphate biosynthesis

MSigDB gene sets: 242 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_PURINE_CONTAINING_COMPOUND_SALVAGE, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GERY_CEBP_TARGETS, SENGUPTA_NASOPHARYNGEAL_CARCINOMA_DN, RAMALHO_STEMNESS_DN, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, TAKEDA_TARGETS_OF_NUP98_HOXA9_FUSION_10D_UP, JECHLINGER_EPITHELIAL_TO_MESENCHYMAL_TRANSITION_UP, GOBP_NUCLEOSIDE_MONOPHOSPHATE_BIOSYNTHETIC_PROCESS

GO Biological Process (13): immune system process (GO:0002376), AMP biosynthetic process (GO:0006167), aspartate metabolic process (GO:0006531), L-glutamine metabolic process (GO:0006541), response to muscle activity (GO:0014850), response to starvation (GO:0042594), ‘de novo’ AMP biosynthetic process (GO:0044208), AMP salvage (GO:0044209), IMP metabolic process (GO:0046040), cellular response to electrical stimulus (GO:0071257), cellular response to xenobiotic stimulus (GO:0071466), purine nucleotide metabolic process (GO:0006163), purine nucleotide biosynthetic process (GO:0006164)

GO Molecular Function (11): magnesium ion binding (GO:0000287), GTPase activity (GO:0003924), adenylosuccinate synthase activity (GO:0004019), GTP binding (GO:0005525), phosphate ion binding (GO:0042301), identical protein binding (GO:0042802), actin filament binding (GO:0051015), nucleotide binding (GO:0000166), protein binding (GO:0005515), ligase activity (GO:0016874), metal ion binding (GO:0046872)

GO Cellular Component (3): cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Nucleotide biosynthesis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
AMP biosynthetic process	2
biological_process	1
purine ribonucleotide biosynthetic process	1
purine ribonucleoside monophosphate biosynthetic process	1
AMP metabolic process	1
amino acid metabolic process	1
dicarboxylic acid metabolic process	1
L-amino acid metabolic process	1
proteinogenic amino acid metabolic process	1
response to activity	1
response to stress	1
response to nutrient levels	1
purine ribonucleotide salvage	1
purine ribonucleotide metabolic process	1
purine ribonucleoside monophosphate metabolic process	1
response to electrical stimulus	1
cellular response to abiotic stimulus	1
response to xenobiotic stimulus	1
cellular response to chemical stimulus	1
nucleotide metabolic process	1
purine-containing compound metabolic process	1
purine nucleotide metabolic process	1
nucleotide biosynthetic process	1
purine-containing compound biosynthetic process	1
metal ion binding	1
ribonucleoside triphosphate phosphatase activity	1
ligase activity, forming carbon-nitrogen bonds	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
protein binding	1
actin binding	1
protein-containing complex binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
cation binding	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2370 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADSS1	ADSL	P30566	809
ADSS1	PPAT	Q06203	665
ADSS1	GMPS	P49915	647
ADSS1	AMPD1	P23109	607
ADSS1	IMPDH1	P20839	591
ADSS1	APRT	P07741	573
ADSS1	GART	P22102	564
ADSS1	IMPDH2	P12268	558
ADSS1	AMPD3	Q01432	558
ADSS1	ATIC	P31939	542
ADSS1	AZIN1	O14977	523
ADSS1	AMPD2	Q01433	521
ADSS1	PNP	P00491	520
ADSS1	PAICS	P22234	517
ADSS1	PRPS1	P09329	515

IntAct

13 interactions, top by confidence:

A	B	Type	Score
ADSS2	ADSS1	psi-mi:“MI:0915”(physical association)	0.720
ADSS1	YY1	psi-mi:“MI:0915”(physical association)	0.400
ADSS1	DES	psi-mi:“MI:0915”(physical association)	0.400
ADSS1	YWHAZ	psi-mi:“MI:0915”(physical association)	0.400
PCNA	ADSS1	psi-mi:“MI:0915”(physical association)	0.370
ADSS1	AZIN1	psi-mi:“MI:0915”(physical association)	0.370
LYAR	ADSS1	psi-mi:“MI:0915”(physical association)	0.370
MATN2	IGLL5	psi-mi:“MI:0914”(association)	0.350
ADSS2	SERPINB7	psi-mi:“MI:0914”(association)	0.350
ADSS1	FABP3	psi-mi:“MI:0914”(association)	0.350
HIRIP3	GPX1	psi-mi:“MI:0914”(association)	0.350

BioGRID (24): ADSSL1 (Affinity Capture-MS), ADSSL1 (Affinity Capture-RNA), ADSSL1 (Affinity Capture-MS), YY1 (Affinity Capture-MS), ADSSL1 (Affinity Capture-MS), DES (Affinity Capture-MS), ADSSL1 (Affinity Capture-MS), ADSSL1 (Co-fractionation), ADSSL1 (Affinity Capture-MS), ADSSL1 (Negative Genetic), ADSSL1 (Cross-Linking-MS (XL-MS)), ADSSL1 (Cross-Linking-MS (XL-MS)), ADSS (Cross-Linking-MS (XL-MS)), EEA1 (Cross-Linking-MS (XL-MS)), ADSSL1 (Proximity Label-MS)

ESM2 similar proteins: A0A0B0SG80, A0A0H3M0L1, A4SYD1, A4Z0B8, A5ED09, A5F1F1, A5PJR4, B0TAU6, B1I6P8, B1XU85, B2I7V8, B3Q6W6, B4RDX2, B7UP20, B9KYV8, C3LUC2, K2PFJ6, O53604, P0A3X5, P0A3X6, P0DV56, P0DV57, P73412, P74304, Q07J18, Q0AB55, Q131X4, Q20Z24, Q2J0H0, Q2JQ36, Q2JQX5, Q2JSC8, Q2LSI8, Q2RG43, Q3AQA7, Q3BWF4, Q3J6M0, Q3SNC6, Q55731, Q6N1V9

Diamond homologs: A0BD92, A2XD35, A3LYS9, A4RYD2, A4Z6H0, A4Z6H1, A5DIP4, A5DSZ3, A5PJR4, A6ZRM0, A7MBG0, A7TID0, A8IW34, A8NDT2, A8Q0E3, A8QE42, A8X7H5, A9SCV9, A9TIK2, A9UTP3, A9XLE1, A9XLE2, A9XLG1, B0DQB9, B0W9B4, B2VXY5, B3LP64, B3M343, B3P321, B3S0D3, B4G518, B4II68, B4JUE4, B4K8W7, B4LWK0, B4NFS5, B4PPT4, B5DGM3, B5DGM4, B5VQJ1

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
ADSS1	“down-regulates quantity”	IMP	“chemical modification”
ADSS1	“down-regulates quantity”	L-aspartate(1-)	“chemical modification”
ADSS1	“up-regulates quantity”	N(6)-(1,2-dicarboxylatoethyl)-AMP(4-)	“chemical modification”
ADSS1	“up-regulates quantity”	GDP	“chemical modification”
ADSS1	up-regulates	Nucleotide_synthesis

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	51
Likely pathogenic	10
Uncertain significance	254
Likely benign	198
Benign	24

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1072836	NM_152328.5(ADSS1):c.233_234del (p.Lys78fs)	Pathogenic
146074	GRCh38/hg38 14q32.2-32.33(chr14:97638520-106855263)x3	Pathogenic
146638	GRCh38/hg38 14q32.12-32.33(chr14:92540983-104863658)x3	Pathogenic
146793	GRCh38/hg38 14q32.13-32.33(chr14:95524407-106879501)x1	Pathogenic
150835	GRCh38/hg38 14q32.31-32.33(chr14:101925670-106876323)x1	Pathogenic
1526437	GRCh37/hg19 14q32.31-32.33(chr14:101732158-107285437)	Pathogenic
154247	GRCh38/hg38 14q32.33(chr14:104051258-106877229)x1	Pathogenic
154386	GRCh38/hg38 14q32.31-32.33(chr14:101665602-106855263)x1	Pathogenic
154526	GRCh38/hg38 14q32.32-32.33(chr14:103322414-106855263)x3	Pathogenic
154736	GRCh38/hg38 14q32.33(chr14:103823600-106879298)x1	Pathogenic
155595	GRCh38/hg38 14q32.2-32.33(chr14:100582059-106877229)x1	Pathogenic
1681849	NC_000014.8:g.(?105204693)(105207600_?)del	Pathogenic
1681960	NM_152328.5(ADSS1):c.741dup (p.Lys248fs)	Pathogenic
1682005	NC_000014.9:g.104744812del	Pathogenic
1911377	NM_152328.5(ADSS1):c.193-5058del	Pathogenic
2017626	NM_152328.5(ADSS1):c.1044del (p.Arg348fs)	Pathogenic
243026	NM_152328.5(ADSS1):c.919del (p.Ile307fs)	Pathogenic
2577008	GRCh37/hg19 14q32.32-32.33(chr14:103636647-107285437)x1	Pathogenic
2684743	GRCh37/hg19 14q31.3-32.33(chr14:88580184-107285437)x3	Pathogenic
2720549	NM_152328.5(ADSS1):c.1226G>A (p.Trp409Ter)	Pathogenic
2892708	NM_152328.5(ADSS1):c.761del (p.Gly254fs)	Pathogenic
2978241	NM_152328.5(ADSS1):c.193-5079C>T	Pathogenic
2992714	NC_000014.9:g.104735024del	Pathogenic
2993158	NM_152328.5(ADSS1):c.697C>T (p.Arg233Ter)	Pathogenic
2997842	NM_152328.5(ADSS1):c.442C>T (p.Gln148Ter)	Pathogenic
3063327	GRCh37/hg19 14q32.31-32.33(chr14:102098959-107285437)x1	Pathogenic
3242321	GRCh37/hg19 14q32.31-32.33(chr14:101522804-107289470)x1	Pathogenic
3244104	NC_000014.8:g.(?105167703)(105213340_?)del	Pathogenic
3244106	NC_000014.8:g.(?105201337)(105201479_?)del	Pathogenic
3617660	NM_152328.5(ADSS1):c.193-5110del	Pathogenic

SpliceAI

2410 predictions. Top by Δscore:

Variant	Effect	Δscore
14:104735122:GGTG:G	donor_loss	1.0000
14:104735123:G:GG	donor_gain	1.0000
14:104735123:GT:G	donor_loss	1.0000
14:104735124:T:A	donor_loss	1.0000
14:104735125:GAGT:G	donor_loss	1.0000
14:104738372:GCAGG:G	acceptor_loss	1.0000
14:104738373:CA:C	acceptor_loss	1.0000
14:104738374:A:AG	acceptor_gain	1.0000
14:104738375:G:GG	acceptor_gain	1.0000
14:104738375:G:GT	acceptor_loss	1.0000
14:104738434:GAAAG:G	donor_gain	1.0000
14:104738435:AAAGG:A	donor_loss	1.0000
14:104738437:AGGTA:A	donor_loss	1.0000
14:104738438:GGTA:G	donor_loss	1.0000
14:104738439:GT:G	donor_loss	1.0000
14:104738440:T:A	donor_loss	1.0000
14:104739325:CA:C	acceptor_loss	1.0000
14:104739377:TGGT:T	donor_loss	1.0000
14:104739379:G:C	donor_loss	1.0000
14:104739379:G:GG	donor_gain	1.0000
14:104739380:T:A	donor_loss	1.0000
14:104739468:G:T	donor_gain	1.0000
14:104739817:G:GG	donor_gain	1.0000
14:104740595:TTTCA:T	acceptor_loss	1.0000
14:104740596:TTCAG:T	acceptor_loss	1.0000
14:104740597:TCAG:T	acceptor_loss	1.0000
14:104740598:CAGTA:C	acceptor_loss	1.0000
14:104740599:A:AG	acceptor_gain	1.0000
14:104740599:A:T	acceptor_loss	1.0000
14:104740600:G:GG	acceptor_gain	1.0000

AlphaMissense

2970 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:104724382:G:C	G38R	0.999
14:104724391:T:A	W41R	0.999
14:104724391:T:C	W41R	0.999
14:104724397:G:C	D43H	0.999
14:104724398:A:T	D43V	0.999
14:104724407:A:T	K46I	0.999
14:104724408:A:C	K46N	0.999
14:104724408:A:T	K46N	0.999
14:104724409:G:C	G47R	0.999
14:104724410:G:A	G47D	0.999
14:104735031:C:A	N68K	0.999
14:104735031:C:G	N68K	0.999
14:104735036:G:A	G70D	0.999
14:104735038:C:G	H71D	0.999
14:104735040:C:A	H71Q	0.999
14:104735040:C:G	H71Q	0.999
14:104738376:G:A	G99D	0.999
14:104740620:G:A	G166R	0.999
14:104740620:G:C	G166R	0.999
14:104740621:G:A	G166E	0.999
14:104740646:A:C	K174N	0.999
14:104740646:A:T	K174N	0.999
14:104741218:C:A	N256K	0.999
14:104741218:C:G	N256K	0.999
14:104741231:G:C	D261H	0.999
14:104741232:A:T	D261V	0.999
14:104741878:G:A	C275Y	0.999
14:104741879:C:G	C275W	0.999
14:104741950:A:T	K299I	0.999
14:104743128:G:T	R337M	0.999

dbSNP variants (sampled 300 via entrez): RS1000017517 (14:104745849 C>A), RS1000050078 (14:104745657 G>A), RS1000203662 (14:104741144 G>A), RS1000226477 (14:104736351 G>A), RS1000283462 (14:104736526 A>G,T), RS1000338046 (14:104744531 A>T), RS1000467283 (14:104731582 G>T), RS1000490466 (14:104742070 G>T), RS1000574117 (14:104741313 C>T), RS1000709596 (14:104743798 A>G), RS1000796983 (14:104732663 G>A), RS1000836089 (14:104731717 G>A), RS1000934608 (14:104730710 GA>G), RS1000939266 (14:104727783 C>T), RS1001016715 (14:104737757 A>C,G)

Disease associations

OMIM: gene MIM:612498 | disease phenotypes: MIM:617030, MIM:614228, MIM:614849, MIM:617468, MIM:208150

GenCC curated gene-disease

Disease	Classification	Inheritance
myopathy, distal, 5	Strong	Autosomal recessive

Mondo (5): myopathy, distal, 5 (MONDO:0014877), Charcot-Marie-Tooth disease axonal type 2O (MONDO:0013644), herpes simplex encephalitis, susceptibility to, 3 (MONDO:0013920), arthrogryposis multiplex congenita (MONDO:0015168), fetal akinesia deformation sequence 1 (MONDO:0100101)

Orphanet (5): Adenylosuccinate synthetase-like 1-related distal myopathy (Orphanet:482601), Herpes simplex virus encephalitis (Orphanet:1930), Autosomal dominant Charcot-Marie-Tooth disease type 2O (Orphanet:284232), Arthrogryposis multiplex congenita (Orphanet:1037), Fetal akinesia deformation sequence (Orphanet:994)

HPO phenotypes

45 total (30 of 45 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0001315	Reduced tendon reflexes
HP:0001639	Hypertrophic cardiomyopathy
HP:0002091	Restrictive ventilatory defect
HP:0002200	Pseudobulbar signs
HP:0002317	Unsteady gait
HP:0002359	Frequent falls
HP:0002540	Inability to walk
HP:0002600	Hyporeflexia of lower limbs
HP:0003198	Myopathy
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003376	Steppage gait
HP:0003458	EMG: myopathic abnormalities
HP:0003474	Somatic sensory dysfunction
HP:0003551	Difficulty climbing stairs
HP:0003555	Muscle fiber splitting
HP:0003621	Juvenile onset
HP:0003677	Slowly progressive
HP:0003693	Distal amyotrophy
HP:0003700	Generalized amyotrophy
HP:0003731	Quadriceps muscle weakness
HP:0003798	Nemaline bodies
HP:0003805	Rimmed vacuoles
HP:0005216	Impaired mastication
HP:0007210	Lower limb amyotrophy
HP:0008180	Mildly elevated creatine kinase
HP:0008944	Distal lower limb amyotrophy
HP:0008959	Distal upper limb muscle weakness
HP:0008994	Proximal lower limb muscle weakness

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST004988_642	Breast cancer	2.000000e-08

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression	2
bisphenol S	decreases expression, decreases methylation	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Valproic Acid	affects expression, increases methylation	2
Cyclosporine	decreases expression	2
GSK-J4	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
lead acetate	decreases expression	1
decabromobiphenyl ether	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
tetrabromobisphenol A	decreases expression	1
cupric chloride	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
(+)-JQ1 compound	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Acetaminophen	decreases expression	1
Arsenic	affects methylation	1
Atrazine	increases expression	1
Carbamazepine	affects expression	1
Cisplatin	affects cotreatment, increases expression	1

Cellosaurus cell lines

6 cell lines: 3 finite cell line, 2 induced pluripotent stem cell, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D6Y0	GM28573	Finite cell line	Female
CVCL_D6Y1	GM28581	Finite cell line	Female
CVCL_D6Y2	GM28582	Finite cell line	Male
CVCL_D6Z7	GM28975	Induced pluripotent stem cell	Male
CVCL_D6Z8	GM28895	Transformed cell line	Male
CVCL_D6Z9	GM28982	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05902351	Not specified	RECRUITING	Natural History Study for Charcot Marie Tooth Disease
NCT05393375	Not specified	COMPLETED	Arthrogryposis Multiplex Congenita in Pediatric Age: Correlation Between MUScular MRI and Functional Evaluation
NCT05673265	Not specified	UNKNOWN	Pediatric and Adult Registry for Patients With ARThrogryposis
NCT06130592	Not specified	UNKNOWN	Technical Feasibility Study of Ultrasound Muscle Imaging in Antenatal Ultrasound
NCT07360574	Not specified	NOT_YET_RECRUITING	Piezo2-related Arthrogryposis & physiopathOLOgy 3