LIAS

Summary

LIAS (lipoic acid synthetase, HGNC:16429) is a protein-coding gene on chromosome 4p14, encoding Lipoyl synthase, mitochondrial (O43766). Catalyzes the radical-mediated insertion of two sulfur atoms into the C-6 and C-8 positions of the octanoyl moiety bound to the lipoyl domains of lipoate-dependent enzymes, thereby converting the octanoylated domains into lipoylated derivatives. It is a selective cancer dependency (DepMap: 33.4% of cell lines).

The protein encoded by this gene belongs to the biotin and lipoic acid synthetases family. Localized in the mitochondrion, this iron-sulfur enzyme catalyzes the final step in the de novo pathway for the biosynthesis of lipoic acid, a potent antioxidant. The deficient expression of this enzyme has been linked to conditions such as diabetes, atherosclerosis and neonatal-onset epilepsy. Alternative splicing occurs at this locus, and several transcript variants encoding distinct isoforms have been identified.

Source: NCBI Gene 11019 — RefSeq curated summary.

At a glance

• Gene–disease (curated): lipoic acid synthetase deficiency (Strong, GenCC) — +2 more curated relationships
• Clinical variants (ClinVar): 458 total — 21 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 25
• Cancer dependency (DepMap): dependent in 33.4% of screened cell lines
• MANE Select transcript: NM_006859

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16429
Approved symbol	LIAS
Name	lipoic acid synthetase
Location	4p14
Locus type	gene with protein product
Status	Approved
Aliases	LAS
Ensembl gene	ENSG00000121897
Ensembl biotype	protein_coding
OMIM	607031
Entrez	11019

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 14 protein_coding, 7 nonsense_mediated_decay, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000261434, ENST00000340169, ENST00000381846, ENST00000424936, ENST00000509519, ENST00000513731, ENST00000515061, ENST00000638422, ENST00000638430, ENST00000638451, ENST00000638816, ENST00000638837, ENST00000639422, ENST00000639475, ENST00000639614, ENST00000640349, ENST00000640381, ENST00000640489, ENST00000640672, ENST00000640689, ENST00000640816, ENST00000640888, ENST00000870880, ENST00000934754, ENST00000934755, ENST00000946185

RefSeq mRNA: 6 — MANE Select: NM_006859 NM_001278590, NM_001278591, NM_001278592, NM_001363700, NM_006859, NM_194451

CCDS: CCDS3453, CCDS3454, CCDS63950, CCDS87217, CCDS87218, CCDS87220

Canonical transcript exons

ENST00000640888 — 11 exons

Exon	Start	End
ENSE00001656351	39471236	39471306
ENSE00001672094	39470019	39470164
ENSE00001740369	39473100	39473211
ENSE00001769251	39467518	39467646
ENSE00003483960	39460790	39460962
ENSE00003495268	39465046	39465202
ENSE00003496213	39463525	39463605
ENSE00003536658	39462196	39462289
ENSE00003638455	39465285	39465342
ENSE00003802311	39459056	39459162
ENSE00003811026	39477063	39479506

Expression profiles

Bgee: expression breadth ubiquitous, 258 present calls, max score 91.39.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.7793 / max 155.1186, expressed in 1787 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
47378	7.7734	1712
47377	5.2813	1662
47376	0.7246	366

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.39	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.61	gold quality
muscle of leg	UBERON:0001383	88.87	gold quality
gastrocnemius	UBERON:0001388	88.73	gold quality
rectum	UBERON:0001052	88.38	gold quality
right testis	UBERON:0004534	87.78	gold quality
right lobe of liver	UBERON:0001114	87.37	gold quality
left testis	UBERON:0004533	86.95	gold quality
right adrenal gland	UBERON:0001233	86.28	gold quality
body of pancreas	UBERON:0001150	86.26	gold quality
muscle organ	UBERON:0001630	86.25	gold quality
mucosa of transverse colon	UBERON:0004991	85.94	gold quality
heart left ventricle	UBERON:0002084	85.77	gold quality
testis	UBERON:0000473	85.64	gold quality
right adrenal gland cortex	UBERON:0035827	85.37	gold quality
transverse colon	UBERON:0001157	85.30	gold quality
adrenal tissue	UBERON:0018303	85.22	gold quality
cardiac ventricle	UBERON:0002082	85.19	gold quality
left adrenal gland	UBERON:0001234	85.05	gold quality
apex of heart	UBERON:0002098	84.97	gold quality
left ovary	UBERON:0002119	84.97	gold quality
biceps brachii	UBERON:0001507	84.71	gold quality
granulocyte	CL:0000094	84.66	gold quality
right uterine tube	UBERON:0001302	84.66	gold quality
calcaneal tendon	UBERON:0003701	84.66	gold quality
left adrenal gland cortex	UBERON:0035825	84.61	gold quality
esophagus mucosa	UBERON:0002469	84.42	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	84.36	gold quality
colonic epithelium	UBERON:0000397	84.33	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.25	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.04

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

33 targeting LIAS, 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-590-3P	99.96	74.34	6478
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-4503	99.85	71.45	1869
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-3913-5P	99.78	67.26	968
HSA-MIR-4679	99.76	69.19	1229
HSA-MIR-452-5P	99.65	69.63	1762
HSA-MIR-4676-3P	99.65	69.31	1733
HSA-MIR-892C-3P	99.65	69.38	1745
HSA-MIR-3122	99.50	66.33	821
HSA-MIR-12132	99.47	68.90	1341
HSA-MIR-653-5P	99.46	67.35	1300
HSA-MIR-183-3P	99.41	69.41	1598
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-324-3P	99.26	66.31	1034
HSA-MIR-6878-3P	99.24	64.23	920
HSA-MIR-3606-3P	99.11	69.84	3254
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-4635	98.74	67.63	1339
HSA-MIR-619-5P	98.57	64.97	1988
HSA-MIR-4726-3P	98.49	63.89	1385
HSA-MIR-6792-5P	98.39	68.16	1330
HSA-MIR-1302	97.92	67.27	844
HSA-MIR-493-3P	97.50	66.44	731
HSA-MIR-4298	97.26	66.59	765

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 33.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 8)

• Lipoic acid synthetase deficiency results in an overall disturbance in the antioxidant defense network, leading to increased inflammation, insulin resistance, and mitochondrial dysfunction. (PMID:19074983)
• We identified the homozygous mutation c.746G>A (p.Arg249His) in LIAS in an individual with neonatal-onset epilepsy, muscular hypotonia, lactic acidosis, and elevated glycine concentration in plasma and urine (PMID:22152680)
• Patients with LIAS nonketotic hyperglycinemia varied in disease severity and cortical involvement. (PMID:24334290)
• heterozygous mutations (c.738-2A>G and c.929T>C (p.Met310Thr)) in LIAS. (PMID:26108146)
• this study used a bioinformatics approach to predict its structure. . A homology model for LIAS protein was generated using X-ray crystallographic structure of Thermosynechococcus elogatsu. The active site of LIAS protein was mapped and docked with S-Adenosyl Methionine (PMID:27717843)
• oxoglutarate dehydrogenase (OGDH) and lipoic acid synthase (LIAS), which when mutated stabilize HIF1alpha in a non-hydroxylated form. (PMID:27923773)
• Characterization and Reconstitution of Human Lipoyl Synthase (LIAS) Supports ISCA2 and ISCU as Primary Cluster Donors and an Ordered Mechanism of Cluster Assembly. (PMID:33562493)
• FDX1 regulates cellular protein lipoylation through direct binding to LIAS. (PMID:37453661)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	lias	ENSDARG00000022845
mus_musculus	Lias	ENSMUSG00000029199
rattus_norvegicus	Lias	ENSRNOG00000002759
drosophila_melanogaster	Las	FBGN0029158
caenorhabditis_elegans		WBGENE00010809

Protein

Protein identifiers

Lipoyl synthase, mitochondrial — O43766 (reviewed: O43766)

Alternative names: Lipoate synthase, Lipoic acid synthase

All UniProt accessions (15): A0A1W2PNQ5, A0A1W2PPM2, A0A1W2PQ02, A0A1W2PQ87, A0A1W2PQE9, A0A1W2PQS9, A0A1W2PR40, A0A1W2PR81, A0A1W2PRD2, A0A1W2PRE7, A0A1X7SBR7, B4E0L7, O43766, D6RCP8, Q6P5Q6

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the radical-mediated insertion of two sulfur atoms into the C-6 and C-8 positions of the octanoyl moiety bound to the lipoyl domains of lipoate-dependent enzymes, thereby converting the octanoylated domains into lipoylated derivatives.

Subcellular location. Mitochondrion.

Disease relevance. Hyperglycinemia, lactic acidosis, and seizures (HGCLAS) [MIM:614462] An enzymatic defect resulting in an autosomal recessive disorder of mitochondrial metabolism. It is characterized by early-onset lactic acidosis, severe encephalomyopathy, and a pyruvate oxidation defect. Affected individuals have neonatal-onset epilepsy, poor growth, psychomotor retardation, muscular hypotonia, lactic acidosis, and elevated glycine concentration in plasma and urine. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 2 [4Fe-4S] clusters per subunit. One cluster is coordinated with 3 cysteines and an exchangeable S-adenosyl-L-methionine.

Pathway. Protein modification; protein lipoylation via endogenous pathway; protein N(6)-(lipoyl)lysine from octanoyl-[acyl-carrier-protein]: step 2/2.

Similarity. Belongs to the radical SAM superfamily. Lipoyl synthase family.

Isoforms (3)

UniProt ID	Names	Canonical?
O43766-1	1	yes
O43766-2	2
O43766-3	3

RefSeq proteins (6): NP_001265519, NP_001265520, NP_001265521, NP_001350629, NP_006850, NP_919433 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003698	Lipoyl_synth	Family
IPR006638	Elp3/MiaA/NifB-like_rSAM	Domain
IPR007197	rSAM	Domain
IPR013785	Aldolase_TIM	Homologous_superfamily
IPR031691	LIAS_N	Domain
IPR058240	rSAM_sf	Homologous_superfamily

Pfam: PF04055, PF16881

Catalyzed reactions (Rhea), 1 shown:

• [[Fe-S] cluster scaffold protein carrying a second 4Fe-4S cluster] + N(6)-octanoyl-L-lysyl-[protein] + 2 oxidized [2Fe-2S]-[ferredoxin] + 2 S-adenosyl-L-methionine + 4 H(+) = [[Fe-S] cluster scaffold protein] + N(6)-[(R)-dihydrolipoyl]-L-lysyl-[protein] + 4 Fe(3+) + 2 hydrogen sulfide + 2 5’-deoxyadenosine + 2 L-methionine + 2 reduced [2Fe-2S]-[ferredoxin] (RHEA:16585)

UniProt features (16 total): binding site 7, splice variant 3, sequence conflict 2, transit peptide 1, chain 1, sequence variant 1, domain 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
8TRW	X-RAY DIFFRACTION	1.54
8TSK	X-RAY DIFFRACTION	1.58
8UGO	X-RAY DIFFRACTION	2.45
8V0J	X-RAY DIFFRACTION	2.58
9C19	X-RAY DIFFRACTION	2.58

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43766-F1	81.30	0.55

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 (7): 106; 111; 117; 137; 141; 144; 352

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-9857492	Protein lipoylation
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 186 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_INFLAMMATORY_RESPONSE, GOBP_NEURAL_TUBE_DEVELOPMENT, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_MORPHOGENESIS_OF_EMBRYONIC_EPITHELIUM, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_PEPTIDYL_LYSINE_MODIFICATION, GOBP_PROTEIN_MATURATION, GOBP_SULFUR_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_FATTY_ACID_BIOSYNTHETIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_BIOSYNTHETIC_PROCESS

GO Biological Process (6): neural tube closure (GO:0001843), inflammatory response (GO:0006954), response to oxidative stress (GO:0006979), lipoate biosynthetic process (GO:0009107), protein lipoylation (GO:0009249), response to lipopolysaccharide (GO:0032496)

GO Molecular Function (7): lipoate synthase activity (GO:0016992), metal ion binding (GO:0046872), 4 iron, 4 sulfur cluster binding (GO:0051539), catalytic activity (GO:0003824), transferase activity (GO:0016740), sulfurtransferase activity (GO:0016783), iron-sulfur cluster binding (GO:0051536)

GO Cellular Component (2): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Post-translational protein modification	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
primary neural tube formation	1
tube closure	1
defense response	1
response to stress	1
fatty acid biosynthetic process	1
lipoate metabolic process	1
sulfur compound biosynthetic process	1
peptidyl-lysine modification	1
protein maturation	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	1
lipoate biosynthetic process	1
sulfurtransferase activity	1
cation binding	1
iron-sulfur cluster binding	1
molecular_function	1
catalytic activity	1
transferase activity, transferring sulphur-containing groups	1
metal cluster binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

1693 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LIAS	ANKRD54	Q6NXT1	942
LIAS	NFU1	Q9UMS0	873
LIAS	LIPT2	A6NK58	846
LIAS	IBA57	Q5T440	846
LIAS	LIPT1	Q9Y234	846
LIAS	BOLA3	Q53S33	845
LIAS	ISCA2	Q86U28	840
LIAS	ISCA1	Q9BUE6	811
LIAS	ISCU	Q9H1K1	772
LIAS	GLRX5	Q86SX6	743
LIAS	ACO2	Q99798	729
LIAS	NFS1	Q9Y697	719
LIAS	BOLA1	Q9Y3E2	717
LIAS	LYRM4	Q9HD34	709
LIAS	NUBPL	Q8TB37	683

IntAct

7 interactions, top by confidence:

A	B	Type	Score
GCSH	LIAS	psi-mi:“MI:0914”(association)	0.530
LIAS	CFTR	psi-mi:“MI:0915”(physical association)	0.370
LIAS	CTSV	psi-mi:“MI:0914”(association)	0.350
LIAS	HMGN4	psi-mi:“MI:0914”(association)	0.350
POLE	LIAS	psi-mi:“MI:0914”(association)	0.350

BioGRID (35): LIAS (Positive Genetic), LIAS (Positive Genetic), LIAS (Negative Genetic), LIAS (Negative Genetic), MED10 (Positive Genetic), MED22 (Positive Genetic), OGFOD1 (Positive Genetic), PTTG1 (Negative Genetic), RPL35 (Positive Genetic), RPLP2 (Positive Genetic), SEH1L (Positive Genetic), SRSF7 (Positive Genetic), TCOF1 (Negative Genetic), TUBGCP3 (Positive Genetic), UBA2 (Positive Genetic)

ESM2 similar proteins: A1U380, A3GGJ5, A4H9Z3, A4XYX3, A5DGI1, A6ZP42, A7EV21, A8PF69, A9NNH7, B0WAU6, B3LJM6, B3M996, B3NIL9, B4IUG3, B4PF83, B5RUV1, B5VS81, B6HFQ1, B6K4J2, B8NUL8, B9WFS9, C3Y3G4, C4QYF2, C4YA37, C5DGZ5, C5DY71, C5M276, C5PIN8, C7GWI3, C8ZGV5, D0A0G6, O13642, O43766, P0CH67, P0CH68, P32875, Q0V6U4, Q16W22, Q21452, Q2LYK1

Diamond homologs: A0Q6Q2, A1CJC4, A1D855, A1U380, A1WT98, A4ISG5, A4IY90, A4XYX3, A5E450, A5FNF9, A5IGG3, A5K883, A7EV21, A7HBU9, A7NBV0, A8I2V9, A8PF69, A9NNH7, B0R7C4, B0TZD6, B0WAU6, B0XYY2, B2SH72, B3L8F2, B3M996, B3NIL9, B3SBB5, B4IAA7, B4IUG3, B4J3F3, B4KYY0, B4MXR6, B4PF83, B6K4J2, B6QSZ4, B6TN12, B7G3Y9, B8AA76, B8B016, B8GW82

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	21
Likely pathogenic	12
Uncertain significance	187
Likely benign	165
Benign	45

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1073123	NM_006859.4(LIAS):c.649C>T (p.Arg217Ter)	Pathogenic
1424012	NM_006859.4(LIAS):c.520del (p.Tyr174fs)	Pathogenic
1451689	NM_006859.4(LIAS):c.999dup (p.Val334fs)	Pathogenic
2005335	NM_006859.4(LIAS):c.130del (p.Asp44fs)	Pathogenic
206046	NM_006859.4(LIAS):c.217del (p.Arg73fs)	Pathogenic
2165560	NM_006859.4(LIAS):c.107dup (p.Glu37fs)	Pathogenic
224601	NM_006859.4(LIAS):c.475_477delinsAAA (p.Glu159Lys)	Pathogenic
253562	GRCh37/hg19 4p14(chr4:39478387-39478807)x1	Pathogenic
2796701	NM_006859.4(LIAS):c.480del (p.Tyr161fs)	Pathogenic
2838766	NM_006859.4(LIAS):c.280A>T (p.Lys94Ter)	Pathogenic
2850745	NM_006859.4(LIAS):c.367_389dup (p.Leu132fs)	Pathogenic
3290638	NM_006859.4(LIAS):c.692T>G (p.Leu231Ter)	Pathogenic
3678499	NM_006859.4(LIAS):c.328C>T (p.Arg110Ter)	Pathogenic
4808299	NM_006859.4(LIAS):c.109G>T (p.Glu37Ter)	Pathogenic
523916	NM_006859.4(LIAS):c.277del (p.Lys92_Leu93insTer)	Pathogenic
540088	NM_006859.4(LIAS):c.64dup (p.Cys22fs)	Pathogenic
540089	NM_006859.4(LIAS):c.363del (p.Glu122fs)	Pathogenic
936919	NM_006859.4(LIAS):c.664_665delinsTA (p.Ala222Ter)	Pathogenic
937476	NM_006859.4(LIAS):c.440dup (p.Thr148fs)	Pathogenic
940068	NM_006859.4(LIAS):c.212del (p.Gly71fs)	Pathogenic
951412	NM_006859.4(LIAS):c.266dup (p.Asn89fs)	Pathogenic
1050308	NM_006859.4(LIAS):c.715del (p.Glu239fs)	Likely pathogenic
1524663	NM_006859.4(LIAS):c.884-1G>A	Likely pathogenic
2814833	NM_006859.4(LIAS):c.218+1G>A	Likely pathogenic
379693	NM_006859.4(LIAS):c.954+1G>A	Likely pathogenic
393113	NM_006859.4(LIAS):c.757G>C (p.Ala253Pro)	Likely pathogenic
4813729	NM_006859.4(LIAS):c.236G>A (p.Trp79Ter)	Likely pathogenic
4845692	NM_006859.4(LIAS):c.313-38_367del	Likely pathogenic
572236	NM_006859.4(LIAS):c.737+1G>A	Likely pathogenic
817587	NM_006859.4(LIAS):c.99dup (p.Lys34Ter)	Likely pathogenic

SpliceAI

1452 predictions. Top by Δscore:

Variant	Effect	Δscore
4:39460785:TTTA:T	acceptor_loss	1.0000
4:39460786:TTAG:T	acceptor_loss	1.0000
4:39460788:A:AG	acceptor_gain	1.0000
4:39460788:A:C	acceptor_loss	1.0000
4:39460789:G:GG	acceptor_gain	1.0000
4:39460789:GGT:G	acceptor_gain	1.0000
4:39460789:GGTA:G	acceptor_gain	1.0000
4:39460789:GGTAT:G	acceptor_gain	1.0000
4:39460958:GAAAG:G	donor_gain	1.0000
4:39460960:AAGG:A	donor_loss	1.0000
4:39460961:AGGTA:A	donor_loss	1.0000
4:39460962:GGTA:G	donor_loss	1.0000
4:39460963:G:GG	donor_gain	1.0000
4:39460963:GTA:G	donor_loss	1.0000
4:39460964:T:A	donor_loss	1.0000
4:39462290:G:GG	donor_gain	1.0000
4:39465339:A:T	donor_gain	1.0000
4:39467644:GAG:G	donor_gain	1.0000
4:39471231:TACA:T	acceptor_loss	1.0000
4:39471232:ACAGC:A	acceptor_loss	1.0000
4:39471233:CAG:C	acceptor_loss	1.0000
4:39471234:A:AG	acceptor_gain	1.0000
4:39471235:G:GT	acceptor_gain	1.0000
4:39471235:GC:G	acceptor_gain	1.0000
4:39471235:GCA:G	acceptor_gain	1.0000
4:39471235:GCAC:G	acceptor_gain	1.0000
4:39471235:GCACT:G	acceptor_gain	1.0000
4:39473208:GCAG:G	donor_gain	1.0000
4:39473212:GT:G	donor_loss	1.0000
4:39473213:TAAG:T	donor_loss	1.0000

AlphaMissense

2417 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:39463528:T:C	C106R	1.000
4:39463529:G:A	C106Y	1.000
4:39463543:T:C	C111R	1.000
4:39463564:T:A	W118R	1.000
4:39463564:T:C	W118R	1.000
4:39463566:G:C	W118C	1.000
4:39463566:G:T	W118C	1.000
4:39465079:T:C	F143L	1.000
4:39465081:T:A	F143L	1.000
4:39465081:T:G	F143L	1.000
4:39465083:G:A	C144Y	1.000
4:39462212:T:A	W79R	0.999
4:39462212:T:C	W79R	0.999
4:39463528:T:A	C106S	0.999
4:39463529:G:C	C106S	0.999
4:39463529:G:T	C106F	0.999
4:39463530:T:G	C106W	0.999
4:39463537:G:C	A109P	0.999
4:39463543:T:A	C111S	0.999
4:39463544:G:A	C111Y	0.999
4:39463544:G:C	C111S	0.999
4:39463545:T:G	C111W	0.999
4:39463551:T:A	N113K	0.999
4:39463551:T:G	N113K	0.999
4:39463561:T:A	C117S	0.999
4:39463561:T:C	C117R	0.999
4:39463562:G:C	C117S	0.999
4:39463563:T:G	C117W	0.999
4:39463595:C:A	A128D	0.999
4:39465061:T:C	C137R	0.999

dbSNP variants (sampled 300 via entrez): RS1000038897 (4:39477979 GA>G,GAA), RS1000123042 (4:39460427 A>G,T), RS1000173649 (4:39460587 A>G), RS1000302361 (4:39463968 T>C), RS1000512622 (4:39462363 T>C), RS1000641249 (4:39476494 A>G), RS1000655260 (4:39469600 T>C), RS10007694 (4:39468835 T>C), RS1001058677 (4:39457117 T>A,C), RS1001112046 (4:39457330 A>AAG), RS1001318576 (4:39462672 C>A,T), RS1001355743 (4:39474037 G>A), RS1001452699 (4:39466716 T>A), RS1001509338 (4:39467032 G>A), RS10016820 (4:39477256 T>C)

Disease associations

OMIM: gene MIM:607031 | disease phenotypes: MIM:614462

GenCC curated gene-disease

Disease	Classification	Inheritance
lipoic acid synthetase deficiency	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
mitochondrial disease	Moderate	AR
Leigh syndrome	Limited	AR

Mondo (1): lipoic acid synthetase deficiency (MONDO:0013762)

Orphanet (1): Lipoic acid synthetase deficiency (Orphanet:401859)

HPO phenotypes

25 total (25 of 25 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001336	Myoclonus
HP:0001510	Growth delay
HP:0001639	Hypertrophic cardiomyopathy
HP:0002059	Cerebral atrophy
HP:0002093	Respiratory insufficiency
HP:0002104	Apnea
HP:0002151	Increased circulating lactate concentration
HP:0002181	Cerebral edema
HP:0002360	Sleep disturbance
HP:0002415	Leukodystrophy
HP:0002510	Spastic tetraplegia
HP:0002928	Decreased activity of the pyruvate dehydrogenase complex
HP:0003128	Lactic acidosis
HP:0003623	Neonatal onset
HP:0011968	Feeding difficulties
HP:0034392	Joint contracture
HP:6000829	Reduced tissue glycine cleavage enzyme activity

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, affects cotreatment	2
bisphenol F	decreases expression, affects cotreatment	1
pirinixic acid	affects binding, increases activity, increases expression	1
sodium arsenite	decreases expression	1
demethoxycurcumin	decreases expression, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
glycidamide	increases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	increases expression	1
abrine	decreases expression	1
Acetaminophen	decreases expression	1
Acetylcysteine	decreases reaction, decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Cisplatin	increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Silicon Dioxide	decreases expression	1
Tretinoin	decreases expression	1
Tunicamycin	increases expression	1
Valproic Acid	increases expression	1
Vanadates	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
Thapsigargin	increases expression	1
Okadaic Acid	decreases expression	1
Acrylamide	increases expression	1
Particulate Matter	decreases expression, increases abundance	1

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1NK	Abcam K-562 LIAS KO	Cancer cell line	Female
CVCL_D2K5	Abcam Raji LIAS KO	Cancer cell line	Male
CVCL_E2B1	HAP1 LIAS (-) 2	Cancer cell line	Male
CVCL_E2B2	HAP1 LIAS (-) 3	Cancer cell line	Male
CVCL_UQ86	Abcam Jurkat LIAS KO	Cancer cell line	Male
CVCL_XQ16	HAP1 LIAS (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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