SERAC1

Summary

SERAC1 (serine active site containing 1, HGNC:21061) is a protein-coding gene on chromosome 6q25.3, encoding Protein SERAC1 (Q96JX3). Facilitates the transport of serine from the cytosol to the mitochondria by interacting with and stabilizing Sideroflexin-1 (SFXN1), a mitochondrial serine transporter, playing a fundamental role in the one-carbon cycle responsible for the synthesis of nucleotides needed for mit….

The protein encoded by this gene is a phosphatidylglycerol remodeling protein found at the interface of mitochondria and endoplasmic reticula, where it mediates phospholipid exchange. The encoded protein plays a major role in mitochondrial function and intracellular cholesterol trafficking. Defects in this gene are a cause of 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL). Two transcript variants, one protein-coding and the other non-protein coding, have been found for this gene.

Source: NCBI Gene 84947 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Leigh syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 512 total — 29 pathogenic, 22 likely-pathogenic
• Phenotypes (HPO): 31
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_032861

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21061
Approved symbol	SERAC1
Name	serine active site containing 1
Location	6q25.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ14917
Ensembl gene	ENSG00000122335
Ensembl biotype	protein_coding
OMIM	614725
Entrez	84947

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 13 protein_coding, 8 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000367101, ENST00000435180, ENST00000606965, ENST00000607000, ENST00000607071, ENST00000607742, ENST00000642244, ENST00000642903, ENST00000643093, ENST00000644972, ENST00000645077, ENST00000645172, ENST00000646190, ENST00000646208, ENST00000646410, ENST00000646562, ENST00000647468, ENST00000648111, ENST00000915172, ENST00000915173, ENST00000915174, ENST00000941711, ENST00000941712, ENST00000941713

RefSeq mRNA: 1 — MANE Select: NM_032861 NM_032861

CCDS: CCDS5255

Canonical transcript exons

ENST00000647468 — 17 exons

Exon	Start	End
ENSE00000894222	158144299	158144420
ENSE00000894223	158143056	158143184
ENSE00000894224	158130373	158130486
ENSE00000894225	158128108	158128270
ENSE00000894226	158120425	158120575
ENSE00000894227	158119029	158119170
ENSE00000894228	158117727	158117821
ENSE00000975866	158150453	158150589
ENSE00000975867	158148865	158148954
ENSE00001028490	158155315	158155351
ENSE00001028492	158158273	158158364
ENSE00001216599	158146782	158146913
ENSE00001344138	158168140	158168262
ENSE00003470812	158113449	158113592
ENSE00003514216	158116185	158116282
ENSE00003570694	158114789	158114971
ENSE00003842392	158109519	158111502

Expression profiles

Bgee: expression breadth ubiquitous, 214 present calls, max score 87.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.1436 / max 30.1615, expressed in 1580 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
76381	3.7611	1548
76380	0.2673	114
76379	0.1152	36

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
epithelial cell of pancreas	CL:0000083	87.66	silver quality
endothelial cell	CL:0000115	87.27	gold quality
islet of Langerhans	UBERON:0000006	83.68	gold quality
secondary oocyte	CL:0000655	83.19	gold quality
lower esophagus mucosa	UBERON:0035834	82.96	gold quality
adrenal tissue	UBERON:0018303	82.13	gold quality
body of pancreas	UBERON:0001150	82.10	gold quality
pancreas	UBERON:0001264	82.10	gold quality
cortical plate	UBERON:0005343	81.92	gold quality
pancreatic ductal cell	CL:0002079	81.86	silver quality
popliteal artery	UBERON:0002250	81.59	gold quality
tibial artery	UBERON:0007610	81.58	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.43	gold quality
right adrenal gland cortex	UBERON:0035827	81.42	gold quality
left adrenal gland	UBERON:0001234	81.17	gold quality
right adrenal gland	UBERON:0001233	81.06	gold quality
esophagus squamous epithelium	UBERON:0006920	80.86	gold quality
aorta	UBERON:0000947	80.82	gold quality
left adrenal gland cortex	UBERON:0035825	80.65	gold quality
adrenal gland	UBERON:0002369	80.61	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	80.19	gold quality
adrenal cortex	UBERON:0001235	80.14	gold quality
ganglionic eminence	UBERON:0004023	79.94	gold quality
thoracic aorta	UBERON:0001515	79.88	gold quality
smooth muscle tissue	UBERON:0001135	79.82	gold quality
ascending aorta	UBERON:0001496	79.79	gold quality
descending thoracic aorta	UBERON:0002345	79.69	gold quality
lower esophagus	UBERON:0013473	79.65	gold quality
lower esophagus muscularis layer	UBERON:0035833	79.61	gold quality
ventricular zone	UBERON:0003053	79.45	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.94

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

100 targeting SERAC1, 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-3646	100.00	73.56	5283
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-570-3P	99.96	72.41	4910
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-548J-3P	99.94	72.61	4881
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-6857-5P	99.87	65.32	985
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-1273H-5P	99.77	66.32	2471

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 10)

• Data identify SERAC1 as a key player in the phosphatidylglycerol remodeling that is essential for both mitochondrial function and intracellular cholesterol trafficking. (PMID:22683713)
• During the course of this project a parallel study identified mutations in SERAC1 as the genetic cause of the disease in 15 patients with MEGDEL syndrome, which was compatible with the clinical and biochemical phenotypes of the patient described here. (PMID:23707711)
• Infantile mitochondrial hepatopathy is a cardinal feature of MEGDEL syndrome (3-methylglutaconic aciduria type IV with sensorineural deafness, encephalopathy and Leigh-like syndrome) caused by novel mutations in SERAC1. (PMID:23918762)
• Here we report two new Turkish sibling patients affected with MEGDEL syndrome due to SERAC1 gene mutation. (PMID:27186703)
• Two novel SERAC1 mutations were identified in two cases of dystonia, 3-methylglutaconic aciduria and intellectual disability syndrome. (PMID:28778788)
• mutations in the phosphatidylglycerol remodelling enzyme SERAC1 can cause juvenile-onset complicated hereditary spastic paraplegia (cHSP) clusters (PMID:28916646)
• Several different SERAC1 variants were identified from individuals with Deafness-Dystonia syndrome. (PMID:29205472)
• Our study indicates that the cochlear CHI is a phenotypic feature of the RRM2B and SERAC1 related defects. (PMID:30909120)
• Severe neonatal MEGDHEL syndrome with a homozygous truncating mutation in SERAC1. (PMID:34751152)
• First description of the MEGDEHL syndrome in the Tunisian population via whole-exome sequencing: Novel nonsense mutation in SERAC1 gene. (PMID:35943861)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	serac1	ENSDARG00000056121
mus_musculus	Serac1	ENSMUSG00000015659
rattus_norvegicus	Serac1	ENSRNOG00000017889
drosophila_melanogaster	CG5455	FBGN0039430
caenorhabditis_elegans		WBGENE00008925

Paralogs (1): POP1 (ENSG00000104356)

Protein

Protein identifiers

Protein SERAC1 — Q96JX3 (reviewed: Q96JX3)

Alternative names: Serine active site-containing protein 1

All UniProt accessions (10): A0A2R8Y3S0, A0A2R8Y511, A0A2R8YCL0, A0A2R8YD19, A0A2R8YFH3, A0A3B3ISE8, Q96JX3, Q5JVM6, U3KQE4, U3KQG3

UniProt curated annotations — full annotation on UniProt →

Function. Facilitates the transport of serine from the cytosol to the mitochondria by interacting with and stabilizing Sideroflexin-1 (SFXN1), a mitochondrial serine transporter, playing a fundamental role in the one-carbon cycle responsible for the synthesis of nucleotides needed for mitochondrial DNA replication. Plays an important role in the phosphatidylglycerol (PG) remodeling that is essential for both mitochondrial function and intracellular cholesterol trafficking. Specifically involved in the exchange of the sn-1 acyl chain from PG 16:0/18:1(9Z) (also known as 1-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phospho-(1’-sn-glycerol)) to PG 18:0/18:1(9Z) (also known as 1-octadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phospho-(1’-sn-glycerol)), a step needed in the bis(monoacylglycerol)phosphate biosynthetic pathway. May have acyltransferase activity although the mechanism for PG remodeling has not been determined.

Subcellular location. Mitochondrion membrane. Endoplasmic reticulum. Mitochondrion.

Tissue specificity. Widely expressed, with predominant expression in skeletal muscle and brain. In the brain, highest levels are found in the frontal and occipital cortices, cerebellum and hippocampus.

Disease relevance. 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL) [MIM:614739] An autosomal recessive disorder characterized by childhood onset of delayed psychomotor development or psychomotor regression, sensorineural deafness, spasticity or dystonia, and increased excretion of 3-methylglutaconic acid. Brain imaging shows cerebral and cerebellar atrophy as well as lesions in the basal ganglia reminiscent of Leigh syndrome. Laboratory studies show increased serum lactate and alanine, mitochondrial oxidative phosphorylation defects, abnormal mitochondria, abnormal phosphatidylglycerol and cardiolipin profiles in fibroblasts, and abnormal accumulation of unesterified cholesterol within cells. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the SERAC1 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96JX3-1	1	yes
Q96JX3-2	2
Q96JX3-3	3

RefSeq proteins (1): NP_116250* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR029058	AB_hydrolase_fold	Homologous_superfamily
IPR052374	SERAC1	Family

UniProt features (13 total): sequence variant 6, splice variant 4, chain 1, transmembrane region 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96JX3-F1	78.66	0.52

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 163 (showing top): GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLGLYCEROL_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANIC_HYDROXY_COMPOUND_TRANSPORT, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, chr6q25, GOCC_MITOCHONDRIAL_ENVELOPE, GOBP_GLYCEROPHOSPHOLIPID_METABOLIC_PROCESS, GOBP_LIPID_METABOLIC_PROCESS, GOBP_LIPID_BIOSYNTHETIC_PROCESS, GOBP_STEROL_TRANSPORT, GOBP_INTRACELLULAR_LIPID_TRANSPORT, GOBP_PHOSPHATIDYLGLYCEROL_ACYL_CHAIN_REMODELING

GO Biological Process (5): phospholipid biosynthetic process (GO:0008654), extracellular matrix organization (GO:0030198), intracellular cholesterol transport (GO:0032367), phosphatidylglycerol acyl-chain remodeling (GO:0036148), lipid metabolic process (GO:0006629)

GO Molecular Function (0):

GO Cellular Component (8): mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), extracellular matrix (GO:0031012), mitochondria-associated endoplasmic reticulum membrane contact site (GO:0044233), membrane (GO:0016020), mitochondrial membrane (GO:0031966)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
intracellular membrane-bounded organelle	2
organelle membrane	2
phospholipid metabolic process	1
lipid biosynthetic process	1
organophosphate biosynthetic process	1
extracellular structure organization	1
external encapsulating structure organization	1
intracellular anatomical structure	1
cholesterol transport	1
intracellular sterol transport	1
phosphatidylglycerol metabolic process	1
primary metabolic process	1
mitochondrial membrane	1
organelle outer membrane	1
endomembrane system	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
external encapsulating structure	1
organelle membrane contact site	1
cellular anatomical structure	1
mitochondrion	1
mitochondrial envelope	1

Protein interactions and networks

STRING

832 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SERAC1	AGK	Q53H12	618
SERAC1	TMEM242	Q9NWH2	606
SERAC1	TULP4	Q9NRJ4	593
SERAC1	DNAJC19	Q96DA6	583
SERAC1	GTF2H5	Q6ZYL4	564
SERAC1	RELT	Q969Z4	555
SERAC1	TMEM70	Q9BUB7	542
SERAC1	SNX9	Q9Y5X1	485
SERAC1	SUCLA2	Q9P2R7	478
SERAC1	MPV17	P39210	477
SERAC1	PARS2	Q7L3T8	476
SERAC1	RAPGEFL1	Q9UHV5	472
SERAC1	SCAF8	Q9UPN6	447
SERAC1	LRPPRC	P42704	426
SERAC1	SMYD4	Q8IYR2	425

IntAct

25 interactions, top by confidence:

A	B	Type	Score
EGFR	CTNND1	psi-mi:“MI:0914”(association)	0.750
CCT8L2	ACSL4	psi-mi:“MI:0914”(association)	0.530
SERAC1	CFTR	psi-mi:“MI:0915”(physical association)	0.370
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
SLC18A1	LIMK2	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
RAMP2	GXYLT2	psi-mi:“MI:0914”(association)	0.350
MAGEA8	METTL15	psi-mi:“MI:0914”(association)	0.350
GPR45	VWA8	psi-mi:“MI:0914”(association)	0.350
HLA-DRA	MGRN1	psi-mi:“MI:0914”(association)	0.350
GARIN1A	RAB2A	psi-mi:“MI:0914”(association)	0.350
SLC25A25	HAX1	psi-mi:“MI:0914”(association)	0.350
FECH	GTPBP10	psi-mi:“MI:0914”(association)	0.350
ASIC4	CLGN	psi-mi:“MI:0914”(association)	0.350
MAGEA8	B4GALT5	psi-mi:“MI:0914”(association)	0.350
SLC1A1	SCD	psi-mi:“MI:0914”(association)	0.350
SLC1A2	UBXN8	psi-mi:“MI:0914”(association)	0.350
SLC1A3	DDX11L8	psi-mi:“MI:0914”(association)	0.350
SLC1A6	ILVBL	psi-mi:“MI:0914”(association)	0.350
SLC22A11	CNOT1	psi-mi:“MI:0914”(association)	0.350
SLC2A2	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC39A11	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC39A12	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC39A3	BTAF1	psi-mi:“MI:0914”(association)	0.350

BioGRID (28): SERAC1 (Affinity Capture-MS), SERAC1 (Affinity Capture-MS), SERAC1 (Reconstituted Complex), SERAC1 (Affinity Capture-MS), SERAC1 (Affinity Capture-MS), SERAC1 (Affinity Capture-MS), SERAC1 (Proximity Label-MS), SERAC1 (Proximity Label-MS), SERAC1 (Affinity Capture-MS), SERAC1 (Affinity Capture-MS), SERAC1 (Affinity Capture-MS), SERAC1 (Affinity Capture-MS), SERAC1 (Affinity Capture-MS), SERAC1 (PCA), SERAC1 (Affinity Capture-MS)

ESM2 similar proteins: A0JMU5, A1A4L5, A2AV36, A2Y8B9, B0X4N1, B3DLB3, B3M1E1, B3MF31, B3P4N5, B4GZ20, B4HJC0, B4I8G2, B4JXV2, B4KA23, B4LVS8, B4NKI9, B4P925, B4PVH6, B4QI55, B4QVW6, B6DMK2, D9IVE5, O14727, O60678, O70467, O88879, Q0V9P1, Q16NS8, Q29B63, Q3EBC8, Q3U213, Q3U3W5, Q4SBY6, Q5RAY7, Q5ZIB9, Q6P2P2, Q6P5U7, Q6PCI6, Q7QIL2, Q80VJ4

Diamond homologs: Q2TBM9, Q3U213, Q5SNQ7, Q95JR3, Q96JX3

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 43 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.

GO biological processes:

GO term	Partners	Fold	FDR
monoatomic ion transport	5	20.0×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	29
Likely pathogenic	22
Uncertain significance	170
Likely benign	187
Benign	48

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1184550	NM_032861.4(SERAC1):c.1850_1851insA (p.Pro618fs)	Pathogenic
1329462	NM_032861.4(SERAC1):c.1504CTT[1] (p.Leu503del)	Pathogenic
1430677	NM_032861.4(SERAC1):c.625G>T (p.Glu209Ter)	Pathogenic
1456235	NM_032861.4(SERAC1):c.1403+1G>A	Pathogenic
1804045	NM_032861.4(SERAC1):c.1211G>A (p.Gly404Glu)	Pathogenic
1957954	NM_032861.4(SERAC1):c.777T>G (p.Tyr259Ter)	Pathogenic
1961244	NM_032861.4(SERAC1):c.1266dup (p.Pro423fs)	Pathogenic
2136486	NM_032861.4(SERAC1):c.310A>T (p.Lys104Ter)	Pathogenic
215142	NM_032861.4(SERAC1):c.1126C>T (p.Gln376Ter)	Pathogenic
215148	NM_032861.4(SERAC1):c.1628_1629dup (p.Val544fs)	Pathogenic
2230760	NM_032861.4(SERAC1):c.966del (p.Ile322fs)	Pathogenic
2584436	NM_032861.4(SERAC1):c.1339C>T (p.Arg447Ter)	Pathogenic
2705467	NM_032861.4(SERAC1):c.116C>G (p.Ser39Ter)	Pathogenic
2759584	NM_032861.4(SERAC1):c.698_699delinsAGTGATA (p.Leu233Ter)	Pathogenic
2782312	NM_032861.4(SERAC1):c.236_237del (p.Thr79fs)	Pathogenic
280568	NM_032861.4(SERAC1):c.227_228dup (p.Val77fs)	Pathogenic
2916178	NM_032861.4(SERAC1):c.134_137del (p.Ser45fs)	Pathogenic
35556	NM_032861.4(SERAC1):c.442C>T (p.Arg148Ter)	Pathogenic
35559	NM_032861.4(SERAC1):c.1432CTT[1] (p.Leu479del)	Pathogenic
3642297	NM_032861.4(SERAC1):c.289G>T (p.Glu97Ter)	Pathogenic
391193	NM_032861.4(SERAC1):c.493C>T (p.Gln165Ter)	Pathogenic
430610	NM_032861.4(SERAC1):c.1403+1G>C	Pathogenic
452315	NM_032861.4(SERAC1):c.1102C>T (p.Arg368Ter)	Pathogenic
4807929	NM_032861.4(SERAC1):c.733C>T (p.Gln245Ter)	Pathogenic
587693	NM_032861.4(SERAC1):c.92-239G>C	Pathogenic
587699	NM_032861.4(SERAC1):c.92-165C>T	Pathogenic
689786	NM_032861.4(SERAC1):c.438del (p.Thr147fs)	Pathogenic
916006	GRCh37/hg19 6q25.3(chr6:158567861-158571603)	Pathogenic
987052	NM_032861.4(SERAC1):c.1488dup (p.His497fs)	Pathogenic
1525175	NM_032861.4(SERAC1):c.1684+1G>T	Likely pathogenic

SpliceAI

2764 predictions. Top by Δscore:

Variant	Effect	Δscore
6:158113444:AATAC:A	donor_loss	1.0000
6:158113445:ATAC:A	donor_loss	1.0000
6:158113446:TAC:T	donor_loss	1.0000
6:158113448:C:T	donor_loss	1.0000
6:158113448:CCTG:C	donor_gain	1.0000
6:158113467:C:CT	donor_gain	1.0000
6:158113589:GAAT:G	acceptor_gain	1.0000
6:158113593:C:CC	acceptor_gain	1.0000
6:158113595:G:C	acceptor_gain	1.0000
6:158113601:T:C	acceptor_gain	1.0000
6:158113601:T:TC	acceptor_gain	1.0000
6:158114784:ATTAC:A	donor_gain	1.0000
6:158114787:AC:A	donor_gain	1.0000
6:158114788:CC:C	donor_gain	1.0000
6:158114809:T:TA	donor_gain	1.0000
6:158114895:T:TA	donor_gain	1.0000
6:158116279:CTTT:C	acceptor_gain	1.0000
6:158116280:TTT:T	acceptor_gain	1.0000
6:158116283:C:CC	acceptor_gain	1.0000
6:158117655:C:A	donor_gain	1.0000
6:158117693:C:A	donor_gain	1.0000
6:158119023:CCTTA:C	donor_loss	1.0000
6:158119024:CTTAC:C	donor_loss	1.0000
6:158119025:TTACC:T	donor_loss	1.0000
6:158119026:TACC:T	donor_loss	1.0000
6:158119027:A:AG	donor_loss	1.0000
6:158119127:CCA:C	acceptor_gain	1.0000
6:158119128:C:T	acceptor_gain	1.0000
6:158119136:C:T	acceptor_gain	1.0000
6:158119136:CA:C	acceptor_gain	1.0000

AlphaMissense

4289 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:158119037:A:G	W434R	0.999
6:158119037:A:T	W434R	0.999
6:158119109:A:G	W410R	0.999
6:158119109:A:T	W410R	0.999
6:158119035:C:A	W434C	0.998
6:158119035:C:G	W434C	0.998
6:158119107:C:A	W410C	0.998
6:158119107:C:G	W410C	0.998
6:158111462:A:C	H623Q	0.997
6:158111462:A:T	H623Q	0.997
6:158114797:A:G	L559P	0.997
6:158114880:A:C	S531R	0.997
6:158114880:A:T	S531R	0.997
6:158114882:T:G	S531R	0.997
6:158116192:G:C	S498R	0.997
6:158116192:G:T	S498R	0.997
6:158116194:T:G	S498R	0.997
6:158116206:A:G	W494R	0.997
6:158116206:A:T	W494R	0.997
6:158111447:C:A	K628N	0.996
6:158111447:C:G	K628N	0.996
6:158111464:G:C	H623D	0.996
6:158117790:C:G	R447P	0.996
6:158119105:C:G	R411P	0.996
6:158111450:A:C	C627W	0.995
6:158111451:C:T	C627Y	0.995
6:158113511:T:A	E589V	0.995
6:158116241:A:G	L482P	0.995
6:158117814:A:G	L439S	0.995
6:158119108:C:G	W410S	0.995

dbSNP variants (sampled 300 via entrez): RS1000095561 (6:158152420 A>G), RS1000120975 (6:158158012 G>A), RS1000130216 (6:158126192 AC>A), RS1000171781 (6:158122918 A>G), RS1000231696 (6:158115330 G>A,C), RS1000286633 (6:158122668 G>A,T), RS1000292610 (6:158125948 T>C), RS1000325134 (6:158145880 T>G), RS1000384742 (6:158159473 T>C), RS1000468732 (6:158131206 C>T), RS1000506531 (6:158113825 G>A), RS1000540366 (6:158151087 G>A,T), RS1000620959 (6:158164076 T>C,G), RS1000712638 (6:158169095 G>A,C), RS1000758036 (6:158131551 G>A)

Disease associations

OMIM: gene MIM:614725 | disease phenotypes: MIM:614739, MIM:256000

GenCC curated gene-disease

Disease	Classification	Inheritance
3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Leigh syndrome	Definitive	AR

Mondo (4): 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MONDO:0013875), Leigh syndrome (MONDO:0009723), SERAC1-related neurological disorder (MONDO:0100548), mitochondrial oxidative phosphorylation disorder (MONDO:0016387)

Orphanet (3): MEGDEL syndrome (Orphanet:352328), Leigh syndrome (Orphanet:506), Mitochondrial oxidative phosphorylation disorder (Orphanet:223713)

HPO phenotypes

31 total (30 of 31 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000407	Sensorineural hearing impairment
HP:0000648	Optic atrophy
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001332	Dystonia
HP:0001344	Absent speech
HP:0001508	Failure to thrive
HP:0001943	Hypoglycemia
HP:0001987	Hyperammonemia
HP:0002071	Abnormality of extrapyramidal motor function
HP:0002151	Increased circulating lactate concentration
HP:0002376	Developmental regression
HP:0002540	Inability to walk
HP:0002719	Recurrent infections
HP:0002977	Aplasia/Hypoplasia involving the central nervous system
HP:0003128	Lactic acidosis
HP:0003256	Abnormality of the coagulation cascade
HP:0003348	Hyperalaninemia
HP:0003535	3-Methylglutaconic aciduria
HP:0011968	Feeding difficulties
HP:0012444	Brain atrophy
HP:0040187	Neonatal sepsis

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002746_8	Lipoprotein (a) - cholesterol levels	2.000000e-08
GCST003127_10	Lipoprotein (a) levels	4.000000e-10
GCST005336_6	Systemic sclerosis	5.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006925	lipoprotein A measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D007888	Leigh Disease	C10.228.140.163.100.412; C16.320.565.189.412; C16.320.565.202.810.444; C18.452.132.100.412; C18.452.648.189.412; C18.452.648.202.810.444; C18.452.660.520

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects expression, decreases expression	3
sodium arsenite	decreases expression, affects methylation	2
perfluorooctane sulfonic acid	decreases expression	2
Air Pollutants	increases abundance, affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Cyclosporine	increases expression, increases methylation	2
aristolochic acid I	decreases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
beta-lapachone	increases expression	1
perfluorooctanoic acid	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
pentabromodiphenyl ether	increases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	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
perfluorohexanesulfonic acid	decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Acrolein	increases abundance, affects cotreatment, decreases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases expression	1
Ethyl Methanesulfonate	increases expression	1
Folic Acid	decreases expression	1
Hydrogen Peroxide	increases expression	1
Methyl Methanesulfonate	increases expression	1
Ozone	increases abundance, affects cotreatment, decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E2JU	HAP1 SERAC1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01721733	PHASE2	COMPLETED	Safety and Efficacy Study of EPI-743 in Children With Leigh Syndrome
NCT02352896	PHASE2	COMPLETED	Long-Term Safety and Efficacy Evaluation of EPI-743 in Children With Leigh Syndrome
NCT03747328	PHASE2	WITHDRAWN	ABI-009 (Nab-sirolimus) in Patients With Genetically-confirmed Leigh or Leigh-like Syndrome
NCT06843811	PHASE2	ENROLLING_BY_INVITATION	Sirolimus for Leigh Syndrome
NCT06990984	PHASE2	NOT_YET_RECRUITING	A Dose-ranging Study of TTI-0102 in Adults and Children With Leigh Syndrome Spectrum (LSS)
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01780168	Not specified	RECRUITING	The NIH MINI Study: Metabolism, Infection, and Immunity in Inborn Errors of Metabolism
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01803906	Not specified	ENROLLING_BY_INVITATION	Tissue Sample Study for Mitochondrial Disorders
NCT03137355	Not specified	RECRUITING	The International Registry for Leigh Syndrome
NCT05277363	Not specified	WITHDRAWN	A Study of the Natural Course of SURF1 Deficiency
NCT05554835	Not specified	RECRUITING	Global Registry and Natural History Study for Mitochondrial Disorders
NCT06967831	Not specified	RECRUITING	Drug Repurposing for Mitochondrial Disorders Using iPSCs Derived Neural Cells