SLC25A12

Summary

SLC25A12 (solute carrier family 25 member 12, HGNC:10982) is a protein-coding gene on chromosome 2q31.1, encoding Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial (O75746). Mitochondrial electrogenic aspartate/glutamate antiporter that favors efflux of aspartate and entry of glutamate and proton within the mitochondria as part of the malate-aspartate shuttle.

This gene encodes a calcium-binding mitochondrial carrier protein. The encoded protein localizes to the mitochondria and is involved in the exchange of aspartate for glutamate across the inner mitochondrial membrane. Polymorphisms in this gene may be associated with autism, and mutations in this gene may also be a cause of global cerebral hypomyelination. Alternatively spliced transcript variants have been observed for this gene.

Source: NCBI Gene 8604 — RefSeq curated summary.

At a glance

• Gene–disease (curated): developmental and epileptic encephalopathy, 39 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 569 total — 15 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 46
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_003705

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10982
Approved symbol	SLC25A12
Name	solute carrier family 25 member 12
Location	2q31.1
Locus type	gene with protein product
Status	Approved
Aliases	Aralar, aralar1, AGC1
Ensembl gene	ENSG00000115840
Ensembl biotype	protein_coding
OMIM	603667
Entrez	8604

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 14 protein_coding, 4 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay, 2 retained_intron

ENST00000263812, ENST00000422440, ENST00000426896, ENST00000464063, ENST00000472070, ENST00000472748, ENST00000475360, ENST00000484227, ENST00000485880, ENST00000494892, ENST00000855498, ENST00000855500, ENST00000855503, ENST00000855506, ENST00000855507, ENST00000855508, ENST00000855509, ENST00000958779, ENST00000958780, ENST00000958781, ENST00000958782, ENST00000958783, ENST00000958784

RefSeq mRNA: 1 — MANE Select: NM_003705 NM_003705

CCDS: CCDS33327

Canonical transcript exons

ENST00000422440 — 18 exons

Exon	Start	End
ENSE00001416764	171894203	171894244
ENSE00001838982	171783405	171785475
ENSE00003460059	171787789	171787947
ENSE00003467252	171815121	171815202
ENSE00003484568	171844369	171844508
ENSE00003534781	171787571	171787661
ENSE00003561429	171809606	171809686
ENSE00003577037	171833963	171834056
ENSE00003578402	171793627	171793767
ENSE00003584071	171826798	171826882
ENSE00003584229	171791451	171791589
ENSE00003588240	171893205	171893258
ENSE00003613223	171837121	171837267
ENSE00003651462	171810224	171810276
ENSE00003657634	171834727	171834865
ENSE00003657821	171868681	171868823
ENSE00003686002	171855834	171855949
ENSE00003690859	171813339	171813497

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 98.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.3479 / max 373.1940, expressed in 1784 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
31781	16.8031	1774
31782	0.9937	557
31783	0.5511	149

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
biceps brachii	UBERON:0001507	98.03	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.78	gold quality
triceps brachii	UBERON:0001509	97.76	gold quality
vastus lateralis	UBERON:0001379	97.35	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.17	gold quality
left ventricle myocardium	UBERON:0006566	96.89	gold quality
skeletal muscle tissue	UBERON:0001134	96.80	gold quality
muscle of leg	UBERON:0001383	96.77	gold quality
muscle organ	UBERON:0001630	96.77	gold quality
skeletal muscle organ	UBERON:0014892	96.77	gold quality
gastrocnemius	UBERON:0001388	96.75	gold quality
diaphragm	UBERON:0001103	96.73	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.73	gold quality
quadriceps femoris	UBERON:0001377	96.52	gold quality
gluteal muscle	UBERON:0002000	96.23	gold quality
heart right ventricle	UBERON:0002080	96.16	gold quality
myocardium	UBERON:0002349	96.04	gold quality
right atrium auricular region	UBERON:0006631	95.89	gold quality
cardiac atrium	UBERON:0002081	95.88	gold quality
muscle tissue	UBERON:0002385	95.87	gold quality
cardiac muscle of right atrium	UBERON:0003379	95.78	gold quality
heart left ventricle	UBERON:0002084	95.70	gold quality
cardiac ventricle	UBERON:0002082	95.66	gold quality
deltoid	UBERON:0001476	95.47	gold quality
endothelial cell	CL:0000115	95.34	gold quality
apex of heart	UBERON:0002098	95.33	gold quality
heart	UBERON:0000948	95.28	gold quality
middle temporal gyrus	UBERON:0002771	95.19	gold quality
body of tongue	UBERON:0011876	95.16	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.12	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	63.95
E-ANND-3	yes	7.66

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

98 targeting SLC25A12, 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-4425	100.00	67.59	1049
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-590-3P	99.96	74.34	6478
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-576-5P	99.84	70.46	2582

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 19)

• SLC25A12 gene is linked to autism (PMID:15056512)
• Aralar1 has a role in determining glucose metabolic fate, mitochondrial activity, and insulin secretion in beta cells (PMID:15494407)
• These results suggest that SLC25A12 is not a major contributor to autism risk in these families. (PMID:16648338)
• it is unlikely that the SLC25A12 polymorphisms investigated play a substantial role in conferring susceptibility to schizophrenia (PMID:17693006)
• rs2056202 polymorphism in SLC25A12 may be associated with levels of routines and rituals in autism and related disorders (PMID:17894412)
• SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects. (PMID:18180767)
• Variants of the AGC1-encoding SLC25A12 gene were neither correlated with AGC activation nor associated with autism-spectrum disorders in 309 simplex and 17 multiplex families. (PMID:18607376)
• SLC25A12 gene is associated with autism. (PMID:19360665)
• This study found no differences in the allele, genotype, or haplotype frequencies of these two SNPs between patients and controls. (PMID:19913066)
• The physiological roles of AGC1, its links to calcium homeostasis, and its involvement in autism pathogenesis, are reviewed. (PMID:21691713)
• Compares and contrasts all the known human SLC25A* genes and includes functional information. (PMID:23266187)
• Structure of the calcium bound and calcium free N- and C-terminal domains is described, elucidating the mechanism of calcium regulation. (PMID:25410934)
• Sensitivity analyses including only studies with family-based design demonstrated significant association between autism spectrum disorders and SNPs rs2292813 and rs2056202. In contrast, sensitivity analyses including case-control design studies only failed to find a significant association. Review. (PMID:25663199)
• rs2056202 and rs2292813 in SLC25A12 may contribute significantly to autism spectrum disorders risk. (PMID:25921325)
• The features of AGC1 structure and function in physiology and pathology, regulation by calcium, dependency on mitochondrial membrane potential, role in cancer cells, and tissue specificity are reviewed. AGC1 is involved in the glutamate-mediated excitotoxicity in neurons and AGC gene or protein alterations were discovered in rare human diseases. Review. (PMID:27132995)
• Genetic variants of SLC25A12 may be associated with risks for childhood ASD. (PMID:28536923)
• The microRNAs miR-302b and miR-372 regulate mitochondrial metabolism via the SLC25A12 transporter, which controls MAVS-mediated antiviral innate immunity. (PMID:31767682)
• High SLC25A12 expression significantly associated with poor prognosis of acute myeloid leukemia patients (PMID:32319366)
• SLC25A12 inhibits Japanese encephalitis virus replication by interacting with the NS1 and enhancing the type I interferon response. (PMID:39096789)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc25a12	ENSDARG00000102362
mus_musculus	Slc25a12	ENSMUSG00000027010
rattus_norvegicus	Slc25a12	ENSRNOG00000022922
drosophila_melanogaster	aralar1	FBGN0028646
caenorhabditis_elegans		WBGENE00019326

Paralogs (49): SLC25A13 (ENSG00000004864), SLC25A5 (ENSG00000005022), SLC25A39 (ENSG00000013306), SLC25A40 (ENSG00000075303), SLC25A3 (ENSG00000075415), SLC25A43 (ENSG00000077713), SLC25A24 (ENSG00000085491), SLC25A1 (ENSG00000100075), SLC25A17 (ENSG00000100372), SLC25A14 (ENSG00000102078), SLC25A15 (ENSG00000102743), SLC25A11 (ENSG00000108528), UCP1 (ENSG00000109424), SLC25A36 (ENSG00000114120), SLC25A2 (ENSG00000120329), SLC25A51 (ENSG00000122696), SLC25A16 (ENSG00000122912), SLC25A35 (ENSG00000125434), SLC25A19 (ENSG00000125454), SLC25A23 (ENSG00000125648), SLC25A47 (ENSG00000140107), SLC25A52 (ENSG00000141437), SLC25A38 (ENSG00000144659), SLC25A26 (ENSG00000144741), SLC25A48 (ENSG00000145832), SLC25A37 (ENSG00000147454), SLC25A25 (ENSG00000148339), SLC25A31 (ENSG00000151475), SLC25A4 (ENSG00000151729), SLC25A27 (ENSG00000153291), SLC25A28 (ENSG00000155287), SLC25A44 (ENSG00000160785), SLC25A45 (ENSG00000162241), SLC25A34 (ENSG00000162461), SLC25A32 (ENSG00000164933), SLC25A6 (ENSG00000169100), SLC25A33 (ENSG00000171612), SLC25A30 (ENSG00000174032), UCP3 (ENSG00000175564), UCP2 (ENSG00000175567)

Protein

Protein identifiers

Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial — O75746 (reviewed: O75746)

Alternative names: Araceli hiperlarga, Mitochondrial aspartate glutamate carrier 1, Solute carrier family 25 member 12

All UniProt accessions (4): O75746, B4DGK6, F8W9J0, H0YFB2

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial electrogenic aspartate/glutamate antiporter that favors efflux of aspartate and entry of glutamate and proton within the mitochondria as part of the malate-aspartate shuttle. Also mediates the uptake of L-cysteinesulfinate (3-sulfino-L-alanine) by mitochondria in exchange of L-glutamate and proton. Can also exchange L-cysteinesulfinate with aspartate in their anionic form without any proton translocation. Lacks transport activity towards L-glutamine or gamma-aminobutyric acid (GABA).

Subunit / interactions. Homodimer (via N-terminus).

Subcellular location. Mitochondrion inner membrane.

Tissue specificity. Expressed predominantly in the heart and skeletal muscle, weakly in brain and kidney.

Disease relevance. Developmental and epileptic encephalopathy 39 with leukodystrophy (DEE39) [MIM:612949] A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE39 is characterized by global hypomyelination of the central nervous system, with the gray matter appearing relatively unaffected. Inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by calcium-binding in the mitochondrial intermembrane space. Inhibited by pyridoxal 5’-phosphate, bathophenathroline, mercurials, diethyl pyrocarbonate and N-ethylmaleimide.

Domain organisation. The EF-hand 2 domain within the regulatory N-terminal domain binds one calcium in the mitochondrial intermembrane space. Calcium triggers the binding of the regulatory N-terminal domain to the C-terminal domain, opening a vestibule which allows the substrates to be translocated through the carrier domain. In the absence of calcium, the linker loop domain may close the vestibule and prevent substrates from entering the carrier domain.

Similarity. Belongs to the mitochondrial carrier (TC 2.A.29) family.

Isoforms (2)

UniProt ID	Names	Canonical?
O75746-1	1	yes
O75746-2	2

RefSeq proteins (1): NP_003696* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR002067	MCP	Family
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018108	MCP_transmembrane	Repeat
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR023395	MCP_dom_sf	Homologous_superfamily
IPR051028	Mito_Solute_Carrier	Family

Pfam: PF00153

Catalyzed reactions (Rhea), 3 shown:

• L-aspartate(in) + L-glutamate(out) + H(+)(out) = L-aspartate(out) + L-glutamate(in) + H(+)(in) (RHEA:70783)
• 3-sulfino-L-alanine(out) + L-glutamate(in) + H(+)(in) = 3-sulfino-L-alanine(in) + L-glutamate(out) + H(+)(out) (RHEA:70967)
• 3-sulfino-L-alanine(out) + L-aspartate(in) = 3-sulfino-L-alanine(in) + L-aspartate(out) (RHEA:70975)

UniProt features (68 total): helix 17, strand 8, topological domain 7, transmembrane region 6, binding site 5, turn 5, domain 4, region of interest 4, repeat 3, sequence variant 3, sequence conflict 2, initiator methionine 1, chain 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4P5X	X-RAY DIFFRACTION	2.26
4P60	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75746-F1	83.50	0.37

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 (5): 65; 67; 69; 71; 76

Post-translational modifications (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-1268020	Mitochondrial protein import
R-HSA-8963693	Aspartate and asparagine metabolism
R-HSA-9856872	Malate-aspartate shuttle
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism
R-HSA-611105	Respiratory electron transport
R-HSA-71291	Metabolism of amino acids and derivatives
R-HSA-9609507	Protein localization

MSigDB gene sets: 344 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, DACOSTA_UV_RESPONSE_VIA_ERCC3_XPCS_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_AMINO_ACID_TRANSMEMBRANE_TRANSPORT, GOBP_NADPLUS_METABOLIC_PROCESS, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_ORGANIC_ACID_TRANSPORT, GOBP_RESPONSE_TO_METAL_ION, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, MAHAJAN_RESPONSE_TO_IL1A_DN, CEBP_Q2, BILD_E2F3_ONCOGENIC_SIGNATURE, MODULE_206, BROWNE_HCMV_INFECTION_14HR_DN

GO Biological Process (9): aspartate transmembrane transport (GO:0015810), L-glutamate transmembrane transport (GO:0015813), malate-aspartate shuttle (GO:0043490), response to calcium ion (GO:0051592), mitochondrial calcium ion transmembrane transport (GO:0006851), neutral amino acid transport (GO:0015804), transmembrane transport (GO:0055085), L-aspartate transmembrane transport (GO:0070778), proton transmembrane transport (GO:1902600)

GO Molecular Function (9): 3-sulfino-L-alanine: proton, glutamate antiporter activity (GO:0000514), aspartate:glutamate, proton antiporter activity (GO:0000515), L-glutamate transmembrane transporter activity (GO:0005313), calcium ion binding (GO:0005509), L-aspartate transmembrane transporter activity (GO:0015183), identical protein binding (GO:0042802), protein binding (GO:0005515), acidic amino acid transmembrane transporter activity (GO:0015172), metal ion binding (GO:0046872)

GO Cellular Component (3): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Metabolism	2
Protein localization	1
Metabolism of amino acids and derivatives	1
Respiratory electron transport	1
Aerobic respiration and respiratory electron transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
L-amino acid transmembrane transporter activity	3
acidic amino acid transport	2
L-alpha-amino acid transmembrane transport	2
dicarboxylic acid transmembrane transporter activity	2
acidic amino acid transmembrane transporter activity	2
amino acid transmembrane transport	1
C4-dicarboxylate transport	1
nitrogen compound transport	1
carboxylic acid transmembrane transport	1
L-glutamate import	1
L-aspartate:2-oxoglutarate transaminase activity	1
NAD+ metabolic process	1
L-malate dehydrogenase (NAD+) activity	1
mitochondrial transmembrane transport	1
response to metal ion	1
calcium ion transmembrane transport	1
amino acid transport	1
transport	1
cellular process	1
aspartate transmembrane transport	1
monoatomic cation transmembrane transport	1
sulfur amino acid transmembrane transporter activity	1
proton transmembrane transporter activity	1
neutral L-amino acid transmembrane transporter activity	1
modified amino acid transmembrane transporter activity	1
amino acid:monoatomic cation antiporter activity	1
L-aspartate transmembrane transporter activity	1
L-glutamate:proton antiporter activity	1
L-glutamate transmembrane transport	1
metal ion binding	1
C4-dicarboxylate transmembrane transporter activity	1
L-aspartate transmembrane transport	1
protein binding	1
binding	1
amino acid transmembrane transporter activity	1
cation binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1

Protein interactions and networks

STRING

1258 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC25A12	TIMM13	P62206	942
SLC25A12	TIMM8A	O60220	880
SLC25A12	TIMM23	O14925	829
SLC25A12	TIMM9	Q9Y5J7	733
SLC25A12	MTCH1	Q9NZJ7	702
SLC25A12	TIMM10	P62072	681
SLC25A12	INPP1	P49441	639
SLC25A12	STK39	Q9UEW8	630
SLC25A12	ASS1	P00966	626
SLC25A12	MTX2	O75431	621
SLC25A12	MTCH2	Q9Y6C9	565
SLC25A12	SLC1A2	P43004	560
SLC25A12	RAPGEF4	Q8WZA2	549
SLC25A12	SLC25A11	Q02978	503
SLC25A12	DLX1	P56177	495

IntAct

106 interactions, top by confidence:

A	B	Type	Score
RAD51D	RAD51B	psi-mi:“MI:0914”(association)	0.850
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
SLC25A13	SLC25A12	psi-mi:“MI:0915”(physical association)	0.690
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
SLC25A12	MAVS	psi-mi:“MI:0915”(physical association)	0.540
SLC25A12	MAVS	psi-mi:“MI:0403”(colocalization)	0.540
NEURL4	APBB1	psi-mi:“MI:0914”(association)	0.530
HTRA2	HAX1	psi-mi:“MI:2364”(proximity)	0.420
FBXO43	SLC25A12	psi-mi:“MI:0915”(physical association)	0.400
SMAD3	FAM83G	psi-mi:“MI:0915”(physical association)	0.400
AATK	DPM1	psi-mi:“MI:0914”(association)	0.350
PAEP	ESYT2	psi-mi:“MI:0914”(association)	0.350
AKAP5	MRPL43	psi-mi:“MI:0914”(association)	0.350
Pafah1b1	ATXN3	psi-mi:“MI:0914”(association)	0.350
NCSTN	ESYT2	psi-mi:“MI:0914”(association)	0.350
Tbck	FAM20B	psi-mi:“MI:0914”(association)	0.350
Tpx2		psi-mi:“MI:0914”(association)	0.350
VAPA		psi-mi:“MI:0914”(association)	0.350
TM9SF4		psi-mi:“MI:0914”(association)	0.350
NFKB1	NFKB1	psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
	ESYT2	psi-mi:“MI:0914”(association)	0.350
	HAX1	psi-mi:“MI:0914”(association)	0.350

BioGRID (281): SLC25A12 (Affinity Capture-MS), SLC25A12 (Affinity Capture-MS), IMMT (Co-fractionation), SLC25A12 (Co-fractionation), SLC25A12 (Proximity Label-MS), SLC25A12 (Proximity Label-MS), SLC25A12 (Affinity Capture-MS), SLC25A12 (Affinity Capture-MS), SLC25A12 (Affinity Capture-MS), SLC25A12 (Affinity Capture-MS), SLC25A12 (Affinity Capture-MS), SLC25A12 (Affinity Capture-MS), SLC25A12 (Affinity Capture-MS), SLC25A12 (Affinity Capture-MS), SLC25A12 (Affinity Capture-MS)

ESM2 similar proteins: A2ASZ8, A2CEQ0, A5PJZ1, B4F8I5, B8ZHC9, F1LX07, F1LZW6, F4HW79, F4JU70, K7VYZ9, O13805, O18757, O65023, O75746, P0C546, Q05AQ3, Q0P483, Q0V7M4, Q19529, Q20799, Q21153, Q5PQ27, Q5RBC8, Q5XH95, Q5XHA0, Q628Z2, Q66L49, Q6C107, Q6GQS1, Q6KCM7, Q6NUK1, Q6NYZ6, Q7T0U6, Q7ZY36, Q7ZYD5, Q86VD7, Q8BH59, Q8BMD8, Q8BVN7, Q8HXW2

Diamond homologs: A0A0G2K5L2, A2ADF7, A4QNX2, B0G143, F1LX07, F1LZW6, F1RFX9, O13844, O43772, O75746, P16261, P39953, Q02978, Q08DK4, Q0II44, Q12482, Q1DRJ3, Q21153, Q26365, Q3KQZ1, Q3TZX3, Q4V8K4, Q505J6, Q54QN2, Q54RB9, Q552L9, Q58DS3, Q5B717, Q5RBC8, Q5RD81, Q5SWT3, Q5XIF9, Q5ZKP7, Q66L49, Q68F18, Q6ZT89, Q75AH6, Q7PQV7, Q86AV5, Q8BH59

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
calcium(2+)	“up-regulates activity”	SLC25A12	“chemical activation”
SLC25A12	“down-regulates quantity”	“glutamic acid”	relocalization
SLC25A12	“up-regulates quantity”	“aspartic acid”	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 126 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Complex IV assembly	6	19.0×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial respiratory chain complex IV assembly	5	31.5×	4e-04
JNK cascade	5	13.7×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	8
Uncertain significance	236
Likely benign	260
Benign	22

Top pathogenic / likely-pathogenic (23)

Variant ID	HGVS	Classification
1427911	NM_003705.5(SLC25A12):c.845+1del	Pathogenic
1459662	NC_000002.11:g.(?172669829)(172671732_?)del	Pathogenic
1712506	NM_003705.5(SLC25A12):c.1295C>T (p.Ala432Val)	Pathogenic
1712507	NM_003705.5(SLC25A12):c.1447-2_1447-1del	Pathogenic
2122126	NM_003705.5(SLC25A12):c.881dup (p.Leu295fs)	Pathogenic
2150869	NM_003705.5(SLC25A12):c.1057C>T (p.Arg353Ter)	Pathogenic
2283010	NM_003705.5(SLC25A12):c.249_255del (p.Cys85fs)	Pathogenic
2424734	NC_000002.11:g.(?172725171)(172725353_?)del	Pathogenic
2579196	GRCh38/hg38 2q31.1(chr2:171833866-171844606)x0	Pathogenic
2831762	NM_003705.5(SLC25A12):c.1029dup (p.Val344fs)	Pathogenic
2844117	NM_003705.5(SLC25A12):c.28C>T (p.Arg10Ter)	Pathogenic
3338991	NM_003705.5(SLC25A12):c.693del (p.Val232fs)	Pathogenic
6148	NM_003705.5(SLC25A12):c.1769A>G (p.Gln590Arg)	Pathogenic
659960	NM_003705.5(SLC25A12):c.16C>T (p.Gln6Ter)	Pathogenic
813326	GRCh37/hg19 2q31.1(chr2:172644081-172644457)	Pathogenic
1341560	NM_003705.5(SLC25A12):c.410T>C (p.Phe137Ser)	Likely pathogenic
1487115	NM_003705.5(SLC25A12):c.1304_1305+2del	Likely pathogenic
2704123	NM_003705.5(SLC25A12):c.13-1_13del	Likely pathogenic
4076175	NM_003705.5(SLC25A12):c.1747C>T (p.Arg583Ter)	Likely pathogenic
488597	NM_003705.5(SLC25A12):c.1618G>A (p.Asp540Asn)	Likely pathogenic
804390	NM_003705.5(SLC25A12):c.326-2A>C	Likely pathogenic
856800	NM_003705.5(SLC25A12):c.1224+1_1224+2del	Likely pathogenic
982872	NM_003705.5(SLC25A12):c.225del (p.Glu76fs)	Likely pathogenic

SpliceAI

5417 predictions. Top by Δscore:

Variant	Effect	Δscore
2:171785471:GTTTG:G	acceptor_gain	1.0000
2:171785472:TTTG:T	acceptor_gain	1.0000
2:171785473:TTG:T	acceptor_gain	1.0000
2:171785474:TG:T	acceptor_gain	1.0000
2:171785475:GCTGT:G	acceptor_loss	1.0000
2:171785476:C:CC	acceptor_gain	1.0000
2:171785476:CT:C	acceptor_loss	1.0000
2:171785477:T:A	acceptor_loss	1.0000
2:171787533:A:AC	donor_gain	1.0000
2:171787569:A:AC	donor_gain	1.0000
2:171787569:ACAGG:A	donor_gain	1.0000
2:171787570:C:CC	donor_gain	1.0000
2:171787570:CAGG:C	donor_gain	1.0000
2:171787570:CAGGC:C	donor_gain	1.0000
2:171787784:CCTA:C	donor_loss	1.0000
2:171787785:CTACC:C	donor_loss	1.0000
2:171787786:TA:T	donor_loss	1.0000
2:171787787:ACCT:A	donor_loss	1.0000
2:171787825:C:A	donor_gain	1.0000
2:171787837:T:TA	donor_gain	1.0000
2:171787945:CAC:C	acceptor_gain	1.0000
2:171787945:CACC:C	acceptor_loss	1.0000
2:171787945:CACCT:C	acceptor_gain	1.0000
2:171787947:CCT:C	acceptor_gain	1.0000
2:171787948:C:CC	acceptor_gain	1.0000
2:171787949:T:C	acceptor_gain	1.0000
2:171787952:C:CT	acceptor_gain	1.0000
2:171787953:A:T	acceptor_gain	1.0000
2:171791519:T:TC	acceptor_gain	1.0000
2:171809597:AATAC:A	donor_loss	1.0000

AlphaMissense

4406 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:171787633:A:C	F591L	1.000
2:171787633:A:T	F591L	1.000
2:171787634:A:C	F591C	1.000
2:171787635:A:G	F591L	1.000
2:171787636:C:A	Q590H	1.000
2:171787636:C:G	Q590H	1.000
2:171787797:C:T	G579E	1.000
2:171787798:C:A	G579W	1.000
2:171787798:C:G	G579R	1.000
2:171787798:C:T	G579R	1.000
2:171787844:A:C	C563W	1.000
2:171787845:C:T	C563Y	1.000
2:171787892:C:A	Q547H	1.000
2:171787892:C:G	Q547H	1.000
2:171787896:A:G	L546P	1.000
2:171787898:T:A	R545S	1.000
2:171787898:T:G	R545S	1.000
2:171787899:C:G	R545T	1.000
2:171787904:C:A	K543N	1.000
2:171787904:C:G	K543N	1.000
2:171787906:T:C	K543E	1.000
2:171787913:A:C	D540E	1.000
2:171787913:A:T	D540E	1.000
2:171787914:T:A	D540V	1.000
2:171787914:T:C	D540G	1.000
2:171787914:T:G	D540A	1.000
2:171787915:C:A	D540Y	1.000
2:171787915:C:G	D540H	1.000
2:171787938:G:T	A532D	1.000
2:171791539:A:C	F499L	1.000

dbSNP variants (sampled 300 via entrez): RS1000007293 (2:171820933 C>A), RS1000011185 (2:171802161 A>G), RS1000019774 (2:171869356 A>G), RS1000025328 (2:171806704 A>G), RS1000043092 (2:171875826 T>A,C), RS1000074765 (2:171806974 T>C), RS1000081169 (2:171830117 G>A,C,T), RS1000137401 (2:171893083 C>T), RS1000145016 (2:171854630 T>C), RS1000159022 (2:171791015 G>A), RS1000173452 (2:171833635 A>G), RS1000206002 (2:171858771 T>C), RS1000215121 (2:171879530 A>C), RS1000246633 (2:171854971 C>T), RS1000283856 (2:171827064 CAA>C)

Disease associations

OMIM: gene MIM:603667 | disease phenotypes: MIM:612949, MIM:308350

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy, 39	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Moderate	AR

Mondo (3): developmental and epileptic encephalopathy, 39 (MONDO:0013056), developmental and epileptic encephalopathy, 1 (MONDO:0010632), autism spectrum disorder (MONDO:0005258)

Orphanet (2): Epileptic encephalopathy with global cerebral demyelination (Orphanet:353217), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

46 total (30 of 46 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000189	Narrow palate
HP:0000300	Oval face
HP:0000316	Hypertelorism
HP:0000389	Chronic otitis media
HP:0000817	Reduced eye contact
HP:0000954	Single transverse palmar crease
HP:0001182	Tapered finger
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001336	Myoclonus
HP:0001344	Absent speech
HP:0001561	Polyhydramnios
HP:0001667	Right ventricular hypertrophy
HP:0002104	Apnea
HP:0002133	Status epilepticus
HP:0002151	Increased circulating lactate concentration
HP:0002197	Generalized-onset seizure
HP:0002230	Generalized hirsutism
HP:0002307	Drooling
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)
HP:0002421	Poor head control
HP:0002705	High, narrow palate
HP:0003557	Increased variability in muscle fiber diameter
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0003803	Type 1 muscle fiber predominance
HP:0005235	Jejunal atresia

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002337_74	Amyotrophic lateral sclerosis (sporadic)	1.000000e-06
GCST010002_404	Refractive error	2.000000e-39

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567847	Hypomyelination, Global Cerebral (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — Mitochondrial amino acid transporter subfamily

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	5
sodium arsenite	decreases expression, increases expression	3
Benzo(a)pyrene	decreases expression	3
bisphenol A	increases expression	2
entinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Phenylmercuric Acetate	increases expression, affects cotreatment	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
trichostatin A	increases expression	1
cobaltous chloride	decreases expression	1
benzo(e)pyrene	decreases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
obeticholic acid	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Temozolomide	decreases expression	1
Vorinostat	affects cotreatment, increases expression	1
Acetaminophen	affects expression	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Carbamazepine	affects expression	1
Cisplatin	affects reaction, decreases expression	1
Diethylhexyl Phthalate	decreases expression	1

Cellosaurus cell lines

7 cell lines: 7 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1QJ	Abcam K-562 SLC25A12 KO	Cancer cell line	Female
CVCL_D2M5	Abcam Raji SLC25A12 KO	Cancer cell line	Male
CVCL_D4JE	HCT116-SLC25A12-KO-c5	Cancer cell line	Male
CVCL_D4JF	HCT116-SLC25A12-KO-c8	Cancer cell line	Male
CVCL_TM10	HAP1 SLC25A12 (-) 1	Cancer cell line	Male
CVCL_TM11	HAP1 SLC25A12 (-) 2	Cancer cell line	Male
CVCL_WQ54	Abcam Jurkat SLC25A12 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	PHASE3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD
NCT06229210	PHASE3	RECRUITING	Safety and Tolerability Trial of Lumateperone in Pediatric Patients With Schizophrenia, Bipolar Disorder or Autism Spectrum Disorder