SLC25A22

Summary

SLC25A22 (solute carrier family 25 member 22, HGNC:19954) is a protein-coding gene on chromosome 11p15.5, encoding Mitochondrial glutamate carrier 1 (Q9H936). Mitochondrial glutamate/H(+) symporter.

This gene encodes a mitochondrial glutamate carrier. Mutations in this gene are associated with early infantile epileptic encephalopathy. Multiple alternatively spliced variants, encoding the same protein, have been identified.

Source: NCBI Gene 79751 — RefSeq curated summary.

At a glance

• Gene–disease (curated): genetic developmental and epileptic encephalopathy (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 604 total — 15 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 89
• MANE Select transcript: NM_001191061

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19954
Approved symbol	SLC25A22
Name	solute carrier family 25 member 22
Location	11p15.5
Locus type	gene with protein product
Status	Approved
Aliases	GC1, FLJ13044, NET44, EIEE3, GC-1
Ensembl gene	ENSG00000177542
Ensembl biotype	protein_coding
OMIM	609302
Entrez	79751

Gene structure

Transcript identifiers

Ensembl transcripts: 58 — 46 protein_coding, 7 retained_intron, 3 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000320230, ENST00000456706, ENST00000481290, ENST00000524891, ENST00000525010, ENST00000525644, ENST00000526152, ENST00000527127, ENST00000527723, ENST00000527734, ENST00000528606, ENST00000528936, ENST00000529066, ENST00000529351, ENST00000530360, ENST00000531214, ENST00000531437, ENST00000531514, ENST00000531534, ENST00000532361, ENST00000532459, ENST00000532484, ENST00000533385, ENST00000625316, ENST00000625419, ENST00000625752, ENST00000627843, ENST00000628067, ENST00000629602, ENST00000629634, ENST00000630809, ENST00000860084, ENST00000860085, ENST00000860086, ENST00000860087, ENST00000860088, ENST00000860089, ENST00000860090, ENST00000860091, ENST00000860092, ENST00000860093, ENST00000860094, ENST00000860095, ENST00000937623, ENST00000937624, ENST00000937625, ENST00000937626, ENST00000937627, ENST00000937628, ENST00000937629, ENST00000937630, ENST00000937631, ENST00000937632, ENST00000948529, ENST00000948530, ENST00000948531, ENST00000948532, ENST00000948533

RefSeq mRNA: 14 — MANE Select: NM_001191061 NM_001191060, NM_001191061, NM_001425334, NM_001425335, NM_001425336, NM_001425337, NM_001425338, NM_001425339, NM_001425340, NM_001425341, NM_001425342, NM_001425343, NM_001425344, NM_024698

CCDS: CCDS7715

Canonical transcript exons

ENST00000628067 — 10 exons

Exon	Start	End
ENSE00001260819	792142	792217
ENSE00001260828	792304	792458
ENSE00001260832	792553	792727
ENSE00001260862	790475	792068
ENSE00002165630	798217	798281
ENSE00003517277	793529	793619
ENSE00003553508	794987	795169
ENSE00003570442	794458	794513
ENSE00003597031	794776	794901
ENSE00003670107	792870	792988

Expression profiles

Bgee: expression breadth ubiquitous, 228 present calls, max score 98.01.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.2568 / max 103.6236, expressed in 1729 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
117827	6.0183	1607
117825	3.1793	1290
117828	0.5292	296
117822	0.2540	58
117824	0.2021	75
117823	0.0460	26
206077	0.0279	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	98.01	gold quality
cerebellar hemisphere	UBERON:0002245	97.73	gold quality
cerebellar cortex	UBERON:0002129	97.68	gold quality
right frontal lobe	UBERON:0002810	97.32	gold quality
anterior cingulate cortex	UBERON:0009835	97.10	gold quality
cingulate cortex	UBERON:0003027	97.01	gold quality
cerebellum	UBERON:0002037	96.49	gold quality
body of pancreas	UBERON:0001150	95.82	gold quality
prefrontal cortex	UBERON:0000451	95.31	gold quality
amygdala	UBERON:0001876	94.82	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.82	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.21	gold quality
adenohypophysis	UBERON:0002196	94.12	gold quality
frontal cortex	UBERON:0001870	93.88	gold quality
neocortex	UBERON:0001950	93.88	gold quality
pituitary gland	UBERON:0000007	93.48	gold quality
nucleus accumbens	UBERON:0001882	93.33	gold quality
cerebellar vermis	UBERON:0004720	92.84	gold quality
cerebral cortex	UBERON:0000956	92.41	gold quality
telencephalon	UBERON:0001893	91.60	gold quality
cortical plate	UBERON:0005343	91.58	gold quality
forebrain	UBERON:0001890	91.52	gold quality
brain	UBERON:0000955	91.45	gold quality
Ammon’s horn	UBERON:0001954	91.21	gold quality
caudate nucleus	UBERON:0001873	91.15	gold quality
putamen	UBERON:0001874	90.78	gold quality
right lobe of liver	UBERON:0001114	90.76	gold quality
temporal lobe	UBERON:0001871	90.66	gold quality
granulocyte	CL:0000094	90.65	gold quality
hypothalamus	UBERON:0001898	90.14	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	13.32
E-ANND-3	yes	7.63

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

61 targeting SLC25A22, 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-4747-5P	100.00	67.90	2681
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-486-3P	99.51	66.82	1901

Literature-anchored findings (GeneRIF, showing 8)

• A novel SLC25A22 mutation in an unrelated patient born from first cousin Algerian parents and presenting severe epileptic encephalopathy, is described. (PMID:19780765)
• Compares and contrasts all the known human SLC25A* genes and includes functional information. (PMID:23266187)
• SLC25A22 is responsible for migrating partial seizures in infancy, demonstrated by combining linkage analysis and whole exome sequencing. (PMID:24596948)
• SLC25A22 promotes proliferation and migration of colorectal cancer (CRC) cells with KRAS mutations, and formation and metastasis of CRC xenograft tumors in mice. Patients with colorectal tumors expressing increased levels of SLC25A22 have shorter survival times. SLC25A22 induces intracellular synthesis of aspartate. (PMID:27451147)
• SLC25A22 is an important mitochondrial glutamate transporter. (PMID:28255779)
• SLC25A22 is highly expressed in osteosarcoma, promoting osteosarcoma cell proliferation and invasion by inhibiting the phosphatase and tensin homolog signaling pathway (PMID:30482097)
• EIEE type 3 is caused by variants affecting function, in SLC25A22, which is also responsible for epilepsy of infancy with migrating focal seizures (EIMFS). (PMID:31285529)
• In Colorectal Cancer Cells With Mutant KRAS, SLC25A22-Mediated Glutaminolysis Reduces DNA Demethylation to Increase WNT Signaling, Stemness, and Drug Resistance. (PMID:32814111)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Slc25a22	ENSMUSG00000019082
rattus_norvegicus	Slc25a22	ENSRNOG00000049944

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), SLC25A12 (ENSG00000115840), 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)

Protein

Protein identifiers

Mitochondrial glutamate carrier 1 — Q9H936 (reviewed: Q9H936)

Alternative names: Glutamate/H(+) symporter 1, Solute carrier family 25 member 22

All UniProt accessions (18): A0A0A6YYN8, A0A0D9SEI9, A0A0D9SFA8, A0A0D9SFE1, A0A0D9SG84, E9PI74, E9PJH7, Q9H936, E9PJY0, E9PQ36, E9PS95, K4DIA2, K4DIA8, K4DIB0, K4DIB3, K4DIB4, K4DIB6, K4DIB8

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial glutamate/H(+) symporter. Responsible for the transport of glutamate from the cytosol into the mitochondrial matrix with the concomitant import of a proton. Plays a role in the control of glucose-stimulated insulin secretion.

Subcellular location. Mitochondrion inner membrane.

Tissue specificity. Expressed at high levels in brain, liver, and pancreas.

Disease relevance. Developmental and epileptic encephalopathy 3 (DEE3) [MIM:609304] A severe form of epilepsy characterized by frequent tonic seizures or spasms beginning in infancy with a specific EEG finding of suppression-burst patterns, characterized by high-voltage bursts alternating with almost flat suppression phases. DEE3 is characterized by a very early onset, erratic and fragmentary myoclonus, massive myoclonus, partial motor seizures and late tonic spasms. The prognosis is poor, with no effective treatment, and children with the condition either die within 1 to 2 years after birth or survive in a persistent vegetative state. The disease is caused by variants affecting the gene represented in this entry.

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

RefSeq proteins (14): NP_001177989, NP_001177990, NP_001412263, NP_001412264, NP_001412265, NP_001412266, NP_001412267, NP_001412268, NP_001412269, NP_001412270, NP_001412271, NP_001412272, NP_001412273, NP_078974 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002067	MCP	Family
IPR018108	MCP_transmembrane	Repeat
IPR023395	MCP_dom_sf	Homologous_superfamily
IPR051028	Mito_Solute_Carrier	Family

Pfam: PF00153

Catalyzed reactions (Rhea), 1 shown:

• L-glutamate(in) + H(+)(in) = L-glutamate(out) + H(+)(out) (RHEA:70955)

UniProt features (11 total): transmembrane region 6, repeat 3, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H936-F1	78.48	0.07

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-442660	SLC-mediated transport of neurotransmitters
R-HSA-9856872	Malate-aspartate shuttle
R-HSA-428643	Organic anion transport by SLC5/17/25 transporters

MSigDB gene sets: 372 (showing top): MODULE_97, GOBP_INSULIN_SECRETION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_HORMONE_TRANSPORT, MODULE_182, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_AMINO_ACID_TRANSMEMBRANE_TRANSPORT, GOBP_NADPLUS_METABOLIC_PROCESS, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CELL_CELL_SIGNALING, GOBP_ORGANIC_ACID_TRANSPORT, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS

GO Biological Process (8): monoatomic ion transport (GO:0006811), aspartate transmembrane transport (GO:0015810), L-glutamate transmembrane transport (GO:0015813), malate-aspartate shuttle (GO:0043490), regulation of insulin secretion (GO:0050796), transmembrane transport (GO:0055085), L-aspartate transmembrane transport (GO:0070778), proton transmembrane transport (GO:1902600)

GO Molecular Function (4): amino acid:proton symporter activity (GO:0005280), L-glutamate transmembrane transporter activity (GO:0005313), L-aspartate transmembrane transporter activity (GO:0015183), symporter activity (GO:0015293)

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

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
SLC-mediated transmembrane transport	1
Respiratory electron transport	1
SLC-mediated transport of organic anions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	2
L-alpha-amino acid transmembrane transport	2
acidic amino acid transmembrane transporter activity	2
L-amino acid transmembrane transporter activity	2
amino acid transmembrane transport	1
C4-dicarboxylate transport	1
acidic amino acid 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
insulin secretion	1
regulation of protein secretion	1
regulation of peptide hormone secretion	1
cellular process	1
aspartate transmembrane transport	1
monoatomic cation transmembrane transport	1
amino acid:monoatomic cation symporter activity	1
solute:proton symporter activity	1
dicarboxylic acid transmembrane transporter activity	1
L-glutamate transmembrane transport	1
C4-dicarboxylate transmembrane transporter activity	1
L-aspartate transmembrane transport	1
secondary active transmembrane transporter activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1112 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC25A22	PCDH19	Q8TAB3	847
SLC25A22	CDKL5	O76039	819
SLC25A22	PCDH10	Q9P2E7	809
SLC25A22	STXBP1	P61764	808
SLC25A22	PNKP	Q96T60	797
SLC25A22	KCNQ2	O43526	784
SLC25A22	SPTAN1	Q13813	782
SLC25A22	ARX	Q96QS3	781
SLC25A22	ARHGEF9	O43307	763
SLC25A22	PLCB1	Q9NQ66	752
SLC25A22	SCN1A	P35498	741
SLC25A22	SCN2A	Q99250	737
SLC25A22	KCNT1	Q5JUK3	629
SLC25A22	TBC1D24	Q9ULP9	612
SLC25A22	PNPO	Q9NVS9	588

IntAct

134 interactions, top by confidence:

A	B	Type	Score
IKBKB	CHUK	psi-mi:“MI:0914”(association)	0.960
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
BRAF	KRAS	psi-mi:“MI:0914”(association)	0.680
RAF1	CALU	psi-mi:“MI:0914”(association)	0.640
ILK	HAX1	psi-mi:“MI:0914”(association)	0.530
SLC25A22	DNLZ	psi-mi:“MI:0914”(association)	0.530
TUBA1A	TUBAL3	psi-mi:“MI:0914”(association)	0.420
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
AATK	DPM1	psi-mi:“MI:0914”(association)	0.350
ARAF	PPP6C	psi-mi:“MI:0914”(association)	0.350
LIMK2	CALU	psi-mi:“MI:0914”(association)	0.350
Cdc16	ANAPC15	psi-mi:“MI:0914”(association)	0.350
Kctd5		psi-mi:“MI:0914”(association)	0.350
KRBOX4	ASXL2	psi-mi:“MI:0914”(association)	0.350
KDM5C	CSNK2A1	psi-mi:“MI:0914”(association)	0.350
Tubg1	RTL8C	psi-mi:“MI:0914”(association)	0.350
NES	RPL10	psi-mi:“MI:0914”(association)	0.350
Cbx7	E2F6	psi-mi:“MI:0914”(association)	0.350
NFKB1	NFKB1	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350
	ESYT2	psi-mi:“MI:0914”(association)	0.350
	PGRMC1	psi-mi:“MI:0914”(association)	0.350

BioGRID (237): SLC25A22 (Affinity Capture-MS), SLC25A22 (Affinity Capture-MS), SLC25A22 (Affinity Capture-MS), SLC25A22 (Affinity Capture-MS), SLC25A22 (Affinity Capture-MS), SLC25A22 (Affinity Capture-MS), ATP1A3 (Affinity Capture-MS), SLC25A18 (Affinity Capture-MS), WDTC1 (Affinity Capture-MS), DNLZ (Affinity Capture-MS), SLC25A22 (Affinity Capture-MS), SLC25A22 (Affinity Capture-MS), SLC25A22 (Affinity Capture-MS), SLC25A22 (Affinity Capture-MS), SLC25A22 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2K5L2, A0JN87, G3XP90, G3YAF3, O04619, O77792, O95847, O97562, P55851, P55916, P56499, P56500, P56501, P70406, Q08DK4, Q1LZB3, Q29RM1, Q2YDD9, Q3SZI5, Q3TZX3, Q3V132, Q4V9P0, Q505J6, Q5IS35, Q5NVC1, Q5R5A8, Q5RD81, Q5RFB7, Q5ZKP7, Q6DG32, Q6P036, Q6PGY3, Q7K566, Q8BZ09, Q922G0, Q96CQ1, Q99JD3, Q9BQT8, Q9BSK2, Q9C5M0

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

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 154 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
CD209 (DC-SIGN) signaling	6	29.1×	4e-05
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	5	24.3×	2e-04
RAF activation	6	18.8×	1e-04
Signaling by high-kinase activity BRAF mutants	6	17.8×	1e-04
FCERI mediated MAPK activation	5	16.2×	5e-04
FLT3 Signaling	5	16.2×	5e-04
MAP2K and MAPK activation	6	16.0×	2e-04
Signaling by RAF1 mutants	6	15.6×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
peptidyl-tyrosine phosphorylation	5	16.3×	3e-03
negative regulation of cytokine production involved in inflammatory response	5	16.3×	3e-03
intrinsic apoptotic signaling pathway	5	13.9×	3e-03
lysosome organization	5	11.9×	5e-03
MAPK cascade	9	10.7×	2e-04
neuron apoptotic process	7	10.1×	3e-03
rhythmic process	5	9.8×	9e-03
somatic stem cell population maintenance	5	9.6×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	5
Uncertain significance	249
Likely benign	241
Benign	31

Top pathogenic / likely-pathogenic (20)

Variant ID	HGVS	Classification
120308	NM_001191061.2(SLC25A22):c.328G>C (p.Gly110Arg)	Pathogenic
1397414	NM_001191061.2(SLC25A22):c.420del (p.Arg141fs)	Pathogenic
1776	NM_001191061.2(SLC25A22):c.706G>T (p.Gly236Trp)	Pathogenic
2019573	NM_001191061.2(SLC25A22):c.439C>T (p.Gln147Ter)	Pathogenic
2031100	NM_001191061.2(SLC25A22):c.760C>T (p.Gln254Ter)	Pathogenic
207163	NM_001191061.2(SLC25A22):c.146+2_146+3del	Pathogenic
212198	NM_001191061.2(SLC25A22):c.418C>T (p.Gln140Ter)	Pathogenic
2700228	NM_001191061.2(SLC25A22):c.8_12del (p.Asp3fs)	Pathogenic
2701842	NM_001191061.2(SLC25A22):c.658G>T (p.Glu220Ter)	Pathogenic
3646933	NM_001191061.2(SLC25A22):c.452C>A (p.Ser151Ter)	Pathogenic
3655302	NM_001191061.2(SLC25A22):c.4del (p.Ala2fs)	Pathogenic
530429	NM_001191061.2(SLC25A22):c.271C>T (p.Arg91Ter)	Pathogenic
618891	NM_001191061.2(SLC25A22):c.813_814del (p.Ala272fs)	Pathogenic
626258	NM_001191061.2(SLC25A22):c.818G>A (p.Arg273Lys)	Pathogenic
833412	NC_000011.10:g.(?791895)(795026_?)del	Pathogenic
1349233	NM_001191061.2(SLC25A22):c.202+1G>A	Likely pathogenic
1524607	NM_001191061.2(SLC25A22):c.568_587+6del	Likely pathogenic
3347365	NM_001191061.2(SLC25A22):c.587+1G>A	Likely pathogenic
3606108	NM_001191061.2(SLC25A22):c.743-2A>C	Likely pathogenic
620342	NM_001191061.2(SLC25A22):c.13C>T (p.Gln5Ter)	Likely pathogenic

SpliceAI

1718 predictions. Top by Δscore:

Variant	Effect	Δscore
11:792065:CTTC:C	acceptor_gain	1.0000
11:792066:TTC:T	acceptor_gain	1.0000
11:792066:TTCC:T	acceptor_loss	1.0000
11:792067:TC:T	acceptor_gain	1.0000
11:792068:CC:C	acceptor_gain	1.0000
11:792069:C:CC	acceptor_gain	1.0000
11:792070:T:C	acceptor_loss	1.0000
11:792071:G:GC	acceptor_gain	1.0000
11:792137:CCCA:C	donor_loss	1.0000
11:792138:CCAC:C	donor_loss	1.0000
11:792139:CA:C	donor_loss	1.0000
11:792140:AC:A	donor_loss	1.0000
11:792141:C:CA	donor_loss	1.0000
11:792151:T:TA	donor_gain	1.0000
11:792213:CACCA:C	acceptor_gain	1.0000
11:792214:ACCA:A	acceptor_gain	1.0000
11:792215:CCA:C	acceptor_gain	1.0000
11:792215:CCAC:C	acceptor_gain	1.0000
11:792216:CA:C	acceptor_gain	1.0000
11:792216:CAC:C	acceptor_gain	1.0000
11:792217:AC:A	acceptor_loss	1.0000
11:792218:C:CC	acceptor_gain	1.0000
11:792218:CT:C	acceptor_loss	1.0000
11:792298:A:AC	donor_gain	1.0000
11:792299:C:CC	donor_gain	1.0000
11:792300:TGA:T	donor_loss	1.0000
11:792302:A:AC	donor_gain	1.0000
11:792303:C:CC	donor_gain	1.0000
11:792303:CCAT:C	donor_gain	1.0000
11:792338:C:CA	donor_gain	1.0000

AlphaMissense

2057 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:791990:G:C	F299L	1.000
11:791990:G:T	F299L	1.000
11:791992:A:G	F299L	1.000
11:792028:C:G	G287R	1.000
11:792210:C:A	K250N	1.000
11:792210:C:G	K250N	1.000
11:792431:G:C	F205L	1.000
11:792431:G:T	F205L	1.000
11:792432:A:C	F205C	1.000
11:792433:A:G	F205L	1.000
11:792446:G:C	F200L	1.000
11:792446:G:T	F200L	1.000
11:792448:A:G	F200L	1.000
11:792553:C:A	R196M	1.000
11:792886:C:A	Q132H	1.000
11:792886:C:G	Q132H	1.000
11:792890:A:G	L131P	1.000
11:792898:C:A	K128N	1.000
11:792898:C:G	K128N	1.000
11:793571:A:G	L84P	1.000
11:793589:G:T	P78H	1.000
11:794458:C:G	G68R	1.000
11:794458:C:T	G68R	1.000
11:794504:G:C	C52W	1.000
11:794811:C:A	Q37H	1.000
11:794811:C:G	Q37H	1.000
11:794815:A:G	L36P	1.000
11:794823:C:A	K33N	1.000
11:794823:C:G	K33N	1.000
11:794830:A:G	L31P	1.000

dbSNP variants (sampled 300 via entrez): RS1000130238 (11:796316 G>C), RS1000896388 (11:798042 G>A,T), RS1001362352 (11:793272 C>A), RS1001873701 (11:797483 G>A), RS1001946057 (11:794370 C>G,T), RS1001977109 (11:794158 G>A), RS1002172217 (11:797310 G>C), RS1002528290 (11:798342 C>G,T), RS1002843348 (11:795446 A>G,T), RS1002951260 (11:795375 TC>T,TCCC,TCCCCCCCCCC), RS1003290288 (11:790558 A>G), RS1003543378 (11:799105 C>T), RS1003815885 (11:796532 C>T), RS1003961442 (11:793842 C>T), RS1004073980 (11:798223 C>G)

Disease associations

OMIM: gene MIM:609302 | disease phenotypes: MIM:609304

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy, 3	Strong	Autosomal recessive
genetic developmental and epileptic encephalopathy	Supportive	Autosomal dominant
early myoclonic encephalopathy	Supportive	Autosomal dominant
malignant migrating partial seizures of infancy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
genetic developmental and epileptic encephalopathy	Definitive	AR

Mondo (7): early-infantile DEE (MONDO:0800491), developmental and epileptic encephalopathy (MONDO:0100620), developmental and epileptic encephalopathy, 3 (MONDO:0012245), prostate cancer (MONDO:0008315), genetic developmental and epileptic encephalopathy (MONDO:0100062), (MONDO:0016022), malignant migrating partial seizures of infancy (MONDO:0017385)

Orphanet (3): Early infantile developmental and epileptic encephalopathy (Orphanet:1934), Familial prostate cancer (Orphanet:1331), Early myoclonic encephalopathy (Orphanet:1935)

HPO phenotypes

89 total (30 of 89 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000054	Micropenis
HP:0000070	Ureterocele
HP:0000110	Renal dysplasia
HP:0000175	Cleft palate
HP:0000252	Microcephaly
HP:0000340	Sloping forehead
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000649	Abnormality of visual evoked potentials
HP:0000729	Autistic behavior
HP:0000752	Hyperactivity
HP:0000826	Precocious puberty
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis
HP:0001272	Cerebellar atrophy
HP:0001273	Abnormal corpus callosum morphology
HP:0001276	Hypertonia
HP:0001302	Pachygyria
HP:0001319	Neonatal hypotonia
HP:0001332	Dystonia
HP:0001336	Myoclonus
HP:0001337	Tremor
HP:0001347	Hyperreflexia

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004217_5	Fuchs’s corneal dystrophy	7.000000e-07
GCST005580_208	Intraocular pressure	2.000000e-24
GCST90013442_17	Keratoconus	1.000000e-26

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004695	intraocular pressure measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

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

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, decreases expression, affects cotreatment, increases abundance	3
Estradiol	decreases expression, increases expression, affects cotreatment	3
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, affects expression	2
Nickel	increases expression	2
Ozone	affects cotreatment, increases oxidation, increases abundance, affects expression	2
Valproic Acid	affects expression, increases methylation	2
GSK-J4	decreases expression	1
bisphenol F	affects cotreatment, increases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	affects expression	1
perfluorooctanoic acid	increases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Hydrogen Peroxide	affects expression	1

Cellosaurus cell lines

4 cell lines: 2 transformed cell line, 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3H5	Abcam HEK293T SLC25A22 KO	Transformed cell line	Female
CVCL_D4JK	HCT116-SLC25A22-KO-c27	Cancer cell line	Male
CVCL_D6YF	GM28764	Transformed cell line	Male
CVCL_TM23	HAP1 SLC25A22 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer