SLC25A1

Summary

SLC25A1 (solute carrier family 25 member 1, HGNC:10979) is a protein-coding gene on chromosome 22q11.21, encoding Tricarboxylate transport protein, mitochondrial (P53007). Mitochondrial electroneutral antiporter that exports citrate from the mitochondria into the cytosol in exchange for malate. It is a selective cancer dependency (DepMap: 12.7% of cell lines).

This gene encodes a member of the mitochondrial carrier subfamily of solute carrier proteins. Members of this family include nuclear-encoded transporters that translocate small metabolites across the mitochondrial membrane. This protein regulates the movement of citrate across the inner membranes of the mitochondria. Mutations in this gene have been associated with combined D-2- and L-2-hydroxyglutaric aciduria. Pseudogenes of this gene have been identified on chromosomes 7, 11, 16, and 19. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 6576 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 240 total — 8 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 125
• Druggable target: yes
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 3 cancer types
• Cancer dependency (DepMap): dependent in 12.7% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_005984

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10979
Approved symbol	SLC25A1
Name	solute carrier family 25 member 1
Location	22q11.21
Locus type	gene with protein product
Status	Approved
Aliases	CTP, CIC
Ensembl gene	ENSG00000100075
Ensembl biotype	protein_coding
OMIM	190315
Entrez	6576

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 9 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000215882, ENST00000451283, ENST00000461267, ENST00000468824, ENST00000470922, ENST00000880508, ENST00000880509, ENST00000880510, ENST00000880511, ENST00000880512, ENST00000880513, ENST00000923188

RefSeq mRNA: 3 — MANE Select: NM_005984 NM_001256534, NM_001287387, NM_005984

CCDS: CCDS13758, CCDS74817

Canonical transcript exons

ENST00000215882 — 9 exons

Exon	Start	End
ENSE00001140789	19178580	19178736
ENSE00001637785	19175581	19176244
ENSE00003467134	19176846	19176950
ENSE00003501561	19176578	19176693
ENSE00003518231	19177942	19178041
ENSE00003518915	19176421	19176494
ENSE00003563318	19178133	19178240
ENSE00003599535	19177727	19177865
ENSE00003606919	19177120	19177204

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 98.06.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 69.5802 / max 1256.0982, expressed in 1819 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193137	37.5703	1790
193138	23.4881	1815
193135	6.8596	1674
193136	1.3071	770
193139	0.3551	161

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endometrium epithelium	UBERON:0004811	98.06	gold quality
mucosa of transverse colon	UBERON:0004991	97.97	gold quality
right lobe of liver	UBERON:0001114	97.95	gold quality
right adrenal gland cortex	UBERON:0035827	97.09	gold quality
right adrenal gland	UBERON:0001233	97.02	gold quality
left adrenal gland cortex	UBERON:0035825	96.54	gold quality
left adrenal gland	UBERON:0001234	96.50	gold quality
omental fat pad	UBERON:0010414	96.42	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.38	gold quality
adipose tissue of abdominal region	UBERON:0007808	96.38	gold quality
peritoneum	UBERON:0002358	96.36	gold quality
transverse colon	UBERON:0001157	96.27	gold quality
ileal mucosa	UBERON:0000331	96.14	gold quality
duodenum	UBERON:0002114	96.08	gold quality
adrenal cortex	UBERON:0001235	96.07	gold quality
adipose tissue	UBERON:0001013	95.78	gold quality
small intestine	UBERON:0002108	95.68	gold quality
left coronary artery	UBERON:0001626	95.67	gold quality
stromal cell of endometrium	CL:0002255	95.60	gold quality
popliteal artery	UBERON:0002250	95.58	gold quality
tibial artery	UBERON:0007610	95.57	gold quality
adrenal gland	UBERON:0002369	95.48	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.47	gold quality
body of stomach	UBERON:0001161	95.44	gold quality
coronary artery	UBERON:0001621	95.42	gold quality
subcutaneous adipose tissue	UBERON:0002190	95.33	gold quality
aorta	UBERON:0000947	95.23	gold quality
adult mammalian kidney	UBERON:0000082	95.04	gold quality
descending thoracic aorta	UBERON:0002345	94.95	gold quality
right coronary artery	UBERON:0001625	94.92	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	14.31
E-MTAB-9388	yes	12.28

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXA2, MAX, MYC, NFKB, NR1I2, SREBF1, ZNF224

miRNA regulators (miRDB)

15 targeting SLC25A1, 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-96-5P	99.95	72.80	2140
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-4753-5P	99.54	68.51	1356
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-4717-3P	99.06	66.34	1072
HSA-MIR-4324	99.04	70.14	1569
HSA-MIR-3196	98.96	63.91	326
HSA-MIR-5001-3P	98.91	67.28	1394
HSA-MIR-3180	98.46	64.68	348
HSA-MIR-3180-3P	98.46	64.68	348
HSA-MIR-6816-5P	98.46	64.35	364
HSA-MIR-4640-5P	97.42	66.33	1543
HSA-MIR-4726-5P	97.24	65.67	1299
HSA-MIR-4693-3P	95.23	65.92	735

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 12.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 28)

• These results show that methylation, histone acetylation and Sp1 are important in the transcriptional regulation of the CIC proximal promoter. (PMID:18706393)
• These results show that FOXA plays a role in the transcriptional regulation of CIC and in insulin secretion. (PMID:19445897)
• CIC silencer activity extends over 26 bp (-595/-569), which specifically bind a protein ZNF224 present in HepG2 cell nuclear extracts. (PMID:19505435)
• Results suggest an evolutionary conserved role for Sea/SLC25A1 in the regulation of chromosome integrity. (PMID:19654186)
• The results of molecular cloning of a citrate transporter from human normal prostate epithelial PNT2-C2 cells, is reported. (PMID:20448665)
• muscular symptoms of CTP deficiency respond to creatine supplementation (PMID:21660517)
• The mitochondrial citrate carrier: a new player in inflammation (PMID:21787310)
• The mitochondrial citrate carrier (CIC) is present and regulates insulin secretion by human male gamete. (PMID:22355067)
• Compares and contrasts all the known human SLC25A* genes and includes functional information. (PMID:23266187)
• We report for the first time a patient with a mitochondrial citrate carrier deficiency. Our data support a role for citric acid cycle defects in agenesis of corpus callosum (PMID:23393310)
• Deficiency in SLC25A1, encoding the mitochondrial citrate carrier, causes combined D-2- and L-2-hydroxyglutaric aciduria. (PMID:23561848)
• we report for the first time on a patient with a genetically confirmed diagnosis of SLC25A1 deficiency and treatment with either malate or citrate (PMID:24687295)
• SLC25A1 has a key role in TNF-alpha and IFNgamma induced inflammation and is induced at the transcriptional level by these two inflammation mediators cytokines. (PMID:25072865)
• Altered metabolism in 22qDS reflected a critical role for the haploinsufficiency of the mitochondrial citrate transporter SLC25A1, further enhanced by HIF-1alpha, MYC, and metabolite controls. (PMID:26221035)
• this study shows increased expression of SLC25A1 gene in cells from children with Down syndrome (PMID:27502741)
• Pathogenic mutations of the human mitochondrial citrate carrier SLC25A1 lead to impaired citrate export required for lipid, dolichol, ubiquinone and sterol synthesis. (PMID:29031613)
• SLC25A1 mutations might be associated with mitochondrial complex V deficiency and should be considered in the differential diagnosis of mitochondrial respiratory chain defects. (PMID:29226520)
• tested the expression specificity of the Cochlin-tomoprotein by testing blood and CSF samples. The concentration was below the detection limit (0.2 ng/ml) in 38 of the 40 blood, and 14 of the 19 CSF samples (PMID:29377917)
• High expression of mitochondrial citrate transporter was associated with invasion and advanced tumor stage across many human cancers. (PMID:29510993)
• SLC25A1 plays a key role in maintaining the mitochondrial pool of citrate and redox balance in cancer stem cells (CSCs), whereas its inhibition leads to reactive oxygen species build-up thereby inhibiting the self-renewal capability of CSCs. (PMID:29651165)
• SLC25A1 and ACLY upregulation suggests that metabolic reprogramming in Behcet’s syndrome involves the citrate pathway dysregulation. (PMID:30050389)
• Congenital myasthenic syndrome with mild intellectual disability caused by a recurrent SLC25A1 variant. (PMID:31527857)
• Missense mutations in SLC25A1 are associated with congenital myasthenic syndrome type 23. (PMID:31808147)
• Mitochondrial SLC25 Carriers: Novel Targets for Cancer Therapy. (PMID:32455902)
• Targeting Citrate Carrier (CIC) in Inflammatory Macrophages as a Novel Metabolic Approach in COVID-19 Patients: A Perspective. (PMID:34503433)
• Increased expression of SLC25A1/CIC causes an autistic-like phenotype with altered neuron morphology. (PMID:35203088)
• The citrate transporters SLC13A5 and SLC25A1 elicit different metabolic responses and phenotypes in the mouse. (PMID:37689798)
• Oncogenic KRASG12D Reprograms Lipid Metabolism by Upregulating SLC25A1 to Drive Pancreatic Tumorigenesis. (PMID:37695315)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc25a1b	ENSDARG00000076381
danio_rerio	SLC25A1	ENSDARG00000080000
mus_musculus	Slc25a1	ENSMUSG00000003528
rattus_norvegicus	Slc25a1	ENSRNOG00000038001

Paralogs (49): SLC25A13 (ENSG00000004864), SLC25A5 (ENSG00000005022), SLC25A39 (ENSG00000013306), SLC25A40 (ENSG00000075303), SLC25A3 (ENSG00000075415), SLC25A43 (ENSG00000077713), SLC25A24 (ENSG00000085491), 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), UCP2 (ENSG00000175567)

Protein

Protein identifiers

Tricarboxylate transport protein, mitochondrial — P53007 (reviewed: P53007)

Alternative names: Citrate transport protein, Mitochondrial citrate carrier, Solute carrier family 25 member 1, Tricarboxylate carrier protein

All UniProt accessions (2): P53007, D3DX16

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial electroneutral antiporter that exports citrate from the mitochondria into the cytosol in exchange for malate. Also able to mediate the exchange of citrate for isocitrate, phosphoenolpyruvate, cis-aconitate and to a lesser extent trans-aconitate, maleate and succinate. Substrate exchange across the membrane occurs consecutively with one substrate being transported first, then dissociating from the substrate binding site before the second substrate binds for transport in the opposite direction. In the cytoplasm, citrate plays important roles in fatty acid and sterol synthesis, regulation of glycolysis, protein acetylation, and other physiopathological processes.

Subunit / interactions. Monomer.

Subcellular location. Mitochondrion inner membrane.

Post-translational modifications. Possesses a short cleavable presequence, which, however, is found to be dispensable both for targeting to mitochondria and insertion into the inner membrane. However, the presequence is required to keep SLC25A1 in a soluble state and thus in an import-competent state. Mature SLC25A1 lacking the presequence is prone to aggregation.

Disease relevance. Combined D-2- and L-2-hydroxyglutaric aciduria (D2L2AD) [MIM:615182] An autosomal recessive neurometabolic disorder characterized by neonatal-onset encephalopathy with severe muscular weakness, intractable seizures, respiratory distress, and lack of psychomotor development resulting in early death. Brain imaging shows abnormalities including enlarged ventricles, delayed myelination, and germinal layer cysts. The disease is caused by variants affecting the gene represented in this entry. Myasthenic syndrome, congenital, 23, presynaptic (CMS23) [MIM:618197] A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features include easy fatigability and muscle weakness. CMS23 inheritance is autosomal recessive. 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 (3): NP_001243463, NP_001274316, NP_005975* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002067	MCP	Family
IPR018108	MCP_transmembrane	Repeat
IPR023395	MCP_dom_sf	Homologous_superfamily
IPR049563	TXTP-like	Family

Pfam: PF00153

Catalyzed reactions (Rhea), 7 shown:

• citrate(out) + succinate(in) = citrate(in) + succinate(out) (RHEA:28835)
• D-threo-isocitrate(in) + citrate(out) = D-threo-isocitrate(out) + citrate(in) (RHEA:72471)
• cis-aconitate(in) + citrate(out) = cis-aconitate(out) + citrate(in) (RHEA:72475)
• trans-aconitate(in) + citrate(out) = trans-aconitate(out) + citrate(in) (RHEA:72479)
• citrate(out) + (S)-malate(in) = citrate(in) + (S)-malate(out) (RHEA:72483)
• phosphoenolpyruvate(in) + citrate(out) = phosphoenolpyruvate(out) + citrate(in) (RHEA:72487)
• maleate(in) + citrate(out) = maleate(out) + citrate(in) (RHEA:72491)

UniProt features (32 total): sequence variant 19, transmembrane region 6, repeat 3, propeptide 1, chain 1, modified residue 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P53007-F1	75.09	0.00

Functional residue map

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

Post-translational modifications (1): 156

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-428643	Organic anion transport by SLC5/17/25 transporters

MSigDB gene sets: 609 (showing top): GOBP_MEMORY, RNGTGGGC_UNKNOWN, SHEPARD_BMYB_MORPHOLINO_UP, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, WANG_CLIM2_TARGETS_UP, GOBP_COGNITION, MYOGENIN_Q6, GOBP_BEHAVIOR, PAX4_01, MORF_RAB5A, TGCACTT_MIR519C_MIR519B_MIR519A, LFA1_Q6, SHEPARD_CRASH_AND_BURN_MUTANT_UP, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, AAGCCAT_MIR135A_MIR135B

GO Biological Process (4): monoatomic ion transport (GO:0006811), mitochondrial citrate transmembrane transport (GO:0006843), negative regulation of ferroptosis (GO:0110076), transmembrane transport (GO:0055085)

GO Molecular Function (4): citrate transmembrane transporter activity (GO:0015137), tricarboxylic acid transmembrane transporter activity (GO:0015142), antiporter activity (GO:0015297), citrate secondary active transmembrane transporter activity (GO:0071913)

GO Cellular Component (6): nucleus (GO:0005634), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial membrane (GO:0031966), extracellular exosome (GO:0070062), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
SLC-mediated transport of organic anions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	2
citrate transport	2
intracellular membrane-bounded organelle	2
mitochondrial tricarboxylic acid transmembrane transport	1
negative regulation of programmed cell death	1
ferroptosis	1
regulation of ferroptosis	1
cellular process	1
tricarboxylic acid transmembrane transporter activity	1
tricarboxylic acid transmembrane transport	1
carboxylic acid transmembrane transporter activity	1
secondary active transmembrane transporter activity	1
tricarboxylate secondary active transmembrane transporter activity	1
citrate transmembrane transporter activity	1
cytoplasm	1
organelle inner membrane	1
mitochondrial membrane	1
mitochondrion	1
mitochondrial envelope	1
organelle membrane	1
extracellular vesicle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2403 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC25A1	MRPL40	Q9NQ50	820
SLC25A1	ESS2	Q96DF8	809
SLC25A1	CLTCL1	P53675	802
SLC25A1	DGCR2	P98153	799
SLC25A1	GSC2	O15499	780
SLC25A1	ACLY	P53396	775
SLC25A1	CS	O75390	734
SLC25A1	UFD1	Q92890	713
SLC25A1	SLC13A5	Q86YT5	667
SLC25A1	TANGO2	Q6ICL3	666
SLC25A1	CLTC	Q00610	657
SLC25A1	PRODH	O43272	655
SLC25A1	HIRA	P54198	639
SLC25A1	HSPA4	P34932	627
SLC25A1	L2HGDH	Q9H9P8	592

IntAct

193 interactions, top by confidence:

A	B	Type	Score
MAP3K14	CHUK	psi-mi:“MI:0914”(association)	0.950
YBX1	HNRNPR	psi-mi:“MI:0915”(physical association)	0.770
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
RAF1	CALU	psi-mi:“MI:0914”(association)	0.640
FES	DSP	psi-mi:“MI:0914”(association)	0.560
ILK	HAX1	psi-mi:“MI:0914”(association)	0.530
MAP4K1	HSP90AA1	psi-mi:“MI:0914”(association)	0.530
P/V	IRS4	psi-mi:“MI:0914”(association)	0.530
ERBB2	NDUFA4	psi-mi:“MI:0914”(association)	0.530
pipB2	SCD	psi-mi:“MI:0914”(association)	0.460
TUBA1A	TUBAL3	psi-mi:“MI:0914”(association)	0.420
SLC25A1	HSP90B1	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
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
SIK2	BAG2	psi-mi:“MI:0914”(association)	0.350
OTUB1		psi-mi:“MI:0914”(association)	0.350
OTUB1	EPM2A	psi-mi:“MI:0914”(association)	0.350
Itgb1	SSR3	psi-mi:“MI:0914”(association)	0.350
KRBOX4	ASXL2	psi-mi:“MI:0914”(association)	0.350
Tubg1	RTL8C	psi-mi:“MI:0914”(association)	0.350
MLH1	CAPZA2	psi-mi:“MI:0914”(association)	0.350
VAPA		psi-mi:“MI:0914”(association)	0.350
CBX4	SDC2	psi-mi:“MI:0914”(association)	0.350
JUN		psi-mi:“MI:0914”(association)	0.350

BioGRID (353): SLC25A1 (Affinity Capture-MS), SLC25A1 (Affinity Capture-MS), SLC25A1 (Affinity Capture-MS), SLC25A1 (Affinity Capture-MS), SLC25A1 (Affinity Capture-MS), SLC25A1 (Affinity Capture-MS), SLC25A1 (Affinity Capture-MS), SLC25A1 (Affinity Capture-MS), IMMT (Co-fractionation), RPL9 (Co-fractionation), LOC101929876 (Co-fractionation), RPS26 (Co-fractionation), RPS4X (Co-fractionation), SLC25A1 (Co-fractionation), SLC25A1 (Affinity Capture-MS)

ESM2 similar proteins: A6QR09, F1R4U0, F1RFX9, O43772, O46373, O77792, O95258, O97562, O97649, P02722, P05141, P12235, P12236, P22292, P32007, P32089, P48962, P51881, P53007, P55851, P70406, P79110, P97700, Q000K2, Q02978, Q05962, Q08DK4, Q09073, Q3SZI5, Q5PQM9, Q5R5A1, Q5R5A8, Q5SVS4, Q5U680, Q5XGI1, Q6GQ22, Q6QRN9, Q70HW3, Q8HXE3, Q8HXY2

Diamond homologs: A0A0U2IR85, A0A3G9HRV8, F1R4U0, G3YC86, G3YD89, O13844, P22292, P29518, P32089, P33303, P34519, P38152, P53007, P79110, Q09461, Q0CEN9, Q2UCW8, Q5PQM9, Q6PGY3, Q7K566, Q8HXE3, Q8J2Q9, Q8JZU2, Q9M038, Q9UTD6, Q9VWG0, Q9W720, Q9W725, A2CEQ0, A6RAY2, A6SL61, A7ER02, B0DK57, B8ZHC9, G3YFS7, O94502, P55851, P56500, P70406, Q07534

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
SLC25A1	“up-regulates quantity”	citrate(3-)	relocalization
SLC25A1	“up-regulates quantity”	D-threo-isocitrate(3-)	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 216 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
Signaling by ERBB2 ECD mutants	5	22.2×	2e-04
CD209 (DC-SIGN) signaling	5	17.2×	5e-04
FCERI mediated MAPK activation	7	16.0×	7e-05
Signaling by ERBB2 TMD/JMD mutants	5	15.8×	7e-04
Signaling by high-kinase activity BRAF mutants	7	14.7×	8e-05
Signaling by ERBB2 KD Mutants	5	14.0×	9e-04
MAP2K and MAPK activation	7	13.2×	1e-04
Signaling by RAF1 mutants	7	12.9×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of fibroblast proliferation	8	13.4×	1e-04
MAPK cascade	11	9.6×	3e-05
protein autophosphorylation	9	7.4×	1e-03
protein phosphorylation	14	5.4×	2e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 3 cancer types — HCC, LGGNOS, LUAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	13
Uncertain significance	92
Likely benign	90
Benign	11

Top pathogenic / likely-pathogenic (21)

Variant ID	HGVS	Classification
1710697	NM_005984.5(SLC25A1):c.18_24dup (p.Ala9fs)	Pathogenic
2187084	NM_005984.5(SLC25A1):c.529del (p.Gly176_Leu177insTer)	Pathogenic
2368692	NM_005984.5(SLC25A1):c.381_382del (p.Cys127fs)	Pathogenic
2580443	NM_005984.5(SLC25A1):c.628C>T (p.Arg210Ter)	Pathogenic
2846385	NM_005984.5(SLC25A1):c.9_18del (p.Pro4fs)	Pathogenic
449593	NM_005984.5(SLC25A1):c.302+1G>T	Pathogenic
590940	NM_005984.5(SLC25A1):c.740G>A (p.Arg247Gln)	Pathogenic
689643	NM_005984.5(SLC25A1):c.821+1G>A	Pathogenic
1068353	NM_005984.5(SLC25A1):c.748-1G>C	Likely pathogenic
1285451	NM_005984.5(SLC25A1):c.578C>T (p.Ser193Leu)	Likely pathogenic
1678757	NM_005984.5(SLC25A1):c.499G>A (p.Gly167Arg)	Likely pathogenic
3032349	NM_005984.5(SLC25A1):c.25_26dup (p.Ala11fs)	Likely pathogenic
3064199	NM_005984.5(SLC25A1):c.121T>C (p.Cys41Arg)	Likely pathogenic
3065266	NM_005984.5(SLC25A1):c.95-3del	Likely pathogenic
3383846	NM_005984.5(SLC25A1):c.890A>G (p.Tyr297Cys)	Likely pathogenic
3644974	NM_005984.5(SLC25A1):c.631+1G>T	Likely pathogenic
420910	NM_005984.5(SLC25A1):c.657_665delinsGACCTC (p.Asn219_Ile222delinsLysThrSer)	Likely pathogenic
42193	NM_005984.5(SLC25A1):c.844C>G (p.Arg282Gly)	Likely pathogenic
42195	NM_005984.5(SLC25A1):c.845G>A (p.Arg282His)	Likely pathogenic
42197	NM_005984.5(SLC25A1):c.821C>T (p.Ala274Val)	Likely pathogenic
4532370	NM_005984.5(SLC25A1):c.548dup (p.Leu184fs)	Likely pathogenic

SpliceAI

4012 predictions. Top by Δscore:

Variant	Effect	Δscore
19:42284772:G:GG	donor_gain	1.0000
19:42286766:CACA:C	acceptor_loss	1.0000
19:42286769:A:AG	acceptor_gain	1.0000
19:42286769:A:AT	acceptor_loss	1.0000
19:42286769:AGT:A	acceptor_gain	1.0000
19:42286769:AGTGT:A	acceptor_gain	1.0000
19:42286770:G:GT	acceptor_gain	1.0000
19:42286770:GT:G	acceptor_gain	1.0000
19:42286770:GTG:G	acceptor_gain	1.0000
19:42286770:GTGT:G	acceptor_gain	1.0000
19:42286770:GTGTG:G	acceptor_gain	1.0000
19:42286917:AAAGG:A	donor_loss	1.0000
19:42286918:AAGG:A	donor_loss	1.0000
19:42286919:AGGT:A	donor_loss	1.0000
19:42286920:GGT:G	donor_loss	1.0000
19:42286921:GTG:G	donor_loss	1.0000
19:42286922:T:G	donor_loss	1.0000
19:42287004:A:AG	acceptor_gain	1.0000
19:42287005:G:A	acceptor_loss	1.0000
19:42287005:G:GT	acceptor_gain	1.0000
19:42287239:GC:G	donor_gain	1.0000
19:42287241:G:GG	donor_gain	1.0000
19:42287317:CA:C	acceptor_loss	1.0000
19:42287318:A:AG	acceptor_gain	1.0000
19:42287318:A:AT	acceptor_loss	1.0000
19:42287319:G:GA	acceptor_gain	1.0000
19:42287319:GC:G	acceptor_gain	1.0000
19:42287319:GCT:G	acceptor_gain	1.0000
19:42287319:GCTT:G	acceptor_gain	1.0000
19:42287319:GCTTC:G	acceptor_gain	1.0000

AlphaMissense

1998 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:19176184:A:C	F294L	1.000
22:19176184:A:T	F294L	1.000
22:19176186:A:G	F294L	1.000
22:19176234:C:G	G278R	1.000
22:19176590:C:A	K245N	1.000
22:19176590:C:G	K245N	1.000
22:19176611:G:C	N238K	1.000
22:19176611:G:T	N238K	1.000
22:19176623:A:C	S234R	1.000
22:19176623:A:T	S234R	1.000
22:19176625:T:G	S234R	1.000
22:19176645:C:T	G227E	1.000
22:19176907:C:A	K190N	1.000
22:19176907:C:G	K190N	1.000
22:19176930:C:G	G183R	1.000
22:19177862:A:C	F102L	1.000
22:19177862:A:T	F102L	1.000
22:19177864:A:G	F102L	1.000
22:19177942:C:A	R101M	1.000
22:19177948:G:T	A99D	1.000
22:19178185:C:A	K50N	1.000
22:19178185:C:G	K50N	1.000
22:19178203:G:C	F44L	1.000
22:19178203:G:T	F44L	1.000
22:19178205:A:G	F44L	1.000
22:19176191:A:T	I292K	0.999
22:19176194:G:T	A291D	0.999
22:19176207:A:G	C287R	0.999
22:19176234:C:A	G278C	0.999
22:19176456:G:C	C262W	0.999

dbSNP variants (sampled 300 via entrez): RS1002117366 (22:19180535 T>C), RS1003274069 (22:19175138 G>A), RS1003912482 (22:19175398 G>A), RS1003990747 (22:19175652 C>T), RS1005725240 (22:19178469 C>T), RS1005836255 (22:19178299 C>T), RS1006027924 (22:19179641 G>T), RS1006124416 (22:19179387 A>C), RS1006748280 (22:19177419 T>G), RS1006842915 (22:19177172 G>C), RS1009180658 (22:19175915 C>T), RS1009817186 (22:19176270 G>A), RS1009984054 (22:19176015 G>A,C), RS1010497494 (22:19180477 G>C), RS1010845328 (22:19175303 A>G)

Disease associations

OMIM: gene MIM:190315 | disease phenotypes: MIM:618197, MIM:615182, MIM:188400

GenCC curated gene-disease

Disease	Classification	Inheritance
D,L-2-hydroxyglutaric aciduria	Definitive	Autosomal recessive
myasthenic syndrome, congenital, 23, presynaptic	Strong	Autosomal recessive
presynaptic congenital myasthenic syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Mondo (5): 2-hydroxyglutaric aciduria (MONDO:0016001), myasthenic syndrome, congenital, 23, presynaptic (MONDO:0032596), D,L-2-hydroxyglutaric aciduria (MONDO:0014072), DiGeorge syndrome (MONDO:0008564), (MONDO:0020345)

Orphanet (3): 2-hydroxyglutaric aciduria (Orphanet:19), D,L-2-hydroxyglutaric aciduria (Orphanet:356978), 22q11.2 deletion syndrome (Orphanet:567)

HPO phenotypes

125 total (30 of 125 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000276	Long face
HP:0000308	Microretrognathia
HP:0000369	Low-set ears
HP:0000407	Sensorineural hearing impairment
HP:0000467	Neck muscle weakness
HP:0000508	Ptosis
HP:0000565	Esotropia
HP:0000602	Ophthalmoplegia
HP:0000639	Nystagmus
HP:0000651	Diplopia
HP:0000729	Autistic behavior
HP:0000733	Motor stereotypy
HP:0000737	Irritability
HP:0000739	Anxiety
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0000768	Pectus carinatum
HP:0000817	Reduced eye contact
HP:0000961	Cyanosis
HP:0000988	Skin rash
HP:0001166	Arachnodactyly
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001391_7	Metabolite levels	3.000000e-16
GCST001639_30	Metabolite levels	3.000000e-11
GCST009391_343	Metabolite levels	6.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004725	metabolite measurement
EFO:0004723	coronary artery calcification
EFO:0010433	triacylglycerol 56:6 measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D004062	DiGeorge Syndrome	C05.660.207.103.500; C14.240.400.021.500; C14.280.400.044.500; C15.604.451.249.500; C16.131.077.019.500; C16.131.240.400.021.500; C16.131.260.019.500; C16.131.482.249.500; C16.131.621.207.103.500; C16.320.180.019.500; C19.642.482.500.500
C535306	2-Hydroxyglutaricaciduria (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5465271 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — Mitochondrial di- and tri-carboxylic acid transporter subfamily

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
CTPI-2	Inhibition	5.46	pKd

ChEMBL bioactivities

5 potent at pChembl≥5 of 7 total, top 5 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.46	Kd	3500	nM	CHEMBL5421017
5.36	Kd	4379	nM	CHEMBL3752910
5.36	ED50	4379	nM	CHEMBL3752910
5.32	Kd	4785	nM	CHEMBL5653589
5.32	ED50	4785	nM	CHEMBL5653589

PubChem BioAssay actives

3 with measured affinity, of 10 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(4-chloro-3-nitrophenyl)sulfonylamino]benzoic acid	1997689: Binding affinity to human SLC25A1 assessed as dissociation constant	kd	3.5000	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149405: Binding affinity to human SLC25A1 incubated for 45 mins by Kinobead based pull down assay	kd	4.3789	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149405: Binding affinity to human SLC25A1 incubated for 45 mins by Kinobead based pull down assay	kd	4.7851	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, increases expression	5
Cyclosporine	decreases expression	4
sodium arsenite	decreases expression, increases expression	2
Benzo(a)pyrene	decreases expression	2
Cisplatin	increases expression, affects cotreatment	2
Dexamethasone	increases expression, affects cotreatment	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Aflatoxin B1	affects expression, decreases expression, decreases methylation	2
Cadmium Chloride	increases abundance, increases expression	2
Particulate Matter	decreases expression, increases abundance, affects expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	increases expression, increases reaction, affects binding, affects cotreatment	1
afimoxifene	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluorooctanoic acid	increases expression	1
sulindac sulfide	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
pentabromodiphenyl ether	decreases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
K 7174	decreases expression	1
obeticholic acid	decreases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
bisphenol S	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5350815	Binding	Inhibition of SLC25A1 (unknown origin) at 1 uM relative to control	Opportunities and Challenges for Inhibitors Targeting Citrate Transport and Metabolism in Drug Discovery. — J Med Chem

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D4J9	HCT116-SLC25A1-KO-c12	Cancer cell line	Male
CVCL_D4JA	HCT116-SLC25A1-KO-c2	Cancer cell line	Male
CVCL_TM03	HAP1 SLC25A1 (-) 1	Cancer cell line	Male
CVCL_TM04	HAP1 SLC25A1 (-) 2	Cancer cell line	Male
CVCL_TM05	HAP1 SLC25A1 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00395538	PHASE3	TERMINATED	Effects of PTH Replacement on Bone in Hypoparathyroidism
NCT00576407	PHASE2	COMPLETED	Thymus Transplantation in DiGeorge Syndrome #668
NCT00576836	PHASE2	COMPLETED	Thymus Transplantation Dose in DiGeorge #932
NCT01821781	PHASE2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT05149898	PHASE2	COMPLETED	Open-Label Study of ZYN002 Administered as a Transdermal Gel to Children and Adolescents With 22q11.2 Deletion Syndrome (INSPIRE)
NCT07284641	PHASE2	RECRUITING	Hematopoietic Stem Cell Transplantation (HSCT) for Common Variable Immunodeficiency (CVID) and Other Autoimmune Manifestations of Primary Immune Regulatory Disorders (PIRD)
NCT00566488	PHASE1	COMPLETED	Parathyroid and Thymus Transplantation in DiGeorge #931
NCT00579709	PHASE1	COMPLETED	Thymus Transplantation With Immunosuppression
NCT00849888	PHASE1	TERMINATED	Serum-Free Thymus Transplantation in DiGeorge Anomaly
NCT02895906	PHASE1	COMPLETED	Safety and Efficacy Study of NFC-1 in Subjects Aged 12-17 Years With 22q11.2DS & Associated Neuropsychiatric Conditions
NCT00579527	PHASE1/PHASE2	COMPLETED	Phase I/II Thymus Transplantation With Immunosuppression #950
NCT00004351	Not specified	COMPLETED	Study of Phenotype and Genotype Correlations in Patients With Contiguous Gene Deletion Syndromes
NCT00005102	Not specified	UNKNOWN	Immunologic Evaluation in Patients With DiGeorge Syndrome or Velocardiofacial Syndrome
NCT00105274	Not specified	COMPLETED	Velocardiofacial (VCFS; 22q11.2; DiGeorge) Syndrome Study
NCT00278005	Not specified	TERMINATED	Infection in DiGeorge Following CHD Surgery
NCT00556530	Not specified	RECRUITING	Examining Genetic Factors That Affect the Severity of 22q11.2 Deletion Syndrome
NCT00916955	Not specified	COMPLETED	Genetic Modifiers for 22q11.2 Syndrome
NCT01220531	Not specified	COMPLETED	Thymus Transplantation Safety-Efficacy
NCT01781923	Not specified	COMPLETED	Cognitive Remediation in 22q11DS
NCT02381457	Not specified	COMPLETED	SNP-based Microdeletion and Aneuploidy RegisTry (SMART)
NCT02430584	Not specified	UNKNOWN	Whole Blood Specimen Collection From Pregnant Subjects
NCT02460328	Not specified	COMPLETED	Resolution of Primary Immune Defect in 22q11.2 Deletion Syndrome
NCT02787486	Not specified	COMPLETED	Expanded Noninvasive Genomic Medical Assessment: The Enigma Study
NCT03284060	Not specified	TERMINATED	Social Cognition Training and Cognitive Remediation
NCT04141540	Not specified	COMPLETED	Molecular Variants Associated With Schizophrenia: Differential Analysis of Monozygotic Twins With Variable Phenotypic 22q11
NCT04373226	Not specified	TERMINATED	Arithmetic Abilities in Children With 22q11.2DS
NCT04639388	Not specified	RECRUITING	Understanding of Psychotic Disorders in Children With 22q11.2DS
NCT04639960	Not specified	TERMINATED	Neuroprotective Effects of Risperdal on Brain and Cognition in 22q11 Deletion Syndrome
NCT04647500	Not specified	COMPLETED	Effects of Methylphenidate on Brain and Cognition in 22q11 Deletion Syndrome
NCT05924347	Not specified	RECRUITING	Early Scoliotic Changes in Children at Increased Risk for Scoliosis Development
NCT07493096	Not specified	RECRUITING	Intensive Multimodal Neurorehabilitation Targeting Neuroplasticity in Pediatric Neurodevelopmental and Chromosomal Disorders