SLC25A46

Summary

SLC25A46 (solute carrier family 25 member 46, HGNC:25198) is a protein-coding gene on chromosome 5q22.1, encoding Mitochondrial outer membrane protein SLC25A46 (Q96AG3). Transmembrane protein of the mitochondrial outer membrane that controls mitochondrial organization.

This gene encodes a mitochondrial solute carrier protein family member. It functions in promoting mitochondrial fission, and prevents the formation of hyperfilamentous mitochondria. Mutation of this gene results in neuropathy and optic atrophy.

Source: NCBI Gene 91137 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neuropathy, hereditary motor and sensory, type 6B (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 35
• Clinical variants (ClinVar): 448 total — 23 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 70
• MANE Select transcript: NM_138773

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25198
Approved symbol	SLC25A46
Name	solute carrier family 25 member 46
Location	5q22.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000164209
Ensembl biotype	protein_coding
OMIM	610826
Entrez	91137

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 6 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000355943, ENST00000447245, ENST00000502462, ENST00000504098, ENST00000508781, ENST00000509432, ENST00000513706, ENST00000513807, ENST00000923605

RefSeq mRNA: 3 — MANE Select: NM_138773 NM_001303249, NM_001303250, NM_138773

CCDS: CCDS4100, CCDS78045

Canonical transcript exons

ENST00000355943 — 8 exons

Exon	Start	End
ENSE00001949622	110739007	110739402
ENSE00003465276	110746269	110746346
ENSE00003492538	110755465	110755521
ENSE00003500299	110742047	110742089
ENSE00003562616	110748163	110748263
ENSE00003593492	110743730	110743787
ENSE00003597520	110756702	110756759
ENSE00003842152	110761204	110765157

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 97.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.3496 / max 434.1932, expressed in 1813 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
57953	28.5600	1813
57954	0.7715	343
57952	0.0122	3
57951	0.0058	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	97.93	gold quality
secondary oocyte	CL:0000655	97.93	gold quality
oocyte	CL:0000023	96.13	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.92	gold quality
heart right ventricle	UBERON:0002080	95.41	gold quality
calcaneal tendon	UBERON:0003701	95.33	gold quality
substantia nigra pars compacta	UBERON:0001965	94.66	gold quality
biceps brachii	UBERON:0001507	94.56	gold quality
male germ cell	CL:0000015	94.46	gold quality
jejunal mucosa	UBERON:0000399	94.18	gold quality
pons	UBERON:0000988	93.99	gold quality
substantia nigra pars reticulata	UBERON:0001966	93.83	gold quality
jejunum	UBERON:0002115	93.64	gold quality
muscle of leg	UBERON:0001383	93.54	gold quality
gastrocnemius	UBERON:0001388	93.49	gold quality
skin of hip	UBERON:0001554	93.47	gold quality
superior vestibular nucleus	UBERON:0007227	93.47	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.41	gold quality
deltoid	UBERON:0001476	93.30	gold quality
skeletal muscle tissue	UBERON:0001134	93.12	gold quality
muscle organ	UBERON:0001630	93.02	gold quality
cortical plate	UBERON:0005343	92.89	gold quality
islet of Langerhans	UBERON:0000006	92.88	gold quality
left ventricle myocardium	UBERON:0006566	92.88	gold quality
tibialis anterior	UBERON:0001385	92.82	gold quality
mucosa of sigmoid colon	UBERON:0004993	92.79	gold quality
adrenal tissue	UBERON:0018303	92.78	gold quality
postcentral gyrus	UBERON:0002581	92.77	gold quality
parietal lobe	UBERON:0001872	92.74	gold quality
colonic mucosa	UBERON:0000317	92.73	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

171 targeting SLC25A46, 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-3163	100.00	77.23	8605
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426

Literature-anchored findings (GeneRIF, showing 15)

• Compares and contrasts all the known human SLC25A* genes and includes functional information. (PMID:23266187)
• Rs17132261 was associated with left ventricular hypertrophy in type 2 diabetic patients. (PMID:23879873)
• Data indicate four families with recessive mutations in solute carrier family 25 member 46 protein (SLC25A46). (PMID:26168012)
• The rs10056340 single nucleotide polymorphism was significantly associated with atopic dermatitis. (PMID:26464032)
• These results show that SLC25A46 plays a role in a mitochondrial/endoplasmic reticulum pathway that facilitates lipid transfer, and link altered mitochondrial dynamics to early-onset neurodegenerative disease and cell fate decisions. (PMID:27390132)
• This study identified of a homozygous missense mutation c.1022T>C and a homozygous genomic deletion involving exon 1 in SLC25A46 encoding a mitochondrial protein leading to lethal pontocerebellar hypoplasia with apnoea and profound weakness. (PMID:27543974)
• SLC25A46 is selectively degraded from the outer membrane independently of mitophagy and apoptosis, providing a framework for mechanistic studies in the proteolysis of outer membrane proteins (PMID:28057766)
• Mutation in SLC25A46 (NM_001303249.2:c.775C>T;p.(Arg259Cys)) causes optic atrophy and progressive limb spasticity, with no cerebellar atrophy or axonal neuropathy. (PMID:28369803)
• we showed that the Slc25a46 disruption caused a fusion/fission imbalance and an abnormal mitochondrial architecture that disturbed mitochondrial metabolism. These data extended the range of phenotypes associated with Slc25a46 dysfunction. Moreover, this Slc25a46 knock-out mouse model should be useful to further elucidate the role of SLC25A46 in mitochondrial dynamics (PMID:28376083)
• Our mutant mice provide a valid model for understanding the mechanistic basis of the complex SLC25A46-mediated pathologies, as well as for screening potential therapeutic interventions. (PMID:28376086)
• This study reported a novel variant (p.Trp160Ser) in SLC25A46 and we broaden the phenotypic spectrum associated with mutations in SLC25A46. (PMID:28558379)
• Mutations in SLC25A46 were linked to three children in a Dutch family with pontocerebellar hypoplasia with spinal muscular dystrophy. (PMID:28637197)
• Using exome sequencing, we identified biallelic disease-segregating loss-of-function mutations in SLC25A46 in both families. Our study adds to the definition of the SLC25A46-associated phenotypic spectrum that includes neonatal fatalities due to pontocerebellar hypoplasia as the severe extreme. (PMID:28653766)
• SLC25A46 mutations in patients with Parkinson’s Disease and optic atrophy. (PMID:32259769)
• The role of the mitochondrial outer membrane protein SLC25A46 in mitochondrial fission and fusion. (PMID:36977595)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc25a46	ENSDARG00000035181
mus_musculus	Slc25a46	ENSMUSG00000024259
rattus_norvegicus	Slc25a46	ENSRNOG00000017091
drosophila_melanogaster	Slc25A46a	FBGN0030717
drosophila_melanogaster	Slc25A46b	FBGN0032664
caenorhabditis_elegans	slc-25A46	WBGENE00012740

Protein

Protein identifiers

Mitochondrial outer membrane protein SLC25A46 — Q96AG3 (reviewed: Q96AG3)

Alternative names: Solute carrier family 25 member 46

All UniProt accessions (3): B7Z6C8, E7EVY2, Q96AG3

UniProt curated annotations — full annotation on UniProt →

Function. Transmembrane protein of the mitochondrial outer membrane that controls mitochondrial organization. May regulate the assembly of the MICOS (mitochondrial contact site and cristae organizing system) complex which is essential to the biogenesis and dynamics of mitochondrial cristae, the inwards folds of the inner mitochondrial membrane. Through its interaction with the EMC (endoplasmic reticulum membrane protein complex), could regulate mitochondrial lipid homeostasis and thereby mitochondrial fission.

Subunit / interactions. Associates with the mitochondrial contact site and cristae organizing system (MICOS) complex. May associate with the endoplasmic reticulum membrane protein complex (EMC).

Subcellular location. Mitochondrion outer membrane.

Disease relevance. Neuropathy, hereditary motor and sensory, 6B, with optic atrophy (HMSN6B) [MIM:616505] An autosomal recessive neurologic disorder characterized by early-onset optic atrophy, progressive visual loss, and peripheral sensorimotor neuropathy manifesting as axonal Charcot-Marie-Tooth disease, with variable age at onset and severity. Charcot-Marie-Tooth disease is a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. It is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies and primary peripheral axonal neuropathies. Peripheral axonal neuropathies are characterized by signs of axonal regeneration in the absence of obvious myelin alterations, and normal or slightly reduced nerve conduction velocities. The disease is caused by variants affecting the gene represented in this entry. Pontocerebellar hypoplasia 1E (PCH1E) [MIM:619303] A form of pontocerebellar hypoplasia, a disorder characterized by structural defects of the pons and cerebellum, evident upon brain imaging. PCH1E is an autosomal recessive form characterized by severe hypotonia and respiratory insufficiency apparent soon after birth. Additional features may include optic atrophy, peripheral neuropathy, dysmorphic features, congenital contracture or foot deformities, and seizures. Death occurs in the first days or weeks of life. Postmortem brain imaging show pontocerebellar atrophy and loss of anterior motor neurons in the spinal cord. The disease is caused by variants affecting the gene represented in this entry.

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

Isoforms (3)

UniProt ID	Names	Canonical?
Q96AG3-1	1	yes
Q96AG3-2	2
Q96AG3-3	3

RefSeq proteins (3): NP_001290178, NP_001290179, NP_620128* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR018108	MCP_transmembrane	Repeat
IPR023395	MCP_dom_sf	Homologous_superfamily
IPR039158	SLC25A46	Family

Pfam: PF00153

UniProt features (25 total): sequence variant 10, transmembrane region 6, region of interest 2, modified residue 2, splice variant 2, repeat 2, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8TMU	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96AG3-F1	74.65	0.42

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 (2): 32, 45

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 347 (showing top): GOBP_DENDRITE_DEVELOPMENT, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_METENCEPHALON_DEVELOPMENT, GOBP_BEHAVIOR, GOBP_RESPIRATORY_CHAIN_COMPLEX_IV_ASSEMBLY, GOBP_SYNAPSE_ASSEMBLY, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_CEREBELLAR_PURKINJE_CELL_LAYER_FORMATION, GOBP_GLIAL_CELL_DEVELOPMENT, GOBP_CEREBELLAR_CORTEX_MORPHOGENESIS, GOBP_NEUROGENESIS, GOBP_CRANIAL_NERVE_DEVELOPMENT, GOBP_MITOCHONDRIAL_TRANSPORT, GOBP_CRISTAE_FORMATION, GOBP_CYTOCHROME_COMPLEX_ASSEMBLY

GO Biological Process (17): mitochondrial fission (GO:0000266), autophagy of mitochondrion (GO:0000422), mitochondrial transport (GO:0006839), synapse assembly (GO:0007416), respiratory chain complex IV assembly (GO:0008535), dendrite development (GO:0016358), optic nerve development (GO:0021554), cerebellar Purkinje cell differentiation (GO:0021702), myelination in peripheral nervous system (GO:0022011), locomotion involved in locomotory behavior (GO:0031987), cristae formation (GO:0042407), peripheral nervous system neuron axonogenesis (GO:0048936), phospholipid homeostasis (GO:0055091), axon development (GO:0061564), protein-containing complex assembly (GO:0065003), mitochondrial membrane fission (GO:0090149), mitochondrion organization (GO:0007005)

GO Molecular Function (2): protein-containing complex binding (GO:0044877), protein binding (GO:0005515)

GO Cellular Component (3): mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
neuron projection development	2
binding	2
mitochondrion organization	1
organelle fission	1
autophagy	1
intracellular transport	1
nervous system development	1
cell junction assembly	1
synapse organization	1
cytochrome complex assembly	1
anatomical structure development	1
cranial nerve development	1
cell differentiation in hindbrain	1
cerebellar Purkinje cell layer formation	1
central nervous system neuron differentiation	1
Schwann cell development	1
peripheral nervous system axon ensheathment	1
myelination	1
locomotory behavior	1
locomotion	1
inner mitochondrial membrane organization	1
axonogenesis	1
peripheral nervous system neuron development	1
lipid homeostasis	1
cellular component assembly	1
protein-containing complex organization	1
mitochondrial fission	1
membrane fission	1
organelle organization	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrial membrane	1
organelle outer membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1136 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC25A46	MFN2	O95140	781
SLC25A46	REEP5	Q00765	670
SLC25A46	OPA1	O60313	657
SLC25A46	TMEM232	C9JQI7	623
SLC25A46	H2BC21	Q16778	507
SLC25A46	H2AC20	Q16777	479
SLC25A46	H2AC19	P20670	479
SLC25A46	EMSY	Q7Z589	474
SLC25A46	OR10A3	P58181	470
SLC25A46	DNAJC11	Q9NVH1	468
SLC25A46	SLC25A48	Q6ZT89	467
SLC25A46	GDAP1	Q8TB36	464
SLC25A46	MFN1	Q8IWA4	453
SLC25A46	CHD7	Q9P2D1	418
SLC25A46	SLC25A17	O43808	417

IntAct

104 interactions, top by confidence:

A	B	Type	Score
SLC25A46	FHL3	psi-mi:“MI:0915”(physical association)	0.720
FHL3	SLC25A46	psi-mi:“MI:0915”(physical association)	0.720
FUNDC1	SLC25A46	psi-mi:“MI:0915”(physical association)	0.560
AQP6	SLC25A46	psi-mi:“MI:0915”(physical association)	0.560
SLC25A46	HSD17B13	psi-mi:“MI:0915”(physical association)	0.560
SLC25A46	AQP6	psi-mi:“MI:0915”(physical association)	0.560
SLC25A46	REEP2	psi-mi:“MI:0915”(physical association)	0.560
SLC66A2	SLC25A46	psi-mi:“MI:0915”(physical association)	0.560
SLC10A1	SLC25A46	psi-mi:“MI:0915”(physical association)	0.560
	SLC25A46	psi-mi:“MI:0915”(physical association)	0.560
ODF4	SLC25A46	psi-mi:“MI:0915”(physical association)	0.560
SLC25A46	SLC7A8	psi-mi:“MI:0915”(physical association)	0.560
SLC25A46	REEP4	psi-mi:“MI:0915”(physical association)	0.560
MFSD14B	SLC25A46	psi-mi:“MI:0915”(physical association)	0.560
SLC10A6	SLC25A46	psi-mi:“MI:0915”(physical association)	0.560
HSD17B13	SLC25A46	psi-mi:“MI:0915”(physical association)	0.560
VMA21	SLC25A46	psi-mi:“MI:0915”(physical association)	0.560
HSD17B11	SLC25A46	psi-mi:“MI:0915”(physical association)	0.560
LEPROTL1	SLC25A46	psi-mi:“MI:0915”(physical association)	0.560
APLNR	METTL15	psi-mi:“MI:0914”(association)	0.530
SLC15A1	METTL15	psi-mi:“MI:0914”(association)	0.530
IL13RA2	METTL15	psi-mi:“MI:0914”(association)	0.530
GCNT1	UBA52	psi-mi:“MI:0914”(association)	0.530

BioGRID (317): SLC25A46 (Two-hybrid), FUNDC1 (Two-hybrid), SLC25A46 (Affinity Capture-MS), OPA1 (Affinity Capture-MS), SLC25A46 (Affinity Capture-MS), SLC25A46 (Affinity Capture-MS), SLC25A46 (Affinity Capture-MS), SLC25A46 (Affinity Capture-MS), SLC25A46 (Affinity Capture-MS), SLC25A46 (Affinity Capture-MS), SLC25A46 (Affinity Capture-MS), SLC25A46 (Affinity Capture-MS), SLC25A46 (Affinity Capture-MS), SLC25A46 (Affinity Capture-MS), SLC25A46 (Affinity Capture-MS)

ESM2 similar proteins: A1D3P4, A2QPL8, A4IIC3, A5DAI1, B0XPV4, B2WFD4, C0NLX2, C0RZV6, C1G565, C1GZK1, C4JDF8, C5GN10, C5JCV0, C6H4B5, D4AT37, D4DGR3, D6WMX4, E0W1I1, O14681, O94502, P0C0R5, Q03327, Q08DE5, Q0V3D6, Q1E4N0, Q20799, Q21153, Q2UBI2, Q4KM77, Q4WJ38, Q568N3, Q5EB62, Q5H9E4, Q5IRJ6, Q5PQZ3, Q5R9I3, Q5ZIG3, Q61070, Q63ZR7, Q6DCE3

Diamond homologs: A4IIC3, F4HT41, Q5EB62, Q5ZIG3, Q63ZR7, Q6DGU5, Q6INQ6, Q96AG3, Q9CQS4

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 95 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
R-HSA-549132	5	60.4×	2e-06
R-HSA-425366	6	17.3×	1e-04
SLC-mediated transmembrane transport	14	13.2×	7e-10
R-HSA-425393	6	12.4×	7e-04
Clathrin-mediated endocytosis	6	8.1×	5e-03
Transport of small molecules	17	6.8×	4e-08

GO biological processes:

GO term	Partners	Fold	FDR
monoatomic ion transport	6	10.4×	1e-02
transport across blood-brain barrier	5	10.0×	1e-02
phospholipase C-activating G protein-coupled receptor signaling pathway	6	8.8×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	23
Likely pathogenic	13
Uncertain significance	211
Likely benign	145
Benign	27

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1066712	NM_138773.4(SLC25A46):c.996C>G (p.Tyr332Ter)	Pathogenic
1068765	NM_138773.4(SLC25A46):c.691C>T (p.Arg231Ter)	Pathogenic
1068766	NM_138773.4(SLC25A46):c.326+549_385-1240del	Pathogenic
1068768	NM_138773.4(SLC25A46):c.42C>G (p.Tyr14Ter)	Pathogenic
1071280	NC_000005.9:g.(?_110074821)_110097482del	Pathogenic
1441240	NM_138773.4(SLC25A46):c.618del (p.Lys206fs)	Pathogenic
2427269	NC_000005.9:g.(?110074821)(110097482_?)del	Pathogenic
2443748	NM_138773.4(SLC25A46):c.479G>C (p.Trp160Ser)	Pathogenic
2762448	NM_138773.4(SLC25A46):c.462+2T>C	Pathogenic
2767905	NM_138773.4(SLC25A46):c.598_599dup (p.His202fs)	Pathogenic
372237	NM_138773.4(SLC25A46):c.166dup (p.His56fs)	Pathogenic
372239	NM_138773.4(SLC25A46):c.1005A>T (p.Glu335Asp)	Pathogenic
372241	NM_138773.4(SLC25A46):c.998C>T (p.Pro333Leu)	Pathogenic
374892	NM_138773.4(SLC25A46):c.1022T>C (p.Leu341Pro)	Pathogenic
374893	NM_138773.4(SLC25A46):c.413T>G (p.Leu138Arg)	Pathogenic
374894	NM_138773.4(SLC25A46):c.425C>T (p.Thr142Ile)	Pathogenic
422422	NM_138773.4(SLC25A46):c.11_12insTG (p.Arg5fs)	Pathogenic
4704727	NM_138773.4(SLC25A46):c.1006del (p.Thr336fs)	Pathogenic
652950	NC_000005.10:g.(?110743720)(110743797_?)del	Pathogenic
655776	NM_138773.4(SLC25A46):c.47del (p.Gly16fs)	Pathogenic
834307	NM_138773.4(SLC25A46):c.185_189del (p.Pro62fs)	Pathogenic
938735	NM_138773.4(SLC25A46):c.462+1G>A	Pathogenic
969384	NM_138773.4(SLC25A46):c.799_800dup (p.Thr268fs)	Pathogenic
1334589	NM_138773.4(SLC25A46):c.479G>A (p.Trp160Ter)	Likely pathogenic
1468442	NM_138773.4(SLC25A46):c.385-2A>T	Likely pathogenic
1768819	NM_138773.4(SLC25A46):c.998del (p.Pro333fs)	Likely pathogenic
3018331	NM_138773.4(SLC25A46):c.620+1G>A	Likely pathogenic
3022230	NM_138773.4(SLC25A46):c.327-2A>C	Likely pathogenic
3382951	NM_138773.4(SLC25A46):c.674T>G (p.Val225Gly)	Likely pathogenic
372240	NM_138773.4(SLC25A46):c.882_885dup (p.Asn296fs)	Likely pathogenic

SpliceAI

1237 predictions. Top by Δscore:

Variant	Effect	Δscore
5:110739400:GTG:G	donor_gain	1.0000
5:110742040:A:AG	acceptor_gain	1.0000
5:110742045:A:AG	acceptor_gain	1.0000
5:110742046:G:GG	acceptor_gain	1.0000
5:110746263:TTACA:T	acceptor_loss	1.0000
5:110746264:TACA:T	acceptor_loss	1.0000
5:110746265:ACAGG:A	acceptor_loss	1.0000
5:110746266:CAGGT:C	acceptor_loss	1.0000
5:110746267:A:AG	acceptor_gain	1.0000
5:110746268:G:A	acceptor_loss	1.0000
5:110746268:G:GG	acceptor_gain	1.0000
5:110746268:GGTT:G	acceptor_gain	1.0000
5:110746268:GGTTA:G	acceptor_gain	1.0000
5:110746344:CAG:C	donor_loss	1.0000
5:110746345:AG:A	donor_loss	1.0000
5:110746346:GGT:G	donor_loss	1.0000
5:110746347:GT:G	donor_loss	1.0000
5:110746348:T:A	donor_loss	1.0000
5:110755519:ATC:A	donor_gain	1.0000
5:110755522:G:GG	donor_gain	1.0000
5:110755995:GATT:G	acceptor_gain	1.0000
5:110756699:T:G	acceptor_gain	1.0000
5:110756700:A:AG	acceptor_gain	1.0000
5:110756701:G:GG	acceptor_gain	1.0000
5:110756701:GCCT:G	acceptor_gain	1.0000
5:110739351:G:GT	donor_gain	0.9900
5:110739429:G:T	donor_gain	0.9900
5:110742041:C:G	acceptor_gain	0.9900
5:110742043:TTAG:T	acceptor_loss	0.9900
5:110742044:TA:T	acceptor_loss	0.9900

AlphaMissense

2740 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:110742074:G:A	G104D	1.000
5:110743777:G:C	R125P	1.000
5:110761544:G:C	R340P	1.000
5:110761558:G:A	G345R	1.000
5:110761558:G:C	G345R	1.000
5:110761571:T:A	I349K	1.000
5:110761687:G:A	G388R	1.000
5:110761687:G:C	G388R	1.000
5:110761688:G:A	G388E	1.000
5:110742065:C:A	A101D	0.999
5:110742073:G:C	G104R	0.999
5:110742083:T:C	L107P	0.999
5:110742086:C:A	A108E	0.999
5:110743732:T:C	L110P	0.999
5:110743759:C:A	P119H	0.999
5:110743761:T:C	C120R	0.999
5:110743768:T:A	V122D	0.999
5:110743774:G:C	R124P	0.999
5:110743782:T:C	C127R	0.999
5:110746270:T:A	V129D	0.999
5:110748178:T:A	W160R	0.999
5:110748178:T:C	W160R	0.999
5:110748182:A:T	K161I	0.999
5:110748184:G:A	G162R	0.999
5:110748184:G:C	G162R	0.999
5:110748185:G:A	G162E	0.999
5:110748193:A:C	S165R	0.999
5:110748195:T:A	S165R	0.999
5:110748195:T:G	S165R	0.999
5:110748211:G:A	G171R	0.999

dbSNP variants (sampled 300 via entrez): RS1000000399 (5:110739565 G>C), RS1000050427 (5:110744610 G>A), RS1000335126 (5:110745612 C>G), RS1000652983 (5:110746995 T>A,C), RS1000761595 (5:110753089 T>G), RS1000806040 (5:110764736 T>A), RS1000863286 (5:110765230 G>C), RS1000907313 (5:110745493 T>C,G), RS1001065967 (5:110746676 A>G), RS1001114029 (5:110752022 C>T), RS1001259232 (5:110763707 A>C), RS1001328690 (5:110759381 C>T), RS1001374854 (5:110758739 G>A), RS1001447591 (5:110753590 G>A,C), RS1001464192 (5:110746620 A>C,G)

Disease associations

OMIM: gene MIM:610826 | disease phenotypes: MIM:616505, MIM:619303, MIM:108600, MIM:118220

GenCC curated gene-disease

Disease	Classification	Inheritance
neuropathy, hereditary motor and sensory, type 6B	Definitive	Autosomal recessive
pontocerebellar hypoplasia, type 1E	Strong	Autosomal recessive
pontocerebellar hypoplasia type 1	Supportive	Autosomal recessive
hereditary motor and sensory neuropathy type 6	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
Leigh syndrome	Limited	AR
neuropathy, hereditary motor and sensory, type 6B	Definitive	AR

Mondo (9): neuropathy, hereditary motor and sensory, type 6B (MONDO:0014671), pontocerebellar hypoplasia, type 1E (MONDO:0030260), intellectual disability (MONDO:0001071), inherited retinal dystrophy (MONDO:0019118), spastic ataxia (MONDO:0017845), optic atrophy (MONDO:0003608), Charcot-Marie-Tooth disease (MONDO:0015626), pontocerebellar hypoplasia type 1 (MONDO:0016396), hereditary motor and sensory neuropathy type 6 (MONDO:0019551)

Orphanet (4): OBSOLETE: Inherited retinal disorder (Orphanet:71862), Spastic ataxia (Orphanet:316226), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

70 total (30 of 70 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000189	Narrow palate
HP:0000253	Progressive microcephaly
HP:0000341	Narrow forehead
HP:0000414	Bulbous nose
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000529	Progressive visual loss
HP:0000565	Esotropia
HP:0000575	Scotoma
HP:0000577	Exotropia
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000750	Delayed speech and language development
HP:0001182	Tapered finger
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0001276	Hypertonia
HP:0001284	Areflexia
HP:0001290	Generalized hypotonia
HP:0001308	Tongue fasciculations
HP:0001310	Dysmetria
HP:0001319	Neonatal hypotonia

GWAS associations

35 associations (top):

Study	Trait	p-value
GCST000441_2	Cardiac structure and function	9.000000e-07
GCST002084_11	Allergic sensitization	5.000000e-14
GCST002322_11	Asthma and hay fever	2.000000e-07
GCST003987_4	Asthma	3.000000e-31
GCST005038_123	Allergic disease (asthma, hay fever or eczema)	1.000000e-22
GCST005038_124	Allergic disease (asthma, hay fever or eczema)	2.000000e-31
GCST005038_19	Allergic disease (asthma, hay fever or eczema)	6.000000e-29
GCST005212_40	Asthma	9.000000e-26
GCST005412_2	Thrombin-activatable fibrinolysis inhibitor levels	3.000000e-07
GCST006617_6	Uterine fibroid size (maximum volume)	8.000000e-07
GCST006862_11	Asthma	2.000000e-25
GCST006862_22	Asthma	8.000000e-11
GCST007563_29	Allergic disease (asthma, hay fever or eczema)	2.000000e-20
GCST007564_23	Asthma or allergic disease (pleiotropy)	1.000000e-19
GCST007797_2	Asthma onset (childhood vs adult)	5.000000e-15
GCST007798_70	Asthma	2.000000e-29
GCST007798_71	Asthma	2.000000e-29
GCST007798_72	Asthma	1.000000e-41
GCST007799_1	Asthma (adult onset)	1.000000e-18
GCST007799_45	Asthma (adult onset)	4.000000e-15
GCST007800_25	Asthma (childhood onset)	2.000000e-30
GCST007800_44	Asthma (childhood onset)	7.000000e-94
GCST007941_32	Medication use (adrenergics, inhalants)	2.000000e-08
GCST007943_4	Medication use (antihistamines for systemic use)	2.000000e-08
GCST007993_11	Asthma (adult onset)	3.000000e-13
GCST007994_13	Asthma (age of onset)	4.000000e-06
GCST007995_18	Asthma (childhood onset)	2.000000e-27
GCST008916_103	Asthma	3.000000e-12
GCST008916_97	Asthma	4.000000e-17
GCST009798_4	Asthma	1.000000e-14

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004298	cardiovascular measurement
EFO:0005298	allergic sensitization measurement
EFO:0009410	uterine fibroid measurement
EFO:0004847	age at onset
EFO:1002011	adult onset asthma
EFO:0009941	Inhalant adrenergic use measurement
EFO:0009943	Antihistamine use measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D058499	Retinal Dystrophies	C11.768.585.658
C548069	Pontocerebellar Hypoplasia Type 1 (supp.)
C564815	Spastic Ataxia (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 — Miscellaneous SLC25 mitochondrial transporters

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression	2
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression, increases expression	1
trichostatin A	increases expression	1
beta-lapachone	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
jinfukang	decreases 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	decreases expression	1
Acetaminophen	decreases expression	1
Acrolein	affects cotreatment, increases oxidation	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation	1
Caffeine	increases phosphorylation	1
Carbamazepine	affects expression	1
Cisplatin	decreases expression	1
Ozone	affects cotreatment, increases oxidation	1
Quercetin	decreases expression	1
Rotenone	increases expression	1
Copper Sulfate	decreases expression	1

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3HB	Abcam HEK293T SLC25A46 KO	Transformed cell line	Female
CVCL_D4CZ	HCT116-SLC25A46-KO-c11	Cancer cell line	Male
CVCL_D4D0	HCT116-SLC25A46-KO-c12	Cancer cell line	Male
CVCL_TM53	HAP1 SLC25A46 (-) 1	Cancer cell line	Male
CVCL_TM54	HAP1 SLC25A46 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT00271635	PHASE2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT02561702	PHASE2	COMPLETED	Mexiletine for Muscle Cramps in Charcot Marie Tooth Disease
NCT02967679	PHASE2	COMPLETED	SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
NCT03124459	PHASE2	TERMINATED	Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
NCT03254199	PHASE2	TERMINATED	A Study to Assess the Safety and Effectiveness of FLX-787 in Subjects With Charcot-Marie-Tooth Disease Experiencing Muscle Cramps.
NCT03943290	PHASE2	TERMINATED	Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
NCT05777226	PHASE2	UNKNOWN	Research of SORD-CMT Natural History and Epalrestat Treatment
NCT06482437	PHASE2	COMPLETED	Safety and Efficacy of NMD670 in Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT06455826	PHASE1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)
NCT01064505	PHASE1	COMPLETED	Safety Study of a Single IVT Injection of QPI-1007 in Chronic Optic Nerve Atrophy and Recent Onset NAION Patients
NCT05147701	PHASE1	RECRUITING	Safety of Cultured Allogeneic Adult Umbilical Cord Derived Mesenchymal Stem Cells for NAION
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills