SLC1A4

Summary

SLC1A4 (solute carrier family 1 member 4, HGNC:10942) is a protein-coding gene on chromosome 2p14, encoding Neutral amino acid transporter A (P43007). Sodium-coupled antiporter of neutral amino acids.

The protein encoded by this gene is a sodium-dependent neutral amino acid transporter for alanine, serine, cysteine, and threonine. Defects in this gene have been associated with developmental delay, microcephaly, and intellectual disability.

Source: NCBI Gene 6509 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 13
• Clinical variants (ClinVar): 449 total — 21 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 54
• Druggable target: yes
• MANE Select transcript: NM_003038

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10942
Approved symbol	SLC1A4
Name	solute carrier family 1 member 4
Location	2p14
Locus type	gene with protein product
Status	Approved
Aliases	SATT, ASCT1, ASCT-1
Ensembl gene	ENSG00000115902
Ensembl biotype	protein_coding
OMIM	600229
Entrez	6509

Gene structure

Transcript identifiers

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

ENST00000234256, ENST00000471551, ENST00000480594, ENST00000493121, ENST00000531327, ENST00000906286, ENST00000906287, ENST00000906288, ENST00000969683

RefSeq mRNA: 4 — MANE Select: NM_003038 NM_001193493, NM_001348406, NM_001348407, NM_003038

CCDS: CCDS1879, CCDS54362

Canonical transcript exons

ENST00000234256 — 8 exons

Exon	Start	End
ENSE00000810190	64989399	64990170
ENSE00001925922	65020912	65023865
ENSE00003469012	65018071	65018265
ENSE00003540347	65018545	65018679
ENSE00003634279	65001448	65001490
ENSE00003653715	65003953	65004015
ENSE00003654516	65016440	65016673
ENSE00003687582	65010597	65010763

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 97.79.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 36.1973 / max 627.5841, expressed in 1815 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
20607	31.7013	1792
20603	3.7868	1246
20609	0.3848	195
20608	0.3244	160

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	97.79	gold quality
sperm	CL:0000019	96.21	gold quality
gluteal muscle	UBERON:0002000	95.82	gold quality
tongue squamous epithelium	UBERON:0006919	95.33	gold quality
dorsal root ganglion	UBERON:0000044	94.98	gold quality
entorhinal cortex	UBERON:0002728	94.95	gold quality
male germ cell	CL:0000015	94.83	gold quality
medial globus pallidus	UBERON:0002477	94.30	gold quality
nucleus accumbens	UBERON:0001882	93.78	gold quality
lateral globus pallidus	UBERON:0002476	93.65	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.51	gold quality
temporal lobe	UBERON:0001871	93.36	gold quality
globus pallidus	UBERON:0001875	93.28	gold quality
biceps brachii	UBERON:0001507	93.20	gold quality
middle temporal gyrus	UBERON:0002771	93.16	gold quality
substantia nigra pars compacta	UBERON:0001965	93.14	gold quality
caudate nucleus	UBERON:0001873	92.82	gold quality
superior vestibular nucleus	UBERON:0007227	92.76	gold quality
synovial joint	UBERON:0002217	92.73	gold quality
amygdala	UBERON:0001876	92.60	gold quality
putamen	UBERON:0001874	92.54	gold quality
substantia nigra pars reticulata	UBERON:0001966	92.38	gold quality
gingival epithelium	UBERON:0001949	92.25	gold quality
trigeminal ganglion	UBERON:0001675	92.18	gold quality
CA1 field of hippocampus	UBERON:0003881	92.10	gold quality
gingiva	UBERON:0001828	91.92	gold quality
postcentral gyrus	UBERON:0002581	91.79	gold quality
nipple	UBERON:0002030	91.74	gold quality
superior frontal gyrus	UBERON:0002661	91.63	gold quality
Brodmann (1909) area 46	UBERON:0006483	91.63	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

Upstream regulators (CollecTRI, top): CREB3L1, EGR1

miRNA regulators (miRDB)

100 targeting SLC1A4, 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-6867-5P	100.00	82.21	3464
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-623	99.76	68.16	1170
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-7856-5P	99.75	69.99	2901

Literature-anchored findings (GeneRIF, showing 13)

• ASCT1 is able to mediate a concentrative transport of alanine, which is Na+-dependent but not coupled to the Na+ gradient (PMID:11824937)
• used as receptor by HERV-W Env glycoprotein (PMID:12050356)
• results strongly suggest that combinations of amino acid sequence changes and N-linked oligosaccharides in a critical carboxyl-terminal region of extracellular loop 2 (ECL2) control retroviral utilization of both the ASCT1 and ASCT2 receptors (PMID:12584318)
• This study revealed genetic associations of SLC1A4, SQSTM1, and EIF4EBP1 with MSA. These results may lend genetic support to the hypothesis that oxidative stress is associated with the pathogenesis of MSA. (PMID:18442140)
• SLC1A4 gene is associated with schizophrenia. (PMID:18638388)
• Na+ interactions with the neutral amino acid transporter ASCT1. (PMID:24808181)
• SLC1A4 disruption may impair brain development and function by decreasing the levels of L-serine in neurons. The identification of additional families with mutations in SLC1A4 would be necessary to confirm its involvement in intellectual disability. (PMID:25930971)
• ASCT1 is essential in brain serine transport. (PMID:26041762)
• SLC1A4 is the disease causing gene of a novel neurologic disorder manifesting with significant intellectual disability, severe postnatal microcephaly, spasticity and thin corpus callosum. (PMID:26138499)
• SLC1A4 deficiency should not be considered a population-specific disorder, and all patients with unexplained severe neurodevelopmental delay and the features outlined should be investigated regardless of ethnicity, as there are no known metabolic markers of this potentially treatable condition. (PMID:27193218)
• ANKRD50 simultaneously engages multiple parts of the SNX27-retromer-WASH complex machinery in a direct and co-operative interaction network that is needed to efficiently recycle the nutrient transporters (PMID:27909246)
• Results suggest that ASCT1/2 may play an important role in regulating extracellular d-serine and NMDA receptor-mediated physiological effects and that ASCT1/2 inhibitors have the potential for therapeutic benefit. (PMID:28807674)
• A rare cause of microcephaly, thin corpus callosum and refractory epilepsy due to a novel SLC1A4 gene mutation. (PMID:35605507)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc1a4	ENSDARG00000000551
mus_musculus	Slc1a4	ENSMUSG00000020142
rattus_norvegicus	Slc1a4	ENSRNOG00000005248

Paralogs (6): SLC1A3 (ENSG00000079215), SLC1A6 (ENSG00000105143), SLC1A5 (ENSG00000105281), SLC1A1 (ENSG00000106688), SLC1A2 (ENSG00000110436), SLC1A7 (ENSG00000162383)

Protein

Protein identifiers

Neutral amino acid transporter A — P43007 (reviewed: P43007)

Alternative names: Alanine/serine/cysteine/threonine transporter 1, Solute carrier family 1 member 4

All UniProt accessions (1): P43007

UniProt curated annotations — full annotation on UniProt →

Function. Sodium-coupled antiporter of neutral amino acids. In a tri-substrate transport cycle, exchanges neutral amino acids between the extracellular and intracellular compartments, coupled to the inward cotransport of at least one sodium ion. Exchanges neutral amino acids such as L- and D-serine, L-threonine, L-asparagine and L-alanine in a bidirectional way. Involved in homeostasis of D-serine, a coagonist of synaptic NMDA receptors. In astrocytes at excitatory synapses, mediates electrogenic D-serine influx coupled to L-serine efflux and L-serine shuttling to neurons for de novo D-serine synthesis. Displays sodium- and amino acid-dependent but uncoupled channel-like anion conductance with a preference SCN(-) > NO3(-) > I(-) > Cl(-).

Subunit / interactions. Homotrimer.

Subcellular location. Cell membrane. Melanosome membrane.

Tissue specificity. Expressed mostly in brain, muscle, and pancreas but detected in all tissues examined.

Disease relevance. Spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM) [MIM:616657] A neurodevelopmental disorder characterized by thin corpus callosum, severe progressive microcephaly, severe intellectual disability, seizures, spasticity, and global developmental delay. Most patients are unable to achieve independent walking or speech. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The transport domain consists of four transmembrane regions 3, 6, 7 and 8 and two helical hairpins HP1 and HP2. According to the one-gate elevator transport model, substrate binding and release is controlled by the helical hairpin 2 (HP2) which acts as a gate for the transport domain. HP2 gate opening enables substrate binding or release. The gate closes once one amino acid and up to three sodium ions bind to the transport domain, which subsequently triggers transmembrane elevator-like motion of the transporter across the plasma membrane. The beta-hairpin (aa 191-216) located between the helical segments of TM4 protrudes in the extracellular space and forms a docking platform for proteins of retroviral origin.

Induction. Up-regulated in the brain cortex upon traumatic brain injury.

Similarity. Belongs to the dicarboxylate/amino acid:cation symporter (DAACS) (TC 2.A.23) family. SLC1A4 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P43007-1	1	yes
P43007-2	2

RefSeq proteins (4): NP_001180422, NP_001335335, NP_001335336, NP_003029* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001991	Na-dicarboxylate_symporter	Family
IPR018107	Na-dicarboxylate_symporter_CS	Conserved_site
IPR036458	Na:dicarbo_symporter_sf	Homologous_superfamily
IPR050746	DAACS	Family

Pfam: PF00375

Catalyzed reactions (Rhea), 12 shown:

• chloride(in) = chloride(out) (RHEA:29823)
• nitrate(in) = nitrate(out) (RHEA:34923)
• iodide(out) = iodide(in) (RHEA:66324)
• D-serine(in) + L-alanine(out) + Na(+)(out) = D-serine(out) + L-alanine(in) + Na(+)(in) (RHEA:75311)
• thiocyanate(in) = thiocyanate(out) (RHEA:75347)
• D-serine(out) + L-serine(in) + Na(+)(out) = D-serine(in) + L-serine(out) + Na(+)(in) (RHEA:84319)
• D-serine(out) + L-alanine(in) + Na(+)(out) = D-serine(in) + L-alanine(out) + Na(+)(in) (RHEA:84323)
• trans-4-hydroxy-L-proline(out) + L-serine(in) + Na(+)(out) = trans-4-hydroxy-L-proline(in) + L-serine(out) + Na(+)(in) (RHEA:84331)
• trans-4-hydroxy-L-proline(out) + L-alanine(in) + Na(+)(out) = trans-4-hydroxy-L-proline(in) + L-alanine(out) + Na(+)(in) (RHEA:84335)
• trans-4-hydroxy-L-proline(out) + L-threonine(in) + Na(+)(out) = trans-4-hydroxy-L-proline(in) + L-threonine(out) + Na(+)(in) (RHEA:84339)
• L-threonine(out) + L-alanine(in) + Na(+)(out) = L-threonine(in) + L-alanine(out) + Na(+)(in) (RHEA:84343)
• L-cysteine(out) + L-alanine(in) + Na(+)(out) = L-cysteine(in) + L-alanine(out) + Na(+)(in) (RHEA:84347)

UniProt features (70 total): binding site 18, topological domain 11, mutagenesis site 11, transmembrane region 8, modified residue 4, sequence variant 4, region of interest 3, intramembrane region 2, compositionally biased region 2, glycosylation site 2, splice variant 2, sequence conflict 2, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
7P4I	ELECTRON MICROSCOPY	4.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P43007-F1	80.96	0.51

Functional residue map

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

Ligand- & substrate-binding residues (18): 121; 124; 125; 345; 374; 376; 378; 378; 380; 417; 418; 420 …

Post-translational modifications (4): 1, 507, 527, 530

Glycosylation sites (2): 201, 206

Mutagenesis-validated functional residues (11):

Position	Phenotype
124	impairs na(+) binding. 3-fold reduction of l-serine transport rate.
125	no effect on affinity for na(+) ions. no effect on l-serine transport rate. causes a shift of na(+):l-serine transport s
380	decreases the affinity for na(+) ions and l-serine. impairs l-serine transport.
380	decreases the affinity for na(+) ions and l-serine. no effect on l-serine transport rate. decreases the affinity for na(
380	no significant effect on affinity for na(+) ions. 3.5-fold reduction of l-serine transport rate.
422	impairs na(+) binding. no effect on l-serine transport rate.
465	no effect on affinity for na(+) ions. 2-fold reduction of l-serine transport rate; when associated with asn-380.
467	decreases the affinity for na(+) ions. impairs l-serine transport.
467	no effect on affinity for na(+) ions. no effect on na(+):l-serine transport stoichiometry. 3-fold decreased l-serine tra
467	no effect on affinity for na(+) ions. no effect on l-serine transport rate and na(+):l-serine transport stoichiometry. d

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-352230	Amino acid transport across the plasma membrane
R-HSA-382551	Transport of small molecules
R-HSA-425393
R-HSA-425407	SLC-mediated transmembrane transport

MSigDB gene sets: 471 (showing top): RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, LEE_NEURAL_CREST_STEM_CELL_DN, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_10, BENPORATH_ES_WITH_H3K27ME3, GOBP_COGNITION, GRUETZMANN_PANCREATIC_CANCER_DN, MCLACHLAN_DENTAL_CARIES_UP, GOBP_CIRCULATORY_SYSTEM_PROCESS, JAEGER_METASTASIS_DN, chr2p14, GOBP_MODIFIED_AMINO_ACID_TRANSPORT, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GOCC_CELL_SURFACE, GOBP_INORGANIC_ANION_TRANSPORT, CHEOK_RESPONSE_TO_HD_MTX_UP

GO Biological Process (18): amino acid transport (GO:0006865), L-glutamine transport (GO:0006868), L-alanine transport (GO:0015808), L-cystine transport (GO:0015811), L-glutamate transmembrane transport (GO:0015813), proline transport (GO:0015824), L-serine transport (GO:0015825), threonine transport (GO:0015826), hydroxyproline transport (GO:0034589), synaptic transmission, glutamatergic (GO:0035249), cognition (GO:0050890), L-aspartate import across plasma membrane (GO:0140009), transport across blood-brain barrier (GO:0150104), L-serine import across plasma membrane (GO:1903812), L-alanine import across plasma membrane (GO:1904273), proline transmembrane transport (GO:0035524), serine import across plasma membrane (GO:0098718), chloride transmembrane transport (GO:1902476)

GO Molecular Function (12): chloride channel activity (GO:0005254), amino acid transmembrane transporter activity (GO:0015171), L-alanine transmembrane transporter activity (GO:0015180), L-aspartate transmembrane transporter activity (GO:0015183), L-cystine transmembrane transporter activity (GO:0015184), L-glutamine transmembrane transporter activity (GO:0015186), L-proline transmembrane transporter activity (GO:0015193), L-serine transmembrane transporter activity (GO:0015194), L-threonine transmembrane transporter activity (GO:0015195), symporter activity (GO:0015293), L-hydroxyproline transmembrane transporter activity (GO:0034590), neutral L-amino acid transmembrane transporter activity (GO:0015175)

GO Cellular Component (10): centrosome (GO:0005813), intermediate filament (GO:0005882), plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020), dendrite (GO:0030425), melanosome (GO:0042470), neuronal cell body (GO:0043025), synapse (GO:0045202), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
SLC-mediated transport of amino acids	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
L-amino acid transmembrane transporter activity	8
neutral amino acid transport	5
L-amino acid transport	5
amino acid import across plasma membrane	3
neutral L-amino acid transmembrane transporter activity	3
modified amino acid transport	2
L-alpha-amino acid transmembrane transport	2
serine transport	2
carboxylic acid transport	2
nitrogen compound transport	2
L-aspartate transmembrane transport	2
L-serine transport	2
amino acid transmembrane transport	2
carboxylic acid transmembrane transport	2
modified amino acid transmembrane transporter activity	2
cellular anatomical structure	2
transport	1
alanine transport	1
sulfur amino acid transport	1
L-glutamate import	1
amino acid transport	1
chemical synaptic transmission	1
nervous system process	1
vascular transport	1
serine import across plasma membrane	1
L-alanine transmembrane transport	1
chloride transport	1
monoatomic anion transmembrane transport	1
monoatomic anion channel activity	1
chloride transmembrane transporter activity	1
transmembrane transporter activity	1
L-alanine transport	1
alanine transmembrane transporter activity	1
acidic amino acid transmembrane transporter activity	1
C4-dicarboxylate transmembrane transporter activity	1
sulfur amino acid transmembrane transporter activity	1
L-cystine transport	1
L-glutamine transport	1
proline transmembrane transport	1
threonine transport	1

Protein interactions and networks

STRING

1212 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC1A4	ERVW-1	Q9UQF0	981
SLC1A4	SLC7A1	P30825	703
SLC1A4	SLC3A2	P08195	697
SLC1A4	SLC38A2	Q96QD8	632
SLC1A4	SLC7A5	Q01650	625
SLC1A4	SLC7A6	Q92536	624
SLC1A4	SLC7A10	Q9NS82	612
SLC1A4	SLC38A1	Q9H2H9	606
SLC1A4	SLC43A2	Q8N370	603
SLC1A4	SHMT1	P34896	593
SLC1A4	SLC38A4	Q969I6	586
SLC1A4	MCHR1	Q99705	584
SLC1A4	PSAT1	Q9Y617	581
SLC1A4	SLC7A7	Q9UM01	577
SLC1A4	SLC6A9	P48067	565

IntAct

141 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
NIPAL1	ESYT2	psi-mi:“MI:0914”(association)	0.640
GGT5	POTEI	psi-mi:“MI:0914”(association)	0.530
SLC1A5	SLC1A4	psi-mi:“MI:0914”(association)	0.530
SLC39A4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
SLC1A5	GPR89A	psi-mi:“MI:0914”(association)	0.530
SLC1A4	SNX27	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A4	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A4	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
PDZD7	SLC1A4	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A4	SNTB1	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A4	MAST1	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A4	SNTA1	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A4	SCRIB	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A4	PDZRN4	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A4	ARHGEF12	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A4	PDZK1	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A4	RHPN1	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A4	PDZRN3	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A4	HTRA1	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A4	NHERF2	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A4	SYNJ2BP	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A4	LIN7C	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A4	PARD3B	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A4	PDZD2	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A4	TAX1BP3	psi-mi:“MI:0407”(direct interaction)	0.440
SNTG2	SLC1A4	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (59): SLC1A4 (Affinity Capture-MS), SLC1A4 (Affinity Capture-MS), SLC1A4 (Proximity Label-MS), SLC1A4 (Affinity Capture-MS), SLC1A4 (Affinity Capture-MS), SLC1A4 (Affinity Capture-MS), SLC1A4 (Proximity Label-MS), SLC1A4 (Proximity Label-MS), SLC1A4 (Affinity Capture-RNA), SLC1A4 (Proximity Label-MS), SLC1A4 (Proximity Label-MS), SLC1A4 (Proximity Label-MS), SLC1A4 (Proximity Label-MS), SLC1A4 (Proximity Label-MS), SLC1A4 (Proximity Label-MS)

ESM2 similar proteins: A0A6P3HVI0, A2VDL4, A4IHB9, D3ZJ25, E7EXX2, O00341, O19105, O35544, O35874, O35921, O43511, O54902, O57321, P24942, P31596, P31597, P43003, P43004, P43005, P43006, P43007, P46411, P48664, P49281, P49282, P51906, P51907, P51912, P55012, P56564, Q10901, Q15758, Q25605, Q4R8W8, Q5BKR2, Q5R6B8, Q5R839, Q86UD5, Q8BJA2, Q8IVJ1

Diamond homologs: A2RGC2, A2VDL4, D3ZJ25, O00341, O19105, O35544, O35874, O35921, O57321, O59010, P0DF78, P0DF79, P24942, P31596, P31597, P43003, P43004, P43005, P43006, P43007, P46411, P48664, P51906, P51907, P51912, P56564, Q10901, Q15758, Q1J8E1, Q1JDG4, Q1JII6, Q1JND7, Q21353, Q21751, Q22682, Q25605, Q48V75, Q4R8W8, Q5XDS5, Q8JZR4

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 103 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
Dopamine Neurotransmitter Release Cycle	5	35.5×	2e-05
Assembly and cell surface presentation of NMDA receptors	9	32.6×	8e-10
Neurexins and neuroligins	11	30.9×	1e-11
Protein-protein interactions at synapses	7	26.6×	6e-07
RHOQ GTPase cycle	5	12.9×	9e-04
Neuronal System	8	5.1×	3e-03
Signaling by Rho GTPases	9	4.4×	3e-03
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	9	4.3×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	8	47.9×	3e-09
protein localization to synapse	6	47.4×	8e-07
receptor clustering	6	38.6×	1e-06
regulation of postsynaptic membrane neurotransmitter receptor levels	6	30.7×	5e-06
cell-cell adhesion	9	9.4×	4e-05
protein-containing complex assembly	8	9.4×	2e-04
transport across blood-brain barrier	5	9.2×	6e-03
chemical synaptic transmission	11	8.8×	6e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	21
Likely pathogenic	9
Uncertain significance	117
Likely benign	245
Benign	30

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1699944	NM_003038.5(SLC1A4):c.971del (p.Asn324fs)	Pathogenic
1699945	NM_003038.5(SLC1A4):c.542C>T (p.Ser181Phe)	Pathogenic
2499988	NM_003038.5(SLC1A4):c.2T>C (p.Met1Thr)	Pathogenic
265259	NM_003038.5(SLC1A4):c.766G>A (p.Glu256Lys)	Pathogenic
2664658	NM_003038.5(SLC1A4):c.407C>A (p.Ala136Glu)	Pathogenic
2701307	NM_003038.5(SLC1A4):c.514dup (p.Leu172fs)	Pathogenic
2704859	NM_003038.5(SLC1A4):c.950_953del (p.Tyr317fs)	Pathogenic
2744387	NM_003038.5(SLC1A4):c.170_192del (p.Gly57fs)	Pathogenic
2748034	NM_003038.5(SLC1A4):c.801G>A (p.Trp267Ter)	Pathogenic
2770938	NM_003038.5(SLC1A4):c.1123del (p.Ala375fs)	Pathogenic
2777052	NM_003038.5(SLC1A4):c.971dup (p.Asn324fs)	Pathogenic
2790726	NM_003038.5(SLC1A4):c.913del (p.His305fs)	Pathogenic
2822746	NM_003038.5(SLC1A4):c.404T>A (p.Leu135Ter)	Pathogenic
2987044	NM_003038.5(SLC1A4):c.951_954del (p.Ile316_Tyr317insTer)	Pathogenic
3247511	NC_000002.11:g.(?65216778)(65248280_?)del	Pathogenic
3640833	NM_003038.5(SLC1A4):c.234_237dup (p.Glu80fs)	Pathogenic
372157	NM_003038.5(SLC1A4):c.944_945del (p.Leu315fs)	Pathogenic
4729912	NM_003038.5(SLC1A4):c.1364+1G>T	Pathogenic
488671	NM_003038.5(SLC1A4):c.1035-381_1230-73del	Pathogenic
587615	NM_003038.5(SLC1A4):c.1364+1G>A	Pathogenic
932143	NM_003038.5(SLC1A4):c.1358G>A (p.Trp453Ter)	Pathogenic
1723373	NM_003038.5(SLC1A4):c.885dup (p.Lys296fs)	Likely pathogenic
2500887	NM_003038.5(SLC1A4):c.925G>T (p.Gly309Ter)	Likely pathogenic
2632949	NM_003038.5(SLC1A4):c.634-1G>C	Likely pathogenic
2768321	NM_003038.5(SLC1A4):c.1229+1G>A	Likely pathogenic
2879073	NM_003038.5(SLC1A4):c.1229+1G>C	Likely pathogenic
3024238	NM_003038.5(SLC1A4):c.344G>A (p.Gly115Asp)	Likely pathogenic
3586846	NM_003038.5(SLC1A4):c.807_810del (p.Pro270fs)	Likely pathogenic
3780612	NM_003038.5(SLC1A4):c.805_808dup (p.Pro270fs)	Likely pathogenic
800961	NM_003038.5(SLC1A4):c.1357T>C (p.Trp453Arg)	Likely pathogenic

SpliceAI

866 predictions. Top by Δscore:

Variant	Effect	Δscore
2:65003944:T:A	acceptor_gain	1.0000
2:65003951:A:AG	acceptor_gain	1.0000
2:65003952:G:GG	acceptor_gain	1.0000
2:65010586:T:TA	acceptor_gain	1.0000
2:65010593:GCA:G	acceptor_loss	1.0000
2:65010594:CAG:C	acceptor_loss	1.0000
2:65010595:A:AG	acceptor_gain	1.0000
2:65010595:A:AT	acceptor_loss	1.0000
2:65010596:G:GG	acceptor_gain	1.0000
2:65010596:G:GT	acceptor_loss	1.0000
2:65010760:TGTGG:T	donor_loss	1.0000
2:65010761:GTG:G	donor_gain	1.0000
2:65010762:TG:T	donor_gain	1.0000
2:65010762:TGG:T	donor_loss	1.0000
2:65010763:GG:G	donor_gain	1.0000
2:65010764:G:GG	donor_gain	1.0000
2:65010765:T:G	donor_loss	1.0000
2:65016568:G:GT	donor_gain	1.0000
2:65018067:CTA:C	acceptor_loss	1.0000
2:65018068:TA:T	acceptor_loss	1.0000
2:65018069:A:AC	acceptor_loss	1.0000
2:65018069:A:AG	acceptor_gain	1.0000
2:65018070:G:GG	acceptor_gain	1.0000
2:65018070:GCTC:G	acceptor_gain	1.0000
2:65018070:GCTCA:G	acceptor_gain	1.0000
2:65018247:G:GT	donor_gain	1.0000
2:65018261:ATTCT:A	donor_gain	1.0000
2:65018262:TTCT:T	donor_gain	1.0000
2:65018263:TCT:T	donor_gain	1.0000
2:65018263:TCTGT:T	donor_loss	1.0000

AlphaMissense

3418 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:65020936:T:A	N463K	0.999
2:65020936:T:G	N463K	0.999
2:65018148:T:A	L371H	0.998
2:65018173:G:A	M379I	0.998
2:65018173:G:C	M379I	0.998
2:65018173:G:T	M379I	0.998
2:65018210:T:C	F392L	0.998
2:65018212:C:A	F392L	0.998
2:65018212:C:G	F392L	0.998
2:65018552:G:C	A413P	0.998
2:65018564:A:C	S417R	0.998
2:65018566:T:A	S417R	0.998
2:65018566:T:G	S417R	0.998
2:65010629:C:A	N222K	0.997
2:65010629:C:G	N222K	0.997
2:65018170:C:A	N378K	0.997
2:65018170:C:G	N378K	0.997
2:65018195:T:C	C387R	0.997
2:65018197:T:G	C387W	0.997
2:65018553:C:A	A413D	0.997
2:65020943:G:T	G466W	0.997
2:64989918:C:G	P92R	0.996
2:64989932:A:C	S97R	0.996
2:64989934:C:A	S97R	0.996
2:64989934:C:G	S97R	0.996
2:65018082:T:C	L349P	0.996
2:65018135:A:C	S367R	0.996
2:65018137:C:A	S367R	0.996
2:65018137:C:G	S367R	0.996
2:65018148:T:C	L371P	0.996

dbSNP variants (sampled 300 via entrez): RS1000054374 (2:65020310 A>G), RS1000108029 (2:65020563 G>C,T), RS1000112573 (2:64988117 G>C), RS1000174704 (2:64987460 T>C), RS1000194535 (2:65006381 A>G), RS1000211409 (2:65002370 T>G), RS1000373479 (2:65015193 A>G), RS1000379347 (2:65014576 C>T), RS1000493147 (2:64988934 CCCCTCCCCT>C,CCCCTCCCCTCCCTCCCCT), RS1000607651 (2:64989230 G>C), RS1000778611 (2:64988915 C>T), RS1000788062 (2:64995191 G>A), RS1000802931 (2:64995937 T>C), RS1000861548 (2:64995484 A>C,G,T), RS1001090792 (2:65008009 C>G,T)

Disease associations

OMIM: gene MIM:600229 | disease phenotypes: MIM:616657

GenCC curated gene-disease

Disease	Classification	Inheritance
spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome	Definitive	Autosomal recessive
complex neurodevelopmental disorder	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome	Definitive	AR

Mondo (3): spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome (MONDO:0014725), microcephaly (MONDO:0001149), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (1): Spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome (Orphanet:447997)

HPO phenotypes

54 total (30 of 54 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000020	Urinary incontinence
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000316	Hypertelorism
HP:0000369	Low-set ears
HP:0000411	Protruding ear
HP:0000431	Wide nasal bridge
HP:0000664	Synophrys
HP:0000733	Motor stereotypy
HP:0000737	Irritability
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001276	Hypertonia
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001348	Brisk reflexes
HP:0001999	Abnormal facial shape
HP:0002015	Dysphagia
HP:0002020	Gastroesophageal reflux
HP:0002059	Cerebral atrophy
HP:0002061	Lower limb spasticity
HP:0002069	Bilateral tonic-clonic seizure
HP:0002079	Hypoplasia of the corpus callosum

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST001391_1	Metabolite levels	3.000000e-22
GCST001639_16	Metabolite levels	3.000000e-10
GCST004373_6	Atrial fibrillation	3.000000e-17
GCST006006_2	Ejection fraction	3.000000e-08
GCST006007_1	Left ventricular internal dimension in systole	5.000000e-08
GCST006029_1	Fractional shortening	2.000000e-08
GCST006192_40	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	7.000000e-09
GCST007096_110	Pulse pressure	6.000000e-11
GCST007099_94	Systolic blood pressure	9.000000e-07
GCST012020_247	Serum metabolite levels	1.000000e-13
GCST012020_248	Serum metabolite levels	1.000000e-18
GCST012251_11	Macular telangiectasia type 2	4.000000e-09
GCST012252_2	Macular telangiectasia type 2	6.000000e-09

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004725	metabolite measurement
EFO:0004723	coronary artery calcification
EFO:0005527	ejection fraction measurement
EFO:0008206	left ventricular systolic function measurement
EFO:0009285	fractional shortening
EFO:0006335	systolic blood pressure
EFO:0006527	smoking status measurement
EFO:0005763	pulse pressure measurement
EFO:1002009	macular telangiectasia type 2

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2315 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs10211524	SLC1A4		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — Alanine/serine/cysteine transporter subfamily

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	8
sodium arsenite	decreases expression, increases expression	5
Tobacco Smoke Pollution	affects expression, decreases expression, increases expression	5
Cyclosporine	increases expression	5
perfluorooctane sulfonic acid	increases expression	3
Benzo(a)pyrene	increases expression, increases methylation	3
Estradiol	increases reaction, increases expression	3
Tunicamycin	increases expression	3
bisphenol A	affects expression, increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
Acetaminophen	increases expression, affects cotreatment	2
Aerosols	increases expression, affects expression	2
Cisplatin	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Zidovudine	affects cotreatment, increases expression	2
Cadmium Chloride	increases expression	2
Thapsigargin	increases expression	2
Genistein	increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
FR900359	affects phosphorylation	1
tremortin	decreases expression	1
chloroacetaldehyde	affects expression	1
methylmercuric chloride	increases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
deoxynivalenol	decreases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
zinc chromate	decreases expression, increases abundance	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3992312	Binding	Inhibition of human ASCT1 expressed in HEK cells assessed as reduction in [3H]-L-serine uptake after 1 min by beta counting analysis	D-serine transporter inhibitors as pharmaceutical compositions for the treatment of central nervous system disorders

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2FK	Abcam HeLa SLC1A4 KO	Cancer cell line	Female
CVCL_D4VC	LS180-SLC1A4-KO-c6	Cancer cell line	Female
CVCL_D4VD	LS180-SLC1A4-KO-c9	Cancer cell line	Female
CVCL_TL85	HAP1 SLC1A4 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.