SLC6A8

Summary

SLC6A8 (solute carrier family 6 member 8, HGNC:11055) is a protein-coding gene on chromosome Xq28, encoding Sodium- and chloride-dependent creatine transporter 1 (P48029). Creatine:sodium symporter which mediates the uptake of creatine. It is haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene is a plasma membrane protein whose function is to transport creatine into and out of cells. Defects in this gene can result in X-linked creatine deficiency syndrome. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 6535 — RefSeq curated summary.

At a glance

• Gene–disease (curated): creatine transporter deficiency (Definitive, ClinGen)
• Clinical variants (ClinVar): 1,271 total — 114 pathogenic, 81 likely-pathogenic
• Phenotypes (HPO): 60
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_005629

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11055
Approved symbol	SLC6A8
Name	solute carrier family 6 member 8
Location	Xq28
Locus type	gene with protein product
Status	Approved
Aliases	CRTR, CT1, CRT, CRT-1, CRT1
Ensembl gene	ENSG00000130821
Ensembl biotype	protein_coding
OMIM	300036
Entrez	6535

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 12 protein_coding, 4 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000253122, ENST00000413787, ENST00000429147, ENST00000430077, ENST00000442457, ENST00000457723, ENST00000466243, ENST00000467402, ENST00000476466, ENST00000485324, ENST00000675713, ENST00000922630, ENST00000922631, ENST00000922632, ENST00000922633, ENST00000955775, ENST00000955776

RefSeq mRNA: 3 — MANE Select: NM_005629 NM_001142805, NM_001142806, NM_005629

CCDS: CCDS14726, CCDS48190

Canonical transcript exons

ENST00000253122 — 13 exons

Exon	Start	End
ENSE00001050303	153687926	153688836
ENSE00001645077	153691975	153692107
ENSE00001659410	153694533	153694633
ENSE00001666515	153693041	153693175
ENSE00001679126	153695074	153696588
ENSE00001703587	153691304	153691553
ENSE00001720965	153694130	153694267
ENSE00001772596	153694344	153694446
ENSE00003466028	153693905	153694017
ENSE00003477986	153694719	153694889
ENSE00003478802	153693462	153693586
ENSE00003488196	153690375	153690506
ENSE00003633750	153693263	153693366

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 98.55.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 49.7377 / max 694.3567, expressed in 1735 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
198091	47.6639	1731
198092	1.3130	333
198093	0.5477	155
198094	0.2131	86

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
inferior olivary complex	UBERON:0002127	98.55	gold quality
apex of heart	UBERON:0002098	97.97	gold quality
ileal mucosa	UBERON:0000331	97.80	gold quality
cranial nerve II	UBERON:0000941	97.54	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	97.52	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.41	gold quality
gastrocnemius	UBERON:0001388	97.38	gold quality
heart left ventricle	UBERON:0002084	97.28	gold quality
right atrium auricular region	UBERON:0006631	97.17	gold quality
cardiac ventricle	UBERON:0002082	97.14	gold quality
postcentral gyrus	UBERON:0002581	97.11	gold quality
cardiac atrium	UBERON:0002081	96.99	gold quality
parietal lobe	UBERON:0001872	96.89	gold quality
lateral globus pallidus	UBERON:0002476	96.74	gold quality
CA1 field of hippocampus	UBERON:0003881	96.73	gold quality
inferior vagus X ganglion	UBERON:0005363	96.73	gold quality
lower esophagus mucosa	UBERON:0035834	96.54	gold quality
left ventricle myocardium	UBERON:0006566	96.49	gold quality
muscle of leg	UBERON:0001383	96.48	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.46	gold quality
parotid gland	UBERON:0001831	96.35	gold quality
Ammon’s horn	UBERON:0001954	96.34	gold quality
globus pallidus	UBERON:0001875	96.31	gold quality
spinal cord	UBERON:0002240	96.26	gold quality
muscle layer of sigmoid colon	UBERON:0035805	96.21	gold quality
ventral tegmental area	UBERON:0002691	96.19	gold quality
right frontal lobe	UBERON:0002810	96.17	gold quality
adult mammalian kidney	UBERON:0000082	96.11	gold quality
muscle organ	UBERON:0001630	96.08	gold quality
medial globus pallidus	UBERON:0002477	96.08	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-3929	yes	815.15
E-CURD-79	yes	260.29
E-GEOD-125970	yes	24.03
E-GEOD-135922	yes	19.81
E-ANND-3	yes	8.43
E-MTAB-9689	no	220.10

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

106 targeting SLC6A8, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-4639-5P	99.81	67.37	1028
HSA-MIR-6842-5P	99.80	67.54	1587

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Regulation of Drosophila IAP1 degradation and apoptosis by reaper and ubcD1. (PMID:12021769)
• the UbcD1 substrate(s) binds chromosomal termini in a sequence-independent manner (PMID:12723710)
• Effete/APC-mediated degradation of Cyclin A is essential for the maintenance of germline stem cells (PMID:19906849)
• eff regulates both telomere position effect and position effect variegation. (PMID:23821599)
• UbcD1 regulates Hedgehog signaling by directly modulating Ci ubiquitination and processing. (PMID:28887318)
• X-linked mental retardation with seizures and carrier manifestations is caused by a mutation in the creatine-transporter gene (SLC6A8) located in Xq28 (PMID:11898126)
• X-linked creatine deficiency syndrome: a novel mutation in creatine transporter gene SLC6A8. (PMID:12210795)
• High prevalence of SLC6A8 deficiency in X-linked mental retardation (PMID:15154114)
• SGK1 and SGK3 increase SLC6A8 activity by increasing the maximal transport rate of the carrier. Deranged SGK1 and/or SGK3 dependent regulation of SLC6A8 may affect energy storage particularly in skeletal muscle, heart, and neurons (PMID:16036218)
• involvement of residues from transmembrane domain 3 is a common feature of the substrate pathway of the creatine transporter (PMID:16049011)
• Creatine transporter deficiency associated with gene deficiency of this protein. (PMID:16086185)
• Mutations in the creatine transporter gene SLC6A8 may be a relatively major contributor in males with mental retardation of unknown cause. (PMID:16738945)
• Exhibition of a developmental apraxia of speech with motor planning and execution deficit in a creatine transporter (SLC6A8) mutation. (PMID:17603797)
• identified two brothers with mental retardation, caused by a c.1059_1061delCTT; p.Phe354del mutation in the SLC6A8 gene (PMID:18350323)
• A novel deletion (c.1690-1703 del) in exon 12 of SLC6A8 resulted in a frameship mutation associated with global developmental delay and premature ventricular beats. (PMID:18443316)
• This study reveals the presence of a novel SLC6A8 splice variant, SLC6A8C in human and mouse. (PMID:18515020)
• The frequency of SLC6A8 deficiency was 2.3% in 157 males at risk. (PMID:19188083)
• report the first two Spanish adult patients with creatine transporter deficiency and compare their clinical phenotype and the evolution of the disease with those of other published cases (PMID:19319661)
• The estimated amount of total creatine in the placenta and brain significantly increased in the second half of pregnancy, coinciding with a significant increase in expression of CrT mRNA. (PMID:19570237)
• Guanidinoacetate is transported from AGAT- to GAMT-expressing cells through SLC6A8 to allow creatine synthesis, thereby explaining creatine deficiency in SLC6A8-deficient CNS. (PMID:19879361)
• symptoms of the creatine transporter defect (mental retardation, learning difficulties, and constipation) can be present in female SLC6A8 heterozygotes (PMID:20528887)
• Hemizygosity for a novel deletion producing a frameshift (c.974_975delCA, p.Thr325SerfsX139) in the creatine transporter gene is associated with X-linked cerebral creatine deficiency. (PMID:20602486)
• Heterozygous SLC6A8 deficiency is a potentially treatable condition and should be considered in females with intractable epilepsy and developmental delay/intellectual disabilit (PMID:20846889)
• impact of creatine deficiency syndrome mutations, CRTR and GAMT on metabolic stress was analyzed in patient fibroblast cultures (PMID:21140503)
• SLC6A8 genes may not be directly involved in human male infertility (PMID:21190923)
• Evidence for a functional involvement of the four mutations affecting ATRX (p.1761M4T), PQBP1 (p.155R4X), and SLC6A8 (p.390P4L and p.477S4L), in the etiology of intellectual disability. (PMID:21267006)
• analysis of X-linked creatine transporter defect in nine boys shows that it has an effect on IQ (PMID:21556832)
• Missense mutations in SLC6A8 gene is associated with X-linked disorder. (PMID:22281021)
• SLC6A8 mutants displayed no electrogenic activity with all Cr analogs tested in X. laevis oocytes. (PMID:22644605)
• study identified a second creatine transporter monocarboxylate transporter 12 (MCT12), encoded by the cataract and glucosuria associated gene SLC16A12; Rssults show SLC6A8 was predominantly found in brain, heart and muscle, while SLC16A12 was more abundant in kidney and retina. In the lens, the two transcripts were found at comparable levels. (PMID:23578822)
• a de novo mutation in the SLC6A8 gene in 101 males with X-linked creatine transporter deficiency (PMID:23644449)
• Creatine transporter deficiency is a relatively common genetic disorder in males with sporadic or familiar mental retardation and diagnostic screening of them should always include screening for SLC6A8 deficiency. (PMID:24137762)
• Combination of deep sequencing technology with long-range PCR revealed a novel intragenic duplication in the SLC6A8 gene, providing a definitive molecular diagnosis of creatine transporter deficiency in a male patient. (PMID:24140398)
• a 1104 bp sequence proximal to the mRNA start site of the SLC6A8 gene with promoter activity in five cell types was identified. (PMID:24144841)
• CTR4 and CTR5 are possible regulators of the creatine transporter since their overexpression results in upregulated CTR1 protein and creatine uptake. (PMID:24561156)
• both BCAP31 and ABCD1 were associated with hepatic cholestasis and death before 1 year. Remarkably, a patient with an isolated deletion at the 3’-end of SLC6A8 had a similar severe phenotype as seen in BCAP31 deficiency (PMID:24597975)
• Understanding the pathogenesis of creatine transporter deficiency is of paramount importance in the development of an effective treatment (PMID:24789340)
• It is likely that the (extracellular) structure of brain cells is also impaired in SLC6A8-deficient patients, and future studies are necessary to confirm this and to reveal the true functions of creatine in the brain. (PMID:24962355)
• Distal Xq28 microdeletions: clarification of the spectrum of contiguous gene deletions involving ABCD1, BCAP31, and SLC6A8 with a new case and review of the literature. (PMID:25044748)
• Klotho protein up-regulates the activity of creatine transporter CreaT (Slc6A8) by stabilizing the carrier protein in the cell membrane (PMID:25531216)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc6a8	ENSDARG00000043646
mus_musculus	Slc6a8	ENSMUSG00000019558
rattus_norvegicus	Slc6a8	ENSRNOG00000057620

Paralogs (19): SLC6A13 (ENSG00000010379), SLC6A7 (ENSG00000011083), SLC6A16 (ENSG00000063127), SLC6A15 (ENSG00000072041), SLC6A2 (ENSG00000103546), SLC6A4 (ENSG00000108576), SLC6A12 (ENSG00000111181), SLC6A6 (ENSG00000131389), SLC6A11 (ENSG00000132164), SLC6A3 (ENSG00000142319), SLC6A1 (ENSG00000157103), SLC6A20 (ENSG00000163817), SLC6A18 (ENSG00000164363), SLC6A5 (ENSG00000165970), SLC6A19 (ENSG00000174358), SLC6A9 (ENSG00000196517), SLC6A17 (ENSG00000197106), SLC6A14 (ENSG00000268104), (ENSG00000273554)

Protein

Protein identifiers

Sodium- and chloride-dependent creatine transporter 1 — P48029 (reviewed: P48029)

Alternative names: Solute carrier family 6 member 8

All UniProt accessions (6): P48029, H7C0F5, H7C1I2, H7C222, H7C249, X5D9C4

UniProt curated annotations — full annotation on UniProt →

Function. Creatine:sodium symporter which mediates the uptake of creatine. Plays an important role in supplying creatine to the brain via the blood-brain barrier.

Subcellular location. Cell membrane. Apical cell membrane.

Tissue specificity. Predominantly expressed in skeletal muscle and kidney. Also found in brain, heart, colon, testis and prostate.

Post-translational modifications. Glycosylated.

Disease relevance. Cerebral creatine deficiency syndrome 1 (CCDS1) [MIM:300352] An X-linked disorder of creatine transport characterized by intellectual disability, severe speech delay, behavioral abnormalities, and seizures. Carrier females may show mild neuropsychologic impairment. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A8 subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
P48029-1	1, CRT1	yes
P48029-2	2, CRT2, SLC6A8B
P48029-3	3, SLC6A8C
P48029-4	4

RefSeq proteins (3): NP_001136277, NP_001136278, NP_005620* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000175	Na/ntran_symport	Family
IPR002984	Na/ntran_symport_creatine	Family
IPR037272	SNS_sf	Homologous_superfamily

Pfam: PF00209

Catalyzed reactions (Rhea), 1 shown:

• creatine(out) + chloride(out) + 2 Na(+)(out) = creatine(in) + chloride(in) + 2 Na(+)(in) (RHEA:71831)

UniProt features (86 total): sequence variant 35, topological domain 13, transmembrane region 12, sequence conflict 10, splice variant 6, modified residue 4, glycosylation site 3, chain 1, region of interest 1, mutagenesis site 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
9V8W	ELECTRON MICROSCOPY	2.75
9V8X	ELECTRON MICROSCOPY	2.85
9V8Y	ELECTRON MICROSCOPY	3.28
9KR7	ELECTRON MICROSCOPY	3.29
9KRI	ELECTRON MICROSCOPY	3.39
9KRH	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48029-F1	85.63	0.71

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 (4): 42, 617, 620, 623

Glycosylation sites (3): 192, 197, 548

Mutagenesis-validated functional residues (1):

Position	Phenotype
285	no effect on creatine transporter activity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-71288	Creatine metabolism
R-HSA-1430728	Metabolism
R-HSA-71291	Metabolism of amino acids and derivatives

MSigDB gene sets: 385 (showing top): MODULE_274, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_MODIFIED_AMINO_ACID_TRANSPORT, GOZGIT_ESR1_TARGETS_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_G_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, HSIAO_HOUSEKEEPING_GENES, GOBP_NEUROTRANSMITTER_TRANSPORT, BROWNE_HCMV_INFECTION_16HR_UP, TGACCTY_ERR1_Q2, CACCAGC_MIR138, BROWNE_HCMV_INFECTION_12HR_UP

GO Biological Process (10): creatine metabolic process (GO:0006600), neurotransmitter transport (GO:0006836), amino acid transport (GO:0006865), muscle contraction (GO:0006936), creatine transmembrane transport (GO:0015881), sodium ion transmembrane transport (GO:0035725), monoatomic ion transport (GO:0006811), sodium ion transport (GO:0006814), gamma-aminobutyric acid transport (GO:0015812), transmembrane transport (GO:0055085)

GO Molecular Function (6): creatine transmembrane transporter activity (GO:0005308), creatine:sodium symporter activity (GO:0005309), gamma-aminobutyric acid:sodium:chloride symporter activity (GO:0005332), symporter activity (GO:0015293), transmembrane transporter activity (GO:0022857), metal ion binding (GO:0046872)

GO Cellular Component (3): plasma membrane (GO:0005886), membrane (GO:0016020), apical plasma membrane (GO:0016324)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	4
modified amino acid metabolic process	1
monocarboxylic acid metabolic process	1
muscle system process	1
monocarboxylic acid transport	1
modified amino acid transport	1
carboxylic acid transmembrane transport	1
sodium ion transport	1
monoatomic cation transmembrane transport	1
metal ion transport	1
amino acid transport	1
carboxylic acid transport	1
nitrogen compound transport	1
cellular process	1
monocarboxylic acid transmembrane transporter activity	1
creatine transmembrane transport	1
modified amino acid transmembrane transporter activity	1
creatine transmembrane transporter activity	1
monocarboxylate:sodium symporter activity	1
amino acid:sodium symporter activity	1
organic acid:sodium symporter activity	1
gamma-aminobutyric acid transmembrane transporter activity	1
secondary active monocarboxylate transmembrane transporter activity	1
sodium:chloride symporter activity	1
secondary active transmembrane transporter activity	1
transporter activity	1
transmembrane transport	1
cation binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1
apical part of cell	1
plasma membrane region	1

Protein interactions and networks

STRING

1190 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC6A8	GAMT	Q14353	944
SLC6A8	GATM	P50440	934
SLC6A8	CKMT1B	P12532	917
SLC6A8	CKB	P12277	850
SLC6A8	HAPLN1	P10915	726
SLC6A8	NME4	O00746	649
SLC6A8	PIKFYVE	Q9Y2I7	644
SLC6A8	MECP2	P51608	604
SLC6A8	SLC16A12	Q6ZSM3	603
SLC6A8	VAC14	Q08AM6	584
SLC6A8	SLC1A2	P43004	556
SLC6A8	SGK1	O00141	546
SLC6A8	L1CAM	P32004	539
SLC6A8	FMR1	Q06787	520
SLC6A8	CKMT2	P17540	511

IntAct

61 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
NT5E	SCAMP1	psi-mi:“MI:0914”(association)	0.530
YIPF3	TMEM120B	psi-mi:“MI:0914”(association)	0.530
PTGIR	TMEM63A	psi-mi:“MI:0914”(association)	0.530
ILVBL	SLC33A1	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
SLC6A8	ILVBL	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
SLC6A8	BDKRB1	psi-mi:“MI:0915”(physical association)	0.370
SLC6A8	CHRM5	psi-mi:“MI:0915”(physical association)	0.370
YIPF3	TMEM223	psi-mi:“MI:0914”(association)	0.350
GRPR	GPR89A	psi-mi:“MI:0914”(association)	0.350
TPRA1	BMPR1B	psi-mi:“MI:0914”(association)	0.350
PTGIR	GPAA1	psi-mi:“MI:0914”(association)	0.350
AGTR1	DCX	psi-mi:“MI:0914”(association)	0.350
CANX	HLA-A	psi-mi:“MI:0914”(association)	0.350
CDS2	PGRMC1	psi-mi:“MI:0914”(association)	0.350
PTDSS1	VCP	psi-mi:“MI:0914”(association)	0.350
CMTM5	TMEM120B	psi-mi:“MI:0914”(association)	0.350
GPR17	TMEM120B	psi-mi:“MI:0914”(association)	0.350
TNFRSF10C	SLC22A23	psi-mi:“MI:0914”(association)	0.350
C5AR1	TCAF2	psi-mi:“MI:0914”(association)	0.350
SLC22A4	RTL8C	psi-mi:“MI:0914”(association)	0.350
FPR1	GPR89A	psi-mi:“MI:0914”(association)	0.350
GCGR	GPR89A	psi-mi:“MI:0914”(association)	0.350
NTSR1	GPR89A	psi-mi:“MI:0914”(association)	0.350

BioGRID (257): SLC6A8 (Affinity Capture-MS), SLC6A8 (Affinity Capture-MS), SLC6A8 (Proximity Label-MS), SLC6A8 (Proximity Label-MS), SLC6A8 (Proximity Label-MS), SLC6A8 (Proximity Label-MS), SLC6A8 (Affinity Capture-MS), SLC6A8 (Affinity Capture-MS), SLC6A8 (Affinity Capture-MS), SLC6A8 (Affinity Capture-MS), SLC6A8 (Affinity Capture-MS), SLC6A8 (Affinity Capture-MS), SLC6A8 (Proximity Label-MS), SLC6A8 (Proximity Label-MS), SLC6A8 (Affinity Capture-MS)

ESM2 similar proteins: A1A4N1, A2VE54, A5PJX7, B0S5Y3, B5X4H8, O00400, O01840, O18875, O54699, P23977, P28570, P28573, P31661, P47040, P48029, P48055, P91679, Q01959, Q08B29, Q14542, Q1KKV8, Q28E13, Q2PG55, Q4HX89, Q4X0S3, Q5SPF7, Q61327, Q61672, Q69JW3, Q6BZ39, Q6BZW3, Q6DDL7, Q6DG19, Q6GMG6, Q710D3, Q758C3, Q80WK7, Q84XI3, Q86WB7, Q8VBW1

Diamond homologs: A5PJX7, A7Y2W8, A7Y2X0, B3MRS1, B3NV41, B4GVM9, B4JMC1, B4L7U0, B4MEG2, B4NDL8, B4PZQ4, B4R4T6, G5EBN9, O18875, O35316, O35899, O45813, O55192, O76689, O88575, O88576, P23975, P23977, P23978, P27799, P27922, P28570, P28571, P28572, P28573, P30531, P31641, P31643, P31645, P31646, P31647, P31648, P31649, P31650, P31651

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
SLC6A8	“up-regulates quantity”	creatine	relocalization
JAK2	“down-regulates activity”	SLC6A8	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 74 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
G alpha (q) signalling events	9	9.6×	7e-05
SLC-mediated transmembrane transport	6	6.6×	9e-03
Neutrophil degranulation	10	4.3×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
mitophagy	5	23.4×	4e-04
positive regulation of cytosolic calcium ion concentration	7	12.1×	4e-04
phospholipase C-activating G protein-coupled receptor signaling pathway	6	11.6×	1e-03
G protein-coupled receptor signaling pathway	9	4.8×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1271 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	114
Likely pathogenic	81
Uncertain significance	352
Likely benign	553
Benign	58

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1013086	NM_005629.4(SLC6A8):c.1289_1299del (p.Leu430fs)	Pathogenic
1064525	NM_005629.4(SLC6A8):c.1394_1399del (p.Gly465_Met467delinsVal)	Pathogenic
1069434	NM_005629.4(SLC6A8):c.1108C>T (p.Gln370Ter)	Pathogenic
1070967	NM_005629.4(SLC6A8):c.1551del (p.Trp518fs)	Pathogenic
1076955	NM_005629.4(SLC6A8):c.1393-12_1395del	Pathogenic
11696	NM_005629.4(SLC6A8):c.1540C>T (p.Arg514Ter)	Pathogenic
11697	NM_005629.4(SLC6A8):c.1141G>C (p.Gly381Arg)	Pathogenic
11698	NM_005629.4(SLC6A8):c.1216TTC[2] (p.Phe408del)	Pathogenic
11699	NM_005629.4(SLC6A8):c.950dup (p.Tyr317Ter)	Pathogenic
11701	NM_005629.4(SLC6A8):c.263-2A>G	Pathogenic
11702	NM_005629.4(SLC6A8):c.1011C>G (p.Cys337Trp)	Pathogenic
1188803	NM_005629.4(SLC6A8):c.249C>A (p.Tyr83Ter)	Pathogenic
1308664	NM_005629.4(SLC6A8):c.1330G>T (p.Glu444Ter)	Pathogenic
1361089	NM_005629.4(SLC6A8):c.1169C>T (p.Pro390Leu)	Pathogenic
1376685	NM_005629.4(SLC6A8):c.1283del (p.Gly428fs)	Pathogenic
1390569	NM_005629.4(SLC6A8):c.453_454insGCTGAGGCGGGAGAATCTCTTGAAGCCGGGAAGCAGAGGTTGCAGTGAACCGACATCGCGCCACTGCACTCCAGCCTGGGTGACAGAGTGAGACTCCATCTCAAAATAAATAAAAATAAAATAAAATAAAACAAGGTCTCATTCTCTTACCCAGGCTGGAGTGCAGTGGTACAATCAGAGCTCACCCCAGCCACAAACTCCTGGACTCAAGTGATCCTCCCACCTCAGCCTCCCTTGAATAGCTAGGACTACAAGTGTATGCCTCCAGGCCTGGCTAATTGTTTTTAATTTTTTGGTAGAGGCAGGGATCTCATTGTATTGCCCAGGCTGGGGTCCCAAACTCCTGATCACAAGTGAACCTCCTGCCTCAGCCTCTGAAAGTGCTGGGATTACAGGCATGAGCCACCGTGCCCAGCTCCCTGACAATTTCTGGCTGCATGGACTTCTGGTTACAAGCAGGGAAACTGAGGCCTGGATACAGCAAACAGGATCTGGCCCAGCTTTAAGTGGGGAACATGCAGTTTGGGGGACCCAGGCTCATGGTG (p.Leu152delinsAlaGluAlaGlyGluSerLeuGluAlaGlyLysGlnArgLeuGlnTer)	Pathogenic
1395238	NM_005629.4(SLC6A8):c.1496-1_1510del	Pathogenic
1397100	NM_005629.4(SLC6A8):c.444_445del (p.Ile149fs)	Pathogenic
1412467	NM_005629.4(SLC6A8):c.1055G>A (p.Ser352Asn)	Pathogenic
1416517	NM_005629.4(SLC6A8):c.1037_1038del (p.Leu346fs)	Pathogenic
1417554	NM_005629.4(SLC6A8):c.1210del (p.Ala404fs)	Pathogenic
1429550	NM_005629.4(SLC6A8):c.844del (p.Leu282fs)	Pathogenic
1679707	NM_005629.4(SLC6A8):c.627del (p.Val210fs)	Pathogenic
1686215	NM_005629.4(SLC6A8):c.980dup (p.Ser329fs)	Pathogenic
1687062	NM_005629.4(SLC6A8):c.1292_1302del (p.Asp431fs)	Pathogenic
1703957	NM_005629.4(SLC6A8):c.1519_1543del (p.Ile507fs)	Pathogenic
1706458	NM_005629.4(SLC6A8):c.1340_1341del (p.Val447fs)	Pathogenic
1802549	NM_005629.4(SLC6A8):c.1428C>G (p.Tyr476Ter)	Pathogenic
1804054	NM_005629.4(SLC6A8):c.149dup (p.Pro51fs)	Pathogenic
1956604	NM_005629.4(SLC6A8):c.755del (p.Lys252fs)	Pathogenic

SpliceAI

1788 predictions. Top by Δscore:

Variant	Effect	Δscore
X:153688834:GAGGT:G	donor_loss	1.0000
X:153688835:AGGTG:A	donor_loss	1.0000
X:153688837:GTGA:G	donor_loss	1.0000
X:153688838:T:A	donor_loss	1.0000
X:153690503:AAAGG:A	donor_loss	1.0000
X:153690504:AAGGT:A	donor_loss	1.0000
X:153690505:AGGTG:A	donor_loss	1.0000
X:153690506:GGTGA:G	donor_loss	1.0000
X:153690507:G:A	donor_loss	1.0000
X:153690508:T:G	donor_loss	1.0000
X:153691550:GGGA:G	donor_gain	1.0000
X:153691551:GGA:G	donor_gain	1.0000
X:153691551:GGAG:G	donor_gain	1.0000
X:153691552:GA:G	donor_gain	1.0000
X:153691552:GAG:G	donor_gain	1.0000
X:153691554:G:GG	donor_gain	1.0000
X:153693258:TCTA:T	acceptor_loss	1.0000
X:153693259:CTAG:C	acceptor_loss	1.0000
X:153693260:TA:T	acceptor_loss	1.0000
X:153693261:A:AT	acceptor_loss	1.0000
X:153693262:GGT:G	acceptor_gain	1.0000
X:153693262:GGTGT:G	acceptor_gain	1.0000
X:153693362:TACAA:T	donor_gain	1.0000
X:153693363:ACAA:A	donor_gain	1.0000
X:153693363:ACAAG:A	donor_loss	1.0000
X:153693364:CAA:C	donor_gain	1.0000
X:153693365:AA:A	donor_gain	1.0000
X:153693365:AAG:A	donor_loss	1.0000
X:153693366:AG:A	donor_loss	1.0000
X:153693367:G:GG	donor_gain	1.0000

AlphaMissense

4135 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:153688737:T:A	W55R	1.000
X:153688737:T:C	W55R	1.000
X:153688739:G:C	W55C	1.000
X:153688739:G:T	W55C	1.000
X:153688755:T:C	F61L	1.000
X:153688757:C:A	F61L	1.000
X:153688757:C:G	F61L	1.000
X:153688773:G:C	G67R	1.000
X:153688774:G:A	G67D	1.000
X:153688785:G:C	G71R	1.000
X:153688791:G:C	G73R	1.000
X:153688792:G:A	G73D	1.000
X:153688796:C:A	N74K	1.000
X:153688796:C:G	N74K	1.000
X:153688800:T:A	W76R	1.000
X:153688800:T:C	W76R	1.000
X:153688806:T:C	F78L	1.000
X:153688808:C:A	F78L	1.000
X:153688808:C:G	F78L	1.000
X:153690380:T:C	F90L	1.000
X:153690382:C:A	F90L	1.000
X:153690382:C:G	F90L	1.000
X:153690449:G:C	G113R	1.000
X:153690450:G:A	G113D	1.000
X:153690482:T:A	W124R	1.000
X:153690482:T:C	W124R	1.000
X:153691414:T:A	W169R	1.000
X:153691414:T:C	W169R	1.000
X:153691416:G:C	W169C	1.000
X:153691416:G:T	W169C	1.000

dbSNP variants (sampled 300 via entrez): RS1007251916 (X:153686216 C>T), RS1027242193 (X:153686153 C>T), RS1037633846 (X:153686135 C>A,T), RS1055102685 (X:153686031 C>T), RS1057520594 (X:153694013 G>A), RS1057521539 (X:153691536 T>C,G), RS1057521561 (X:153691380 T>C), RS1057522460 (X:153694799 C>T), RS1057522627 (X:153688604 C>T), RS1057523082 (X:153691548 C>T), RS1057523301 (X:153693340 C>T), RS1057523404 (X:153694198 C>G,T), RS1057523669 (X:153694454 A>G), RS1057524229 (X:153693246 C>G,T), RS1057524586 (X:153688622 C>A,T)

Disease associations

OMIM: gene MIM:300036 | disease phenotypes: MIM:300352, MIM:213000

GenCC curated gene-disease

Disease	Classification	Inheritance
creatine transporter deficiency	Definitive	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
creatine transporter deficiency	Definitive	XL

Mondo (5): creatine transporter deficiency (MONDO:0010305), neurodevelopmental disorder (MONDO:0700092), intellectual disability (MONDO:0001071), isolated cerebellar hypoplasia/agenesis (MONDO:0008939), rhombencephalosynapsis (MONDO:0018946)

Orphanet (5): X-linked creatine transporter deficiency (Orphanet:52503), Isolated cerebellar agenesis (Orphanet:1398), Cerebellar hypoplasia-tapetoretinal degeneration syndrome (Orphanet:2246), Rhombencephalosynapsis (Orphanet:59315), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

60 total (30 of 60 shown, HPO-id order):

HPO	Term
HP:0000098	Tall stature
HP:0000194	Open mouth
HP:0000252	Microcephaly
HP:0000272	Malar flattening
HP:0000275	Narrow face
HP:0000276	Long face
HP:0000298	Mask-like facies
HP:0000303	Mandibular prognathia
HP:0000337	Broad forehead
HP:0000508	Ptosis
HP:0000540	Hypermetropia
HP:0000577	Exotropia
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000733	Motor stereotypy
HP:0000742	Self-mutilation
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001276	Hypertonia
HP:0001288	Gait disturbance
HP:0001319	Neonatal hypotonia
HP:0001332	Dystonia
HP:0001382	Joint hypermobility

GWAS associations

0 associations (top):

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
C562568	Cerebellar Hypoplasia (supp.)
C535598	Creatine deficiency, X-linked (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5209634 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 61,777 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL283800	CREATINE	3	61,777

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — GABA transporter subfamily

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

Ligand	Action	Affinity	Parameter
ompenaclid	Inhibition	5.47	pKd

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
5.30	EC50	5000	nM	CREATINE

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, increases expression, increases methylation	7
Cyclosporine	decreases expression	4
trichostatin A	affects cotreatment, decreases expression	3
mercuric bromide	affects cotreatment, decreases expression	2
entinostat	decreases expression, affects cotreatment	2
(+)-JQ1 compound	increases expression	2
Vorinostat	affects cotreatment, decreases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Acetaminophen	decreases expression, increases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Cisplatin	increases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tretinoin	decreases expression, increases expression	2
Cadmium Chloride	decreases expression, increases abundance	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
dicrotophos	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
bisphenol A	affects expression	1
sodium arsenate	increases abundance, increases expression	1
trimellitic anhydride	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
periodate-oxidized adenosine	affects expression	1
resorcinol	increases expression	1
beta-methylcholine	affects expression	1

ChEMBL screening assays

1 unique, capped per target: 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5209599	Functional	Substrate uptake by the Sodium- and Chloride-Dependent Creatine Transporter 1 (CRTR, SLC6A8) as assessed by the fluorescent FLIPR membrane potential dye in HEK-293 JumpIN-SLC6A8 cells (PubChem AID: 1794823)	Membrane potential based assay for SLC6A8 using HEK-293 JumpIN SLC6A8 OE cells

Cellosaurus cell lines

44 cell lines: 22 transformed cell line, 14 finite cell line, 4 induced pluripotent stem cell, 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A2SN	GM27857	Induced pluripotent stem cell	Male
CVCL_A2TU	GM27903	Transformed cell line	Male
CVCL_B0IC	GM28213	Finite cell line	Female
CVCL_B5LB	GM28047	Transformed cell line	Male
CVCL_C0LF	GM28075	Transformed cell line	Male
CVCL_C0LK	GM28466	Finite cell line	Male
CVCL_C0LL	GM28467	Transformed cell line	Male
CVCL_C7M0	GM28937	Induced pluripotent stem cell	Male
CVCL_C7M1	GM28028	Transformed cell line	Male
CVCL_C7M2	GM28048	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
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
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
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
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
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
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
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)
NCT02931682	Not specified	TERMINATED	Observational Study of Males With Creatine Transporter Deficiency
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05642221	Not specified	COMPLETED	Functional Near-Infrared Spectroscopy (fNIRS) Combined With Diffuse Correlation Spectroscopy (DCS) in Neurocognitive Disease as Compared to Healthy Neurotypical Controls
NCT06139172	Not specified	RECRUITING	Web Intervention for Parents of Youth With Genetic Syndromes (WINGS)
NCT06292884	Not specified	UNKNOWN	Optical Imaging as a Tool for Monitoring Brain Function in Creatine Deficiency Syndromes
NCT06868979	Not specified	RECRUITING	Optical Imaging in X-linked Disorders.
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants