SNX27

Summary

SNX27 (sorting nexin 27, HGNC:20073) is a protein-coding gene on chromosome 1q21.3, encoding Sorting nexin-27 (Q96L92). Involved in the retrograde transport from endosome to plasma membrane, a trafficking pathway that promotes the recycling of internalized transmembrane proteins.

This gene encodes a member of the sorting nexin family, a diverse group of cytoplasmic and membrane-associated proteins involved in endocytosis of plasma membrane receptors and protein trafficking through these compartments. All members of this protein family contain a phosphoinositide binding domain (PX domain). A highly similar protein in mouse is responsible for the specific recruitment of an isoform of serotonin 5-hydroxytryptamine 4 receptor into early endosomes, suggesting the analogous role for the human protein.

Source: NCBI Gene 81609 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 443 total — 14 pathogenic, 3 likely-pathogenic
• MANE Select transcript: NM_001330723

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20073
Approved symbol	SNX27
Name	sorting nexin 27
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Aliases	MY014, KIAA0488, MGC20471
Ensembl gene	ENSG00000143376
Ensembl biotype	protein_coding
OMIM	611541
Entrez	81609

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 11 protein_coding, 5 protein_coding_CDS_not_defined, 5 retained_intron, 3 nonsense_mediated_decay

ENST00000368838, ENST00000368841, ENST00000368843, ENST00000458013, ENST00000482791, ENST00000642349, ENST00000642376, ENST00000642479, ENST00000642582, ENST00000643179, ENST00000643814, ENST00000643845, ENST00000643937, ENST00000644113, ENST00000644970, ENST00000647328, ENST00000647454, ENST00000647551, ENST00000891330, ENST00000891331, ENST00000891332, ENST00000891333, ENST00000920342, ENST00000920343

RefSeq mRNA: 2 — MANE Select: NM_001330723 NM_001330723, NM_030918

CCDS: CCDS1001, CCDS81377

Canonical transcript exons

ENST00000458013 — 12 exons

Exon	Start	End
ENSE00001512835	151612050	151612512
ENSE00001784771	151694370	151699080
ENSE00003459023	151692435	151692584
ENSE00003460700	151692911	151693039
ENSE00003462181	151668472	151668635
ENSE00003511664	151693424	151693483
ENSE00003548764	151683356	151683445
ENSE00003563976	151658235	151658427
ENSE00003605210	151665933	151666011
ENSE00003625895	151660798	151660862
ENSE00003652960	151662166	151662270
ENSE00003687148	151638888	151639119

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 94.09.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.5015 / max 379.9191, expressed in 1816 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
5235	16.9168	1804
5237	9.8639	1712
5236	1.9115	992
5240	1.3281	659
5234	0.3693	180
5233	0.1118	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
medial globus pallidus	UBERON:0002477	94.09	gold quality
globus pallidus	UBERON:0001875	93.85	gold quality
cranial nerve II	UBERON:0000941	93.55	gold quality
lateral globus pallidus	UBERON:0002476	93.06	gold quality
superior vestibular nucleus	UBERON:0007227	93.05	gold quality
inferior vagus X ganglion	UBERON:0005363	92.89	gold quality
lateral nuclear group of thalamus	UBERON:0002736	92.87	gold quality
ventral tegmental area	UBERON:0002691	92.80	gold quality
subthalamic nucleus	UBERON:0001906	92.54	gold quality
monocyte	CL:0000576	92.24	gold quality
mononuclear cell	CL:0000842	92.16	gold quality
substantia nigra pars compacta	UBERON:0001965	92.08	gold quality
substantia nigra pars reticulata	UBERON:0001966	91.97	gold quality
leukocyte	CL:0000738	91.91	gold quality
corpus callosum	UBERON:0002336	91.87	gold quality
dorsal plus ventral thalamus	UBERON:0001897	91.63	gold quality
colonic epithelium	UBERON:0000397	91.54	gold quality
parietal lobe	UBERON:0001872	91.43	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	91.25	gold quality
cerebellar vermis	UBERON:0004720	91.17	gold quality
postcentral gyrus	UBERON:0002581	91.04	gold quality
middle frontal gyrus	UBERON:0002702	91.03	gold quality
medulla oblongata	UBERON:0001896	90.97	gold quality
renal medulla	UBERON:0000362	90.74	gold quality
blood	UBERON:0000178	90.69	gold quality
nipple	UBERON:0002030	90.61	gold quality
Brodmann (1909) area 46	UBERON:0006483	90.55	gold quality
Brodmann (1909) area 10	UBERON:0013541	90.52	gold quality
biceps brachii	UBERON:0001507	90.51	gold quality
pons	UBERON:0000988	90.47	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7051	yes	1147.33
E-ANND-3	yes	15.15

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): YY1

miRNA regulators (miRDB)

315 targeting SNX27, 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-5011-5P	100.00	83.46	5820
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-19A-3P	99.98	75.33	2762

Literature-anchored findings (GeneRIF, showing 40)

• SNX27a redirects part of the 5-HT4(a)R to early endosomes. (PMID:15466885)
• These data support a previously unreported role for diacylglycerol kinase zeta in the modulation of membrane trafficking, which may also help to define SNX27 function. (PMID:17351151)
• These results suggest that endosomal SNX27 may recruit CASP to orchestrate intracellular trafficking and/or signaling complexes. (PMID:17577583)
• This study shows that SNX27 promotes the endosomal movement of Kir3 (or GIRK) channels, leading to reduced surface expression, increased degradation and smaller Kir3 potassium currents. (PMID:17828261)
• regulation of Kir3 channels by SNX27 depends critically on the combination of Kir3 subunits (PMID:18690037)
• Results identify a discrete role of SNX27 in PDZ-directed recycling of a physiologically important signaling receptor, and extend the concept of cargo-specific molecular sorting in the recycling pathway. (PMID:20733053)
• indicate that SNX27 may function to regulate endocytosis and/or endosomal sorting of NR2C (PMID:21300787)
• These results identify SNX27 as a PDZ-containing component of the T cell immunological synapse, and demonstrate a role for this protein in the regulation of the Ras-ERK pathway, suggesting a functional relationship between SNX27 and DGKzeta. (PMID:21303929)
• show that sorting nexin 27 (SNX27) serves as an essential adaptor protein linking beta2ARs to the retromer tubule (PMID:21602791)
• a model by which SNX27 regulates trafficking of beta-Pix to focal adhesions and thereby influences cell motility. (PMID:21926430)
• SNX27 interacts with MRP4 near the plasma membrane and promotes endocytosis of MRP4 and thereby negatively regulates its cell surface expression and transport function. (PMID:22411990)
• Ras-association domain of sorting Nexin 27 is critical for regulating expression of GIRK potassium channels. (PMID:23536889)
• Direct interaction of the SNX27 PDZ domain with the retromer subunit VPS26 is necessary and sufficient to prevent lysosomal entry of SNX27 cargo. (PMID:23563491)
• VPS26A binding increases the affinity of the SNX27 PDZ domain for PDZ- binding motifs by an order of magnitude, revealing cooperativity in cargo selection. (PMID:25136126)
• RNAi-mediated suppression of ANKRD50 phenocopies loss of SNX27-retromer function. (PMID:25278552)
• a function of SNX27 in regulating beta-amyloid (Abeta) generation by modulating gamma-secretase activity. (PMID:25437557)
• The results suggest that SNX27 undergoes dynamic partitioning between different membrane domains during immunological synapse assembly, and underscore the contribution of unique lipid interactions for SNX27 orchestration of cargo trafficking. (PMID:25472716)
• SNX27 deficiency is now added to the growing list of neurodegenerative disorders associated with retromer dysfunction. (PMID:25894286)
• The double knockdown of SNX17 and SNX27 results in a striking reduction of papillomavirus 16 infection due to interruption of their binding to the L2 viral protein. (PMID:26202251)
• SNX27 inhibits the Wnt regulated transcription activity of TCF/LEF. Our results suggested that SNX27 interacts with Frizzled receptors to regulate the endocytosis and stability of Fzds (PMID:26744382)
• SNX27 interaction with FAM21 is required for the precise localization of SNX27 at an endosomal subdomain. (PMID:26956659)
• PTHR recycles rapidly through at least two pathways, one involving the ASRT complex of actin, SNX27, and retromer and another possibly involving N-ethylmaleimide-sensitive factor. (PMID:27008860)
• Results show a crucial role of SNX27 in modulating GPR17 levels by means of a post-translational mechanism and highlights the relationship between the trafficking of the receptor through the endomembrane system and oligodendrocyte differentiation; and provide novel evidence of impairment of GPR17 expression and oligodendrocyte maturation in a mouse model of Down syndrome that is characterized by SNX27 down-regulation. (PMID:27270750)
• This study defines specific acidic amino acid sequences upstream of the PDZ-binding motif required for high-affinity engagement of the human SNX27 PDZ domain. (PMID:27595347)
• The viral oncoprotein E6 interaction with SNX27 can alter the recycling of cargo molecules, one consequence of which is modulation of nutrient availability in HPV transformed tumour cells. (PMID:27649450)
• Biochemistry and microscopy approaches in T cells confirmed SNX27/ZO-2 PDZ-dependent interaction, and demonstrated its role controlling the dynamic localization of ZO-2 at the IS (PMID:28477369)
• This study broadens our understanding of SNX27 as an integrator of lipid-based signals with the control of transcription and metabolic pathways. (PMID:29180720)
• data reveal a role for SNX27 in glutamine uptake and amino acid-stimulated mTORC1 activation via modulation of ASCT2 intracellular trafficking (PMID:29563155)
• HTLV-1 Tax-1 alters GLUT1 localization via its interaction with SNX27. We demonstrate that over expression of Tax-1 in cells causes a reduction of GLUT1 on the plasma membrane. Furthermore, we show that knockdown of SNX27 results in increased virion release and decreased HTLV-1 infectivity. (PMID:30897179)
• these data have demonstrate that SNX27 plays a crucial role in breast cancer growth in vitro and in vivo (PMID:31182056)
• crystal structure of human SNX27 PX domain by X-ray crystallography (PMID:31216973)
• Authors define an additional, non-catalytic function of OTULIN in the regulation of SNX27-retromer assembly and recycling to the cell surface. (PMID:31541095)
• Sorting nexin 27 (SNX27) variants associated with seizures, developmental delay, behavioral disturbance, and subcortical brain abnormalities. (PMID:31721175)
• SNX27-Mediated Recycling of Neuroligin-2 Regulates Inhibitory Signaling. (PMID:31775031)
• High SNX27 expression is associated with breast cancer metastasis. (PMID:31820782)
• SNX27 directly interacts with DRA in early endosomes at the apical pole of intestinal Caco2 cells and mediates its direct recycling to facilitate high activity in lipid rafts in the apical plasma membrane. (PMID:32116023)
• Interplay Between SNX27 and DAG Metabolism in the Control of Trafficking and Signaling at the IS. (PMID:32549284)
• The human box C/D snoRNA U3 is a miRNA source and miR-U3 regulates expression of sortin nexin 27. (PMID:32609813)
• Sorting Nexin 27 as a potential target in G proteincoupled receptor recycling for cancer therapy (Review). (PMID:33000258)
• Phosphorylation of SNX27 by MAPK11/14 links cellular stress-signaling pathways with endocytic recycling. (PMID:33605979)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	snx27b	ENSDARG00000016977
danio_rerio	snx27a	ENSDARG00000033804
mus_musculus	Snx27	ENSMUSG00000028136
rattus_norvegicus	Snx27	ENSRNOG00000020893
drosophila_melanogaster	Snx27	FBGN0052758
caenorhabditis_elegans	snx-27	WBGENE00009116

Paralogs (2): SNX17 (ENSG00000115234), SNX31 (ENSG00000174226)

Protein

Protein identifiers

Sorting nexin-27 — Q96L92 (reviewed: Q96L92)

All UniProt accessions (7): Q96L92, A0A2R8Y3S6, A0A2R8Y871, A0A2R8Y8A7, A0A2R8YD75, A0A5H1ZRP6, H7C603

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the retrograde transport from endosome to plasma membrane, a trafficking pathway that promotes the recycling of internalized transmembrane proteins. Following internalization, endocytosed transmembrane proteins are delivered to early endosomes and recycled to the plasma membrane instead of being degraded in lysosomes. SNX27 specifically binds and directs sorting of a subset of transmembrane proteins containing a PDZ-binding motif at the C-terminus: following interaction with target transmembrane proteins, associates with the retromer complex, preventing entry into the lysosomal pathway, and promotes retromer-tubule based plasma membrane recycling. SNX27 also binds with the WASH complex. Interacts with membranes containing phosphatidylinositol-3-phosphate (PtdIns(3P)). May participate in establishment of natural killer cell polarity. Recruits CYTIP to early endosomes.

Subunit / interactions. Core component of the SNX27-retromer, a multiprotein complex composed of SNX27, the WASH complex and the retromer complex. Interacts (via PDZ domain) with a number of target transmembrane proteins (via PDZ-binding motif): ABCC4, ADRB2, ARHGEF7, GRIA1, GRIA2, GRIN1, GRIN2A GRIN2C, KCNJ6, KCNJ9 and SLC2A1/GLUT1. Interacts (via the FERM-like regions) with the WASH complex. Interacts with SNX1. Interacts with CYTIP. Isoform 1 and isoform 2 directly interact with DGKZ. Isoform 1 and isoform 2 interact with HT4R isoform 5-HTA(A). Interacts with MCC. Interacts (via PDZ domains) with SLC9A3; directs SLC9A3 membrane insertion from early endosomes to the plasma membrane.

Subcellular location. Early endosome membrane. Cytoplasm. Cytosol.

Tissue specificity. Widely expressed. Expressed in cells of hematopoietic origin (at protein level).

Domain organisation. The PDZ domain mediates binding to a subset of proteins containing a PDZ-binding motif at the C-terminus: the specificity for PDZ-binding motif is provided by the 2 residues located upstream of the canonical PDZ-binding motif. The PDZ domain also mediates binding to the retromer complex via direct interaction with VPS26 (VPS26A or VPS26B). The PX domain mediates binding to phosphatidylinositol 3-phosphate (PtdIns(3P)) and localization to early endosome membranes.

Miscellaneous. May be due to intron retention.

Similarity. Belongs to the sorting nexin family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96L92-1	1, SNX27a	yes
Q96L92-3	2, SNX27b
Q96L92-2	3

RefSeq proteins (2): NP_001317652, NP_112180 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000159	RA_dom	Domain
IPR001478	PDZ	Domain
IPR001683	PX_dom	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily
IPR036871	PX_dom_sf	Homologous_superfamily
IPR037827	SNX27_FERM-like_dom	Domain
IPR037833	SNX27_PX	Domain
IPR037835	SNX27_RA	Domain

Pfam: PF00595, PF00787, PF00788

UniProt features (63 total): strand 23, helix 18, turn 5, region of interest 4, domain 3, splice variant 3, modified residue 2, chain 1, sequence variant 1, mutagenesis site 1, sequence conflict 1, compositionally biased region 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
7E0B	X-RAY DIFFRACTION	1.29
4HAS	X-RAY DIFFRACTION	1.74
5ZN9	X-RAY DIFFRACTION	1.78
7CT1	X-RAY DIFFRACTION	1.95
6SAK	X-RAY DIFFRACTION	2
7PCB	X-RAY DIFFRACTION	2
8TTV	X-RAY DIFFRACTION	2
7P72	X-RAY DIFFRACTION	2.15
8TTT	X-RAY DIFFRACTION	2.35
8TTU	X-RAY DIFFRACTION	2.36

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96L92-F1	85.03	0.60

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): 62, 51

Mutagenesis-validated functional residues (1):

Position	Phenotype
114	abolishes interaction with adrb2, sorting and recycling of adrb2.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 234 (showing top): GCM_MAP4K4, RRAGTTGT_UNKNOWN, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_LYSOSOMAL_TRANSPORT, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, ATACCTC_MIR202, GOBP_ENDOSOME_TO_LYSOSOME_TRANSPORT, GOBP_VACUOLAR_TRANSPORT, GOBP_VESICLE_MEDIATED_TRANSPORT, ACTGCAG_MIR173P, PATIL_LIVER_CANCER, GOBP_ESTABLISHMENT_OF_CELL_POLARITY, CEBP_Q2, GOBP_CELL_JUNCTION_ORGANIZATION

GO Biological Process (10): establishment of natural killer cell polarity (GO:0001770), intracellular protein transport (GO:0006886), signal transduction (GO:0007165), endosome to lysosome transport (GO:0008333), endosomal transport (GO:0016197), endocytic recycling (GO:0032456), regulation of synapse maturation (GO:0090128), regulation of postsynaptic membrane neurotransmitter receptor levels (GO:0099072), protein transport (GO:0015031), vesicle-mediated transport (GO:0016192)

GO Molecular Function (4): phosphatidylinositol-3-phosphate binding (GO:0032266), phosphatidylinositol binding (GO:0035091), protein binding (GO:0005515), lipid binding (GO:0008289)

GO Cellular Component (16): immunological synapse (GO:0001772), endosome (GO:0005768), early endosome (GO:0005769), cytosol (GO:0005829), early endosome membrane (GO:0031901), Schaffer collateral - CA1 synapse (GO:0098685), postsynaptic recycling endosome (GO:0098837), postsynaptic early endosome (GO:0098842), glutamatergic synapse (GO:0098978), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), endomembrane system (GO:0012505), membrane (GO:0016020), retromer complex (GO:0030904), WASH complex (GO:0071203), postsynapse (GO:0098794)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
synapse	3
intracellular protein localization	2
intracellular transport	2
cellular process	2
vesicle-mediated transport	2
transport	2
binding	2
plasma membrane	2
endomembrane system	2
cytoplasm	2
early endosome	2
postsynapse	2
postsynaptic endosome	2
establishment of lymphocyte polarity	1
natural killer cell activation	1
protein transport	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
lysosomal transport	1
intercellular transport	1
endosomal transport	1
vesicle-mediated transport to the plasma membrane	1
regulation of developmental process	1
regulation of synapse organization	1
synapse maturation	1
regulation of biological quality	1
establishment of protein localization	1
phosphatidylinositol phosphate binding	1
anion binding	1
cytoplasmic vesicle	1
endosome	1
endosome membrane	1
recycling endosome	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
vacuole	1
membrane protein complex	1

Protein interactions and networks

STRING

1898 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SNX27	SNX1	Q13596	987
SNX27	VPS26A	O75436	986
SNX27	DGKZ	Q13574	975
SNX27	SNX2	P82862	969
SNX27	ADRB2	P07550	958
SNX27	CYTIP	O60759	957
SNX27	VPS35	Q96QK1	957
SNX27	VPS29	Q9UBQ0	957
SNX27	SNX5	Q9Y5X3	919
SNX27	VPS26B	Q4G0F5	913
SNX27	SNX3	O60493	908
SNX27	SNX6	Q9UNH7	861
SNX27	OTULIN	Q96BN8	805
SNX27	SERPINE2	P07093	801
SNX27	SORL1	Q92673	785

IntAct

518 interactions, top by confidence:

A	B	Type	Score
E6	SNX27	psi-mi:“MI:0407”(direct interaction)	0.790
SNX27	E6	psi-mi:“MI:0915”(physical association)	0.790
PHLPP2	NHERF1	psi-mi:“MI:0914”(association)	0.760
VPS29	VPS26C	psi-mi:“MI:0914”(association)	0.760
SNX27	ACE2	psi-mi:“MI:0915”(physical association)	0.720
ACE2	SNX27	psi-mi:“MI:0407”(direct interaction)	0.720
E	SNX27	psi-mi:“MI:0915”(physical association)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
SNX27	E	psi-mi:“MI:0407”(direct interaction)	0.710
SNX27	E	psi-mi:“MI:0915”(physical association)	0.710
PTEN	PTEN	psi-mi:“MI:0915”(physical association)	0.710
E	SNX27	psi-mi:“MI:0407”(direct interaction)	0.710
SNX27	MCC	psi-mi:“MI:0914”(association)	0.700
MCC	SNX27	psi-mi:“MI:0407”(direct interaction)	0.700
TANC2	TAX1BP3	psi-mi:“MI:0914”(association)	0.690
CIT	TAX1BP3	psi-mi:“MI:0914”(association)	0.690
CFTR	SNX27	psi-mi:“MI:0407”(direct interaction)	0.670
S	SNX27	psi-mi:“MI:0915”(physical association)	0.660
S	SNX27	psi-mi:“MI:0403”(colocalization)	0.660
GPR156	PLD2	psi-mi:“MI:0914”(association)	0.640
SNX27	E6	psi-mi:“MI:0407”(direct interaction)	0.640

BioGRID (684): SNX27 (Reconstituted Complex), INSR (Affinity Capture-Western), NTRK1 (Affinity Capture-Western), SNX27 (Reconstituted Complex), SNX27 (Affinity Capture-MS), SNX27 (Affinity Capture-MS), SNX27 (Affinity Capture-MS), SNX27 (Co-fractionation), SNX27 (Affinity Capture-MS), SNX27 (Proximity Label-MS), SNX27 (Affinity Capture-MS), SNX27 (Affinity Capture-MS), SNX27 (Affinity Capture-MS), SNX27 (Affinity Capture-MS), APOA1 (Affinity Capture-MS)

ESM2 similar proteins: A4FUN7, A5D9H7, A5PKA5, A5WWB0, A6H8I0, A6NNY8, C0HB46, D0RB01, F1M625, O75317, O89050, P0C8Z3, P50876, P50904, P62068, P62069, Q09LZ8, Q3TIX9, Q3UHD6, Q52KZ6, Q53GS9, Q5DU02, Q5F415, Q5F450, Q5IFJ9, Q5IS37, Q5IS82, Q5M981, Q5R4Q7, Q5R573, Q5R761, Q5RB35, Q5RBQ4, Q5RDP3, Q5VU57, Q60969, Q6DCJ1, Q6GNI6, Q8CEG8, Q8K4V4

Diamond homologs: A0A140LI67, A5PKA5, A7UA95, E1JIT7, O14910, O15018, O19132, O35274, O35867, O35889, O62666, O62674, O62675, O62676, O62677, O62678, O88951, O88952, P11434, P29475, P29476, P31016, P51140, P55196, P57105, P78352, Q07436, Q0P5F3, Q12923, Q14005, Q29498, Q2KIB6, Q32LM6, Q3T0C9, Q3UHD6, Q4KL35, Q5F425, Q5RAA5, Q62108, Q64512

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MAPK14	“down-regulates activity”	SNX27	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	3
Uncertain significance	169
Likely benign	217
Benign	13

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
1374398	NM_001330723.2(SNX27):c.1426C>T (p.Arg476Ter)	Pathogenic
1445084	NM_001330723.2(SNX27):c.977dup (p.His326fs)	Pathogenic
1448025	NM_001330723.2(SNX27):c.652C>T (p.Arg218Ter)	Pathogenic
1452778	NM_001330723.2(SNX27):c.1216_1217dup (p.Glu407fs)	Pathogenic
1458723	NM_001330723.2(SNX27):c.1431G>A (p.Trp477Ter)	Pathogenic
2021048	NM_001330723.2(SNX27):c.1492C>T (p.Arg498Ter)	Pathogenic
2710701	NM_001330723.2(SNX27):c.1072C>T (p.Arg358Ter)	Pathogenic
2809384	NM_001330723.2(SNX27):c.1474C>T (p.Arg492Ter)	Pathogenic
3726469	NM_001330723.2(SNX27):c.556del (p.Tyr186fs)	Pathogenic
462810	NM_001330723.2(SNX27):c.1356dup (p.Leu453fs)	Pathogenic
531722	NM_001330723.2(SNX27):c.1218C>G (p.Tyr406Ter)	Pathogenic
644220	NM_001330723.2(SNX27):c.265dup (p.Ala89fs)	Pathogenic
947628	NM_001330723.2(SNX27):c.629_630del (p.Glu210fs)	Pathogenic
955542	NM_001330723.2(SNX27):c.873del (p.Lys293fs)	Pathogenic
1098325	NM_001330723.2(SNX27):c.782dup (p.Leu262fs)	Likely pathogenic
1098326	NM_001330723.2(SNX27):c.989G>A (p.Arg330His)	Likely pathogenic
3658784	NM_001330723.2(SNX27):c.1240-2A>G	Likely pathogenic

SpliceAI

2250 predictions. Top by Δscore:

Variant	Effect	Δscore
1:151612438:GCAT:G	donor_gain	1.0000
1:151615859:G:GG	donor_gain	1.0000
1:151658230:A:AG	acceptor_gain	1.0000
1:151658230:ACCAG:A	acceptor_gain	1.0000
1:151658231:C:G	acceptor_gain	1.0000
1:151658231:CCA:C	acceptor_loss	1.0000
1:151658234:GGT:G	acceptor_gain	1.0000
1:151658234:GGTAT:G	acceptor_gain	1.0000
1:151658354:G:GT	donor_gain	1.0000
1:151658354:G:T	donor_gain	1.0000
1:151658425:AAGGT:A	donor_loss	1.0000
1:151658426:AGGT:A	donor_loss	1.0000
1:151658427:GGTA:G	donor_loss	1.0000
1:151660793:TACAG:T	acceptor_loss	1.0000
1:151660794:A:AG	acceptor_gain	1.0000
1:151660794:ACAGT:A	acceptor_gain	1.0000
1:151660795:C:G	acceptor_gain	1.0000
1:151660795:CA:C	acceptor_loss	1.0000
1:151660796:A:AG	acceptor_gain	1.0000
1:151660796:A:T	acceptor_loss	1.0000
1:151660796:AGT:A	acceptor_gain	1.0000
1:151660796:AGTGT:A	acceptor_gain	1.0000
1:151660797:G:GA	acceptor_gain	1.0000
1:151660797:GT:G	acceptor_gain	1.0000
1:151660797:GTG:G	acceptor_gain	1.0000
1:151660797:GTGT:G	acceptor_gain	1.0000
1:151660797:GTGTG:G	acceptor_gain	1.0000
1:151660861:AG:A	donor_loss	1.0000
1:151660862:GG:G	donor_loss	1.0000
1:151662164:A:AG	acceptor_gain	1.0000

AlphaMissense

3554 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:151612356:G:A	G52D	1.000
1:151612361:G:C	G54R	1.000
1:151612362:G:A	G54D	1.000
1:151612362:G:T	G54V	1.000
1:151612364:T:C	F55L	1.000
1:151612364:T:G	F55V	1.000
1:151612365:T:C	F55S	1.000
1:151612365:T:G	F55C	1.000
1:151612366:C:A	F55L	1.000
1:151612366:C:G	F55L	1.000
1:151612367:A:G	N56D	1.000
1:151612369:C:A	N56K	1.000
1:151612369:C:G	N56K	1.000
1:151612370:G:A	V57M	1.000
1:151612371:T:A	V57E	1.000
1:151612371:T:C	V57A	1.000
1:151612376:G:C	G59R	1.000
1:151612376:G:T	G59C	1.000
1:151612377:G:A	G59D	1.000
1:151612434:T:C	L78P	1.000
1:151612438:G:C	Q79H	1.000
1:151612438:G:T	Q79H	1.000
1:151612443:T:A	V81E	1.000
1:151612470:C:A	A90D	1.000
1:151612497:A:C	D99A	1.000
1:151612497:A:G	D99G	1.000
1:151612497:A:T	D99V	1.000
1:151612503:T:A	I101N	1.000
1:151612503:T:C	I101T	1.000
1:151612503:T:G	I101S	1.000

dbSNP variants (sampled 300 via entrez): RS1000002451 (1:151629258 A>G), RS1000004700 (1:151662970 A>C,T), RS1000027863 (1:151634525 A>C), RS1000053487 (1:151629422 C>T), RS1000078419 (1:151648826 T>G), RS1000095163 (1:151669547 G>A), RS1000137664 (1:151643483 T>C), RS1000207576 (1:151610179 C>T), RS1000244251 (1:151643118 C>G,T), RS1000247396 (1:151655154 T>C), RS1000287860 (1:151623191 G>C), RS1000408062 (1:151694816 C>T), RS1000444569 (1:151662534 G>A,C), RS1000466942 (1:151684625 G>A), RS1000482492 (1:151629332 T>C)

Disease associations

OMIM: gene MIM:611541 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Strong	Autosomal recessive

Mondo (2): Dravet syndrome (MONDO:0100135), neurodevelopmental disorder (MONDO:0700092)

Orphanet (1): Dravet syndrome (Orphanet:33069)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST005951_38	Body mass index	4.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Dronabinol	increases expression	2
bisphenol F	affects cotreatment, increases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	decreases expression	1
beta-lapachone	decreases expression	1
butyraldehyde	decreases expression	1
CGP 52608	affects binding, increases reaction	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases expression	1
Cisplatin	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Thiram	decreases expression	1
Tretinoin	increases expression	1
Valproic Acid	increases expression	1
1-Methyl-3-isobutylxanthine	increases expression, affects cotreatment	1
Cyclosporine	decreases expression	1
Antirheumatic Agents	affects expression	1

Clinical trials (associated diseases)

291 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,
NCT05044819	PHASE4	ACTIVE_NOT_RECRUITING	Assessment of Potential for Chronic Liver Injury in Participants Treated With Epidiolex (Cannabidiol) Oral Solution
NCT06598449	PHASE4	RECRUITING	Assessment of Safety of the Use of Fenfluramine in Children With Dravet Syndrome Under 24 Months of Age
NCT06924827	PHASE4	NOT_YET_RECRUITING	A Study to Investigate the Transition of Children From ‘Artisanal Cannabidiol (CBD) to Epidiolex
NCT07112365	PHASE4	NOT_YET_RECRUITING	The FINTEPLA as an Anti-SUDEP Therapy in Dravet Syndrome Project
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
NCT00098475	PHASE3	ACTIVE_NOT_RECRUITING	Lenalidomide and Dexamethasone With or Without Thalidomide in Treating Patients With Multiple Myeloma
NCT00114101	PHASE3	ACTIVE_NOT_RECRUITING	Lenalidomide in Treating Patients With Multiple Myeloma Undergoing Autologous Stem Cell Transplant
NCT00644228	PHASE3	ACTIVE_NOT_RECRUITING	Lenalidomide and Dexamethasone With or Without Bortezomib in Treating Patients With Previously Untreated Multiple Myeloma
NCT00869206	PHASE3	COMPLETED	Zoledronic Acid in Treating Patients With Metastatic Breast Cancer, Metastatic Prostate Cancer, or Multiple Myeloma With Bone Involvement
NCT02091375	PHASE3	COMPLETED	Antiepileptic Efficacy Study of GWP42003-P in Children and Young Adults With Dravet Syndrome (GWPCARE1)
NCT02174094	PHASE3	WITHDRAWN	Clobazam as Adjunctive Therapy in Paediatric Patients Aged ≥1 to ≤16 Years With Dravet Syndrome
NCT02187809	PHASE3	TERMINATED	Safety and Tolerability of Clobazam as Adjunctive Therapy in Paediatric Patients Aged ≥1 to ≤16 Years With Dravet Syndrome
NCT02224573	PHASE3	COMPLETED	An Open Label Extension Study of Cannabidiol (GWP42003-P) in Children and Adults With Dravet or Lennox-Gastaut Syndromes
NCT02224703	PHASE3	COMPLETED	GWPCARE2 A Study to Investigate the Efficacy and Safety of Cannabidiol (GWP42003-P) in Children and Young Adults With Dravet Syndrome
NCT02318563	PHASE3	WITHDRAWN	Cannabidiol Oral Solution as an Adjunctive Therapy for Treatment of Participants With Inadequately Controlled Dravet Syndrome
NCT02682927	PHASE3	COMPLETED	A Trial of Two Fixed Doses of ZX008 (Fenfluramine HCl) in Children and Young Adults With Dravet Syndrome
NCT02823145	PHASE3	COMPLETED	An Open-Label Extension Trial to Assess the Long-Term Safety of ZX008 (Fenfluramine Hydrochloride HCl) Oral Solution in Children and Young Adults With Dravet Syndrome
NCT02926898	PHASE3	COMPLETED	A 2-Part Study to Investigate the Dose-Ranging Safety and Pharmacokinetics, Followed by the Efficacy and Safety of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy in Children ≥ 2 Years Old and Young Adults With Dravet Syndrome
NCT03299842	PHASE3	TERMINATED	A Study to Assess the Usability of the Embrace Seizure Detection Watch in Children and Young Adults With Dravet Syndrome
NCT03936777	PHASE3	COMPLETED	A Study to Investigate the Long-Term Safety of ZX008 (Fenfluramine Hydrochloride) Oral Solution in Children and Adults With Epileptic Encephalopathy Including Dravet Syndrome and Lennox-Gastaut Syndrome
NCT04462770	PHASE3	RECRUITING	A Study of EPX-100 (Clemizole Hydrochloride) in Participants With Dravet Syndrome
NCT04611438	PHASE3	UNKNOWN	Research on Cognitive Effect of Cannabidiol on Dravet Syndrome and Lennox-Gastaut SyndromeGastaut Syndrome
NCT04940624	PHASE3	COMPLETED	A Study of Soticlestat as an Add-on Therapy in Children and Young Adults With Dravet Syndrome
NCT05163314	PHASE3	TERMINATED	A Study of Soticlestat as an Add-on Therapy in Children and Adults With Dravet Syndrome or Lennox-Gastaut Syndrome
NCT05560282	PHASE3	TERMINATED	Fenfluramine for Adult Dravet Patients
NCT06118255	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Fenfluramine (Hydrochloride) in Infants 1 Year to Less Than 2 Years of Age With Dravet Syndrome
NCT06422377	PHASE3	TERMINATED	A Study Evaluating Soticlestat in Participants With Dravet Syndrome or Lennox-Gastaut Syndrome Who Have Been Exposed to Fenfluramine
NCT06660394	PHASE3	RECRUITING	A Phase 3, Placebo-Controlled Study to Investigate LP352 in Children and Adults With Dravet Syndrome (DS)
NCT06872125	PHASE3	RECRUITING	A Double-blind Study Evaluating the Efficacy, Safety, and Tolerability of Zorevunersen in Patients With Dravet Syndrome
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
NCT00066638	PHASE2	COMPLETED	FR901228 in Treating Patients With Relapsed or Refractory Multiple Myeloma
NCT00088855	PHASE2	COMPLETED	Bortezomib and Pegylated Liposomal Doxorubicin Hydrochloride in Treating Patients With Previously Untreated Symptomatic Multiple Myeloma
NCT00445692	PHASE2	COMPLETED	Lenalidomide, Dexamethasone, and Clarithromycin in Treating Patients Who Have Undergone Stem Cell Transplant for Multiple Myeloma