VPS50

Summary

VPS50 (VPS50 subunit of EARP/GARPII complex, HGNC:25956) is a protein-coding gene on chromosome 7q21.2-q21.3, encoding Syndetin (Q96JG6). Acts as a component of the EARP complex that is involved in endocytic recycling.

Enables SNARE binding activity. Acts upstream of or within endocytic recycling. Located in recycling endosome. Part of EARP complex.

Source: NCBI Gene 55610 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• Gene–disease (curated): neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 160 total — 4 pathogenic, 5 likely-pathogenic
• Expression (HPA): Low tissue specificity — highest in white matter, corpus callosum, spinal cord
• GTEx eGene: eQTL in 27 tissues, sQTL in 18 (q < 0.05)
• Phenotypes (HPO): 22
• Constraint (gnomAD): pLI 0.11 (intermediate), LOEUF 0.78 (unconstrained)
• MANE Select transcript: NM_017667

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25956
Approved symbol	VPS50
Name	VPS50 subunit of EARP/GARPII complex
Location	7q21.2-q21.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1861, FLJ20097, DKFZp313I2429, VPS54L
Ensembl gene	ENSG00000004766
Ensembl biotype	protein_coding
OMIM	616465
Entrez	55610

Gene structure

Transcript identifiers

Ensembl transcripts: 39 — 21 protein_coding, 8 retained_intron, 7 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

MANE Select: ENST00000305866

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 5, TSL 2: 5, TSL 3: 1, TSL 4: 5, TSL 5: 4

ENST00000305866, ENST00000251739, ENST00000436177, ENST00000438395, ENST00000441602, ENST00000443443, ENST00000458530, ENST00000458707, ENST00000467326, ENST00000471188, ENST00000474412, ENST00000476413, ENST00000477572, ENST00000477935, ENST00000480943, ENST00000484954, ENST00000485140, ENST00000485994, ENST00000495039, ENST00000544910, ENST00000649152, ENST00000869628, ENST00000869629, ENST00000869630, ENST00000869631, ENST00000869632, ENST00000869633, ENST00000920042, ENST00000963423, ENST00000963424, ENST00000963425, ENST00000963426, ENST00000963427, ENST00001032288, ENST00001032289, ENST00001032290, ENST00001117558, ENST00001122932, ENST00001142416

RefSeq mRNA: 3 — MANE Select: NM_017667 NM_001257998, NM_017667, NM_024553

CCDS: CCDS43617, CCDS5630, CCDS59065

Canonical transcript exons

ENST00000305866 — 28 exons

Exon	Start	End
ENSE00001349954	93349875	93350033
ENSE00001879893	93358317	93361123
ENSE00003468743	93271220	93271262
ENSE00003469430	93272635	93272733
ENSE00003479133	93256509	93256562
ENSE00003483098	93353640	93353761
ENSE00003492725	93239866	93239934
ENSE00003511769	93355891	93356080
ENSE00003530590	93341427	93341575
ENSE00003533024	93303460	93303550
ENSE00003534212	93334117	93334197
ENSE00003540140	93305828	93306004
ENSE00003543253	93291703	93291835
ENSE00003554361	93323611	93323732
ENSE00003556503	93276165	93276305
ENSE00003556643	93311166	93311272
ENSE00003562954	93297145	93297243
ENSE00003566532	93294545	93294636
ENSE00003573662	93296742	93296836
ENSE00003592176	93232366	93232500
ENSE00003592963	93258159	93258276
ENSE00003599572	93259550	93259632
ENSE00003605983	93308824	93308942
ENSE00003633039	93257394	93257464
ENSE00003649318	93253860	93253931
ENSE00003649326	93252653	93252775
ENSE00003687917	93258357	93258392
ENSE00003692642	93348711	93348807

Expression profiles

Bgee: expression breadth ubiquitous, 257 present calls, max score 95.97.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.6909 / max 488.0229, expressed in 1802 samples.

Highest expression (Bgee): calcaneal tendon, endothelial cell, tibialis anterior, adrenal tissue, Brodmann (1909) area 46.

Genetic regulation across tissues (GTEx eQTL / sQTL)

VPS50 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 27 tissues and its splicing (sQTL) in 18 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 45 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Nerve Tibial	eqtl	2.3e-34	+0.83	7:93308804:A:G
Skin Sun Exposed Lower leg	eqtl	2.2e-15	+0.41	7:93308804:A:G
Artery Tibial	eqtl	7.7e-14	+0.41	7:93308804:A:G
Artery Tibial	sqtl	9.3e-14	-0.80	7:93232313:C:T
Skin Not Sun Exposed Suprapubic	eqtl	4.6e-13	+0.42	7:93308804:A:G
Thyroid	eqtl	1.0e-12	+0.48	7:93308804:A:G
Testis	eqtl	5.3e-12	-0.38	7:93178064:C:T
Stomach	eqtl	1.2e-11	+0.63	7:93308804:A:G
Skin Sun Exposed Lower leg	sqtl	2.1e-11	+0.48	7:93340651:G:A
Nerve Tibial	sqtl	9.2e-11	+0.51	7:93340651:G:A
Pancreas	eqtl	9.8e-11	+0.87	7:93309939:G:A
Adipose Subcutaneous	eqtl	1.2e-09	+0.58	7:93236689:TAAG:T
Lung	eqtl	1.4e-09	+0.27	7:93308804:A:G
Colon Transverse	eqtl	2.5e-09	+0.44	7:93308804:A:G
Brain Cerebellar Hemisphere	sqtl	6.5e-09	-0.43	7:93355940:T:C
Artery Aorta	eqtl	2.1e-08	+0.39	7:93308804:A:G
Breast Mammary Tissue	sqtl	8.6e-08	+0.45	7:93340651:G:A
Esophagus Muscularis	eqtl	4.0e-07	-0.16	7:93355940:T:C
Adipose Subcutaneous	sqtl	5.5e-07	+0.38	7:93316698:T:G
Colon Sigmoid	eqtl	1.2e-06	+0.41	7:93309939:G:A

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
79554	23.6867	1802
79555	0.0042	1

Top tissues by expression

showing 100 of 266 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	95.97	gold quality
endothelial cell	CL:0000115	94.74	gold quality
tibialis anterior	UBERON:0001385	94.49	gold quality
adrenal tissue	UBERON:0018303	94.47	gold quality
Brodmann (1909) area 46	UBERON:0006483	93.35	gold quality
middle temporal gyrus	UBERON:0002771	92.11	gold quality
tendon	UBERON:0000043	91.92	gold quality
cortical plate	UBERON:0005343	91.55	gold quality
Brodmann (1909) area 23	UBERON:0013554	90.97	gold quality
secondary oocyte	CL:0000655	90.78	gold quality
superior frontal gyrus	UBERON:0002661	90.50	gold quality
postcentral gyrus	UBERON:0002581	90.38	gold quality
sperm	CL:0000019	90.37	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.33	gold quality
ileal mucosa	UBERON:0000331	90.29	gold quality
oocyte	CL:0000023	90.27	gold quality
colonic epithelium	UBERON:0000397	90.12	gold quality
prefrontal cortex	UBERON:0000451	89.96	gold quality
left ventricle myocardium	UBERON:0006566	89.72	gold quality
oviduct epithelium	UBERON:0004804	89.50	gold quality
deltoid	UBERON:0001476	89.08	silver quality
mucosa of sigmoid colon	UBERON:0004993	88.68	gold quality
frontal cortex	UBERON:0001870	88.51	gold quality
rectum	UBERON:0001052	88.28	gold quality
bone marrow cell	CL:0002092	88.27	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	88.04	gold quality
colonic mucosa	UBERON:0000317	87.94	gold quality
parietal lobe	UBERON:0001872	87.94	gold quality
neocortex	UBERON:0001950	87.90	gold quality
right hemisphere of cerebellum	UBERON:0014890	87.74	gold quality
cerebellar hemisphere	UBERON:0002245	87.63	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.58	gold quality
smooth muscle tissue	UBERON:0001135	87.55	gold quality
primary visual cortex	UBERON:0002436	87.55	gold quality
cerebellar cortex	UBERON:0002129	87.54	gold quality
islet of Langerhans	UBERON:0000006	87.50	gold quality
Brodmann (1909) area 9	UBERON:0013540	87.42	gold quality
cerebral cortex	UBERON:0000956	87.37	gold quality
corpus callosum	UBERON:0002336	87.25	gold quality
monocyte	CL:0000576	87.09	gold quality
entorhinal cortex	UBERON:0002728	87.06	gold quality
cardiac muscle of right atrium	UBERON:0003379	87.06	gold quality
leukocyte	CL:0000738	86.90	gold quality
embryo	UBERON:0000922	86.80	gold quality
ganglionic eminence	UBERON:0004023	86.80	gold quality
cerebellum	UBERON:0002037	86.76	gold quality
right frontal lobe	UBERON:0002810	86.61	gold quality
ventricular zone	UBERON:0003053	86.45	gold quality
corpus epididymis	UBERON:0004359	86.26	gold quality
muscle of leg	UBERON:0001383	86.17	gold quality
visceral pleura	UBERON:0002401	85.97	gold quality
gastrocnemius	UBERON:0001388	85.83	gold quality
right adrenal gland	UBERON:0001233	85.45	gold quality
skin of hip	UBERON:0001554	85.45	gold quality
anterior cingulate cortex	UBERON:0009835	85.39	gold quality
muscle tissue	UBERON:0002385	85.28	gold quality
esophagus squamous epithelium	UBERON:0006920	85.18	gold quality
right adrenal gland cortex	UBERON:0035827	85.17	gold quality
forebrain	UBERON:0001890	85.11	gold quality
brain	UBERON:0000955	84.98	gold quality
biceps brachii	UBERON:0001507	84.95	gold quality
occipital lobe	UBERON:0002021	84.95	gold quality
adrenal gland	UBERON:0002369	84.95	gold quality
trabecular bone tissue	UBERON:0002483	84.94	gold quality
cauda epididymis	UBERON:0004360	84.94	gold quality
large intestine	UBERON:0000059	84.93	gold quality
colon	UBERON:0001155	84.90	gold quality
left adrenal gland	UBERON:0001234	84.90	gold quality
Ammon’s horn	UBERON:0001954	84.90	gold quality
skeletal muscle tissue	UBERON:0001134	84.86	gold quality
pancreas	UBERON:0001264	84.84	gold quality
minor salivary gland	UBERON:0001830	84.80	gold quality
quadriceps femoris	UBERON:0001377	84.78	gold quality
lower esophagus	UBERON:0013473	84.72	gold quality
lower esophagus muscularis layer	UBERON:0035833	84.72	gold quality
intestine	UBERON:0000160	84.63	gold quality
esophagus	UBERON:0001043	84.61	gold quality
buccal mucosa cell	CL:0002336	84.60	gold quality
vastus lateralis	UBERON:0001379	84.59	gold quality
vagina	UBERON:0000996	84.57	gold quality
popliteal artery	UBERON:0002250	84.57	gold quality
tibial artery	UBERON:0007610	84.56	gold quality
right coronary artery	UBERON:0001625	84.55	gold quality
lymph node	UBERON:0000029	84.53	gold quality
transverse colon	UBERON:0001157	84.51	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	84.48	gold quality
esophagus mucosa	UBERON:0002469	84.46	gold quality
endometrium	UBERON:0001295	84.43	gold quality
left coronary artery	UBERON:0001626	84.38	gold quality
parietal pleura	UBERON:0002400	84.36	gold quality
decidua	UBERON:0002450	84.36	gold quality
upper arm skin	UBERON:0004263	84.36	gold quality
left adrenal gland cortex	UBERON:0035825	84.36	gold quality
urinary bladder	UBERON:0001255	84.35	gold quality
body of pancreas	UBERON:0001150	84.29	gold quality
muscle layer of sigmoid colon	UBERON:0035805	84.27	gold quality
body of uterus	UBERON:0009853	84.25	gold quality
gall bladder	UBERON:0002110	84.22	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	84.21	gold quality
descending thoracic aorta	UBERON:0002345	84.19	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	6.57

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Corpus callosum	tissue	114.3
Spinal cord	tissue	91.9
Medulla oblongata	tissue	74.4
Midbrain	tissue	73.1
Thalamus	tissue	63.8
Pons	tissue	62.8
Putamen	tissue	57.3
Substantia nigra	tissue	57.2
Superior colliculi	tissue	56.4
Hippocampal formation	tissue	49.9
Periaqueductal gray	tissue	46.4
Ventral forebrain	tissue	45.8
Cerebral cortex	tissue	42.4	medium
Somatosensory cortex	tissue	42.4
Septum	tissue	41.9
Occipital cortex	tissue	41.6
Motor cortex	tissue	41.0
Cerebellum	tissue	40.0	medium
Retrosplenial cortex	tissue	39.9
Hypothalamus	tissue	39.1
Retrosplenial and cingulate cortex	tissue	38.0
Entorhinal cortex	tissue	37.4
Prefrontal cortex	tissue	36.7
Temporal cortex	tissue	35.2
Basal ganglia	tissue	34.7	medium
Frontal cortex	tissue	33.2
Amygdala	tissue	32.9
Insular cortex	tissue	32.5
Olfactory bulb	tissue	28.1
Caudate putamen	tissue	27.1
Choroid plexus	tissue	12.3
Nucleus accumbens	tissue	12.1
Postcentral gyrus	tissue	12.1
Hippocampus	tissue	11.3	medium
Locus coeruleus	tissue	9.3
Breast	tissue	6.6	medium
Parathyroid gland	tissue	5.6	low
Rectum	tissue	4.9	medium
Skin 1	tissue	4.7	medium
Retina	tissue	4.7
Tongue	tissue	4.6
Thyroid gland	tissue	4.6	medium
Kidney	tissue	4.6	medium
Lymph node	tissue	4.5	medium
Esophagus	tissue	4.5	medium
Placenta	tissue	4.5	medium
Tonsil	tissue	4.4	medium
Colon	tissue	4.3	medium
Endometrium 1	tissue	4.3	medium
Spleen	tissue	4.0	low
Thymus	tissue	4.0
Epididymis	tissue	3.9	medium
Lung	tissue	3.7	medium
Salivary gland	tissue	3.5	medium
Testis	tissue	3.4	medium
Ovary	tissue	3.4	medium
Stomach 1	tissue	3.2	medium
Smooth muscle	tissue	3.2	low
Pancreas	tissue	3.2	medium
Prostate	tissue	3.2	low

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — White matter (114.3), Ventral spinal cord (91.9), Dorsal spinal cord (75.9), Dorsal hippocampus (49.9), Ventral hippocampus (38.6).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting VPS50 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 109 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220

Functional genomics

gnomAD constraint: pLI 0.106, LOEUF 0.781, missense Z 1.21 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000305866 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
7:93,232,468–93,349,953	744 / 930.6	0.80	no
7:93,349,954–93,353,681	19 / 46.8	0.41	no
7:93,353,682–93,358,433	158 / 156.3	1.01	no

Literature-anchored findings (GeneRIF, showing 1)

• Biallelic variants in VPS50 cause a neurodevelopmental disorder with neonatal cholestasis. (PMID:34037727)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	vps50	ENSDARG00000002880
danio_rerio	vps50	ENSDARG00000096912
mus_musculus	Vps50	ENSMUSG00000001376
rattus_norvegicus	Vps50	ENSRNOG00000009894
drosophila_melanogaster	Vps50	FBGN0034271
caenorhabditis_elegans		WBGENE00008078

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Gallus gallus	Q5ZKV9	89.5%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
SAMD9L	protein-coding	219285
HEPACAM2	protein-coding	253012
MIR489	ncRNA	574442
MIR653	ncRNA	724023
CALCR	protein-coding	799
SAMD9	protein-coding	54809
MIR4652	ncRNA	100616206

Protein

Protein identifiers

Syndetin — Q96JG6 (reviewed: Q96JG6)

Alternative names: Coiled-coil domain-containing protein 132, EARP/GARPII complex subunit VPS50

All UniProt accessions (8): A0A3B3IRQ5, B4DS55, C9JA29, Q96JG6, F2Z3F0, F8WDT1, H0Y7Q2, H7BZP1

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a component of the EARP complex that is involved in endocytic recycling. The EARP complex associates with Rab4-positive endosomes and promotes recycling of internalized transferrin receptor (TFRC) to the plasma membrane. Within the EARP complex, required to tether the complex to recycling endosomes. Not involved in retrograde transport from early and late endosomes to the trans-Golgi network (TGN).

Subunit / interactions. Component of the endosome-associated retrograde protein (EARP) complex, composed of VPS51, VPS52, VPS53 and VPS50/Syndetin. The EARP complex interacts with EIPR1. Interacts with VPS51 and VPS53 in an EIPR1-independent manner.

Subcellular location. Recycling endosome. Membrane.

Tissue specificity. Ubiquitous, with higher expression in brain and skeletal muscle.

Disease relevance. Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis (NEDMSC) [MIM:619685] An autosomal recessive disorder with onset at birth, characterized by severe global developmental delay, profoundly impaired intellectual development, progressive microcephaly, seizures, and transient neonatal cholestasis. Brain imaging shows agenesis or hypoplasia of the corpus callosum. Death in early childhood may occur. The disease may be caused by variants affecting the gene represented in this entry.

Miscellaneous. Was named ‘syndetin’ after the Greek ‘syndeo’, which means ‘connect’ or ’tether’.

Similarity. Belongs to the syndetin family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96JG6-1	1	yes
Q96JG6-2	2
Q96JG6-3	3

RefSeq proteins (3): NP_001244927, NP_060137, NP_078829 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019514	Syndetin_C	Domain
IPR019515	VPS54_N	Domain
IPR040047	VPS50	Family

Pfam: PF10474, PF10475

UniProt features (22 total): modified residue 6, sequence conflict 4, splice variant 3, region of interest 2, cross-link 2, coiled-coil region 2, chain 1, sequence variant 1, compositionally biased region 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96JG6-F1	71.19	0.10

Human Protein Atlas

Protein class: Predicted intracellular proteins, Disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; plasma membrane; basal body; end piece; mid piece; primary cilium; principal piece

Antibody reliability (HPA): IH approved · IF uncertain

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 (8)

Type	Positions
Phosphoserine	559, 561, 15, 494, 498
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in sumo1)	963
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in sumo2)	963
N-acetylmethionine	1

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

MSigDB gene sets: 221 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_VESICLE_MEDIATED_TRANSPORT, USF_C, PATIL_LIVER_CANCER, MODULE_239, GFI1_01, GOBP_ENDOCYTIC_RECYCLING, GOBP_RETROGRADE_TRANSPORT_ENDOSOME_TO_GOLGI, GOBP_LOCALIZATION_WITHIN_MEMBRANE, GOBP_CYTOSOLIC_TRANSPORT, GOCC_RECYCLING_ENDOSOME, VECCHI_GASTRIC_CANCER_EARLY_UP

GO Biological Process (3): protein transport (GO:0015031), endocytic recycling (GO:0032456), retrograde transport, endosome to Golgi (GO:0042147)

GO Molecular Function (2): SNARE binding (GO:0000149), protein binding (GO:0005515)

GO Cellular Component (6): membrane (GO:0016020), perinuclear region of cytoplasm (GO:0048471), recycling endosome (GO:0055037), extracellular exosome (GO:0070062), EARP complex (GO:1990745), cytosol (GO:0005829)

GO top-level categories

14 GO namespaces:

Category	Terms
cellular anatomical structure	3
endosomal transport	2
cytoplasm	2
transport	1
intracellular protein localization	1
establishment of protein localization	1
vesicle-mediated transport to the plasma membrane	1
cytosolic transport	1
protein binding	1
binding	1
endosome	1
extracellular vesicle	1
protein-containing complex	1
recycling endosome	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 6 of 11 annotations. The rest are phylogenetic / computational / electronic (IEA).

6 experimentally-supported GO terms:

GO term	NS	Evidence
endocytic recycling	BP	direct assay
EARP complex	CC	direct assay
extracellular exosome	CC	high-throughput assay
membrane	CC	high-throughput assay
recycling endosome	CC	direct assay
SNARE binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 880 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VPS50	VPS53	Q5VIR6	814
VPS50	VPS54	Q9P1Q0	813
VPS50	VPS51	Q9UID3	789
VPS50	VPS52	Q8N1B4	774
VPS50	HEPACAM2	A8MVW5	632
VPS50	CCDC186	Q7Z3E2	632
VPS50	EIPR1	Q53HC9	625
VPS50	CCDC138	Q96M89	499
VPS50	RUNDC1	Q96C34	483
VPS50	ARL5A	Q9Y689	474
VPS50	RBM26	Q5T8P6	468
VPS50	ARFRP1	Q13795	462
VPS50	PCED1A	Q9H1Q7	460
VPS50	STX6	O43752	450
VPS50	DYM	Q7RTS9	445

IntAct

Human interaction partners of VPS50 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 33 partners by confidence:

Partner	Interaction type	MIscore	Records
VPS53	physical association	0.840	4
VPS52	physical association	0.830	2
VPS51	physical association	0.640	3
CTNNBL1	physical association	0.400	1
BMAL1	physical association	0.000	1
CAVIN1	physical association	0.000	1
CCDC93	physical association	0.000	1
CCHCR1	physical association	0.000	1
CLOCK	physical association	0.000	1
DZIP3	physical association	0.000	1
EIPR1	physical association	0.000	1
GIT2	physical association	0.000	1
GOLGA5	physical association	0.000	1
GRIPAP1	physical association	0.000	1
HAUS6	physical association	0.000	1
HMG20A	physical association	0.000	1
KDM1A	physical association	0.000	1
MAX	physical association	0.000	1
NCKAP5L	physical association	0.000	1
NUF2	physical association	0.000	1
OIP5	physical association	0.000	1
PHF21A	physical association	0.000	1
PHLDB3	physical association	0.000	1
PKN3	physical association	0.000	1
PSMD9	physical association	0.000	1
RABGAP1L	physical association	0.000	1
RABGEF1	physical association	0.000	1
RCOR1	physical association	0.000	1
RPRD1A	physical association	0.000	1
TFPT	physical association	0.000	1

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexe by size:

Complex	Subunits	Members
EARP complex	4	VPS50, VPS51, VPS52, VPS53

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 33 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.

GO biological processes:

GO term	Partners	Fold	FDR
endocytic recycling	5	41.8×	1e-05
protein transport	6	8.2×	2e-03

Disease & clinical

Genetic variants

Variant evidence for VPS50: 160 ClinVar records (9 pathogenic / likely pathogenic); 1 GWAS association. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	5
Uncertain significance	90
Likely benign	14
Benign	2

Top pathogenic / likely-pathogenic (9)

Showing all 9 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
3064458	NM_017667.4(VPS50):c.1705C>T (p.Arg569Ter)	Likely pathogenic	criteria provided, single submitter	1
3235924	NM_017667.4(VPS50):c.1723C>T (p.Gln575Ter)	Likely pathogenic	criteria provided, single submitter	1
3388705	NM_017667.4(VPS50):c.2464-1G>C	Likely pathogenic	criteria provided, single submitter	1
3388706	NM_017667.4(VPS50):c.2208-2A>G	Likely pathogenic	criteria provided, single submitter	1
4535162	NM_017667.4(VPS50):c.1739del (p.Pro580fs)	Likely pathogenic	criteria provided, single submitter	1
1331700	NM_017667.4(VPS50):c.1978-1G>T	Pathogenic	no assertion criteria provided	1
1331701	NM_017667.4(VPS50):c.1823_1825del (p.Thr608del)	Pathogenic	no assertion criteria provided	1
4853803	NM_017667.4(VPS50):c.13A>T (p.Lys5Ter)	Pathogenic	no assertion criteria provided	1
4853804	VPS50, GENE DELETION, 428-KB	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore VPS50’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 38 predictions of 2,676):

Position(s)	Effect	Δscore	Sites
7:93253843	acceptor_gain	1.0000
7:93256507–93256508	acceptor_loss	1.0000	4
7:93256563–93256564	donor_loss	1.0000	6
7:93258393–93258394	donor_loss	1.0000	5
7:93259633–93259634	donor_loss	1.0000	5
7:93271263–93271264	donor_loss	1.0000	4
7:93272626–93272627	acceptor_gain	1.0000	2
7:93272630–93272632	acceptor_gain	1.0000	2
7:93272633–93272634	acceptor_loss	1.0000	4
7:93272734–93272735	donor_loss	1.0000	5

AlphaMissense

3,018 missense substitutions predicted likely pathogenic (of 6,390 scored), across 685 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M877	9	0.985	1.000
M275	9	0.947	0.999
M624	9	0.889	0.992
M462	9	0.871	0.995
D880	8	0.999	1.000
D238	8	0.997	0.999
H453	8	0.993	0.999
D271	8	0.989	0.996
H812	8	0.988	0.998
H276	8	0.983	0.998
D228	8	0.982	0.998
F463	8	0.982	1.000
F524	8	0.979	0.997
F654	8	0.976	0.997
F478	8	0.971	0.997
D644	8	0.970	0.996
D184	8	0.959	0.992
F429	8	0.958	0.998
D327	8	0.957	0.983
N466	8	0.952	0.996

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	2.03e-06
Colon Adenocarcinoma (TCGA)	unfavorable	0.000608

Disease associations

OMIM: gene MIM:616465 | disease phenotypes: MIM:619685 (Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis)

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis	Strong	Autosomal recessive	2

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (11 panels, 1 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

11 panels:

Panel	Rating
Fetal anomalies	green
Cerebral malformation	amber
Cholestasis	amber
Early onset or syndromic epilepsy	amber
Hypotonic infant	amber
Intellectual disability	amber
Leukodystrophy, childhood onset	amber
Malformations of cortical development	amber
Paediatric disorders	amber
Severe microcephaly	amber
Unexplained death in infancy and sudden unexplained death in childhood	amber

Mondo (1): neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis (MONDO:0859216)

HPO phenotypes

22 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000737	Irritability
HP:0001272	Cerebellar atrophy
HP:0001406	Intrahepatic cholestasis
HP:0002079	Hypoplasia of the corpus callosum
HP:0002179	Opisthotonus
HP:0002421	Poor head control
HP:0002904	Hyperbilirubinemia
HP:0003623	Neonatal onset
HP:0003819	Death in childhood
HP:0005484	Secondary microcephaly
HP:0008689	Bilateral cryptorchidism
HP:0010818	Generalized tonic seizure
HP:0011003	High myopia
HP:0011344	Severe global developmental delay
HP:0011968	Feeding difficulties
HP:0012202	Increased serum bile acid concentration
HP:0012595	Mild proteinuria
HP:0020045	Esodeviation
HP:0031956	Elevated circulating aspartate aminotransferase concentration
HP:0031964	Elevated circulating alanine aminotransferase concentration
HP:0040288	Nasogastric tube feeding

GWAS associations

1 association:

Study	Trait	p-value
GCST009153_6	Adverse response to chemotherapy (amenorrhea) in breast cancer	8e-7

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression	3
Valproic Acid	increases expression, decreases expression	2
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
TAK-243	decreases sumoylation	1
dicrotophos	decreases expression	1
geldanamycin	increases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	decreases expression	1
2-bromopalmitate	increases palmitoylation, decreases reaction, increases abundance	1
ochratoxin A	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
coumarin	increases phosphorylation	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	decreases expression	1
Cadmium	decreases reaction, increases abundance, increases palmitoylation	1
Caffeine	affects phosphorylation	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SH19	HAP1 CCDC132 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.