VAC14

Summary

VAC14 (VAC14 component of PIKFYVE complex, HGNC:25507) is a protein-coding gene on chromosome 16q22.1-q22.2, encoding Protein VAC14 homolog (Q08AM6). Scaffold protein component of the PI(3,5)P2 regulatory complex which regulates both the synthesis and turnover of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2).

This gene encodes a scaffold protein that is a component of the PIKfyve protein kinase complex. This complex is responsible for the synthesis of phosphatidylinositol 3,5-bisphosphate, an important component of cellular membranes, from phosphatidylinositol 3-phosphate. Mice lacking a functional copy of this gene exhibit severe neurodegeneration. Mutations in the human gene have been identified in patients with a childhood onset progressive neurological disorder characterized by impaired movement, dystonia, and striatal abnormalities.

Source: NCBI Gene 55697 — RefSeq curated summary.

At a glance

• Gene–disease (curated): striatonigral degeneration, childhood-onset (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 534 total — 10 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 109
• Druggable target: yes
• MANE Select transcript: NM_018052

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25507
Approved symbol	VAC14
Name	VAC14 component of PIKFYVE complex
Location	16q22.1-q22.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10305, ArPIKfyve
Ensembl gene	ENSG00000103043
Ensembl biotype	protein_coding
OMIM	604632
Entrez	55697

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 13 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 1 non_stop_decay

ENST00000261776, ENST00000536184, ENST00000561879, ENST00000563662, ENST00000564512, ENST00000564685, ENST00000566416, ENST00000566655, ENST00000567648, ENST00000568548, ENST00000568886, ENST00000571759, ENST00000889831, ENST00000889832, ENST00000889833, ENST00000924550, ENST00000924551, ENST00000951931, ENST00000951932, ENST00000951933, ENST00000951934

RefSeq mRNA: 2 — MANE Select: NM_018052 NM_001351157, NM_018052

CCDS: CCDS10896

Canonical transcript exons

ENST00000261776 — 19 exons

Exon	Start	End
ENSE00002233227	70786215	70786365
ENSE00002628307	70800797	70801158
ENSE00003465272	70698637	70698811
ENSE00003510803	70695544	70695623
ENSE00003531934	70784113	70784220
ENSE00003552167	70744423	70744579
ENSE00003565760	70780790	70780939
ENSE00003571273	70692821	70692971
ENSE00003571921	70731495	70731627
ENSE00003594619	70762881	70763025
ENSE00003599152	70781869	70782003
ENSE00003613225	70783445	70783554
ENSE00003614909	70762540	70762605
ENSE00003631828	70697139	70697257
ENSE00003640380	70783033	70783139
ENSE00003649953	70772109	70772172
ENSE00003668534	70687439	70688090
ENSE00003679249	70784776	70784838
ENSE00003685846	70785702	70785869

Expression profiles

Bgee: expression breadth ubiquitous, 233 present calls, max score 92.77.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 45.1760 / max 347.4939, expressed in 1820 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
157991	43.7485	1820
157989	0.6846	339
157990	0.3553	174
157988	0.3125	148
157987	0.0620	14
157974	0.0131	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	92.77	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.00	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.38	gold quality
mucosa of transverse colon	UBERON:0004991	90.08	gold quality
prefrontal cortex	UBERON:0000451	89.95	gold quality
apex of heart	UBERON:0002098	89.27	gold quality
right lobe of liver	UBERON:0001114	89.26	gold quality
anterior cingulate cortex	UBERON:0009835	89.17	gold quality
cingulate cortex	UBERON:0003027	89.16	gold quality
right frontal lobe	UBERON:0002810	89.15	gold quality
right lobe of thyroid gland	UBERON:0001119	89.10	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	89.07	gold quality
left adrenal gland cortex	UBERON:0035825	89.07	gold quality
granulocyte	CL:0000094	89.00	gold quality
ventricular zone	UBERON:0003053	88.98	gold quality
right adrenal gland cortex	UBERON:0035827	88.98	gold quality
right adrenal gland	UBERON:0001233	88.94	gold quality
left adrenal gland	UBERON:0001234	88.92	gold quality
cortical plate	UBERON:0005343	88.89	gold quality
left lobe of thyroid gland	UBERON:0001120	88.79	gold quality
ganglionic eminence	UBERON:0004023	88.54	gold quality
spleen	UBERON:0002106	88.39	gold quality
lymph node	UBERON:0000029	88.37	gold quality
metanephros cortex	UBERON:0010533	88.26	gold quality
adrenal cortex	UBERON:0001235	88.15	gold quality
skin of leg	UBERON:0001511	88.13	gold quality
amygdala	UBERON:0001876	88.00	gold quality
thyroid gland	UBERON:0002046	87.88	gold quality
adrenal gland	UBERON:0002369	87.82	gold quality
lower esophagus muscularis layer	UBERON:0035833	87.81	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	8.27
E-ANND-3	yes	6.20

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

20 targeting VAC14, 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-8485	100.00	77.57	4731
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-4677-3P	99.49	67.91	1246
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-4652-3P	99.33	70.02	2742
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-5100	99.11	67.52	1098
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-4664-5P	98.17	65.07	1020
HSA-MIR-124-5P	98.11	67.65	1095
HSA-MIR-6819-5P	97.96	66.59	1071
HSA-MIR-6737-5P	97.75	66.54	1044
HSA-MIR-6812-5P	97.56	65.39	1059
HSA-MIR-342-5P	97.25	64.10	817
HSA-MIR-4536-3P	97.06	66.88	175

Literature-anchored findings (GeneRIF, showing 18)

• the PIKfyve-associated hVac14 protein has a major role in activating PIKfyve and thereby regulating PtdIns(3,5)P(2) synthesis and endomembrane homeostasis in mammalian cells (PMID:15542851)
• describe a novel interaction between the PDZ domain of nitric oxide synthase and Vac14 (PMID:17161399)
• demonstrate a coupling between the machinery for PtdIns(3,5)P2 synthesis and turnover achieved through a physical assembly of PIKfyve, ArPIKfyve, and Sac3. (PMID:17556371)
• The authors data indicate that the PAS complex is organized to provide optimal PIKfyve functionality and is maintained via ArPIKfyve homomeric and heteromeric interactions. (PMID:18950639)
• PIKfyve-ArPIKfyve-Sac3 core complex: contact sites and their consequence for Sac3 phosphatase activity and endocytic membrane homeostasis (PMID:19840946)
• a novel regulatory mechanism whereby ArPIKfyve enhances Sac3 abundance by attenuating Sac3 proteasome-dependent degradation and suggest that a failure of this mechanism could be the primary molecular defect in the pathogenesis of CMT4J. (PMID:20630877)
• Rab7 GAP TBC1D15 with Vac14. (PMID:24578385)
• A genome-wide association study of a prospectively enrolled patient cohort identified an single nucleotide polymorphism in VAC14 that predicts sensitivity to docetaxel-induced peripheral neuropathy. (PMID:27143689)
• The similar age of onset and neurological decline in the two unrelated children define a recessive disorder resulting from compound heterozygosity for deleterious variants of VAC14. (PMID:27292112)
• Biallelic rare coding variants in VAC14 was identified in a female neonate with Yunis-Varon syndrome. Cultured patient fibroblasts exhibited a YVS-like vacuolation ameliorated by ML-SA1. (PMID:28635952)
• The association data demonstrated strong correlations between rs8060947 and VAC14 expression and between rs8060947 and S. Typhi invasion. The direction of effects for the different alleles led to the hypothesis that reducing VAC14 expression would increase S. Typhi invasion. (PMID:28827342)
• Nbeal2 interacts with Dock7, Sec16a, and Vac14. (PMID:29187380)
• Increased albuminuria in Vac14(L156R)-overexpressing mice is a consequence of a lowered endo- and transcytosis of albumin in renal tubules. (PMID:30066585)
• The patient fibroblasts showed extensive vacuolization, characteristic of VAC14-related disorders. (PMID:31591492)
• Novel VAC14 variants identified in two Chinese siblings with childhood-onset striatonigral degeneration. (PMID:31876398)
• Altered homodimer formation and increased iron accumulation in VAC14-related disease: Case report and review of the literature. (PMID:32949958)
• Proximity Interactome Map of the Vac14-Fig4 Complex Using BioID. (PMID:34554760)
• TIG1 Inhibits the mTOR Signaling Pathway in Malignant Melanoma Through the VAC14 Protein. (PMID:37247911)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	vac14	ENSDARG00000014303
mus_musculus	Vac14	ENSMUSG00000010936
rattus_norvegicus	Vac14	ENSRNOG00000017219
drosophila_melanogaster	CG5608	FBGN0038058
caenorhabditis_elegans	vacl-14	WBGENE00010565

Protein

Protein identifiers

Protein VAC14 homolog — Q08AM6 (reviewed: Q08AM6)

Alternative names: Tax1-binding protein 2

All UniProt accessions (6): Q08AM6, A0A087WT26, H3BN23, H3BQD9, H3BUU8, J3QLC3

UniProt curated annotations — full annotation on UniProt →

Function. Scaffold protein component of the PI(3,5)P2 regulatory complex which regulates both the synthesis and turnover of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2). Pentamerizes into a star-shaped structure and nucleates the assembly of the complex. The pentamer binds a single copy each of PIKFYVE and FIG4 and coordinates both PIKfyve kinase activity and FIG4 phosphatase activity, being required to maintain normal levels of phosphatidylinositol 3-phosphate (PtdIns(3)P) and phosphatidylinositol 5-phosphate (PtdIns(5)P). Plays a role in the biogenesis of endosome carrier vesicles (ECV) / multivesicular bodies (MVB) transport intermediates from early endosomes.

Subunit / interactions. Forms pentamers. Component of the PI(3,5)P2 regulatory complex/PAS complex, at least composed of PIKFYVE, FIG4 and VAC14. VAC14 nucleates the assembly of the complex and serves as a scaffold by pentamerizing into a star-shaped structure, which can bind a single copy each of PIKFYVE and FIG4 and coordinates their activities. Interacts with NOS1. (Microbial infection) Interacts with HTLV-1 Tax.

Subcellular location. Endosome membrane. Microsome membrane.

Tissue specificity. Ubiquitously expressed.

Disease relevance. Striatonigral degeneration, childhood-onset (SNDC) [MIM:617054] An autosomal recessive neurological disorder characterized by sudden childhood onset of developmental regression. Affected children develop impaired movements with dystonia, progressively become non-ambulatory and non-verbal, and exhibit striatal abnormalities on MRI. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The C-terminal domain (residues 523-782) mediates pentameric interactions and is necessary for the formation and maintenance of the PI(3,5)P2 regulatory complex.

Similarity. Belongs to the VAC14 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q08AM6-1	1	yes
Q08AM6-2	2

RefSeq proteins (2): NP_001338086, NP_060522* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR021841	VAC14_Fig4p-bd	Domain
IPR026825	Vac14	Family

Pfam: PF11916, PF12755

UniProt features (30 total): repeat 6, mutagenesis site 6, modified residue 5, sequence variant 3, sequence conflict 3, region of interest 3, compositionally biased region 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
7K1Y	ELECTRON MICROSCOPY	5.25

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q08AM6-F1	84.63	0.75

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 (5): 1, 11, 499, 517, 743

Mutagenesis-validated functional residues (6):

Position	Phenotype
773	reduces interaction with nos1.
774	reduces interaction with nos1.
776	reduces interaction with nos1.
777	abolishes interaction with nos1.
780–782	reduces interaction with nos1.
782	reduces interaction with nos1.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1660514	Synthesis of PIPs at the Golgi membrane
R-HSA-1660516	Synthesis of PIPs at the early endosome membrane
R-HSA-1660517	Synthesis of PIPs at the late endosome membrane

MSigDB gene sets: 468 (showing top): GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, chr16q22, GOCC_VACUOLAR_MEMBRANE, AACYNNNNTTCCS_UNKNOWN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GOBP_REGULATION_OF_RECEPTOR_INTERNALIZATION, GOBP_REGULATION_OF_RECEPTOR_MEDIATED_ENDOCYTOSIS, GOBP_RECEPTOR_INTERNALIZATION, GOBP_GLYCEROLIPID_BIOSYNTHETIC_PROCESS

GO Biological Process (3): phosphatidylinositol biosynthetic process (GO:0006661), signal transduction (GO:0007165), regulation of postsynaptic neurotransmitter receptor internalization (GO:0099149)

GO Molecular Function (3): signaling receptor activity (GO:0038023), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (11): Golgi membrane (GO:0000139), cytosol (GO:0005829), endosome membrane (GO:0010008), early endosome membrane (GO:0031901), late endosome membrane (GO:0031902), PAS complex (GO:0070772), presynaptic endosome (GO:0098830), endosome (GO:0005768), endoplasmic reticulum (GO:0005783), endomembrane system (GO:0012505), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
PI Metabolism	3

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
bounding membrane of organelle	2
cytoplasm	2
endosome	2
endosome membrane	2
endomembrane system	2
biosynthetic process	1
phosphatidylinositol metabolic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
regulation of receptor internalization	1
regulation of biological quality	1
postsynaptic neurotransmitter receptor internalization	1
molecular transducer activity	1
protein binding	1
binding	1
Golgi apparatus	1
cytoplasmic vesicle membrane	1
early endosome	1
late endosome	1
vacuolar membrane	1
transferase complex, transferring phosphorus-containing groups	1
membrane protein complex	1
presynapse	1
cytoplasmic vesicle	1
intracellular membrane-bounded organelle	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

1462 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VAC14	FIG4	Q92562	999
VAC14	PIKFYVE	Q9Y2I7	999
VAC14	WIPI1	Q5MNZ9	945
VAC14	LAMP2	P13473	784
VAC14	NAAA	Q02083	761
VAC14	MAP1LC3A	Q9H492	761
VAC14	APP	P05067	702
VAC14	SQSTM1	Q13501	661
VAC14	TGOLN2	O43493	592
VAC14	SLC6A8	P48029	584
VAC14	CNTN2	P78432	560
VAC14	MTSS2	Q765P7	539
VAC14	PIK3C3	Q8NEB9	525
VAC14	COG4	Q9H9E3	525
VAC14	CACNA1C	Q13936	510

IntAct

615 interactions, top by confidence:

A	B	Type	Score
VAC14	DNAAF19	psi-mi:“MI:0915”(physical association)	0.830
C4orf33	VAC14	psi-mi:“MI:0915”(physical association)	0.830
VAC14	C4orf33	psi-mi:“MI:0915”(physical association)	0.830
PIKFYVE	VAC14	psi-mi:“MI:0915”(physical association)	0.800
VAC14	CDRT4	psi-mi:“MI:0915”(physical association)	0.780
VAC14	COL8A1	psi-mi:“MI:0915”(physical association)	0.780
CDRT4	VAC14	psi-mi:“MI:0915”(physical association)	0.780
COL8A1	VAC14	psi-mi:“MI:0915”(physical association)	0.780
NTAQ1	VAC14	psi-mi:“MI:0915”(physical association)	0.740
VAC14	NTAQ1	psi-mi:“MI:0915”(physical association)	0.740
BHLHE40	VAC14	psi-mi:“MI:0915”(physical association)	0.720
VAC14	SIGLEC5	psi-mi:“MI:0915”(physical association)	0.720
VAC14	TP53BP1	psi-mi:“MI:0915”(physical association)	0.720
VAC14	MPPED2	psi-mi:“MI:0915”(physical association)	0.720
KRTAP19-5	VAC14	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (280): VAC14 (Two-hybrid), VAC14 (Two-hybrid), VAC14 (Two-hybrid), VAC14 (Two-hybrid), VAC14 (Two-hybrid), VAC14 (Two-hybrid), VAC14 (Two-hybrid), VAC14 (Two-hybrid), VAC14 (Two-hybrid), VAC14 (Two-hybrid), VAC14 (Two-hybrid), VAC14 (Two-hybrid), VAC14 (Two-hybrid), VAC14 (Two-hybrid), VAC14 (Two-hybrid)

ESM2 similar proteins: A0JMW2, A2VE70, A5WW24, A7E2Y6, B9EJR8, E0CZ22, E1BP36, E7FBU4, O35638, O43156, O70576, O75155, Q08AM6, Q0P5A6, Q0V9L1, Q16401, Q5IFJ8, Q5JTH9, Q5R6L5, Q5ZIW5, Q5ZKD5, Q66L58, Q68F38, Q6DCF2, Q6P5B0, Q6ZQ73, Q7TMY7, Q80W92, Q80WQ2, Q84ZC0, Q86Y56, Q8C0Y0, Q8K2V6, Q8NDA8, Q8WVM7, Q91V83, Q96T76, Q99M76, Q9BPX3, Q9D071

Diamond homologs: A2VE70, P87145, Q08AM6, Q5ZIW5, Q66L58, Q68F38, Q80W92, Q80WQ2, Q9ZU97, Q06708

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
VAC14	“form complex”	“PAS complex”	binding
NBEAL2	unknown	VAC14	binding
VAC14	“up-regulates quantity by stabilization”	FIG4	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	5
Uncertain significance	168
Likely benign	259
Benign	55

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
1964695	NM_018052.5(VAC14):c.2073del (p.Tyr692fs)	Pathogenic
253140	NM_018052.5(VAC14):c.1271G>T (p.Trp424Leu)	Pathogenic
253141	NM_018052.5(VAC14):c.1528+1G>A	Pathogenic
253142	NM_018052.5(VAC14):c.1744G>T (p.Ala582Ser)	Pathogenic
253143	NM_018052.5(VAC14):c.1748C>T (p.Ser583Leu)	Pathogenic
2767639	NM_018052.5(VAC14):c.56del (p.Asn19fs)	Pathogenic
3660543	NM_018052.5(VAC14):c.1011dup (p.Glu338fs)	Pathogenic
3709120	NM_018052.5(VAC14):c.1096+1G>C	Pathogenic
3725579	NM_018052.5(VAC14):c.536del (p.Leu179fs)	Pathogenic
397536	NM_018052.5(VAC14):c.923T>A (p.Leu308Ter)	Pathogenic
1367992	NM_018052.5(VAC14):c.595-10_595del	Likely pathogenic
1805191	NM_018052.5(VAC14):c.104+2T>G	Likely pathogenic
2664898	NM_018052.5(VAC14):c.921C>A (p.Cys307Ter)	Likely pathogenic
397535	NM_018052.5(VAC14):c.1895C>T (p.Thr632Met)	Likely pathogenic
488760	NM_018052.5(VAC14):c.486+3A>G	Likely pathogenic

SpliceAI

4461 predictions. Top by Δscore:

Variant	Effect	Δscore
16:70692819:A:AC	donor_gain	1.0000
16:70692820:C:CC	donor_gain	1.0000
16:70692820:CT:C	donor_gain	1.0000
16:70692967:CAGAT:C	acceptor_gain	1.0000
16:70692968:AGAT:A	acceptor_gain	1.0000
16:70692969:GAT:G	acceptor_gain	1.0000
16:70692970:AT:A	acceptor_gain	1.0000
16:70692972:C:CC	acceptor_gain	1.0000
16:70692972:C:G	acceptor_loss	1.0000
16:70697138:CAA:C	donor_gain	1.0000
16:70697143:T:TA	donor_gain	1.0000
16:70697253:CTCTC:C	acceptor_gain	1.0000
16:70697255:CTC:C	acceptor_gain	1.0000
16:70697258:C:CC	acceptor_gain	1.0000
16:70697258:CTGTG:C	acceptor_loss	1.0000
16:70697259:T:A	acceptor_loss	1.0000
16:70698669:G:C	donor_gain	1.0000
16:70744418:CTT:C	donor_loss	1.0000
16:70744419:TTA:T	donor_loss	1.0000
16:70744420:TA:T	donor_loss	1.0000
16:70744421:ACCA:A	donor_loss	1.0000
16:70762535:CCTA:C	donor_loss	1.0000
16:70762536:CTACC:C	donor_loss	1.0000
16:70762537:TACC:T	donor_loss	1.0000
16:70762539:C:CG	donor_loss	1.0000
16:70762876:CTCA:C	donor_loss	1.0000
16:70762877:TCA:T	donor_loss	1.0000
16:70762878:CACCT:C	donor_loss	1.0000
16:70762879:ACCT:A	donor_loss	1.0000
16:70762879:ACCTT:A	donor_gain	1.0000

AlphaMissense

5135 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:70697221:A:G	W625R	1.000
16:70697221:A:T	W625R	1.000
16:70698665:C:A	R603M	1.000
16:70762903:A:G	L428P	1.000
16:70762916:A:G	W424R	1.000
16:70762916:A:T	W424R	1.000
16:70781974:A:G	W281R	1.000
16:70781974:A:T	W281R	1.000
16:70784115:A:G	W198R	1.000
16:70784115:A:T	W198R	1.000
16:70784783:A:G	L160P	1.000
16:70784786:C:G	R159P	1.000
16:70784792:A:G	L157P	1.000
16:70784795:A:G	L156P	1.000
16:70784804:C:T	G153E	1.000
16:70785759:C:A	K122N	1.000
16:70785759:C:G	K122N	1.000
16:70785761:T:C	K122E	1.000
16:70785768:G:C	N119K	1.000
16:70785768:G:T	N119K	1.000
16:70785770:T:C	N119D	1.000
16:70785775:A:G	L117P	1.000
16:70785779:C:G	A116P	1.000
16:70785780:C:A	E115D	1.000
16:70785780:C:G	E115D	1.000
16:70785781:T:A	E115V	1.000
16:70785782:C:T	E115K	1.000
16:70785787:G:T	A113D	1.000
16:70785794:A:G	Y111H	1.000
16:70786237:G:T	A78D	1.000

dbSNP variants (sampled 300 via entrez): RS1000029975 (16:70769107 T>C), RS1000032091 (16:70796640 C>A,T), RS1000048326 (16:70754653 C>A), RS1000052600 (16:70721939 C>T), RS1000073871 (16:70735833 C>A), RS1000129576 (16:70726476 A>G), RS1000150627 (16:70712076 C>T), RS1000153430 (16:70687105 T>C), RS1000174376 (16:70759509 T>G), RS1000240990 (16:70765309 G>C,T), RS1000252119 (16:70796475 C>A), RS1000255369 (16:70740593 C>A,G,T), RS1000257929 (16:70774579 G>A), RS1000312747 (16:70749948 A>G), RS1000334539 (16:70730828 C>G,T)

Disease associations

OMIM: gene MIM:604632 | disease phenotypes: MIM:617054, MIM:216340

GenCC curated gene-disease

Disease	Classification	Inheritance
striatonigral degeneration, childhood-onset	Strong	Autosomal recessive
hereditary neurological disease	Moderate	Autosomal recessive
Yunis-Varon syndrome	Supportive	Autosomal recessive

Mondo (5): neurodegenerative disease (MONDO:0005559), striatonigral degeneration, childhood-onset (MONDO:0014889), myoepithelial tumor (MONDO:0002380), Yunis-Varon syndrome (MONDO:0008995), hereditary neurological disease (MONDO:0100545)

Orphanet (2): Childhood-onset basal ganglia degeneration syndrome (Orphanet:497906), Yunis-Varon syndrome (Orphanet:3472)

HPO phenotypes

109 total (30 of 109 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000059	Hypoplastic labia majora
HP:0000162	Glossoptosis
HP:0000188	Short upper lip
HP:0000216	Broad secondary alveolar ridge
HP:0000233	Thin vermilion border
HP:0000238	Hydrocephalus
HP:0000268	Dolichocephaly
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000331	Short chin
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000463	Anteverted nares
HP:0000518	Cataract
HP:0000520	Proptosis
HP:0000568	Microphthalmia
HP:0000582	Upslanted palpebral fissure
HP:0000647	Sclerocornea
HP:0000653	Sparse eyelashes
HP:0000750	Delayed speech and language development
HP:0000773	Short ribs
HP:0000822	Hypertension
HP:0000954	Single transverse palmar crease

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST003672_1	Docetaxel-induced peripheral neuropathy in metastatic castrate-resistant prostate cancer	2.000000e-08
GCST004278_19	Pulse pressure	4.000000e-12
GCST004537_3	High density lipoprotein cholesterol levels	2.000000e-11
GCST005553_1	Diffuse cutaneous systemic sclerosis	1.000000e-06
GCST006993_12	Hippocampal volume in Alzheimer’s disease dementia	1.000000e-07
GCST010725_47	Malaria	6.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005763	pulse pressure measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0005035	hippocampal volume

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D009208	Myoepithelioma	C04.557.435.585
D019636	Neurodegenerative Diseases	C10.574
C536719	Yunis Varon syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066525 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs875858	Toxicity	3	docetaxel	Prostatic Neoplasms

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs875858	VAC14	3	0.00	1	docetaxel

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.21	Kd	619	nM	CHEMBL3752910
6.19	ED50	647.5	nM	CHEMBL3752910
5.44	Kd	3667	nM	CHEMBL5653589
5.42	ED50	3836	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149750: Binding affinity to human VAC14 incubated for 45 mins by Kinobead based pull down assay	kd	0.6190	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149750: Binding affinity to human VAC14 incubated for 45 mins by Kinobead based pull down assay	kd	3.6673	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, affects cotreatment, decreases expression	3
sodium arsenite	decreases expression, increases expression	2
Benzo(a)pyrene	decreases expression	2
Cadmium	decreases reaction, increases abundance, increases palmitoylation, decreases expression	2
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, decreases expression	2
FR900359	decreases phosphorylation	1
bisphenol F	increases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	increases expression	1
beta-lapachone	increases expression	1
cobaltous chloride	decreases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
cylindrospermopsin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
bisphenol B	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
bisphenol S	increases expression	1
jinfukang	increases expression	1
LDN 193189	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Temozolomide	decreases expression	1
Arsenic	affects methylation	1
Catechin	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Dimethyl Sulfoxide	increases expression	1
Doxorubicin	decreases expression	1
Hydrogen Peroxide	affects expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652792	Binding	Binding affinity to human VAC14 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2KT	Abcam HeLa VAC14 KO	Cancer cell line	Female
CVCL_D8DB	Ubigene A-549 VAC14 KO	Cancer cell line	Male
CVCL_TX23	HAP1 VAC14 (-) 1	Cancer cell line	Male
CVCL_TX24	HAP1 VAC14 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01662414	PHASE4	COMPLETED	Effect of Undenatured Cysteine-Rich Whey Protein Isolate (HMS 90®) in Patients With Parkinson’s Disease
NCT04871464	PHASE4	UNKNOWN	Role and Mechanism of Probiotics in Improving Motor Symptoms in Mild to Moderate Parkinson’s Disease
NCT05357612	PHASE4	RECRUITING	Characterization of the Serotonin 2A Receptor Selective PET Tracer [18F]MH.MZ in Patients With Neurodegenerative Diseases
NCT05508789	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Donanemab (LY3002813) in Participants With Early Symptomatic Alzheimer’s Disease (TRAILBLAZER-ALZ 5)
NCT05738486	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Different Donanemab (LY3002813) Dosing Regimens in Adults With Early Alzheimer’s Disease (TRAILBLAZER-ALZ 6)
NCT06111014	PHASE3	TERMINATED	Continuation Study for Latozinemab
NCT06672237	PHASE3	RECRUITING	A Phase 3 Study of NTLA-2001 in ATTRv-PN
NCT00001365	PHASE2	COMPLETED	Dextromethorphan for the Treatment of Parkinson’s Disease and Similar Conditions of the Nervous System
NCT00406029	PHASE2	COMPLETED	Dyskinesia in Parkinson’s Disease (Study P04501)
NCT00537017	PHASE2	COMPLETED	Follow Up Safety Study of SCH 420814 in Subjects With Parkinson’s Disease (P05175)
NCT00907283	PHASE2	UNKNOWN	Ferrochelating Treatment in Patients Affected by Neurodegeneration With Brain Iron Accumulation (NBIA)
NCT01518374	PHASE2	COMPLETED	Clinical Evaluation of Florbetapir F 18 (18F-AV-45)
NCT02656498	PHASE2	COMPLETED	[18F]THK-5351 Positron Emission Computed Tomography Study of Normal, Mild Cognitive Impairment, Alzheimer’s Disease and Other Neurodegenerative Disease
NCT03127514	PHASE2	COMPLETED	AMX0035 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT03538522	PHASE2	COMPLETED	A Double-Blind, Placebo-Controlled Safety and Efficacy Study of NA-831
NCT04838301	PHASE2	RECRUITING	Allopregnanolone Regenerative Therapeutic for Mild Alzheimer’s Disease
NCT04937452	PHASE2	COMPLETED	Dopaminergic Therapy for Frontotemporal Dementia Patients
NCT05318976	PHASE2	COMPLETED	A Study of XPro1595 in Patients With Early Alzheimer’s Disease With Biomarkers of Inflammation
NCT05321498	PHASE2	WITHDRAWN	Study to Assess the Efficacy of XPro1595 in Patients With Mild Cognitive Impairment With Biomarkers of Inflammation
NCT05479981	PHASE2	COMPLETED	Extension of AOC 1001-CS1 (MARINA) Study in Adult Myotonic Dystrophy Type 1 (DM1) Patients
NCT05522387	PHASE2	TERMINATED	An Open-Label Extension of XPro1595 in Patients With Alzheimer’s Disease
NCT00316797	PHASE1	COMPLETED	Biodistribution and Safety of a Radiopharmaceutical in Healthy Subjects
NCT01758510	PHASE1	COMPLETED	Safety Study of HLA-haplo Matched Allogenic Bone Marrow Derived Stem Cell Treatment in Amyotrophic Lateral Sclerosis
NCT02267434	PHASE1	COMPLETED	Study Assessing Tolerability and Safety of AFFITOPE® PD03A in Patients With Early Parkinson’s Disease
NCT02270489	PHASE1	COMPLETED	Study Assessing Safety and Therapeutic Activity of AFFITOPE® PD01A and PD03A in Patients With Early MSA
NCT03065192	PHASE1	COMPLETED	Safety and Efficacy Study of VY-AADC01 for Advanced Parkinson’s Disease
NCT04578028	PHASE1	COMPLETED	A First in Human Study to Assess the Safety, Tolerability and Pharmacokinetics of ONO-2808-01 in Healthy Participants
NCT05143463	PHASE1	COMPLETED	A FIH Study to Assess the Safety and Tolerability of NS Intravenous NS101 Infusion
NCT05490576	PHASE1	UNKNOWN	Tau And Connectomics In TES Study
NCT05792163	PHASE1	COMPLETED	A First Time in Human Study of SNP318 as a Treatment for Neurodegenerative Diseases Including Alzheimer’s Disease
NCT07232147	PHASE1	NOT_YET_RECRUITING	Clinical Research on Stem Cell Therapy for Parkinson’s Disease
NCT03600649	PHASE1	UNKNOWN	Clinical Trial of SP-2577 (Seclidemstat) in Patients With Relapsed or Refractory Ewing or Ewing-related Sarcomas
NCT06955624	Not specified	RECRUITING	Use of Omics Methods to Classify Variations of Uncertain Significance and Improve Diagnosis of Neurogenetic Diseases
NCT03143374	PHASE2/PHASE3	RECRUITING	PET Tau - Neurodegenerative Disease Imaging
NCT06122662	PHASE2/PHASE3	COMPLETED	AMX0035 and Progressive Supranuclear Palsy
NCT03295786	PHASE1/PHASE2	COMPLETED	Clinical Study to Test the Safety of CDNF by Brain Infusion in Patients With Parkinson’s Disease
NCT05853471	PHASE1/PHASE2	UNKNOWN	[18F]MC225-PET in Neurodegenerative Disease
NCT06447194	PHASE1/PHASE2	WITHDRAWN	Effect of RECK in Posterior Spinal Fusion
NCT06934720	PHASE1/PHASE2	NOT_YET_RECRUITING	VR-based Physical Activity and Reminiscence Therapy
NCT02452216	EARLY_PHASE1	COMPLETED	Using Ferumoxytol-Enhanced MRI to Measure Inflammation in Patients With Brain Tumors or Other Conditions of the CNS