VPS13D

Summary

VPS13D (vacuolar protein sorting 13 homolog D, HGNC:23595) is a protein-coding gene on chromosome 1p36.22-p36.21, encoding Intermembrane lipid transfer protein VPS13D (Q5THJ4). Mediates the transfer of lipids between membranes at organelle contact sites. It is a selective cancer dependency (DepMap: 85.7% of cell lines).

This gene encodes a protein belonging to the vacuolar-protein-sorting-13 gene family. In yeast, vacuolar-protein-sorting-13 proteins are involved in trafficking of membrane proteins between the trans-Golgi network and the prevacuolar compartment. While several transcript variants may exist for this gene, the full-length natures of only two have been described to date. These two represent the major variants of this gene and encode distinct isoforms.

Source: NCBI Gene 55187 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive cerebellar ataxia-saccadic intrusion syndrome (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 1,835 total — 39 pathogenic, 31 likely-pathogenic
• Phenotypes (HPO): 46
• Cancer dependency (DepMap): dependent in 85.7% of screened cell lines
• MANE Select transcript: NM_015378

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23595
Approved symbol	VPS13D
Name	vacuolar protein sorting 13 homolog D
Location	1p36.22-p36.21
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10619, KIAA0453, BLTP5D
Ensembl gene	ENSG00000048707
Ensembl biotype	protein_coding
OMIM	608877
Entrez	55187

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 7 protein_coding_CDS_not_defined, 6 retained_intron, 4 protein_coding, 3 nonsense_mediated_decay

ENST00000011700, ENST00000460333, ENST00000466732, ENST00000469054, ENST00000473099, ENST00000476045, ENST00000476169, ENST00000481484, ENST00000487188, ENST00000489961, ENST00000543710, ENST00000543766, ENST00000613099, ENST00000620676, ENST00000643711, ENST00000645148, ENST00000645371, ENST00000646411, ENST00000646917, ENST00000647414

RefSeq mRNA: 2 — MANE Select: NM_015378 NM_015378, NM_018156

CCDS: CCDS30588, CCDS30589

Canonical transcript exons

ENST00000620676 — 70 exons

Exon	Start	End
ENSE00000747906	12279499	12279650
ENSE00000747987	12282705	12283736
ENSE00000748102	12288223	12288313
ENSE00000748163	12290998	12291124
ENSE00000748232	12293524	12293704
ENSE00000748304	12299202	12299384
ENSE00000819007	12455998	12456130
ENSE00000819008	12460201	12460396
ENSE00001408105	12338231	12338305
ENSE00001469869	12349164	12349374
ENSE00003462200	12321809	12321964
ENSE00003471275	12379488	12379596
ENSE00003492690	12323706	12323780
ENSE00003497139	12355899	12356090
ENSE00003502548	12314115	12314327
ENSE00003506338	12353974	12354221
ENSE00003516444	12385260	12385373
ENSE00003518656	12329829	12329918
ENSE00003520834	12368468	12368591
ENSE00003521857	12322536	12322746
ENSE00003531665	12382976	12383155
ENSE00003540046	12311813	12311925
ENSE00003545189	12319497	12319630
ENSE00003551655	12342899	12343051
ENSE00003553180	12369467	12369702
ENSE00003562483	12416660	12416827
ENSE00003562688	12356398	12356524
ENSE00003568816	12358459	12358601
ENSE00003578564	12403825	12403973
ENSE00003581304	12308431	12308641
ENSE00003590880	12363072	12363247
ENSE00003591497	12378428	12378591
ENSE00003596742	12333226	12333366
ENSE00003596772	12415087	12415221
ENSE00003602859	12327648	12327854
ENSE00003611965	12400181	12400330
ENSE00003617955	12348823	12348973
ENSE00003622826	12401608	12401704
ENSE00003629435	12335705	12335827
ENSE00003631914	12304506	12304728
ENSE00003641243	12386185	12386334
ENSE00003653511	12362720	12362850
ENSE00003657845	12318072	12318337
ENSE00003668572	12346605	12346652
ENSE00003682549	12311454	12311625
ENSE00003682816	12345374	12345509
ENSE00003693075	12373750	12373858
ENSE00003714523	12256333	12256503
ENSE00003717983	12244537	12244617
ENSE00003717994	12266881	12267011
ENSE00003718339	12497500	12497631
ENSE00003719605	12242513	12242590
ENSE00003721436	12341780	12341885
ENSE00003723441	12260693	12260794
ENSE00003727409	12249223	12249339
ENSE00003732320	12253722	12253826
ENSE00003732820	12506853	12507093
ENSE00003733997	12273003	12273135
ENSE00003735414	12508893	12512047
ENSE00003740245	12261901	12262080
ENSE00003740589	12270994	12271124
ENSE00003743286	12256987	12257087
ENSE00003743305	12267845	12267920
ENSE00003743378	12244246	12244436
ENSE00003745718	12260948	12261149
ENSE00003747079	12268706	12268876
ENSE00003747926	12257935	12258103
ENSE00003750645	12234191	12234363
ENSE00003754641	12275825	12278038
ENSE00003823555	12230030	12230120

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 95.70.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.9868 / max 175.8677, expressed in 1784 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
723	11.5521	1759
724	1.9083	1041
730	0.8096	163
740	0.4182	147
739	0.3915	160
731	0.2720	111
732	0.2381	117
201355	0.2312	104
729	0.0577	26
728	0.0510	23

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skin of leg	UBERON:0001511	95.70	gold quality
skin of abdomen	UBERON:0001416	95.59	gold quality
sural nerve	UBERON:0015488	95.46	gold quality
heart left ventricle	UBERON:0002084	94.68	gold quality
lower esophagus mucosa	UBERON:0035834	94.65	gold quality
right lobe of thyroid gland	UBERON:0001119	94.63	gold quality
left lobe of thyroid gland	UBERON:0001120	94.61	gold quality
popliteal artery	UBERON:0002250	94.61	gold quality
tibial artery	UBERON:0007610	94.61	gold quality
cardiac ventricle	UBERON:0002082	94.55	gold quality
apex of heart	UBERON:0002098	94.54	gold quality
zone of skin	UBERON:0000014	94.19	gold quality
cervix squamous epithelium	UBERON:0006922	94.02	gold quality
thyroid gland	UBERON:0002046	93.91	gold quality
nerve	UBERON:0001021	93.75	gold quality
tibial nerve	UBERON:0001323	93.75	gold quality
esophagus mucosa	UBERON:0002469	93.56	gold quality
aorta	UBERON:0000947	93.46	gold quality
endocervix	UBERON:0000458	93.22	gold quality
esophagus	UBERON:0001043	93.22	gold quality
tendon	UBERON:0000043	93.21	gold quality
descending thoracic aorta	UBERON:0002345	93.17	gold quality
gastrocnemius	UBERON:0001388	93.06	gold quality
lower esophagus	UBERON:0013473	92.93	gold quality
lower esophagus muscularis layer	UBERON:0035833	92.93	gold quality
tendon of biceps brachii	UBERON:0008188	92.90	gold quality
heart	UBERON:0000948	92.88	gold quality
calcaneal tendon	UBERON:0003701	92.88	gold quality
muscle of leg	UBERON:0001383	92.85	gold quality
lateral nuclear group of thalamus	UBERON:0002736	92.79	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-100618	yes	302.38
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

112 targeting VPS13D, 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-5011-5P	100.00	83.46	5820
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 85.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 18)

• genetic polymorphism is associated with il-6 production and mortality in patients with septic shock (PMID:25896417)
• findings underline the importance of the VPS13 complex in neurological diseases and a possible role in mitochondrial function (PMID:29518281)
• heterozygous mutations in VPS13D cause movement disorders along the ataxia-spasticity spectrum (PMID:29604224)
• VPS13D-related disorders presenting as a pure and complicated form of hereditary spastic paraplegia. (PMID:31876103)
• A VPS13D spastic ataxia mutation disrupts the conserved adaptor-binding site in yeast Vps13. (PMID:31943017)
• Genetic heterogeneity in Leigh syndrome: Highlighting treatable and novel genetic causes. (PMID:32020600)
• An ESCRT-dependent step in fatty acid transfer from lipid droplets to mitochondria through VPS13D-TSG101 interactions. (PMID:33623047)
• The lncRNA Snhg1-Vps13D vesicle trafficking system promotes memory CD8 T cell establishment via regulating the dual effects of IL-7 signaling. (PMID:33758164)
• VPS13D promotes peroxisome biogenesis. (PMID:33891012)
• VPS13D bridges the ER to mitochondria and peroxisomes via Miro. (PMID:33891013)
• Vmp1, Vps13D, and Marf/Mfn2 function in a conserved pathway to regulate mitochondria and ER contact in development and disease. (PMID:34019822)
• VPS13D interacts with VCP/p97 and negatively regulates endoplasmic reticulum-mitochondria interactions. (PMID:34133214)
• VPS13D-based disease: Expansion of the clinical phenotype in two brothers and mutation diversity in the Turkish population. (PMID:36156252)
• Screening of candidate genes at GLC3B and GLC3C loci in Chinese primary congenital glaucoma patients with targeted next generation sequencing. (PMID:36193031)
• Not to Miss: Intronic Variants, Treatment, and Review of the Phenotypic Spectrum in VPS13D-Related Disorder. (PMID:36768210)
• Clinical and molecular heterogeneity of VPS13D-related neurodevelopmental and movement disorders. (PMID:38160741)
• Autosomal recessive spinocerebellar ataxia type 4 due to a novel homozygous mutation in the VPS13D gene in a Saudi family. (PMID:38569247)
• Clinical, genetic, and neuroimaging profiles of autosomal recessive spinocerebellar ataxia type 4 caused by novel VPS13D variants in Chinese. (PMID:39058251)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	vps13d	ENSDARG00000017986
mus_musculus	Vps13d	ENSMUSG00000020220
rattus_norvegicus	Vps13d	ENSRNOG00000016443
drosophila_melanogaster	Vps13D	FBGN0052113
caenorhabditis_elegans		WBGENE00016120

Paralogs (2): VPS13C (ENSG00000129003), VPS13A (ENSG00000197969)

Protein

Protein identifiers

Intermembrane lipid transfer protein VPS13D — Q5THJ4 (reviewed: Q5THJ4)

Alternative names: Vacuolar protein sorting-associated protein 13D

All UniProt accessions (6): A0A2R8Y876, A0A2R8YD87, Q5THJ4, F5GX56, H3BLS7, R4GMW1

UniProt curated annotations — full annotation on UniProt →

Function. Mediates the transfer of lipids between membranes at organelle contact sites. Functions in promoting mitochondrial clearance by mitochondrial autophagy (mitophagy), also possibly by positively regulating mitochondrial fission. Mitophagy plays an important role in regulating cell health and mitochondrial size and homeostasis.

Tissue specificity. Widely expressed.

Disease relevance. Spinocerebellar ataxia, autosomal recessive 4 (SCAR4) [MIM:607317] A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR4 patients manifest ataxic gait with spasticity and hyperreflexia of the lower limbs resulting in difficulty walking. The age at onset is highly variable, ranging from early childhood to adulthood. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The UBA domain is required for mitochondrial size regulation.

Similarity. Belongs to the VPS13 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q5THJ4-1	1, 1A	yes
Q5THJ4-2	2, 2A

RefSeq proteins (2): NP_056193, NP_060626 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009060	UBA-like_sf	Homologous_superfamily
IPR009543	VPS13_VAB	Domain
IPR015940	UBA	Domain
IPR026847	VPS13	Family
IPR026854	VPS13_N	Domain
IPR041969	VP13D_UBA	Domain
IPR056747	VPS13-like_M	Domain

Pfam: PF12624, PF25033, PF25036

UniProt features (63 total): sequence variant 22, modified residue 17, sequence conflict 11, region of interest 5, domain 3, compositionally biased region 3, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

No AlphaFold model available for Q5THJ4 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

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 (17): 663, 1034, 1038, 1042, 1138, 1341, 1598, 1603, 1699, 1761, 1765, 2435, 2671, 2861, 2864, 2983, 3524

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 215 (showing top): GOBP_REGULATION_OF_AUTOPHAGY, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_PROTEIN_TARGETING, GOBP_VACUOLAR_TRANSPORT, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_MACROAUTOPHAGY, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATABOLIC_PROCESS, GOBP_MAINTENANCE_OF_LOCATION, GOBP_PROTEIN_LOCALIZATION_TO_VACUOLE, VANHARANTA_UTERINE_FIBROID_WITH_7Q_DELETION_DN, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_5, GOBP_PROTEIN_LOCALIZATION_TO_GOLGI_APPARATUS, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_VACUOLE

GO Biological Process (5): protein targeting to vacuole (GO:0006623), lipid transport (GO:0006869), mitochondrion organization (GO:0007005), protein retention in Golgi apparatus (GO:0045053), positive regulation of mitophagy (GO:1901526)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (3): mitochondrion (GO:0005739), extracellular exosome (GO:0070062), lipid droplet (GO:0005811)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein targeting	1
intracellular protein transport	1
vacuolar transport	1
protein localization to vacuole	1
establishment of protein localization to vacuole	1
transport	1
lipid localization	1
organelle organization	1
maintenance of protein location in cell	1
protein localization to Golgi apparatus	1
mitophagy	1
positive regulation of macroautophagy	1
regulation of mitophagy	1
positive regulation of autophagy of mitochondrion	1
binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
extracellular vesicle	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1050 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VPS13D	RHOT1	Q8IXI2	615
VPS13D	PLIN5	Q00G26	522
VPS13D	VPS13A	Q96RL7	513
VPS13D	VPS13B	Q7Z7G8	492
VPS13D	MIGA2	Q7L4E1	482
VPS13D	KIAA2013	Q8IYS2	474
VPS13D	IGSF21	Q96ID5	427
VPS13D	VPS13C	Q709C8	404
VPS13D	VAPA	Q9P0L0	401
VPS13D	PARK7	Q99497	395
VPS13D	VAPB	O95292	395
VPS13D	XK	P51811	385
VPS13D	ARHGAP27	Q6ZUM4	375
VPS13D	CISD3	P0C7P0	368
VPS13D	RDM1	Q8NG50	362

IntAct

39 interactions, top by confidence:

A	B	Type	Score
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
NIPAL1	ESYT2	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
YWHAQ	IGLC7	psi-mi:“MI:0914”(association)	0.530
TMEM31	PSMD11	psi-mi:“MI:0914”(association)	0.530
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
YWHAQ	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
ESR1		psi-mi:“MI:0914”(association)	0.460
GSK3B	SEC16A	psi-mi:“MI:2364”(proximity)	0.420
VPS13D	P4HA2	psi-mi:“MI:0915”(physical association)	0.400
MADD	VPS13D	psi-mi:“MI:0915”(physical association)	0.370
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
YWHAG	C1orf226	psi-mi:“MI:0914”(association)	0.350
YWHAZ	SPEG	psi-mi:“MI:0914”(association)	0.350
YWHAB	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAG	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAQ	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAH	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAZ	HECTD4	psi-mi:“MI:0914”(association)	0.350
BAG2	PIK3C2A	psi-mi:“MI:0914”(association)	0.350
CALM1	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
CREB3L2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
MGST3	DNM1L	psi-mi:“MI:2364”(proximity)	0.270
PLGRKT	PGRMC1	psi-mi:“MI:2364”(proximity)	0.270
TOMM20	NUDT19	psi-mi:“MI:2364”(proximity)	0.270
TOMM22	DNM1L	psi-mi:“MI:2364”(proximity)	0.270
YWHAB	E2F8	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (82): PPP2R1A (Co-fractionation), PSMC1 (Co-fractionation), VPS13D (Affinity Capture-MS), VPS13D (Proximity Label-MS), VPS13D (Proximity Label-MS), VPS13D (Proximity Label-MS), VPS13D (Proximity Label-MS), VPS13D (Proximity Label-MS), VPS13D (Affinity Capture-RNA), VPS13D (Affinity Capture-MS), VPS13D (Affinity Capture-MS), VPS13D (Affinity Capture-MS), VPS13D (Proximity Label-MS), VPS13D (Proximity Label-MS), VPS13D (Proximity Label-MS)

ESM2 similar proteins: A0A0R4IXF6, A0JMR6, A0JNW5, A2RSJ4, F4HRV8, O17482, O95876, P49021, P79457, Q08D51, Q28C33, Q3B7T1, Q3UD82, Q498F0, Q5H8C4, Q5JSH3, Q5JTW2, Q5QNQ6, Q5R9R1, Q5THJ4, Q5ZLG9, Q6BDS2, Q6GLR7, Q6GQV7, Q6INA9, Q6NRZ1, Q6NVE8, Q6ZMT4, Q6ZWJ1, Q709C8, Q80T23, Q80XK6, Q812E4, Q8BX70, Q8BXR9, Q8C5W4, Q8IWB9, Q8N3A8, Q8N7X0, Q8TDW5

Diamond homologs: Q21480, Q5THJ4, Q80TY5, Q54KX3, Q709C8, Q7Z7G8, Q86K84, Q8BX70, A2RSJ4, G0S3B8

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 34 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	6	163.1×	7e-11
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	143.9×	1e-10
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	143.9×	1e-10
Activation of BH3-only proteins	6	106.4×	7e-10
RHO GTPases activate PKNs	6	68.0×	1e-08
Intrinsic Pathway for Apoptosis	6	62.8×	2e-08
FOXO-mediated transcription	5	60.0×	4e-07
Translocation of SLC2A4 (GLUT4) to the plasma membrane	7	38.6×	2e-08

GO biological processes:

GO term	Partners	Fold	FDR
intracellular protein localization	6	20.9×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

1835 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	39
Likely pathogenic	31
Uncertain significance	943
Likely benign	596
Benign	95

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070403	NM_015378.4(VPS13D):c.229_232dup (p.Trp78fs)	Pathogenic
1351520	NM_015378.4(VPS13D):c.3559_3562del (p.Glu1187fs)	Pathogenic
1369904	NM_015378.4(VPS13D):c.4507dup (p.Glu1503fs)	Pathogenic
1703244	NM_015378.4(VPS13D):c.11926del (p.Gln3976fs)	Pathogenic
1916160	NM_015378.4(VPS13D):c.9421C>T (p.Arg3141Ter)	Pathogenic
1919522	NM_015378.4(VPS13D):c.3856_3875del (p.Leu1286_Lys1287insTer)	Pathogenic
1966717	NM_015378.4(VPS13D):c.4117_4118del (p.Val1373fs)	Pathogenic
2016492	NM_015378.4(VPS13D):c.11825_11826del (p.Glu3942fs)	Pathogenic
2028769	NM_015378.4(VPS13D):c.844C>T (p.Gln282Ter)	Pathogenic
2031321	NM_015378.4(VPS13D):c.7038T>G (p.Tyr2346Ter)	Pathogenic
2033943	NM_015378.4(VPS13D):c.1798_1799del (p.Pro600fs)	Pathogenic
2071139	NM_015378.4(VPS13D):c.10168C>T (p.Arg3390Ter)	Pathogenic
2080966	NM_015378.4(VPS13D):c.8821C>T (p.Arg2941Ter)	Pathogenic
2114147	NM_015378.4(VPS13D):c.1228C>T (p.Gln410Ter)	Pathogenic
2126854	NM_015378.4(VPS13D):c.12499del (p.Ser4167fs)	Pathogenic
2444418	NM_015378.4(VPS13D):c.9871+2T>C	Pathogenic
2500953	NM_015378.4(VPS13D):c.10142-2A>G	Pathogenic
2664706	NM_015378.4(VPS13D):c.5725+2dup	Pathogenic
2762452	NM_015378.4(VPS13D):c.10150dup (p.Val3384fs)	Pathogenic
2804508	NM_015378.4(VPS13D):c.8068C>T (p.Arg2690Ter)	Pathogenic
2810538	NM_015378.4(VPS13D):c.5581dup (p.Ala1861fs)	Pathogenic
2853729	NM_015378.4(VPS13D):c.2453C>A (p.Ser818Ter)	Pathogenic
2858272	NM_015378.4(VPS13D):c.10701del (p.Ala3569fs)	Pathogenic
3016121	NM_015378.4(VPS13D):c.9388C>T (p.Arg3130Ter)	Pathogenic
3255090	NM_015378.4(VPS13D):c.1055dup (p.Tyr352Ter)	Pathogenic
3381398	NM_015378.4(VPS13D):c.1513C>T (p.Arg505Ter)	Pathogenic
3614956	NM_015378.4(VPS13D):c.6580C>T (p.Arg2194Ter)	Pathogenic
3651733	NM_015378.4(VPS13D):c.5682dup (p.Lys1895fs)	Pathogenic
3655596	NM_015378.4(VPS13D):c.1390C>T (p.Gln464Ter)	Pathogenic
3680876	NM_015378.4(VPS13D):c.6805C>T (p.Gln2269Ter)	Pathogenic

SpliceAI

12380 predictions. Top by Δscore:

Variant	Effect	Δscore
1:12242587:GCTG:G	donor_gain	1.0000
1:12242590:GGTAT:G	donor_loss	1.0000
1:12242591:G:GG	donor_gain	1.0000
1:12242591:GTAT:G	donor_loss	1.0000
1:12242592:T:A	donor_loss	1.0000
1:12244391:GGAAC:G	donor_gain	1.0000
1:12244392:GAAC:G	donor_gain	1.0000
1:12244392:GAACG:G	donor_gain	1.0000
1:12244393:A:T	donor_gain	1.0000
1:12244396:G:GG	donor_gain	1.0000
1:12244433:G:GT	donor_gain	1.0000
1:12244457:GCCA:G	donor_gain	1.0000
1:12244535:A:AG	acceptor_gain	1.0000
1:12244536:G:GG	acceptor_gain	1.0000
1:12244615:GAA:G	donor_gain	1.0000
1:12244618:G:GG	donor_gain	1.0000
1:12249221:A:AG	acceptor_gain	1.0000
1:12249222:G:GA	acceptor_gain	1.0000
1:12249222:GTTA:G	acceptor_gain	1.0000
1:12249222:GTTAA:G	acceptor_gain	1.0000
1:12249336:GCCT:G	donor_gain	1.0000
1:12249340:G:GG	donor_gain	1.0000
1:12253715:A:AG	acceptor_gain	1.0000
1:12253822:TACAG:T	donor_loss	1.0000
1:12253824:CAGGT:C	donor_loss	1.0000
1:12253827:GTA:G	donor_loss	1.0000
1:12253828:T:G	donor_loss	1.0000
1:12256978:A:AG	acceptor_gain	1.0000
1:12256979:A:G	acceptor_gain	1.0000
1:12256981:A:AG	acceptor_gain	1.0000

AlphaMissense

28869 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:12273018:T:A	W707R	1.000
1:12273018:T:C	W707R	1.000
1:12276581:T:C	L998P	1.000
1:12242519:T:A	V35D	0.999
1:12242525:T:C	L37S	0.999
1:12244267:T:C	L66P	0.999
1:12244302:T:A	W78R	0.999
1:12244302:T:C	W78R	0.999
1:12273031:T:C	L711P	0.999
1:12276155:T:C	L856P	0.999
1:12276212:T:C	L875P	0.999
1:12276218:G:A	G877D	0.999
1:12276587:T:A	V1000D	0.999
1:12276599:T:C	L1004P	0.999
1:12276608:A:T	D1007V	0.999
1:12276641:T:C	L1018P	0.999
1:12277168:G:C	A1194P	0.999
1:12277169:C:A	A1194E	0.999
1:12277174:G:C	A1196P	0.999
1:12277745:T:A	V1386D	0.999
1:12277796:G:T	G1403V	0.999
1:12283578:T:A	W1826R	0.999
1:12283578:T:C	W1826R	0.999
1:12291040:T:C	L1923P	0.999
1:12291082:T:C	F1937S	0.999
1:12293658:T:C	L1996P	0.999
1:12314318:T:C	L2380P	0.999
1:12319554:T:C	L2491P	0.999
1:12322575:G:C	D2582H	0.999
1:12322576:A:C	D2582A	0.999

dbSNP variants (sampled 300 via entrez): RS1000004030 (1:12399825 CA>C,CAA), RS1000008972 (1:12437949 A>T), RS1000016302 (1:12393311 C>G), RS1000018274 (1:12354427 A>G), RS1000020165 (1:12258358 A>C), RS1000022804 (1:12434603 C>A), RS1000030599 (1:12486631 C>T), RS1000042104 (1:12370199 T>C), RS1000054509 (1:12294928 A>G), RS1000094943 (1:12406766 A>T), RS1000102119 (1:12451904 C>A), RS1000129198 (1:12510477 ATCT>A), RS1000140184 (1:12481066 A>C), RS1000168673 (1:12295173 G>C), RS1000176391 (1:12329358 C>A,T)

Disease associations

OMIM: gene MIM:608877 | disease phenotypes: MIM:607317, MIM:236750, MIM:256000, MIM:213200, MIM:617468, MIM:208150, MIM:600223

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive cerebellar ataxia-saccadic intrusion syndrome	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Leigh syndrome	Limited	AR

Mondo (8): autosomal recessive cerebellar ataxia-saccadic intrusion syndrome (MONDO:0011811), non-immune hydrops fetalis (MONDO:0009369), Leigh syndrome (MONDO:0009723), autosomal recessive cerebellar ataxia (MONDO:0015244), neurodevelopmental disorder (MONDO:0700092), arthrogryposis multiplex congenita (MONDO:0015168), fetal akinesia deformation sequence 1 (MONDO:0100101), spinocerebellar ataxia type 4 (MONDO:0010847)

Orphanet (7): Autosomal recessive cerebellar ataxia-movement disorder syndrome (Orphanet:95434), Non-immune hydrops fetalis (Orphanet:363999), Leigh syndrome (Orphanet:506), Autosomal recessive cerebellar ataxia (Orphanet:1172), Arthrogryposis multiplex congenita (Orphanet:1037), Fetal akinesia deformation sequence (Orphanet:994), Spinocerebellar ataxia type 4 (Orphanet:98765)

HPO phenotypes

46 total (30 of 46 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000473	Torticollis
HP:0000496	Abnormality of eye movement
HP:0000570	Abnormal saccadic eye movements
HP:0000640	Gaze-evoked nystagmus
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001256	Mild intellectual disability
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0001332	Dystonia
HP:0001336	Myoclonus
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0001761	Pes cavus
HP:0002066	Gait ataxia
HP:0002070	Limb ataxia
HP:0002073	Progressive cerebellar ataxia
HP:0002078	Truncal ataxia
HP:0002317	Unsteady gait
HP:0002359	Frequent falls
HP:0002366	Abnormal lower motor neuron morphology
HP:0002380	Fasciculations
HP:0002460	Distal muscle weakness
HP:0002493	Upper motor neuron dysfunction
HP:0002500	Abnormal cerebral white matter morphology
HP:0003474	Somatic sensory dysfunction

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002858_1	Cytokine and corticosteroid-stimulated IL-6 production	4.000000e-07
GCST002859_1	Cytokine-stimulated IL-6 production	4.000000e-07
GCST009724_82	Vertical cup-disc ratio (multi-trait analysis)	4.000000e-15

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004810	interleukin-6 measurement
EFO:0006939	cup-to-disc ratio measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D007888	Leigh Disease	C10.228.140.163.100.412; C16.320.565.189.412; C16.320.565.202.810.444; C18.452.132.100.412; C18.452.648.189.412; C18.452.648.202.810.444; C18.452.660.520
D065886	Neurodevelopmental Disorders	F03.625
C537310	Spinocerebellar ataxia, autosomal recessive 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs138385713	VPS13D		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases methylation	2
Tobacco Smoke Pollution	increases expression, decreases expression	2
Valproic Acid	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	decreases expression, affects cotreatment	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
uranyl acetate	affects expression	1
bisphenol A	decreases methylation	1
trichostatin A	increases expression	1
arsenite	decreases reaction, affects binding	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
methacrylaldehyde	affects cotreatment, increases expression	1
epigallocatechin gallate	increases expression, affects cotreatment, decreases expression	1
pentanal	decreases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
(+)-JQ1 compound	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Acetaminophen	decreases expression	1
Acrolein	increases expression, affects cotreatment	1
Arsenic	affects methylation	1
Caffeine	affects phosphorylation	1
Cisplatin	decreases expression	1
Demecolcine	increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Estradiol	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_E4PZ	KOLF2.1J VPS13D 157.2kbdel DEL/WT	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

223 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,
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
NCT01721733	PHASE2	COMPLETED	Safety and Efficacy Study of EPI-743 in Children With Leigh Syndrome
NCT02352896	PHASE2	COMPLETED	Long-Term Safety and Efficacy Evaluation of EPI-743 in Children With Leigh Syndrome
NCT03747328	PHASE2	WITHDRAWN	ABI-009 (Nab-sirolimus) in Patients With Genetically-confirmed Leigh or Leigh-like Syndrome
NCT06843811	PHASE2	ENROLLING_BY_INVITATION	Sirolimus for Leigh Syndrome
NCT06990984	PHASE2	NOT_YET_RECRUITING	A Dose-ranging Study of TTI-0102 in Adults and Children With Leigh Syndrome Spectrum (LSS)
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
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT04308603	Not specified	COMPLETED	Multicentric Prospective Study to Screen Inborn Errors of Metabolism in Non-immune Hydrops (NIH) Fetalis by Massively Parallel Sequencing
NCT05528796	Not specified	ENROLLING_BY_INVITATION	Uncovering the Etiologies of Non-immune Hydrops Fetalis
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01780168	Not specified	RECRUITING	The NIH MINI Study: Metabolism, Infection, and Immunity in Inborn Errors of Metabolism
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01803906	Not specified	ENROLLING_BY_INVITATION	Tissue Sample Study for Mitochondrial Disorders
NCT03137355	Not specified	RECRUITING	The International Registry for Leigh Syndrome
NCT05277363	Not specified	WITHDRAWN	A Study of the Natural Course of SURF1 Deficiency
NCT05554835	Not specified	RECRUITING	Global Registry and Natural History Study for Mitochondrial Disorders
NCT06967831	Not specified	RECRUITING	Drug Repurposing for Mitochondrial Disorders Using iPSCs Derived Neural Cells
NCT04261127	Not specified	RECRUITING	Validation of the RADIAL Algorithm for Diagnosis of Autosomal Recessive Cerebellar Ataxia
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants