VPS13A-related neurodegenerative disease

Summary

VPS13A-related neurodegenerative disease (MONDO:0008695) is a disease caused by VPS13A (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: VPS13A (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 836
• Phenotypes (HPO): 86

Clinical features

Signs & symptoms

Clinical features (HPO)

86 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0002072	Chorea	Very frequent (80-99%)
HP:0004305	Involuntary movements	Very frequent (80-99%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001300	Parkinsonism	Frequent (30-79%)
HP:0001315	Reduced tendon reflexes	Frequent (30-79%)
HP:0001927	Acanthocytosis	Frequent (30-79%)
HP:0002275	Poor motor coordination	Frequent (30-79%)
HP:0002340	Caudate atrophy	Frequent (30-79%)
HP:0002451	Limb dystonia	Frequent (30-79%)
HP:0002460	Distal muscle weakness	Frequent (30-79%)
HP:0002495	Impaired vibratory sensation	Frequent (30-79%)
HP:0002527	Falls	Frequent (30-79%)
HP:0003198	Myopathy	Frequent (30-79%)
HP:0003236	Elevated circulating creatine kinase concentration	Frequent (30-79%)
HP:0003438	Absent Achilles reflex	Frequent (30-79%)
HP:0003445	EMG: neuropathic changes	Frequent (30-79%)
HP:0003477	Peripheral axonal neuropathy	Frequent (30-79%)
HP:0003693	Distal amyotrophy	Frequent (30-79%)
HP:0006956	Dilation of lateral ventricles	Frequent (30-79%)
HP:0007078	Decreased amplitude of sensory action potentials	Frequent (30-79%)
HP:0012049	Laryngeal dystonia	Frequent (30-79%)
HP:0025402	Square-wave jerks	Frequent (30-79%)
HP:0030272	Abnormal erythrocyte enzyme activity	Frequent (30-79%)
HP:0100034	Motor tics	Frequent (30-79%)
HP:0100035	Phonic tics	Frequent (30-79%)
HP:0100295	Muscle fiber atrophy	Frequent (30-79%)
HP:0000496	Abnormality of eye movement	Occasional (5-29%)
HP:0000514	Slow saccadic eye movements	Occasional (5-29%)
HP:0000643	Blepharospasm	Occasional (5-29%)
HP:0000712	Emotional lability	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000718	Aggressive behavior	Occasional (5-29%)
HP:0000722	Compulsive behaviors	Occasional (5-29%)
HP:0000736	Short attention span	Occasional (5-29%)
HP:0000737	Irritability	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)
HP:0000741	Apathy	Occasional (5-29%)
HP:0000752	Hyperactivity	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001268	Mental deterioration	Occasional (5-29%)
HP:0001276	Hypertonia	Occasional (5-29%)
HP:0001350	Slurred speech	Occasional (5-29%)
HP:0001369	Arthritis	Occasional (5-29%)
HP:0001744	Splenomegaly	Occasional (5-29%)
HP:0001824	Weight loss	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002067	Bradykinesia	Occasional (5-29%)
HP:0002069	Bilateral tonic-clonic seizure	Occasional (5-29%)
HP:0002120	Cerebral cortical atrophy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	VPS13A-related neurodegenerative disease
Mondo ID	MONDO:0008695
OMIM	200150
Orphanet	2388
DOID	DOID:0050766
SNOMED CT	66881004
UMLS	C0393576
MedGen	98277
GARD	0003956
Is cancer (heuristic)	no

Also known as: CHAC · Chac · chorea-acanthocytosis · choreoacanthocytosis · Levine-Critchley syndrome · VPS13A disease

Data availability: 836 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › movement disorder › neuroacanthocytosis › VPS13A-related neurodegenerative disease

Related subtypes (1): XK-related neurodegenerative disease

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

246 uncertain significance, 127 likely pathogenic, 54 benign, 44 pathogenic/likely pathogenic, 39 likely benign, 32 pathogenic, 32 conflicting classifications of pathogenicity, 25 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
4689	NC_000009.12:g.77390734_77428010del	GNA14	Pathogenic	no assertion criteria provided
1028512	NM_033305.3(VPS13A):c.2326C>T (p.Arg776Ter)	VPS13A	Pathogenic	criteria provided, multiple submitters, no conflicts
1068735	NM_033305.3(VPS13A):c.7486C>T (p.Gln2496Ter)	VPS13A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069304	NM_033305.3(VPS13A):c.8375C>G (p.Ser2792Ter)	VPS13A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070414	NM_033305.3(VPS13A):c.7005G>A (p.Trp2335Ter)	VPS13A	Pathogenic	criteria provided, multiple submitters, no conflicts
1070929	NM_033305.3(VPS13A):c.3232G>T (p.Glu1078Ter)	VPS13A	Pathogenic	criteria provided, multiple submitters, no conflicts
1071099	NM_033305.3(VPS13A):c.6841G>T (p.Gly2281Ter)	VPS13A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074484	NM_033305.3(VPS13A):c.4692_4693del (p.Phe1565fs)	VPS13A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076265	NM_033305.3(VPS13A):c.994del (p.Ala332fs)	VPS13A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1184557	NM_033305.3(VPS13A):c.672_676del (p.Tyr224_Ser226delinsTer)	VPS13A	Pathogenic	no assertion criteria provided
1323748	NM_033305.3(VPS13A):c.7419+1G>A	VPS13A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323749	NM_033305.3(VPS13A):c.6367_6374del (p.Tyr2123fs)	VPS13A	Pathogenic	criteria provided, single submitter
1350569	NM_033305.3(VPS13A):c.7072C>T (p.Gln2358Ter)	VPS13A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1353858	NM_033305.3(VPS13A):c.1596-2A>G	VPS13A	Pathogenic	criteria provided, multiple submitters, no conflicts
1355990	NM_033305.3(VPS13A):c.9094G>T (p.Glu3032Ter)	VPS13A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1361410	NM_033305.3(VPS13A):c.1290G>A (p.Trp430Ter)	VPS13A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1371394	NM_033305.3(VPS13A):c.7339dup (p.Tyr2447fs)	VPS13A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1375001	NM_033305.3(VPS13A):c.4246dup (p.Ser1416fs)	VPS13A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1382001	NM_033305.3(VPS13A):c.6877C>T (p.Gln2293Ter)	VPS13A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1415055	NM_033305.3(VPS13A):c.3866dup (p.Leu1289fs)	VPS13A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1426013	NM_033305.3(VPS13A):c.2716del (p.Val905_Val906insTer)	VPS13A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452225	NM_033305.3(VPS13A):c.6482_6483del (p.Leu2161fs)	VPS13A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452296	NM_033305.3(VPS13A):c.3456_3459del (p.Ile1152fs)	VPS13A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454850	NM_033305.3(VPS13A):c.1125_1128del (p.Ser375fs)	VPS13A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456540	NM_033305.3(VPS13A):c.2500del (p.Val834fs)	VPS13A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457402	NM_033305.3(VPS13A):c.2593C>T (p.Arg865Ter)	VPS13A	Pathogenic	criteria provided, multiple submitters, no conflicts
1458993	NM_033305.3(VPS13A):c.4242+1G>T	VPS13A	Pathogenic	criteria provided, multiple submitters, no conflicts
1458994	NM_033305.3(VPS13A):c.5881C>T (p.Arg1961Ter)	VPS13A	Pathogenic	criteria provided, multiple submitters, no conflicts
1458998	NM_033305.3(VPS13A):c.7867C>T (p.Arg2623Ter)	VPS13A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1709453	NM_033305.3(VPS13A):c.7214T>G (p.Leu2405Ter)	VPS13A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
VPS13A	Definitive	Autosomal recessive	VPS13A-related neurodegenerative disease	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VPS13A	Orphanet:2388	Choreoacanthocytosis
TCIRG1	Orphanet:1782	Dysosteosclerosis
TCIRG1	Orphanet:210110	Intermediate osteopetrosis
TCIRG1	Orphanet:486	Autosomal dominant severe congenital neutropenia
TCIRG1	Orphanet:667	Autosomal recessive malignant osteopetrosis
GNA14	Orphanet:1063	Tufted angioma
GNA14	Orphanet:2122	Kaposiform hemangioendothelioma
GNA14	Orphanet:675359	Anastomosing haemangioma

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
VPS13A	HGNC:1908	ENSG00000197969	Q96RL7	Intermembrane lipid transfer protein VPS13A	gencc,clinvar
TCIRG1	HGNC:11647	ENSG00000110719	Q13488	V-type proton ATPase 116 kDa subunit a 3	clinvar
GNA14	HGNC:4382	ENSG00000156049	O95837	Guanine nucleotide-binding protein subunit alpha-14	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VPS13A	Intermembrane lipid transfer protein VPS13A	Mediates the transfer of lipids between membranes at organelle contact sites.
TCIRG1	V-type proton ATPase 116 kDa subunit a 3	Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.
GNA14	Guanine nucleotide-binding protein subunit alpha-14	Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VPS13A	Other/Unknown	no		VPS13_VAB, VPS13, VPS13_N
TCIRG1	Other/Unknown	no		V-ATPase_116kDa_su, V-type_ATPase_116kDa_su_euka
GNA14	Other/Unknown	no		Gprotein_alpha_Q, Gprotein_alpha_su, GproteinA_insert

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
biceps brachii	1
jejunal mucosa	1
skeletal muscle tissue of biceps brachii	1
blood	1
granulocyte	1
spleen	1
bronchial epithelial cell	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VPS13A	287	ubiquitous	marker	jejunal mucosa, biceps brachii, skeletal muscle tissue of biceps brachii
TCIRG1	148	ubiquitous	marker	granulocyte, blood, spleen
GNA14	208	broad	marker	secondary oocyte, oocyte, bronchial epithelial cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VPS13A	2,092
TCIRG1	1,931
GNA14	1,081

Structural data

PDB: 0 · AlphaFold-only: 3 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GNA14	O95837	93.68
TCIRG1	Q13488	83.52
VPS13A	Q96RL7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 3 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion	1	713.8×	0.010	GNA14
Acetylcholine regulates insulin secretion	1	571.0×	0.010	GNA14
G-protein activation	1	237.9×	0.010	GNA14
Thromboxane signalling through TP receptor	1	237.9×	0.010	GNA14
ADP signalling through P2Y purinoceptor 1	1	228.4×	0.010	GNA14
Insulin receptor recycling	1	190.3×	0.010	TCIRG1
Transferrin endocytosis and recycling	1	184.2×	0.010	TCIRG1
Thrombin signalling through proteinase activated receptors (PARs)	1	178.4×	0.010	GNA14
ROS and RNS production in phagocytes	1	167.9×	0.010	TCIRG1
Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding	1	150.3×	0.010	GNA14
PLC beta mediated events	1	132.8×	0.010	GNA14
Amino acids regulate mTORC1	1	100.2×	0.012	TCIRG1
Ion channel transport	1	48.0×	0.024	TCIRG1
G alpha (q) signalling events	1	28.7×	0.037	GNA14
Neutrophil degranulation	1	11.5×	0.085	TCIRG1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to silver ion	1	5617.3×	0.005	TCIRG1
dentin mineralization	1	5617.3×	0.005	TCIRG1
protein catabolic process in the vacuole	1	2808.7×	0.005	TCIRG1
memory T cell activation	1	2808.7×	0.005	TCIRG1
response to environmental enrichment	1	2808.7×	0.005	VPS13A
regulation of proton transport	1	1872.4×	0.005	TCIRG1
T-helper 1 cell activation	1	1872.4×	0.005	TCIRG1
gene expression	2	53.2×	0.005	VPS13A, TCIRG1
sperm mitochondrion organization	1	1404.3×	0.005	VPS13A
osteoclast proliferation	1	1123.5×	0.005	TCIRG1
brain-derived neurotrophic factor receptor signaling pathway	1	1123.5×	0.005	VPS13A
tooth eruption	1	1123.5×	0.005	TCIRG1
protein retention in Golgi apparatus	1	1123.5×	0.005	VPS13A
pH reduction	1	802.5×	0.005	TCIRG1
establishment of vesicle localization	1	802.5×	0.005	TCIRG1
phagosome acidification	1	802.5×	0.005	TCIRG1
phospholipase C-activating dopamine receptor signaling pathway	1	702.2×	0.006	GNA14
neuron projection arborization	1	624.1×	0.006	VPS13A
microglia differentiation	1	510.7×	0.007	VPS13A
neuroinflammatory response	1	510.7×	0.007	VPS13A
protein targeting to vacuole	1	432.1×	0.007	VPS13A
ruffle organization	1	432.1×	0.007	TCIRG1
regulation of osteoblast differentiation	1	432.1×	0.007	TCIRG1
optic nerve development	1	401.2×	0.007	TCIRG1
enamel mineralization	1	401.2×	0.007	TCIRG1
cellular response to osmotic stress	1	401.2×	0.007	VPS13A
Golgi to endosome transport	1	351.1×	0.007	VPS13A
lysosomal protein catabolic process	1	351.1×	0.007	VPS13A
long-term synaptic depression	1	295.6×	0.008	VPS13A
vacuolar acidification	1	244.2×	0.010	TCIRG1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
VPS13A	0	0
TCIRG1	0	0
GNA14	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	VPS13A, TCIRG1, GNA14

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
VPS13A	0	—
TCIRG1	0	—
GNA14	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.