EPG5

Summary

EPG5 (ectopic P-granules 5 autophagy tethering factor, HGNC:29331) is a protein-coding gene on chromosome 18q12.3-q21.1, encoding Ectopic P granules protein 5 homolog (Q9HCE0). Involved in autophagy.

This gene encodes a large coiled coil domain-containing protein that functions in autophagy during starvation conditions. Mutations in this gene cause Vici syndrome.

Source: NCBI Gene 57724 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Vici syndrome (Definitive, ClinGen)
• GWAS associations: 3
• Clinical variants (ClinVar): 2,753 total — 158 pathogenic, 54 likely-pathogenic
• Phenotypes (HPO): 90
• MANE Select transcript: NM_020964

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29331
Approved symbol	EPG5
Name	ectopic P-granules 5 autophagy tethering factor
Location	18q12.3-q21.1
Locus type	gene with protein product
Status	Approved
Aliases	hEPG5
Ensembl gene	ENSG00000152223
Ensembl biotype	protein_coding
OMIM	615068
Entrez	57724

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 8 protein_coding, 6 retained_intron, 5 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000282041, ENST00000585906, ENST00000586655, ENST00000587262, ENST00000587884, ENST00000587973, ENST00000587974, ENST00000590884, ENST00000592272, ENST00000696480, ENST00000696481, ENST00000696482, ENST00000696483, ENST00000696484, ENST00000696485, ENST00000696489, ENST00000696490, ENST00000696491, ENST00000696785, ENST00000869408, ENST00000936086

RefSeq mRNA: 3 — MANE Select: NM_020964 NM_001410858, NM_001410859, NM_020964

CCDS: CCDS11926, CCDS92453, CCDS92454

Canonical transcript exons

ENST00000282041 — 44 exons

Exon	Start	End
ENSE00002242720	45847609	45852649
ENSE00002773601	45855573	45855687
ENSE00002930528	45857853	45858068
ENSE00002955908	45858566	45858782
ENSE00003497721	45967177	45967329
ENSE00003967488	45860104	45860346
ENSE00003967489	45951102	45951238
ENSE00003967490	45866798	45867007
ENSE00003967491	45916009	45916206
ENSE00003967492	45948503	45948576
ENSE00003967493	45880075	45880223
ENSE00003967494	45879013	45879214
ENSE00003967495	45867563	45867748
ENSE00003967497	45922341	45922600
ENSE00003967498	45870567	45870742
ENSE00003967499	45865615	45865759
ENSE00003967500	45934809	45934966
ENSE00003967501	45946663	45946768
ENSE00003967502	45903973	45904117
ENSE00003967503	45930676	45930830
ENSE00003967504	45887751	45887907
ENSE00003967505	45916438	45916582
ENSE00003967506	45943161	45943311
ENSE00003967507	45882274	45882487
ENSE00003967508	45884617	45884811
ENSE00003967510	45954394	45955338
ENSE00003967512	45878376	45878448
ENSE00003967513	45925738	45925902
ENSE00003967514	45900996	45901167
ENSE00003967516	45899404	45899566
ENSE00003967517	45949484	45949591
ENSE00003967519	45910521	45910742
ENSE00003967520	45907958	45908081
ENSE00003967521	45952400	45952643
ENSE00003967522	45944005	45944119
ENSE00003967523	45912290	45912456
ENSE00003967524	45939600	45939755
ENSE00003967525	45889798	45889940
ENSE00003967526	45913706	45913828
ENSE00003967528	45876236	45876342
ENSE00003967529	45923268	45923387
ENSE00003967530	45915511	45915621
ENSE00003967531	45917679	45917819
ENSE00003967532	45928869	45929009

Expression profiles

Bgee: expression breadth ubiquitous, 260 present calls, max score 94.02.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.2072 / max 182.7254, expressed in 1795 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
171779	18.2072	1795

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	94.02	gold quality
buccal mucosa cell	CL:0002336	90.16	gold quality
bone marrow cell	CL:0002092	88.81	gold quality
sural nerve	UBERON:0015488	88.48	gold quality
calcaneal tendon	UBERON:0003701	87.58	gold quality
Brodmann (1909) area 23	UBERON:0013554	86.92	gold quality
tibialis anterior	UBERON:0001385	86.73	gold quality
right uterine tube	UBERON:0001302	86.40	gold quality
lower esophagus mucosa	UBERON:0035834	86.15	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.80	gold quality
skin of leg	UBERON:0001511	85.34	gold quality
stromal cell of endometrium	CL:0002255	85.33	gold quality
esophagus squamous epithelium	UBERON:0006920	85.33	gold quality
amniotic fluid	UBERON:0000173	85.27	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.26	gold quality
mucosa of stomach	UBERON:0001199	84.94	gold quality
adrenal tissue	UBERON:0018303	84.89	gold quality
bone marrow	UBERON:0002371	84.84	gold quality
left lobe of thyroid gland	UBERON:0001120	84.80	gold quality
thyroid gland	UBERON:0002046	84.67	gold quality
right lobe of thyroid gland	UBERON:0001119	84.53	gold quality
left ovary	UBERON:0002119	84.48	gold quality
blood	UBERON:0000178	84.32	gold quality
upper leg skin	UBERON:0004262	84.24	gold quality
skin of abdomen	UBERON:0001416	84.16	gold quality
visceral pleura	UBERON:0002401	84.11	gold quality
granulocyte	CL:0000094	83.95	gold quality
muscle of leg	UBERON:0001383	83.80	gold quality
gastrocnemius	UBERON:0001388	83.80	gold quality
cardiac muscle of right atrium	UBERON:0003379	83.77	silver quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	4.79
E-ANND-3	no	6.52

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

191 targeting EPG5, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775

Literature-anchored findings (GeneRIF, showing 19)

• We characterized the KIAA1632 gene by computational methods: detailed investigation of the genomic structure, protein prediction, identification of orthologs in other species and phylogenetic analysis. (PMID:17549423)
• Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. (PMID:23222957)
• A mutation affecting the penultimate exon of EPG5 and presenting with typical clinical manifestations of Vici syndrome. (PMID:25331754)
• We report two sisters with a nonsense mutation within exon 14 of the EPG5 gene and a phenotype consistent with Vici syndrome (PMID:26854214)
• This article confirms in silico predictions of aberrant splicing in the EPG5 gene due to the mutation NM_020964.2; c.1007A>G p.Gln336Arg (PMID:27343256)
• Seven SNPs were significantly associated with the risk of Alzheimer disease, and eight SNPs were associated with the age at onset of AD. (PMID:27586004)
• The Vici syndrome protein EPG5 is a Rab7 effector that determines the fusion specificity of autophagosomes with late endosomes/lysosomes. (PMID:27588602)
• Our report further reinforces that EPG5-related Vici syndrome is both a neurodevelopmental disorder, which can be diagnosed as early as the second trimester of pregnancy, as well as a neurodegenerative disorder. (PMID:28168853)
• To investigate the function of EPG5, siRNA based EPG5 knock-down, and CRISPR/Cas9 mediated EPG5 knock-out HeLa cells were generated. EPG5-depleted cells exhibited a complete block of autophagic flux caused by defective autophagosome-lysosome fusion. (PMID:28615637)
• Our findings expand the phenotypical spectrum of EPG5-related Vici syndrome and suggest that this severe condition may already present in utero (PMID:28748650)
• these findings indicate that EPG5, by controlling nucleic acids intracellular trafficking, links macroautophagy/autophagy to innate and adaptive immunity. (PMID:29130391)
• this is a report of a novel EPG5 mutation in a 21 week fetus and its sibling affected with Vici syndrome. This is the second report of brain histology in Vici syndrome in the prenatal period, at earliest reported gestation till date; with previously unreported finding of focal cortical microdysgenesis, thereby expanding the spectrum of disordered cortical development in this syndrome (PMID:29227033)
• we successfully identified novel compound heterozygous mutations in EPG5 in a patient who was clinically considered to have Vici syndrome. (PMID:30152144)
• EPG5 c.1007A > G mutation in a sibling pair with rapidly progressing Vici syndrome. (PMID:31184778)
• C-myc/miR-150/EPG5 axis mediated dysfunction of autophagy promotes development of non-small cell lung cancer. (PMID:31410206)
• Insights on autophagosome-lysosome tethering from structural and biochemical characterization of human autophagy factor EPG5. (PMID:33674710)
• Ophthalmic findings as clues for early diagnosis of Vici syndrome in a neonate. (PMID:34264147)
• Human platelets display dysregulated sepsis-associated autophagy, induced by altered LC3 protein-protein interaction of the Vici-protein EPG5. (PMID:34689707)
• Phenotypic expansion of EGP5-related Vici syndrome: 15 Dutch patients carrying a founder variant. (PMID:36410285)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	epg5	ENSDARG00000059846
mus_musculus	Epg5	ENSMUSG00000039840
rattus_norvegicus	Epg5	ENSRNOG00000052894
drosophila_melanogaster	Epg5	FBGN0038651

Paralogs (2): LIX1 (ENSG00000145721), LIX1L (ENSG00000271601)

Protein

Protein identifiers

Ectopic P granules protein 5 homolog — Q9HCE0 (reviewed: Q9HCE0)

All UniProt accessions (10): Q9HCE0, A0A8Q3SIJ2, A0A8Q3SIJ4, A0A8Q3SIP5, A0A8Q3SIU6, A0A8Q3SJD2, A0A8Q3WLI3, K7EM87, K7ENK5, K7EPN4

UniProt curated annotations — full annotation on UniProt →

Function. Involved in autophagy. May play a role in a late step of autophagy, such as clearance of autophagosomal cargo. Plays a key role in innate and adaptive immune response triggered by unmethylated cytidine-phosphate-guanosine (CpG) dinucleotides from pathogens, and mediated by the nucleotide-sensing receptor TLR9. It is necessary for the translocation of CpG dinucleotides from early endosomes to late endosomes and lysosomes, where TLR9 is located.

Subunit / interactions. Interacts with RAN.

Subcellular location. Cytoplasm. Perinuclear region. Lysosome.

Disease relevance. Vici syndrome (VICIS) [MIM:242840] A rare congenital multisystem disorder characterized by agenesis of the corpus callosum, cataracts, pigmentary defects, progressive cardiomyopathy, and variable immunodeficiency. Affected individuals also have profound psychomotor retardation and hypotonia due to a myopathy. The disease is caused by variants affecting the gene represented in this entry. Affected individuals show homozygosity or compound heterozygosity for truncating mutations, aberrant splicing and/or missense mutations. Parental studies suggest recessive inheritance with no carrier manifestation.

Similarity. Belongs to the EPG5 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9HCE0-1	1	yes
Q9HCE0-2	2

RefSeq proteins (3): NP_001397787, NP_001397788, NP_066015* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR051436	Autophagy-related_EPG5	Family
IPR058750	TPR_Epg5	Domain
IPR059030	TPR_Epg5_mid	Domain

Pfam: PF26103, PF26573

UniProt features (48 total): sequence variant 33, sequence conflict 5, region of interest 3, compositionally biased region 3, chain 1, coiled-coil region 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
7JHX	X-RAY DIFFRACTION	1.91

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HCE0-F1	74.24	0.09

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 (1): 134

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 346 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_LYSOSOMAL_TRANSPORT, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_TOLL_LIKE_RECEPTOR_9_SIGNALING_PATHWAY, GOBP_ENDOSOME_TO_LYSOSOME_TRANSPORT, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_VACUOLAR_TRANSPORT, GOBP_MODULATION_OF_PROCESS_OF_ANOTHER_ORGANISM, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_NUCLEOTIDE_TRANSPORT, GOBP_ORGAN_OR_TISSUE_SPECIFIC_IMMUNE_RESPONSE, GOBP_MACROAUTOPHAGY, GOBP_ORGANOPHOSPHATE_ESTER_TRANSPORT

GO Biological Process (29): mucosal immune response (GO:0002385), ubiquitin-dependent protein catabolic process (GO:0006511), nucleotide transport (GO:0006862), inflammatory response (GO:0006954), response to unfolded protein (GO:0006986), endosome to lysosome transport (GO:0008333), gene expression (GO:0010467), endocytic recycling (GO:0032456), toll-like receptor 9 signaling pathway (GO:0034162), response to type III interferon (GO:0034342), photoreceptor cell differentiation (GO:0046530), host-mediated modulation of intestinal microbiota composition (GO:0048874), homeostasis of number of retina cells (GO:0048877), neuron apoptotic process (GO:0051402), defense response to virus (GO:0051607), inclusion body assembly (GO:0070841), autophagosome maturation (GO:0097352), maintenance of protein complex location (GO:0098544), protein aggregate center assembly (GO:0140454), interferon-mediated signaling pathway (GO:0140888), cellular response to dsDNA (GO:1990786), autophagy (GO:0006914), apoptotic process (GO:0006915), response to virus (GO:0009615), protein catabolic process (GO:0030163), intracellular receptor signaling pathway (GO:0030522), innate immune response (GO:0045087), homeostasis of number of cells (GO:0048872), anatomical structure homeostasis (GO:0060249)

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

GO Cellular Component (3): cytoplasm (GO:0005737), lysosome (GO:0005764), perinuclear region of cytoplasm (GO:0048471)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
defense response	2
cellular component assembly	2
cellular anatomical structure	2
organ or tissue specific immune response	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
organophosphate ester transport	1
nucleobase-containing compound transport	1
response to topologically incorrect protein	1
lysosomal transport	1
intercellular transport	1
vesicle-mediated transport	1
macromolecule biosynthetic process	1
endosomal transport	1
vesicle-mediated transport to the plasma membrane	1
endolysosomal toll-like receptor signaling pathway	1
response to cytokine	1
innate immune response	1
neuron differentiation	1
homeostasis of number of cells	1
host-mediated perturbation of symbiont process	1
retina homeostasis	1
homeostasis of number of cells within a tissue	1
apoptotic process	1
response to virus	1
macroautophagy	1
protein-containing complex disassembly	1
maintenance of location	1
cytokine-mediated signaling pathway	1
binding	1
intracellular anatomical structure	1
lytic vacuole	1
cytoplasm	1

Protein interactions and networks

STRING

1016 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EPG5	WDR45	Q9Y484	807
EPG5	STX17	P56962	803
EPG5	ATG5	Q9H1Y0	800
EPG5	PLEKHM1	Q9Y4G2	737
EPG5	EI24	O14681	732
EPG5	SNAP29	O95721	718
EPG5	ATG14	Q6ZNE5	708
EPG5	ATG12	O94817	704
EPG5	VMP1	Q96GC9	665
EPG5	VAMP8	Q9BV40	664
EPG5	ATG7	O95352	647
EPG5	WIPI1	Q5MNZ9	631
EPG5	RB1CC1	Q8TDY2	614
EPG5	TECPR2	O15040	607
EPG5	ATG3	Q9NT62	606

IntAct

19 interactions, top by confidence:

A	B	Type	Score
ILVBL	SLC33A1	psi-mi:“MI:0914”(association)	0.530
ATF7IP	EPG5	psi-mi:“MI:0915”(physical association)	0.370
Psmb5		psi-mi:“MI:0914”(association)	0.350
	NBAS	psi-mi:“MI:0914”(association)	0.350
BTNL9	GPR89A	psi-mi:“MI:0914”(association)	0.350
BTNL9	TNPO2	psi-mi:“MI:0914”(association)	0.350
CCKBR	BTAF1	psi-mi:“MI:0914”(association)	0.350
CD40	IPO5	psi-mi:“MI:0914”(association)	0.350
CD80	RIMOC1	psi-mi:“MI:0914”(association)	0.350
FPR1	NBAS	psi-mi:“MI:0914”(association)	0.350
GPR17	C1QTNF9B	psi-mi:“MI:0914”(association)	0.350
HTR1E	ESYT2	psi-mi:“MI:0914”(association)	0.350
OCIAD1	DCTN6	psi-mi:“MI:0914”(association)	0.350
P2RY8	CIT	psi-mi:“MI:0914”(association)	0.350
S1PR3	STXBP3	psi-mi:“MI:0914”(association)	0.350
VIPR1	ATP9A	psi-mi:“MI:0914”(association)	0.350
VSIG1	RIMOC1	psi-mi:“MI:0914”(association)	0.350
SLC35A4	PGRMC1	psi-mi:“MI:0914”(association)	0.350

BioGRID (19): EPG5 (Synthetic Growth Defect), EPG5 (Affinity Capture-MS), EPG5 (Proximity Label-MS), EPG5 (Affinity Capture-RNA), USP8 (Affinity Capture-Western), EPG5 (Affinity Capture-Western), EPG5 (Co-localization), EPG5 (Affinity Capture-Western), EPG5 (Affinity Capture-RNA), EPG5 (Two-hybrid), EPG5 (Affinity Capture-RNA), EPG5 (Affinity Capture-MS), EPG5 (Affinity Capture-MS), EPG5 (Affinity Capture-MS), EPG5 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A0R4I9Y1, A0A0R4IBK5, A2AN08, A2ARZ3, A5WUT8, A6NKT7, B1WBT0, B8RJM0, C9JQI7, E9Q3L2, E9Q555, H2QII6, O08662, O14715, O15050, O43310, O75592, O75969, P0DJD0, P0DJD1, P13864, P42356, P49792, Q0V9S3, Q0VF22, Q24K09, Q2TL32, Q4R6W9, Q4V847, Q63HN8, Q6PB60, Q6PEE2, Q71HP2, Q7TPH6, Q7TPV2, Q7Z3J3, Q80930, Q80TA9, Q810N5, Q811D2

Diamond homologs: A5WUT8, Q80TA9, Q9HCE0

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 30 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
G protein-coupled receptor signaling pathway	6	8.4×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

2753 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	158
Likely pathogenic	54
Uncertain significance	1042
Likely benign	1237
Benign	149

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1072330	NM_020964.3(EPG5):c.2662A>T (p.Lys888Ter)	Pathogenic
1075179	NM_020964.3(EPG5):c.7459C>T (p.Arg2487Ter)	Pathogenic
1175160	NM_020964.3(EPG5):c.5869+1G>A	Pathogenic
1252004	NC_000018.9:g.43547114_43604673del	Pathogenic
1322825	NM_020964.3(EPG5):c.2863C>T (p.Arg955Ter)	Pathogenic
1339537	NM_020964.3(EPG5):c.5774del (p.Ala1925fs)	Pathogenic
1356590	NM_020964.3(EPG5):c.5653_5654del (p.Leu1885fs)	Pathogenic
1403207	NM_020964.3(EPG5):c.5382_5388del (p.Ala1795fs)	Pathogenic
1408314	NM_020964.3(EPG5):c.7057C>T (p.Gln2353Ter)	Pathogenic
1413281	NM_020964.3(EPG5):c.2450C>A (p.Ser817Ter)	Pathogenic
1423367	NM_020964.3(EPG5):c.5022_5023insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNACCTCATGATCCACCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCTAGCCTTTTCTTT (p.Thr1675delinsPhePhePhePhePhePheXaaXaaXaaXaaThrSerTer)	Pathogenic
1424550	NM_020964.3(EPG5):c.2427del (p.Leu810fs)	Pathogenic
1425424	NC_000018.9:g.(?43547123)(43547205_?)del	Pathogenic
1433186	NM_020964.3(EPG5):c.2041del (p.Gln681fs)	Pathogenic
1444421	NM_020964.3(EPG5):c.5617G>T (p.Glu1873Ter)	Pathogenic
1452102	NM_020964.3(EPG5):c.4020dup (p.Gln1341fs)	Pathogenic
1459687	NC_000018.9:g.(?43502287)(43505888_?)del	Pathogenic
1677242	NM_020964.3(EPG5):c.3544G>T (p.Glu1182Ter)	Pathogenic
1928829	NM_020964.3(EPG5):c.1777_1781del (p.Leu592_Gly593insTer)	Pathogenic
2095515	NM_020964.3(EPG5):c.3882_3883del (p.Trp1294fs)	Pathogenic
2124929	NM_020964.3(EPG5):c.6898dup (p.Met2300fs)	Pathogenic
2138148	NM_020964.3(EPG5):c.2355del (p.Arg786fs)	Pathogenic
2228941	NM_020964.3(EPG5):c.3949_3952del (p.Leu1317fs)	Pathogenic
2279111	NM_020964.3(EPG5):c.5314A>T (p.Lys1772Ter)	Pathogenic
2412757	NM_020964.3(EPG5):c.6724del (p.Met2242fs)	Pathogenic
2500954	NM_020964.3(EPG5):c.2413-2A>G	Pathogenic
2500955	NM_020964.3(EPG5):c.1252+1G>A	Pathogenic
267450	Single allele	Pathogenic
267454	NM_020964.3(EPG5):c.2461C>T (p.Arg821Ter)	Pathogenic
2693661	NM_020964.3(EPG5):c.5322del (p.Trp1774fs)	Pathogenic

SpliceAI

7319 predictions. Top by Δscore:

Variant	Effect	Δscore
18:45839092:CCAG:C	donor_loss	1.0000
18:45839093:CAG:C	donor_loss	1.0000
18:45839097:T:A	donor_loss	1.0000
18:45840197:T:A	acceptor_gain	1.0000
18:45840209:A:AG	acceptor_gain	1.0000
18:45840210:G:GA	acceptor_gain	1.0000
18:45840210:GA:G	acceptor_gain	1.0000
18:45840210:GAGC:G	acceptor_gain	1.0000
18:45840240:CGG:C	donor_loss	1.0000
18:45840242:G:A	donor_loss	1.0000
18:45840242:G:GG	donor_gain	1.0000
18:45842103:CA:C	acceptor_loss	1.0000
18:45857848:CTTA:C	donor_loss	1.0000
18:45857849:TTACC:T	donor_loss	1.0000
18:45857850:TACCT:T	donor_loss	1.0000
18:45857851:A:AC	donor_gain	1.0000
18:45857852:C:CC	donor_gain	1.0000
18:45857852:C:CG	donor_loss	1.0000
18:45858064:CGGAG:C	acceptor_gain	1.0000
18:45858067:AG:A	acceptor_gain	1.0000
18:45858067:AGCTA:A	acceptor_loss	1.0000
18:45858068:GCTAG:G	acceptor_loss	1.0000
18:45858069:C:CC	acceptor_gain	1.0000
18:45858069:CTAGG:C	acceptor_loss	1.0000
18:45858070:T:G	acceptor_loss	1.0000
18:45858082:C:CT	acceptor_gain	1.0000
18:45858082:C:T	acceptor_gain	1.0000
18:45858083:G:T	acceptor_gain	1.0000
18:45858562:GTACC:G	donor_loss	1.0000
18:45858563:TA:T	donor_loss	1.0000

AlphaMissense

16991 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:45908059:A:G	W1410R	0.999
18:45908059:A:T	W1410R	0.999
18:45912393:A:G	W1294R	0.999
18:45912393:A:T	W1294R	0.999
18:45946692:A:G	W550R	0.999
18:45946692:A:T	W550R	0.999
18:45878404:A:G	W1972R	0.998
18:45878404:A:T	W1972R	0.998
18:45912339:A:G	W1312R	0.998
18:45912339:A:T	W1312R	0.998
18:45912395:C:G	R1293P	0.998
18:45922587:G:T	A951D	0.998
18:45928954:A:G	L823P	0.998
18:45928960:C:G	R821P	0.998
18:45928963:C:T	G820D	0.998
18:45858759:A:G	W2345R	0.997
18:45858759:A:T	W2345R	0.997
18:45907983:A:G	L1435P	0.997
18:45910719:C:T	G1336E	0.997
18:45913710:A:G	L1271P	0.997
18:45913825:A:G	W1233R	0.997
18:45913825:A:T	W1233R	0.997
18:45916146:A:G	W1149R	0.997
18:45916146:A:T	W1149R	0.997
18:45922578:A:T	V954D	0.997
18:45928964:C:G	G820R	0.997
18:45930761:A:G	L776P	0.997
18:45930764:A:G	L775P	0.997
18:45943173:C:T	G644D	0.997
18:45867685:A:G	W2097R	0.996

dbSNP variants (sampled 300 via entrez): RS1000002195 (18:45822027 G>A,T), RS1000026460 (18:45864549 G>A), RS1000037657 (18:45912342 T>C,G), RS1000048632 (18:45944938 T>C), RS1000056198 (18:45957103 T>C), RS1000127272 (18:45897527 A>C), RS1000135281 (18:45829617 AC>A,ACC), RS1000146526 (18:45828474 G>A), RS1000188013 (18:45927887 G>A), RS1000192772 (18:45841457 G>C), RS1000195320 (18:45932172 T>C), RS1000199630 (18:45856470 T>C), RS1000204696 (18:45906048 C>T), RS1000240142 (18:45876099 A>G), RS1000293294 (18:45942221 T>A)

Disease associations

OMIM: gene MIM:615068 | disease phenotypes: MIM:242840, MIM:621506

GenCC curated gene-disease

Disease	Classification	Inheritance
Vici syndrome	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Vici syndrome	Definitive	AR

Mondo (5): Vici syndrome (MONDO:0009452), limb-girdle muscular dystrophy (MONDO:0016971), neurodevelopmental disorder with parkinsonism or other movement abnormalities (MONDO:0980990), intellectual disability (MONDO:0001071), microcephaly (MONDO:0001149)

Orphanet (4): Vici syndrome (Orphanet:1493), Limb-girdle muscular dystrophy (Orphanet:263), OBSOLETE: Syndromic rod-cone dystrophy (Orphanet:98661), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

90 total (30 of 90 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000161	Median cleft upper lip
HP:0000175	Cleft palate
HP:0000204	Cleft upper lip
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000325	Triangular face
HP:0000341	Narrow forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000407	Sensorineural hearing impairment
HP:0000437	Depressed nasal tip
HP:0000445	Wide nose
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000519	Developmental cataract
HP:0000601	Hypotelorism
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000777	Abnormal thymus morphology
HP:0001010	Hypopigmentation of the skin
HP:0001022	Albinism
HP:0001103	Abnormal macular morphology
HP:0001104	Macular hypoplasia
HP:0001107	Ocular albinism
HP:0001249	Intellectual disability
HP:0001250	Seizure

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST010538_9	Sum of carotid plaque area	5.000000e-06
GCST010539_8	Sum of stenosis	3.000000e-07
GCST90014243_13	Kawasaki disease	2.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006501	carotid plaque build

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D049288	Muscular Dystrophies, Limb-Girdle	C05.651.534.500.280; C10.668.491.175.500.149; C16.320.577.280
C535566	Absent corpus callosum cataract immunodeficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, decreases methylation, increases expression	2
Benzo(a)pyrene	affects methylation	2
aristolochic acid I	increases expression	1
GSK-J4	increases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	affects expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
aflatoxin B2	increases methylation	1
epigallocatechin gallate	increases expression, affects cotreatment, decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
NSC 689534	affects binding, increases expression	1
PCI 5002	increases expression, affects cotreatment	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	decreases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Air Pollutants	decreases expression	1
Caffeine	decreases phosphorylation	1
Copper	affects binding, increases expression	1
Demecolcine	increases expression	1
Dimethyl Sulfoxide	increases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Hydrogen Peroxide	decreases expression, affects cotreatment	1
Methapyrilene	increases methylation	1
Methyl Methanesulfonate	increases expression	1
Theophylline	affects cotreatment, decreases expression	1

Cellosaurus cell lines

9 cell lines: 4 transformed cell line, 3 finite cell line, 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_D2ZJ	GM28930	Induced pluripotent stem cell	Male
CVCL_LH30	GM26249	Transformed cell line	Male
CVCL_LH31	GM26250	Transformed cell line	Male
CVCL_LH32	GM26251	Transformed cell line	Female
CVCL_LH34	GM26636	Finite cell line	Male
CVCL_VV62	GM27291	Induced pluripotent stem cell	Male
CVCL_ZI03	GM27898	Finite cell line	Female
CVCL_ZI04	GM27900	Transformed cell line	Female
CVCL_ZW57	GM27894	Finite cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT03783923	PHASE3	TERMINATED	A Study of Deflazacort (Emflaza®) in Participants With Limb-Girdle Muscular Dystrophy 2I (LGMD2I)
NCT06246513	PHASE3	ACTIVE_NOT_RECRUITING	A Trial to Learn More About an Experimental Gene Therapy Called Bidridistrogene Xeboparvovec (SRP-9003) as a Possible Treatment for Limb Girdle Muscular Dystrophy 2E/R4
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT04054375	PHASE2	COMPLETED	Weekly Steroids in Muscular Dystrophy
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00873782	PHASE1	COMPLETED	Safety Study of Transvenous Limb Perfusion in Human Muscular Dystrophy
NCT01344798	PHASE1	COMPLETED	Clinical Study of AAV1-gamma-sarcoglycan Gene Therapy for Limb Girdle Muscular Dystrophy Type 2C
NCT02050776	PHASE1	WITHDRAWN	Stem Cell Therapy in Limb Girdle Muscular Dystrophy
NCT02245711	PHASE1	WITHDRAWN	Cell Therapy in Limb Girdle Muscular Dystrophy
NCT05876780	PHASE1	ACTIVE_NOT_RECRUITING	A Gene Transfer Single Dose Study to Evaluate the Safety, Tolerability and Efficacy of SRP-9003 in Non-Ambulatory and Ambulatory Participants With Limb Girdle Muscular Dystrophy, Type 2E/R4 (Beta-Sarcoglycan [β-SG] Deficiency)
NCT05906251	PHASE1	TERMINATED	A Gene Transfer Study to Evaluate the Safety, Tolerability and Efficacy of SRP-6004 in Ambulatory Participants With Limb Girdle Muscular Dystrophy, Type 2B/R2 (LGMD2B/R2, Dysferlin [DYSF] Related)
NCT06747273	PHASE1	TERMINATED	Study to Evaluate the Safety, Tolerability, and Efficacy of SRP-9004 Administered by Systemic Infusion in Limb Girdle Muscular Dystrophy Type 2D/R3 Participants in the United States
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT01126697	PHASE2/PHASE3	COMPLETED	Clinical Trial of Coenzyme Q10 and Lisinopril in Muscular Dystrophies
NCT00104078	PHASE1/PHASE2	COMPLETED	Study Evaluating MYO-029 in Adult Muscular Dystrophy
NCT02579239	PHASE1/PHASE2	COMPLETED	Evaluate Safety and Biological Activity of ATYR1940 in Participants With Limb Girdle Muscular Dystrophy 2B (LGMD2B) and Facioscapulohumeral Muscular Dystrophy (FSHD)
NCT02836418	PHASE1/PHASE2	COMPLETED	Study to Evaluate the Long-Term Safety, Tolerability, and Biological Activity of ATYR1940 in Participants With Limb Girdle and Facioscapulohumeral Muscular Dystrophy (FSHD)
NCT05230459	PHASE1/PHASE2	RECRUITING	A Study to Evaluate the Safety of AB-1003 (Previously LION-101) in Subjects With Genetic Confirmation of LGMD2I/R9 (Part1)
NCT05588401	PHASE1/PHASE2	UNKNOWN	Evaluating Safety and Efficacy of Autologous Gene-edited Muscle Stem Cells (GenPHSats-bASKet)
NCT00390104	Not specified	RECRUITING	Molecular Analysis of Patients With Neuromuscular Disease
NCT00457912	Not specified	COMPLETED	Genetic Characterization of Individuals With Limb Girdle Muscular Dystrophy
NCT01066455	Not specified	COMPLETED	Cardiac Outcome Measures in Children With Muscular Dystrophy
NCT01081080	Not specified	COMPLETED	Cardiac Magnetic Resonance in Children With Muscular Dystrophy
NCT01403402	Not specified	RECRUITING	Congenital Muscle Disease Study of Patient and Family Reported Medical Information
NCT02635321	Not specified	COMPLETED	MRI and Muscle Involvement in Patients With Mutations in GMPPB
NCT02759302	Not specified	COMPLETED	MRI on Persons With Mutations in POMT2 Gene (LGMD2N)
NCT03930628	Not specified	UNKNOWN	Limb-Girdle Muscular Dystrophy Type 2I in Norway
NCT03981289	Not specified	COMPLETED	Defining Clinical Endpoints in Limb Girdle Muscular Dystrophy (LGMD)
NCT04001595	Not specified	UNKNOWN	Global FKRP Registry