EPG5

Chr 18AR

ectopic P-granules 5 autophagy tethering factor

Also known as: HEEW1, KIAA1632, NEDPAM, VICIS

NCBI Gene: 57724 ENSG00000152223 UniProt: Q9HCE0 OMIM: 615068

This gene encodes a protein that functions in autophagy and plays a key role in immune responses by facilitating the translocation of pathogen-derived CpG dinucleotides to lysosomes where TLR9 is located. Mutations cause Vici syndrome and neurodevelopmental disorder with parkinsonism or other movement abnormalities, both inherited in an autosomal recessive pattern. The gene is highly constrained against loss-of-function variants, indicating its critical importance for normal cellular function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a large coiled coil domain-containing protein that functions in autophagy during starvation conditions. Mutations in this gene cause Vici syndrome. [provided by RefSeq, Aug 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with parkinsonism or other movement abnormalitiesMIM #621506

Vici syndromeMIM #242840

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Vici syndrome · AR · ClinGen 2024

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.46

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — EPG5

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.46LOEUF

pLI 0.000

Z-score 6.88

OE 0.36 (0.28–0.46)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.08Z-score

OE missense 0.92 (0.87–0.96)

1233 obs / 1344.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.36 (0.28–0.46)

0≤0.351.4

Missense OE?0.92 (0.87–0.96)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 48 / 134.0Missense obs/exp: 1233 / 1344.4Syn Z: -0.95

Background carrier burden — how many people carry a rare variant somewhere in EPG5?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 19

3,075 rare PASS variants

Rare truncating (LoF)

1 in 690

347 rare PASS variants

Rare synonymous (reference)

1 in 35

1,232 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for EPG5. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 27	1 in 690
South Asian	~43k	1 in 20	1 in 410
Remaining (unassigned)	~30k	1 in 18	1 in 640
European (Finnish)	~27k	1 in 84	1 in 1,300
Admixed American	~22k	1 in 17	1 in 400
African / African American	~21k	1 in 18	1 in 640
East Asian	~20k	1 in 25	1 in 580
Ashkenazi Jewish	~13k	1 in 74	≈ 1 in 4,300
Middle Eastern	~2,884	1 in 20	≈ 1 in 960

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 40 of 44 coding exons well covered in gnomAD exomes; exons 4, 14, 24, 34 marginal. Genomes: all 44.? see exons ↓