ATP6V1E1

Chr 22AR

ATPase H+ transporting V1 subunit E1

Also known as: ARCL2C, ATP6E, ATP6E2, ATP6V1E, P31, Vma4

NCBI Gene: 529ENSG00000131100UniProt: P36543

This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A, three B, and two G subunits, as well as a C, D, E, F, and H subunit. The V1 domain contains the ATP catalytic site. This gene encodes alternate transcriptional splice variants, encoding different V1 domain E subunit isoforms. Pseudogenes for this gene have been found in the genome. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Cutis laxa, autosomal recessive, type IICMIM #617402
AR
282
ClinVar variants
66
Pathogenic / LP
0.53
pLI score
0
Active trials
Clinical Summary— ATP6V1E1
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.53) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
66 Pathogenic / Likely Pathogenic· 57 VUS of 282 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.51LOEUF
pLI 0.528
Z-score 2.88
OE 0.20 (0.09–0.51)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.59Z-score
OE missense 0.59 (0.48–0.72)
68 obs / 116.2 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.20 (0.09–0.51)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.59 (0.48–0.72)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.97
0≤1.21.6
LoF obs/exp: 3 / 15.1Missense obs/exp: 68 / 116.2Syn Z: 0.16

ClinVar Variant Classifications

282 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic64
Likely Pathogenic2
VUS57
Likely Benign97
Benign47
Conflicting1
64
Pathogenic
2
Likely Pathogenic
57
VUS
97
Likely Benign
47
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
64
0
64
Likely Pathogenic
0
1
1
0
2
VUS
1
43
11
2
57
Likely Benign
0
2
67
28
97
Benign
0
0
46
1
47
Conflicting
—1
Total14618931268

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

ATP6V1E1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

ATP6V1E1-related cutis laxa

strong
ARUndeterminedAltered Gene Product Structure
Dev. DisordersSkin
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Cutis laxa, autosomal recessive, type IIC

MIM #617402

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review.
Conte F et al.·Int J Mol Sci
2023Review
Mutations in ATP6V1E1 or ATP6V1A Cause Autosomal-Recessive Cutis Laxa.
Van Damme T et al.·Am J Hum Genet
2017
Clinical and molecular cytogenetic findings of cat eye syndrome and a 2-year-old patient with congenital aural atresia and hearing loss.
Xu L et al.·BMC Pediatr
2024Review
Construction and validation of a novel cuproptosis-mitochondrion prognostic model related with tumor immunity in osteosarcoma.
Feng J et al.·PLoS One
2023Functional
Clinical and Molecular Delineation of Cutis Laxa Syndromes: Paradigms for Homeostasis.
Beyens A et al.·Adv Exp Med Biol
2021Review
SCG5 and MITF may be novel markers of copper metabolism immunorelevance in Alzheimer's disease.
Zhuang X et al.·Sci Rep
2024
Expanding the clinical and genetic heterogeneity of hereditary disorders of connective tissue.
Alazami AM et al.·Hum Genet
2016
A Novel Oxidative Phosphorylation-Associated Gene Signature for Prognosis Prediction in Patients with Hepatocellular Carcinoma.
Chen W et al.·Dis Markers
2022Cohort
Identification of Autophagy-Related Candidate Genes in the Early Diagnosis of Alzheimer's Disease and Exploration of Potential Molecular Mechanisms.
Wang J et al.·Mol Neurobiol
2024Functional
A 600 kb triplication in the cat eye syndrome critical region causes anorectal, renal and preauricular anomalies in a three-generation family.
Knijnenburg J et al.·Eur J Hum Genet
2012
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools