VMA21

Chr XXLR

vacuolar ATPase assembly factor VMA21

Also known as: MEAX, XMEA

NCBI Gene: 203547ENSG00000160131UniProt: Q3ZAQ7

This gene encodes a chaperone for assembly of lysosomal vacuolar ATPase.[provided by RefSeq, Jul 2012]

Primary Disease Associations & Inheritance

Myopathy, X-linked, with excessive autophagyMIM #310440
XLR
200
ClinVar variants
94
Pathogenic / LP
0.57
pLI score
0
Active trials
Clinical Summary— VMA21
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.57) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
94 Pathogenic / Likely Pathogenic· 53 VUS of 200 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.
1.11LOEUF
pLI 0.572
Z-score 1.50
OE 0.00 (0.00–1.11)
Moderately constrained

Highly tolerant — LoF variants common in population

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.
0.78Z-score
OE missense 0.65 (0.48–0.91)
26 obs / 39.8 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.0.00 (0.00–1.11)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.65 (0.48–0.91)
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.1.39
0≤1.21.6
LoF obs/exp: 0 / 2.6Missense obs/exp: 26 / 39.8Syn Z: -1.26

ClinVar Variant Classifications

200 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic92
Likely Pathogenic2
VUS53
Likely Benign35
Benign14
Conflicting4
92
Pathogenic
2
Likely Pathogenic
53
VUS
35
Likely Benign
14
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
92
0
92
Likely Pathogenic
0
0
2
0
2
VUS
0
37
15
1
53
Likely Benign
0
2
9
24
35
Benign
0
2
8
4
14
Conflicting
—4
Total04112629200

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

View in ClinVar →

Protein Context — Lollipop Plot

VMA21 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Myopathy, X-linked, with excessive autophagy

MIM #310440

Molecular basis of disorder known

X-linked recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy.
Deneubourg C et al.·Autophagy
2022
Recent advances in the clinical spectrum and pathomechanisms associated with X-linked myopathy with excessive autophagy and other VMA21-related disorders.
Cocchiararo I et al.·J Neuromuscul Dis
2025Review
Identification of a muscle-specific isoform of VMA21 as a potent actor in X-linked myopathy with excessive autophagy pathogenesis.
Cocchiararo I et al.·Hum Mol Genet
2023
Novel Intronic Mutation in VMA21 Causing Severe Phenotype of X-Linked Myopathy with Excessive Autophagy-Case Report.
Pegat A et al.·Genes (Basel)
2022Case report
Severe congenital X-linked myopathy with excessive autophagy secondary to an apparently synonymous but pathogenic novel variant.
Blanco-Arias P et al.·Neuromuscul Disord
2023Case report
A novel variant in VMA21 causing adult-onset phenotype of X-linked myopathy with excessive autophagy with cardiac involvement in a Chinese patient.
Chen L et al.·J Neuromuscul Dis
2025Case report
Hsa_circ_0001361 facilitates the progress of lung adenocarcinoma cells via targeting miR-525-5p/VMA21 axis.
Shen HY et al.·J Transl Med
2021
Phenotype variability and natural history of X-linked myopathy with excessive autophagy.
Fernández-Eulate G et al.·J Neurol
2024Natural history
Follicular lymphoma-associated mutations in the V-ATPase chaperone VMA21 activate autophagy creating a targetable dependency.
Wang F et al.·Autophagy
2022
Late adult-onset of X-linked myopathy with excessive autophagy.
Crockett CD et al.·Muscle Nerve
2014
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