ZMPSTE24

Chr 1AR

zinc metallopeptidase STE24

Also known as: FACE-1, FACE1, HGPS, PRO1, RSDM1, STE24, Ste24p

NCBI Gene: 10269ENSG00000084073UniProt: O75844

This gene encodes a member of the peptidase M48A family. The encoded protein is a zinc metalloproteinase involved in the two step post-translational proteolytic cleavage of carboxy terminal residues of farnesylated prelamin A to form mature lamin A. Mutations in this gene have been associated with mandibuloacral dysplasia and restrictive dermopathy. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Mandibuloacral dysplasia with type B lipodystrophyMIM #608612
AR
Restrictive dermopathy 1MIM #275210
AR
273
ClinVar variants
45
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— ZMPSTE24
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
45 Pathogenic / Likely Pathogenic· 96 VUS of 273 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
1.33LOEUF
pLI 0.000
Z-score 0.26
OE 0.94 (0.68–1.33)
Tolerant

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.
0.37Z-score
OE missense 0.93 (0.84–1.04)
228 obs / 244.4 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.0.94 (0.68–1.33)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.93 (0.84–1.04)
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.0.88
0≤1.21.6
LoF obs/exp: 24 / 25.4Missense obs/exp: 228 / 244.4Syn Z: 0.91

ClinVar Variant Classifications

273 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic36
Likely Pathogenic9
VUS96
Likely Benign64
Benign25
Conflicting9
36
Pathogenic
9
Likely Pathogenic
96
VUS
64
Likely Benign
25
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
16
3
17
0
36
Likely Pathogenic
3
0
6
0
9
VUS
1
67
25
3
96
Likely Benign
0
2
34
28
64
Benign
0
0
22
3
25
Conflicting
—9
Total207210434239

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

View in ClinVar →

Protein Context — Lollipop Plot

ZMPSTE24 · protein map & ClinVar variants

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

Gene2Phenotype Curations

ZMPSTE24-related lethal restrictive dermopathy

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersSkin
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Mandibuloacral dysplasia with type B lipodystrophy

MIM #608612

Molecular basis of disorder known

Autosomal recessive

Restrictive dermopathy 1

MIM #275210

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
mtDNA release promotes cGAS-STING activation and accelerated aging of postmitotic muscle cells.
Li Y et al.·Cell Death Dis
2024
Lonafarnib: First Approval.
Dhillon S·Drugs
2021Review
Rare ZMPSTE24 variants increase risk of hypertriglyceridemia and metabolic syndrome.
Le Collen L et al.·Eur J Endocrinol
2025Case report
ZMPSTE24 defends against influenza and other pathogenic viruses.
Fu B et al.·J Exp Med
2017
[Primary lipodystrophies].
Capeau J et al.·Ann Endocrinol (Paris)
2007
Pathological aging is alleviated by neutralization of the autophagy-repressive tissue hormone DBI/ACBP.
Montégut L et al.·Autophagy
2025
Mutational and expressional alterations of ZMPSTE24, DNA damage response-related gene, in gastric and colorectal cancers.
Lee JH et al.·Pathol Res Pract
2016
The NLRP3 inhibitor Dapansutrile improves the therapeutic action of lonafarnib on progeroid mice.
Muela-Zarzuela I et al.·Aging Cell
2024
Phenotypic heterogeneity of ZMPSTE24 deficiency.
Cassini TA et al.·Am J Med Genet A
2018Case report
Restrictive dermopathy: Three new patients with ZMPSTE24 mutations and a review of the literature.
Scott JB et al.·Pediatr Dermatol
2021Review
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
Lipodystrophy (Genetic or Acquired, Non HIV)

The LD Lync Study - Natural History Study of Lipodystrophy Syndromes

RECRUITING
NCT03087253University of MichiganStarted 2018-02-27

External Resources

Links to major genomics databases and tools