ZMPSTE24

Chr 1AR

zinc metallopeptidase STE24

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

NCBI Gene: 10269 ENSG00000084073 UniProt: O75844 OMIM: 606480

The protein is a zinc metalloproteinase that processes prelamin A to form mature lamin A on the inner nuclear membrane and clears clogged translocons on the endoplasmic reticulum. Mutations cause mandibuloacral dysplasia with type B lipodystrophy and restrictive dermopathy, both inherited in an autosomal recessive pattern. The gene shows extremely low constraint to loss-of-function variation (pLI near zero), consistent with the recessive inheritance pattern where heterozygous carriers are typically unaffected.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.332 OMIM phenotypes

Clinical Summary— ZMPSTE24

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Gene-Disease Validity (ClinGen)

mandibuloacral dysplasia with type B lipodystrophy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

38 unique Pathogenic / Likely Pathogenic· 90 VUS of 259 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ZMPSTE24

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

0.37Z-score

OE missense 0.93 (0.84–1.04)

228 obs / 244.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.94 (0.68–1.33)

0≤0.351.4

Missense OE?0.93 (0.84–1.04)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 24 / 25.4Missense obs/exp: 228 / 244.4Syn Z: 0.91

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveZMPSTE24-related lethal restrictive dermopathyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7228th %ile

GOF

0.6736th %ile

LOF

0.2969th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

259 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic30

Likely Pathogenic8

VUS90

Likely Benign64

Benign25

Conflicting9

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	27	3	0	0	30
Likely Pathogenic	6	2	0	0	8
VUS	1	67	19	3	90
Likely Benign	0	2	34	28	64
Benign	0	0	22	3	25
Conflicting	—				9
Total	34	74	75	34	226

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

View in ClinVar →

8 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap ZMPSTE24 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →