GGPS1

Chr 1AR

geranylgeranyl diphosphate synthase 1

Also known as: GGPPS, GGPPS1, MDHLO, MUDHLOV

NCBI Gene: 9453ENSG00000152904UniProt: O95749

This gene is a member of the prenyltransferase family and encodes a protein with geranylgeranyl diphosphate (GGPP) synthase activity. The enzyme catalyzes the synthesis of GGPP from farnesyl diphosphate and isopentenyl diphosphate. GGPP is an important molecule responsible for the C20-prenylation of proteins and for the regulation of a nuclear hormone receptor. Alternate transcriptional splice variants, both protein-coding and non-protein-coding, have been found for this gene. [provided by RefSeq, Sep 2010]

Primary Disease Associations & Inheritance

Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndromeMIM #619518
AR
0
Active trials
51
Pathogenic / LP
95
ClinVar variants
10
Pubs (1 yr)
1.2
Missense Z
0.64
LOEUF
Clinical Summary— GGPS1
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.
📋
ClinVar Variants
51 Pathogenic / Likely Pathogenic· 43 VUS of 95 total submissions
📖
GeneReview available — GGPS1
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
0.64LOEUF
pLI 0.269
Z-score 2.43
OE 0.25 (0.11–0.64)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
1.22Z-score
OE missense 0.73 (0.62–0.85)
113 obs / 155.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.25 (0.11–0.64)
0≤0.351.4
Missense OE0.73 (0.62–0.85)
0≤0.61.4
Synonymous OE1.16
0≤1.21.6
LoF obs/exp: 3 / 12.1Missense obs/exp: 113 / 155.7Syn Z: -0.94
DNGOF
DN
0.7133th %ile
GOF
0.7028th %ile
LOF
0.2483th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median
GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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

ClinVar Variant Classifications

95 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic48
Likely Pathogenic3
VUS43
Conflicting1
48
Pathogenic
3
Likely Pathogenic
43
VUS
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
3
45
0
48
Likely Pathogenic
0
1
2
0
3
VUS
1
32
10
0
43
Likely Benign
0
0
0
0
0
Benign
0
0
0
0
0
Conflicting
—1
Total13657095

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

View in ClinVar →

GGPS1 · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Ggps1 deficiency in the uterus results in dystocia by disrupting uterine contraction
Sang YJ et al.·J Mol Cell Biol
2021
Oocytes orchestrate protein prenylation for mitochondrial function through selective inactivation of cholesterol biosynthesis in murine species
Sang Y et al.·J Biol Chem
2023
Disruption of protein geranylgeranylation in the cerebellum causes cerebellar hypoplasia and ataxia via blocking granule cell progenitor proliferation
Cheng Q et al.·Mol Brain
2023
Therapeutic targeting of the mevalonate-geranylgeranyl diphosphate pathway with statins overcomes chemotherapy resistance in small cell lung cancer.
Guo C et al.·Nat Cancer
2022
Transcriptome analysis revealing the effect of Bupleurum scorzonerifolium Willd association with endophytic fungi CHS3 on the production of saikosaponin D
Liu G et al.·Heliyon
2024
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients