GGPS1

Chr 1AR

geranylgeranyl diphosphate synthase 1

Also known as: GGPPS, GGPPS1, MDHLO, MUDHLOV

NCBI Gene: 9453 ENSG00000152904 UniProt: O95749 OMIM: 606982

The protein catalyzes the synthesis of geranylgeranyl diphosphate (GGPP), which is essential for protein prenylation and regulation of nuclear hormone receptors. Biallelic mutations cause muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome with autosomal recessive inheritance. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.64), and the syndrome involves multiple organ systems including muscle, auditory, and reproductive systems.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.641 OMIM phenotype

Clinical Summary— GGPS1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.

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ClinVar Variants

4 unique Pathogenic / Likely Pathogenic· 33 VUS of 48 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GGPS1

Authoritative clinical overview · Recommended first read

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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 OE?0.25 (0.11–0.64)

0≤0.351.4

Missense OE?0.73 (0.62–0.85)

0≤0.61.4

Synonymous OE?1.16

0≤1.21.6

LoF obs/exp: 3 / 12.1Missense obs/exp: 113 / 155.7Syn Z: -0.94

This gene — mechanism propensity

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

48 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic1

VUS33

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	3	0	0	3
Likely Pathogenic	0	1	0	0	1
VUS	1	32	0	0	33
Likely Benign	0	0	0	0	0
Benign	0	0	0	0	0
Conflicting	—				1
Total	1	36	0	0	38

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

View in ClinVar →

48 pathogenic / likely-pathogenic (of 59) ClinVar copy-number / structural variants overlap GGPS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →