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…

Primary Disease Associations & Inheritance

Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndromeMIM #619518

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome; no ClinGen or GenCC tier

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.64

LOEUF

Multiple*

Mechanism· predicted

📖

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 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

Background carrier burden — how many people carry a rare variant somewhere in GGPS1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 260

306 rare PASS variants

Rare truncating (LoF)

1 in 4,100

52 rare PASS variants

Rare synonymous (reference)

1 in 530

142 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GGPS1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 360	1 in 4,500
South Asian	~43k	1 in 390	1 in 1,800
Remaining (unassigned)	~30k	1 in 160	1 in 3,700
European (Finnish)	~27k	1 in 780	≈ 1 in 27,000
Admixed American	~22k	1 in 320	≈ 1 in 6,800
African / African American	~21k	1 in 370	≈ 1 in 4,500
East Asian	~20k	1 in 550	≈ 1 in 9,900
Ashkenazi Jewish	~13k	1 in 2,600	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 180	≈ 1 in 2,700

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 1 of 3 coding exons well covered in gnomAD exomes; exons 2, 3 marginal. Genomes: all 3.? see exons ↓