GPER1

Chr 7

G protein-coupled estrogen receptor 1

Also known as: CEPR, CMKRL2, DRY12, FEG-1, GPCR-Br, GPER, GPR30, LERGU

NCBI Gene: 2852 ENSG00000164850 UniProt: Q99527 OMIM: 601805

This protein functions as a G-protein coupled estrogen receptor that binds 17-beta-estradiol and activates multiple intracellular signaling pathways including cAMP production, calcium mobilization, and PI3K/Akt signaling, with roles in cardiovascular, endocrine, reproductive, and nervous system functions. Mutations in this gene cause neurodevelopmental disorder with seizures and brain atrophy, which is inherited in an autosomal dominant pattern. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.695), reflecting its importance in human development and function.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a multi-pass membrane protein that localizes to the endoplasmic reticulum and a member of the G-protein coupled receptor 1 family. This receptor binds estrogen and activates multiple downstream signaling pathways, leading to stimulation of adenylate cyclase and an increase in cyclic AMP levels, while also promoting intracellular calcium mobilization and synthesis of phosphatidylinositol 3,4,5-trisphosphate in the nucleus. This protein therefore plays a role in the rapid nongenomic signaling events widely observed following stimulation of cells and tissues with estrogen. This receptor has been shown to play a role in diverse biological processes, including bone and nervous system development, metabolism, cognition, male fertility and uterine function. [provided by RefSeq, Aug 2017]

OMIM ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.69

Clinical Summary— GPER1

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.57) — some intolerance to loss-of-function variants.

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ClinVar Variants

59 VUS of 64 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.69LOEUF

pLI 0.574

Z-score 2.07

OE 0.15 (0.05–0.69)

Moderately constrained

Typical tolerance to LoF variation

Missense Constraint?

1.11Z-score

OE missense 0.81 (0.72–0.91)

218 obs / 269.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.15 (0.05–0.69)

0≤0.351.4

Missense OE?0.81 (0.72–0.91)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 1 / 6.8Missense obs/exp: 218 / 269.2Syn Z: -0.20

This gene — mechanism propensity

0.6163th %ile

GOF

0.74top 25%

LOF

0.4134th %ile

The highest-scoring mechanism for this gene is gain-of-function.

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

64 submitted variants in ClinVar

ClinVar

Classification Summary

VUS59

Likely Benign3

Benign2

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	59	0	59
Likely Benign	2	1	3
Benign	2	0	2
Total	63	1	64

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

View in ClinVar →

40 pathogenic / likely-pathogenic (of 60) ClinVar copy-number / structural variants overlap GPER1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →