GPRC6A

Chr 6

G protein-coupled receptor class C group 6 member A

Also known as: GPCR, bA86F4.3

NCBI Gene: 222545ENSG00000173612UniProt: Q5T6X5

Members of family C of the G protein-coupled receptor (GPCR) superfamily, such as GPRC6A, are characterized by an evolutionarily conserved amino acid-sensing motif linked to an intramembranous 7-transmembrane loop region. Several members of GPCR family C, including GPRC6A, also have a long N-terminal domain (summary by Pi et al., 2005 [PubMed 16199532]).[supplied by OMIM, Nov 2010]

168
ClinVar variants
28
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— GPRC6A
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
28 Pathogenic / Likely Pathogenic· 125 VUS of 168 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.30LOEUF
pLI 0.000
Z-score 0.30
OE 0.94 (0.69–1.30)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.18Z-score
OE missense 0.98 (0.91–1.05)
473 obs / 484.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.94 (0.69–1.30)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.98 (0.91–1.05)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.96
0≤1.21.6
LoF obs/exp: 26 / 27.7Missense obs/exp: 473 / 484.0Syn Z: 0.42

ClinVar Variant Classifications

168 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic23
Likely Pathogenic5
VUS125
Likely Benign11
Benign4
23
Pathogenic
5
Likely Pathogenic
125
VUS
11
Likely Benign
4
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
23
0
23
Likely Pathogenic
0
0
5
0
5
VUS
0
121
4
0
125
Likely Benign
0
10
0
1
11
Benign
2
1
1
0
4
Total2132331168

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

View in ClinVar →

Protein Context — Lollipop Plot

GPRC6A · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Explaining Divergent Observations Regarding Osteocalcin/GPRC6A Endocrine Signaling.
Pi M et al.·Endocrinology
2021Review
Osteocalcin‑GPRC6A: An update of its clinical and biological multi‑organic interactions (Review).
Diaz-Franco MC et al.·Mol Med Rep
2019Review
An overview of osteocalcin progress.
Li J et al.·J Bone Miner Metab
2016Review
Undercarboxylated OCN Inhibits Chondrocyte Hypertrophy and Osteoarthritis Development through GPRC6A/HIF-1α Cascade.
Du Z et al.·Int J Biol Sci
2025
Nutrient sensing receptor GPRC6A regulates mTORC1 signaling and Tau biology.
Ma C et al.·Neurobiol Dis
2025
CRISPR/Cas9 targeting of GPRC6A suppresses prostate cancer tumorigenesis in a human xenograft model.
Ye R et al.·J Exp Clin Cancer Res
2017Functional
Molecular Characterization of Membrane Steroid Receptors in Hormone-Sensitive Cancers.
Masi M et al.·Cells
2021Review
RS 2247911 polymorphism of GPRC6A gene and serum undercarboxylated-osteocalcin are associated with testis function.
Jawich K et al.·J Endocrinol Invest
2022
Humanized GPRC6A(KGKY) is a gain-of-function polymorphism in mice.
Pi M et al.·Sci Rep
2020
Broadening the role of osteocalcin in the hypothalamic-pituitary-gonadal axis.
Shan C et al.·J Endocrinol
2021Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools