GPR161

Chr 1q24.2

G protein-coupled receptor 161

Aliases:: RE2
MANE:: ENST00000682931.1

OMIM: 612250 ↗NCBI: 23432 ↗Ensembl ↗

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Predicted protein structure

AlphaFold predicted structure

GPR161 · Q8N6U8

v62025-08-01

Predicted Aligned Error matrix for GPR161 — diagonal shows residue index, colour shows pairwise prediction confidence (lower is better) — Predicted Aligned Error

Mean pLDDT

68.6/ 100

Low

529 residues

Confidence breakdown

Very high(≥ 90)32%
Confident(70–90)21%
Low(50–70)17%
Very low(< 50)30%

Open interactive 3D viewer

AlphaFold (Jumper et al., 2021) · CC BY 4.0

Clinical relevance (Genomics England PanelApp)

Diagnostic Grade (Green)

Childhood solid tumours
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Childhood solid tumours cancer susceptibility
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Embryonal tumour of possible germline origin
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
IUGR and IGF abnormalities
BIALLELIC, autosomal or pseudoautosomal
Monogenic short stature
BIALLELIC, autosomal or pseudoautosomal
Pituitary hormone deficiency
BIALLELIC, autosomal or pseudoautosomal

Disease associations (Open Targets)

medulloblastoma
0.64
pituitary stalk interruption syndrome
0.44
prostatitis
0.25
early-onset non-syndromic cataract
0.08
Prata-Liberal-Goncalves syndrome
0.08
Posterior polar cataract
0.08
early-onset zonular cataract
0.07
Total congenital cataract
0.07
retinitis pigmentosa
0.07
neural tube defects, folate-sensitive
0.07

Score is the Open Targets composite evidence score (0-1). Higher = stronger gene-disease association.

Protein function (UniProt)

G protein-coupled receptor 161

G protein-coupled receptor that acts as a key inhibitor of the smoothened signaling pathway in primary cilia (PubMed:38326651). Inhibits the smoothened signaling pathway in absence of hedgehog (DHH, IHH or SHH) by promoting formation of the transcription repressor form of GLI2 and GLI3 transcription factors (PubMed:38326651). GPR161 activation triggers signaling via guanine nucleotide-binding protein G(s)/GNAS, mediating activation of adenylate cyclase activity and production of cAMP (PubMed:38326651). Increased cAMP levels activate PKA, promoting PKA-dependent processing of GLI2 and GLI3 transcription factors, leading to formation of transcription repressor GLI2R and GLI3R, which repress expression of target genes (PubMed:38326651). GPR161 also activates PKA by acting as a PKA-anchoring protein, which directly associates with type I PKA regulatory subunits (PRKAR1A and/or PRKAR1B), recruiting PKA followed by PKA-dependent processing of GLI2 and GLI3 transcription factors (PubMed:38326651). In presence of hedgehog, GPR161 is removed from primary cilia by smoothened (SMO), preventing its activity and allowing activation of the smoothened signaling (By similarity). In contrast to the majority of G protein-coupled receptors, it is not activated by a ligand and it either acts as a constitutively active receptor or as a mechanosensitive receptor (PubMed:38326651). Involved in regulation of the smoothened signaling pathway during early neural tube development, forelimb formation, skeletal development, embryonic cerebellar development and forebrain development (By similarity). Involved in the saltatory migration of neurons during brain development by acting as a mechanosensitive receptor that senses mechanical forces generated by fluid shear stress (By similarity)