GPR161

protein-coding

G protein-coupled receptor 161, the group of G protein-coupled receptors, Class A orphans

Gene summary

The protein encoded by this gene is an orphan G protein-coupled receptor whose ligand is unknown. This gene is overexpressed in triple-negative breast cancer, and disruption of this gene slows the proliferation of basal breast cancer cells. Therefore, this gene is a potential drug target for triple-negative breast cancer. [provided by RefSeq, Mar 2017]

MANE transcript

NM_001375883.1

Inheritance

AD, AR, Ad

ClinVar variants

P:3U:117B:36

Top phenotype

Medulloblastoma predisposition syndrome

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr1:168,079,542-168,137,667

External References & Databases

Ensembl (ENSG00000143147)

Transcript & Mutation Effects

hg38 • Region Span ~58.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

medulloblastomaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007959

Submitter: PanelApp Australia

pituitary stalk interruption syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019828

Submitter: PanelApp Australia

GPR161-related medulloblastoma predispositionSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:1010204

Submitter: ClinGen

GPR161 was first reported in relation to autosomal dominant GPR161-related medulloblastoma predisposition in 2019 (Begemann et al., PMID: 31609649). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities: GPR161-related medulloblastoma predisposition, Pituitary stalk interruption syndrome, Spina bifida. Five variants (missense, in-frame indel, nonsense, frameshift) that have been reported in seven probands in two publications (PMIDs: 31609649, 39184053) are included in this curation. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by experimental evidence including animal and cell culture models, expression studies and biochemical assays (PMIDs: 29386106, 23332756, 38326651). In summary, there is strong evidence supporting the relationship between GPR161 and autosomal dominant GPR161-related medulloblastoma predisposition. Three years must elapse from the first proposal of the assertion to reach a definitive classification without any valid contradictory evidence. We will re-evaluate this gene-disease relationship at that time to determine if an upgraded classification of definitive is warranted. This classification was approved by the ClinGen Childhood, Adolescent, and Young Adult Cancer Predisposition GCEP on the meeting date January 13, 2026 (SOP Version 11).

pituitary stalk interruption syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019828

Submitter: Orphanet

Clinical Genomic Database (CGD)

Medulloblastoma predisposition syndromeAd

Manifestation: Oncologic

Intervention: Oncologic

Rationale: The condition can involve increased risk of medulloblastoma (and possibly other cancer types), and awareness may allow early disease detection and management

Refs: 31609649

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GPR161 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 83

not specifiedTotal: 78

MedulloblastomaTotal: 18

GPR161-related disorderTotal: 1

Predisposition to medulloblastomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001375883.1. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	20 clinvar	12 clinvar	33
missense			108 clinvar	4 clinvar		112
nonsense		1 clinvar	3 clinvar			4
start loss						0
frameshift	1 clinvar	1 clinvar	2 clinvar			4
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	1	2	117	24	12	156

Highest pathogenic variant AF is 0.0000030980855

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 125 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001375883.1	RefSeq	NP_001362812.1	5	MANE Select
ENST00000682931.1	Ensembl	ENSP00000506967.1	5	MANE Select
NM_001267609.1	RefSeq	NP_001254538.1	6	Standard
NM_001267610.2	RefSeq	NP_001254539.1	5	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
gpr161	Danio rerio	Structure: anterior lateral plate mesoderm Quality: morphology abnormal

Gene / Model

Organism

Observed Phenotype

gpr161

Danio rerio

Structure: anterior lateral plate mesoderm

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Hedgehog signaling pathway - Homo sapiens (human)
Hedgehog Signaling Pathway
GPCRs, Class A Rhodopsin-like
Signal Transduction
Hedgehog ,off, state

Biological Process

adenylate cyclase-activating G protein-coupled receptor signaling pathway
multicellular organism development
negative regulation of smoothened signaling pathway involved in dorsal/ventral neural tube patterning

Molecular Function

G protein-coupled receptor activity

Cellular Component

cilium
integral component of membrane
endocytic vesicle membrane
recycling endosome
ciliary membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000537209
Coding exons: 6
Length: 52825
Individuals with no LoFs: 125693
Homozygous LoFs: 0
Heterozygous LoFs: 55
Defined: 125748
p: 0.000219

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.51	254	332	0.766	0.0000196	3568
Missense (PolyPhen)		71	109.12	0.65066		1177
Synonymous	-1.54	161	138	1.17	0.00000858	1146
Loss of Function	2.28	9	20.0	0.450	0.00000104	212

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00038	0.00029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00029	0.00029	rare
South Asian	0.00026	0.00026	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Key negative regulator of Shh signaling, which promotes the processing of GLI3 into GLI3R during neural tube development. Recruited by TULP3 and the IFT-A complex to primary cilia and acts as a regulator of the PKA-dependent basal repression machinery in Shh signaling by increasing cAMP levels, leading to promote the PKA-dependent processing of GLI3 into GLI3R and repress the Shh signaling. In presence of SHH, it is removed from primary cilia and is internalized into recycling endosomes, preventing its activity and allowing activation of the Shh signaling. Its ligand is unknown (By similarity). {ECO:0000250}.;

Recessive Scores

pRec: 0.154

Intolerance Scores

LoFtool: 0.584
RVIS EVS: -0.8
RVIS percentile EVS: 12.33

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: N
Indispensability score: 0.0652

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium