GPR161

Chr 1ADARSomatic

G protein-coupled receptor 161

Also known as: RE2

NCBI Gene: 23432 ENSG00000143147 UniProt: Q8N6U8 OMIM: 612250

GPR161 encodes an orphan G protein-coupled receptor that serves as a key negative regulator of Sonic hedgehog (Shh) signaling by promoting GLI3 processing during neural tube development. Mutations cause hepatorenocardiac degenerative fibrosis with autosomal recessive inheritance and medulloblastoma predisposition syndrome with autosomal dominant inheritance. The gene is extremely tolerant to loss-of-function variants in the general population (LOEUF 0.786), suggesting different pathogenic mechanisms may underlie these distinct clinical presentations.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/AR/SomaticLOEUF 0.798 OMIM phenotypes

Clinical Summary— GPR161

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 118 VUS of 185 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GPR161

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?

0.79LOEUF

pLI 0.000

Z-score 2.28

OE 0.45 (0.27–0.79)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.51Z-score

OE missense 0.77 (0.69–0.85)

254 obs / 331.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.45 (0.27–0.79)

0≤0.351.4

Missense OE?0.77 (0.69–0.85)

0≤0.61.4

Synonymous OE?1.17

0≤1.21.6

LoF obs/exp: 9 / 20.0Missense obs/exp: 254 / 331.6Syn Z: -1.54

This gene — mechanism propensity

0.75top 25%

GOF

0.80top 10%

LOF

0.3357th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports dominant-negative. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

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.

Literature Evidence

DNDominant negative GPR161 rare variants are risk factors of human spina bifida.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 30256984 ↗

ClinVar Variant Classifications

185 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic1

VUS118

Likely Benign28

Benign19

Conflicting2

Pathogenic

Likely Pathogenic

118

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	0	0	1
Likely Pathogenic	1	0	0	0	1
VUS	7	109	2	0	118
Likely Benign	0	3	4	21	28
Benign	1	2	2	14	19
Conflicting	—				2
Total	10	114	8	35	169

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

View in ClinVar →

19 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap GPR161 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →