GPR137B

Chr 1

G protein-coupled receptor 137B

Also known as: TM7SF1

NCBI Gene: 7107 ENSG00000077585 UniProt: O60478 OMIM: 604658

GPR137B encodes a lysosomal integral membrane protein that regulates mTORC1 signaling complex localization and activity by interacting with Rag GTPases, and controls lysosomal morphology and autophagy. Mutations cause autosomal recessive developmental delays and seizures. This gene shows minimal constraint against loss-of-function variants based on population data.

OMIM ResearchSummary from RefSeq, UniProt

Involved in positive regulation of TORC1 signaling; positive regulation of protein localization to lysosome; and regulation of autophagy. Located in lysosomal membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.32

Clinical Summary— GPR137B

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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

56 VUS of 61 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.32LOEUF

pLI 0.000

Z-score 0.46

OE 0.89 (0.61–1.32)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.24Z-score

OE missense 1.05 (0.94–1.17)

229 obs / 219.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.89 (0.61–1.32)

0≤0.351.4

Missense OE?1.05 (0.94–1.17)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 18 / 20.2Missense obs/exp: 229 / 219.0Syn Z: 0.22

This gene — mechanism propensity

0.7228th %ile

GOF

0.73top 25%

LOF

0.3939th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction 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

61 submitted variants in ClinVar

ClinVar

Classification Summary

VUS56

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	56	56
Likely Benign	0	0
Benign	0	0
Total	56	56

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

View in ClinVar →

50 pathogenic / likely-pathogenic (of 64) ClinVar copy-number / structural variants overlap GPR137B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →