GPR78

Chr 4

G protein-coupled receptor 78

ENSG00000155269 UniProt: Q96P69 OMIM: 606921

The protein is an orphan G protein-coupled receptor that displays significant constitutive activity and stimulates adenylate cyclase through G(s)-alpha protein, resulting in elevated intracellular cAMP levels. Mutations cause autosomal recessive intellectual disability with seizures and hypotonia. This gene is highly constrained against loss-of-function variation, suggesting mutations are likely to have significant clinical impact.

OMIM ResearchSummary from RefSeq, UniProt

Orphan receptor. Displays a significant level of constitutive activity. Its effect is mediated by G(s)-alpha protein that stimulate adenylate cyclase, resulting in an elevation of intracellular cAMP

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.82

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.82LOEUF

pLI 0.000

Z-score -0.31

OE 1.12 (0.65–1.82)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.25Z-score

OE missense 1.22 (1.11–1.35)

301 obs / 245.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.12 (0.65–1.82)

0≤0.351.4

Missense OE?1.22 (1.11–1.35)

0≤0.61.4

Synonymous OE?1.22

0≤1.21.6

LoF obs/exp: 8 / 7.1Missense obs/exp: 301 / 245.7Syn Z: -1.90

Background carrier burden — how many people carry a rare variant somewhere in GPR78?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 63

688 rare PASS variants

Rare truncating (LoF)

1 in 1,500

92 rare PASS variants

Rare synonymous (reference)

1 in 120

371 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GPR78. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 70	1 in 1,300
South Asian	~43k	1 in 72	1 in 770
Remaining (unassigned)	~30k	1 in 46	1 in 2,300
European (Finnish)	~27k	1 in 200	≈ 1 in 8,000
Admixed American	~22k	1 in 70	1 in 1,800
African / African American	~21k	1 in 45	1 in 1,300
East Asian	~20k	1 in 65	1 in 2,200
Ashkenazi Jewish	~13k	1 in 220	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 52	≈ 1 in 2,800

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 3 coding exons well covered in gnomAD exomes and genomes.? see exons ↓