RGS5

Chr 1Multi

regulator of G protein signaling 5

Also known as: MST092, MST106, MST129, MSTP032, MSTP092, MSTP106, MSTP129

NCBI Gene: 8490 ENSG00000143248 UniProt: O15539 OMIM: 603276

The protein inhibits G-protein signaling by increasing GTPase activity of G protein alpha subunits, driving them into their inactive GDP-bound form. Mutations are associated with blood pressure regulation as a quantitative trait locus with multifactorial inheritance. The gene shows low constraint to loss-of-function variation (pLI 0.0005, LOEUF 1.345).

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This locus represents naturally occurring readthrough transcription between the neighboring LOC127814295 (uncharacterized LOC127814295) and RGS5 (regulator of G-protein signaling 5) genes on chromosome 1. Some variants of the readthrough transcript encode novel proteins with unique N-termini. [provided by RefSeq, Nov 2022]

OMIM ResearchGenerating clinical summary…

MultiplemechanismMultiLOEUF 1.341 OMIM phenotype

Clinical Summary— RGS5

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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

22 VUS of 27 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.34LOEUF

pLI 0.001

Z-score 0.87

OE 0.68 (0.37–1.34)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.15Z-score

OE missense 0.96 (0.81–1.14)

91 obs / 95.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.68 (0.37–1.34)

0≤0.351.4

Missense OE?0.96 (0.81–1.14)

0≤0.61.4

Synonymous OE?0.69

0≤1.21.6

LoF obs/exp: 6 / 8.8Missense obs/exp: 91 / 95.1Syn Z: 1.46

This gene — mechanism propensity

0.7227th %ile

GOF

0.73top 25%

LOF

0.2190th %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

27 submitted variants in ClinVar

ClinVar

Classification Summary

VUS22

Benign1

VUS

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	22	0	22
Likely Benign	0	0	0
Benign	0	1	1
Total	22	1	23

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 18) ClinVar copy-number / structural variants overlap RGS5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →