RGS4

Chr 1

regulator of G protein signaling 4

Also known as: RGP4, SCZD9

NCBI Gene: 5999 ENSG00000117152 UniProt: P49798 OMIM: 602516

RGS4 encodes a regulator of G protein signaling that inhibits signal transduction by increasing GTPase activity of G protein alpha subunits, driving them into their inactive GDP-bound form. Mutations cause autosomal dominant developmental and epileptic encephalopathy with onset in infancy, characterized by severe seizures, developmental delay, and intellectual disability. This gene shows extremely high constraint against loss-of-function variants (pLI near 1), indicating it is essential for normal cellular function.

OMIM ResearchSummary from RefSeq, UniProt

Regulator of G protein signaling (RGS) family members are regulatory molecules that act as GTPase activating proteins (GAPs) for G alpha subunits of heterotrimeric G proteins. RGS proteins are able to deactivate G protein subunits of the Gi alpha, Go alpha and Gq alpha subtypes. They drive G proteins into their inactive GDP-bound forms. Regulator of G protein signaling 4 belongs to this family. All RGS proteins share a conserved 120-amino acid sequence termed the RGS domain. Regulator of G protein signaling 4 protein is 37% identical to RGS1 and 97% identical to rat Rgs4. This protein negatively regulate signaling upstream or at the level of the heterotrimeric G protein and is localized in the cytoplasm. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.44

Clinical Summary— RGS4

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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

37 VUS of 42 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?

1.44LOEUF

pLI 0.000

Z-score 0.37

OE 0.89 (0.57–1.44)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.12Z-score

OE missense 0.97 (0.85–1.11)

151 obs / 155.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.89 (0.57–1.44)

0≤0.351.4

Missense OE?0.97 (0.85–1.11)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 12 / 13.5Missense obs/exp: 151 / 155.2Syn Z: -0.09

This gene — mechanism propensity

0.6647th %ile

GOF

0.6736th %ile

LOF

0.3356th %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

42 submitted variants in ClinVar

ClinVar

Classification Summary

VUS37

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	37	37
Likely Benign	1	1
Benign	0	0
Total	38	38

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

View in ClinVar →

15 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap RGS4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →