RGS14

Chr 5

regulator of G protein signaling 14

NCBI Gene: 10636 ENSG00000169220 UniProt: O43566

This protein regulates G protein-coupled receptor signaling by acting as a GTPase activating protein and GDP-dissociation inhibitor, terminating G protein signals and modulating cellular processes including neurite outgrowth and learning/memory. Mutations cause autosomal recessive spinocerebellar ataxia with developmental delay and intellectual disability, typically presenting in childhood. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.58), affecting primarily neurological and cerebellar systems.

ResearchSummary from RefSeq, UniProt

This gene encodes a member of the regulator of G-protein signaling family. This protein contains one RGS domain, two Raf-like Ras-binding domains (RBDs), and one GoLoco domain. The protein attenuates the signaling activity of G-proteins by binding, through its GoLoco domain, to specific types of activated, GTP-bound G alpha subunits. Acting as a GTPase activating protein (GAP), the protein increases the rate of conversion of the GTP to GDP. This hydrolysis allows the G alpha subunits to bind G beta/gamma subunit heterodimers, forming inactive G-protein heterotrimers, thereby terminating the signal. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.58

Clinical Summary— RGS14

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.

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ClinVar Variants

66 VUS of 88 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.58LOEUF

pLI 0.002

Z-score 3.32

OE 0.34 (0.21–0.58)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.54Z-score

OE missense 0.92 (0.83–1.01)

309 obs / 337.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.34 (0.21–0.58)

0≤0.351.4

Missense OE?0.92 (0.83–1.01)

0≤0.61.4

Synonymous OE?0.79

0≤1.21.6

LoF obs/exp: 10 / 29.4Missense obs/exp: 309 / 337.1Syn Z: 2.06

This gene — mechanism propensity

0.6937th %ile

GOF

0.73top 25%

LOF

0.3550th %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

88 submitted variants in ClinVar

ClinVar

Classification Summary

VUS66

Likely Benign5

Benign2

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	66	0	66
Likely Benign	5	0	5
Benign	1	1	2
Total	72	1	73

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

View in ClinVar →

59 pathogenic / likely-pathogenic (of 71) ClinVar copy-number / structural variants overlap RGS14 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →