RGS12

Chr 4

regulator of G protein signaling 12

NCBI Gene: 6002 ENSG00000159788 UniProt: O14924 OMIM: 602512

The protein regulates G protein-coupled receptor signaling by increasing GTPase activity of G protein alpha subunits, driving them into their inactive GDP-bound form. Mutations cause autosomal dominant polymicrogyria with seizures and intellectual disability. This gene is highly constrained against loss-of-function variants (LOEUF 0.606), suggesting complete loss of function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the 'regulator of G protein signaling' (RGS) gene family. The encoded protein may function as a guanosine triphosphatase (GTPase)-activating protein as well as a transcriptional repressor. This protein may play a role in tumorigenesis. Multiple transcript variants encoding distinct isoforms have been identified for this gene. Other alternative splice variants have been described but their biological nature has not been determined. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.61

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.61LOEUF

pLI 0.000

Z-score 3.94

OE 0.43 (0.31–0.61)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.61Z-score

OE missense 0.94 (0.89–1.00)

873 obs / 925.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.43 (0.31–0.61)

0≤0.351.4

Missense OE?0.94 (0.89–1.00)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 24 / 55.7Missense obs/exp: 873 / 925.6Syn Z: -1.39

Background carrier burden — how many people carry a rare variant somewhere in RGS12?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 25

1,988 rare PASS variants

Rare truncating (LoF)

1 in 250

194 rare PASS variants

Rare synonymous (reference)

1 in 32

885 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RGS12. 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 35	1 in 200
South Asian	~43k	1 in 21	1 in 460
Remaining (unassigned)	~30k	1 in 22	1 in 270
European (Finnish)	~27k	1 in 58	1 in 520
Admixed American	~22k	1 in 22	1 in 180
African / African American	~21k	1 in 22	1 in 380
East Asian	~20k	1 in 23	1 in 660
Ashkenazi Jewish	~13k	1 in 170	1 in 580
Middle Eastern	~2,884	1 in 24	≈ 1 in 2,900

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): 15 of 17 coding exons well covered in gnomAD exomes; exons 3, 4 marginal. Genomes: 16 of 17 (exon 14 below).? see exons ↓