GNG4

Chr 1

G protein subunit gamma 4

Also known as: HG3C

NCBI Gene: 2786 ENSG00000168243 UniProt: P50150 OMIM: 604388

The GNG4 protein is the gamma-4 subunit of heterotrimeric G proteins, which are essential for transmembrane signaling by modulating GTPase activity and enabling G protein-effector interactions. Mutations cause autosomal recessive neurodevelopmental disorders with intellectual disability, seizures, and growth abnormalities. This gene has relatively low constraint against loss-of-function variants and is covered in GeneReviews, indicating established clinical significance.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable G-protein beta-subunit binding activity. Involved in negative regulation of cell growth. Located in extracellular exosome. [provided by Alliance of Genome Resources, Jul 2025]

GeneReviews OMIM ResearchGenerating clinical summary…

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

1.71

LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — GNG4

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.71LOEUF

pLI 0.156

Z-score 0.72

OE 0.47 (0.16–1.71)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.68Z-score

OE missense 0.72 (0.54–0.96)

32 obs / 44.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.47 (0.16–1.71)

0≤0.351.4

Missense OE?0.72 (0.54–0.96)

0≤0.61.4

Synonymous OE?0.59

0≤1.21.6

LoF obs/exp: 1 / 2.1Missense obs/exp: 32 / 44.7Syn Z: 1.26

Background carrier burden — how many people carry a rare variant somewhere in GNG4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 510

100 rare PASS variants

Rare truncating (LoF)

1 in 13,000

14 rare PASS variants

Rare synonymous (reference)

1 in 1,600

31 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GNG4. 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 450	1 in 10,000
South Asian	~43k	1 in 1,400	none seen
Remaining (unassigned)	~30k	1 in 590	≈ 1 in 15,000
European (Finnish)	~27k	1 in 4,500	none seen
Admixed American	~22k	1 in 510	none seen
African / African American	~21k	1 in 770	≈ 1 in 5,600
East Asian	~20k	1 in 1,000	≈ 1 in 9,900
Ashkenazi Jewish	~13k	1 in 1,500	none seen
Middle Eastern	~2,884	≈ 1 in 1,400	none seen

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 2 coding exons well covered in gnomAD exomes and genomes.? see exons ↓