GNB4

Chr 3AD

G protein subunit beta 4

Also known as: CMTD1F, HG2B

NCBI Gene: 59345 ENSG00000114450 UniProt: Q9HAV0 OMIM: 610863

The GNB4 protein is a beta subunit of heterotrimeric G proteins that regulates G protein alpha subunits and enables G protein-effector interactions in transmembrane signaling pathways. Mutations cause Charcot-Marie-Tooth disease, dominant intermediate F, which follows autosomal dominant inheritance. This gene is moderately constrained against loss-of-function variants (LOEUF 0.698), and the condition primarily affects the peripheral nervous system.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

Heterotrimeric guanine nucleotide-binding proteins (G proteins), which integrate signals between receptors and effector proteins, are composed of an alpha, a beta, and a gamma subunit. These subunits are encoded by families of related genes. This gene encodes a beta subunit. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismADLOEUF 0.701 OMIM phenotype

Clinical Summary— GNB4

🧬

Gene-Disease Validity (ClinGen)

Charcot-Marie-Tooth disease · ADModerate

Moderate evidence — consider for supplementary testing

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 144 VUS of 335 total submissions

💊

Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — GNB4

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?

0.70LOEUF

pLI 0.002

Z-score 2.58

OE 0.39 (0.23–0.70)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.11Z-score

OE missense 0.57 (0.49–0.67)

112 obs / 194.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.39 (0.23–0.70)

0≤0.351.4

Missense OE?0.57 (0.49–0.67)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 8 / 20.7Missense obs/exp: 112 / 194.9Syn Z: 0.70

This gene — mechanism propensity

0.6647th %ile

GOF

0.5366th %ile

LOF

0.4232th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median · 1 literature citation

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.

Literature Evidence

DNOur functional studies have shown that both the p.Gly53Asp and p.Lys89Glu GÎ²4 alterations impair GPCR signaling pathways via a dominant-negative effect.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 23434117 ↗

ClinVar Variant Classifications

335 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic4

VUS144

Likely Benign129

Benign29

Conflicting10

Pathogenic

Likely Pathogenic

144

VUS

129

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	2	0	0	2
Likely Pathogenic	0	4	0	0	4
VUS	18	107	15	4	144
Likely Benign	0	9	60	60	129
Benign	0	0	26	3	29
Conflicting	—				10
Total	18	122	101	67	318

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

View in ClinVar →

27 pathogenic / likely-pathogenic (of 34) ClinVar copy-number / structural variants overlap GNB4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →