GNB4

Chr 3AD

G protein subunit beta 4

Also known as: CMTD1F, HG2B

NCBI Gene: 59345ENSG00000114450UniProt: Q9HAV0

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]

Primary Disease Associations & Inheritance

Charcot-Marie-Tooth disease, dominant intermediate FMIM #615185
AD
350
ClinVar variants
33
Pathogenic / LP
0.00
pLI score
1
Active trials
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
33 Pathogenic / Likely Pathogenic· 147 VUS of 350 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.70LOEUF
pLI 0.002
Z-score 2.58
OE 0.39 (0.23–0.70)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.39 (0.23–0.70)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.57 (0.49–0.67)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.89
0≤1.21.6
LoF obs/exp: 8 / 20.7Missense obs/exp: 112 / 194.9Syn Z: 0.70

ClinVar Variant Classifications

350 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic25
Likely Pathogenic8
VUS147
Likely Benign131
Benign29
Conflicting10
25
Pathogenic
8
Likely Pathogenic
147
VUS
131
Likely Benign
29
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
2
23
0
25
Likely Pathogenic
0
4
4
0
8
VUS
10
105
28
4
147
Likely Benign
0
9
62
60
131
Benign
0
0
26
3
29
Conflicting
—10
Total1012014367350

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

View in ClinVar →

Protein Context — Lollipop Plot

GNB4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Charcot-Marie-Tooth disease, dominant intermediate F

MIM #615185

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — GNB4
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Helicobacter pylori-induced aberrant demethylation and expression of GNB4 promotes gastric carcinogenesis via the Hippo-YAP1 pathway.
Liu D et al.·BMC Med
2023
Prognostic and Immunological Value of GNB4 in Gastric Cancer by Analyzing TCGA Database.
Liu B et al.·Dis Markers
2022
Recent advances in Charcot-Marie-Tooth disease.
Baets J et al.·Curr Opin Neurol
2014Review
Plasma methylated GNB4 and Riplet as a novel dual-marker panel for the detection of hepatocellular carcinoma.
Zhao Y et al.·Epigenetics
2024
Biopsy proteome-based classification of T cell-mediated kidney allograft rejection.
Kania D et al.·J Transl Med
2025
A novel missense variant (Gln220Arg) of GNB4 encoding guanine nucleotide-binding protein, subunit beta-4 in a Japanese family with autosomal dominant motor and sensory neuropathy.
Miura S et al.·Eur J Med Genet
2017Case report
Identification of Crucial Genes and Diagnostic Value Analysis in Major Depressive Disorder Using Bioinformatics Analysis.
Gao Y et al.·Comb Chem High Throughput Screen
2022
MiR-133b Modulates the Osteoblast Differentiation to Prevent Osteoporosis Via Targeting GNB4.
Wang J et al.·Biochem Genet
2021
Analytical and Diagnostic Performance of a Dual-Target Blood Detection Test for Hepatocellular Carcinoma.
Yang Q et al.·Cancer Rep (Hoboken)
2024
Association of GNB4 intron-1 haplotypes with survival in patients with UICC stage III and IV colorectal carcinoma.
Riemann K et al.·Anticancer Res
2009Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
HCCMinimal Residual DiseaseRecurrence

Predictive Value of Minimal Residual Disease for Postoperative Recurrence and Adjuvant PD-1 Inhibitor in HCC

NOT YET RECRUITING
NCT07350824Phase NATongji HospitalStarted 2025-12-31
Adjuvant PD-1 inhibitorsActive monitoring

External Resources

Links to major genomics databases and tools