Is GNB3 p.Leu55fs (c.164_192del) pathogenic?

GNB3 p.Leu55fs (c.164192del) is classified Uncertain significance in GNB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-21). Very rare (popmax 8.62e-05%, nfe).

How common is GNB3 p.Leu55fs (c.164_192del) in the general population?

GNB3 p.Leu55fs (c.164_192del) is very rare (popmax 8.62e-05%, nfe) (gnomAD).

GNB3 p.Leu55fs

c.164_192del · VCV3614694

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.62e-05%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 10
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.62e-05% European (non-Finnish) · 1/1,159,542 alleles

Overall 6.99e-05% 1/1,430,870 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: GNB3
Protein: p.Leu55fs
Coding: c.164_192del
MANE Select: NM_002075
Type: Deletion
Location: chr12:6843035 (GRCh38)
Gene constraint: LOEUF 1.072 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.19 · 2 PDB

Full GNB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GNB3 p.Leu55Val Uncertain significance ★ ⚠ same residue
GNB3 c.699+115del Benign/Likely benign ★★ same type
GNB3 p.Glu38fs Likely pathogenic ★ same type
GNB3 p.Val39fs Likely pathogenic ★ same type
GNB3 c.58-25_60del Uncertain significance ★ same type
GNB3 p.Asn237fs Conflicting classifications of pathogenicity ★ same type
GNB3 p.His183fs Uncertain significance ★ same type
GNB3 p.Leu198fs Uncertain significance ★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/gnb3-p-leu55fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown