Is GNB3 p.Phe180fs (c.536dup) pathogenic?

GNB3 p.Phe180fs (c.536dup) is classified Uncertain significance in GNB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-16). Very rare (popmax 0.00445%, eas).

How common is GNB3 p.Phe180fs (c.536dup) in the general population?

GNB3 p.Phe180fs (c.536dup) is very rare (popmax 0.00445%, eas) (gnomAD).

GNB3 p.Phe180fs

c.536dup · rs1565518931 · VCV1377674

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 0.00445%, eas)

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 8 of 10
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 8.6	GERP 1.5, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00445% East Asian · 2/44,902 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000124% 2/1,614,054 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.Phe180fs
Coding: c.536dup
MANE Select: NM_002075
dbSNP: rs1565518931
Type: Duplication
Location: chr12:6843814 (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 c.203+16dup Likely benign ★★ same type
GNB3 c.699+140_699+141dup Likely benign ★ same type
GNB3 c.699+141dup Benign ★ same type
GNB3 c.699+15dup Benign ★ same type
GNB3 c.96+11dup Benign ★ 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-phe180fs (accessed [today's date]).

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