Is GNB3 p.Phe335Leu (c.1005C>A) pathogenic?

GNB3 p.Phe335Leu (c.1005C>A) is classified Uncertain significance in GNB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-17). AlphaMissense: likely pathogenic (0.9604); Absent from gnomAD v4.1.

How common is GNB3 p.Phe335Leu (c.1005C>A) in the general population?

GNB3 p.Phe335Leu (c.1005C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GNB3 p.Phe335Leu (c.1005C>A)?

AlphaMissense predicts likely pathogenic (score 0.9604) — an in-silico prediction, not a clinical call.

GNB3 p.Phe335Leu

c.1005C>A · rs782320266 · VCV2850275

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9604 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9604	likely pathogenic
REVEL	0.291	indeterminate
SaProt	LLR -8.66	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 3.3	GERP 1.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 5,607 bp · p 0.03 · regional, not allelic
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GNB3
Protein: p.Phe335Leu
Coding: c.1005C>A
MANE Select: NM_031299 · reported on NM_002075
dbSNP: rs782320266
Type: single nucleotide variant
Location: chr12:6846880 (GRCh38)

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

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-phe335leu (accessed [today's date]).

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