Is GNB5 p.His366Arg (c.1097A>G) pathogenic?

GNB5 p.His366Arg (c.1097A>G) is classified Uncertain significance in GNB5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-09). AlphaMissense: likely pathogenic (0.9984); Very rare (popmax 8.48e-05%, nfe).

How common is GNB5 p.His366Arg (c.1097A>G) in the general population?

GNB5 p.His366Arg (c.1097A>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about GNB5 p.His366Arg (c.1097A>G)?

AlphaMissense predicts likely pathogenic (score 0.9984) — an in-silico prediction, not a clinical call.

GNB5 p.His366Arg

c.1097A>G · VCV4078803

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9984 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9984	likely pathogenic · top 10% in GNB5
REVEL	0.851	moderately pathogenic-leaning
SaProt	LLR -14.20	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 62 kb · p 0.083 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,662 alleles

Overall 6.2e-05% 1/1,613,840 alleles · very rare exomes 1/1,461,464 · genomes 0/152,376 · joint denominator

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: GNB5
Protein: p.His366Arg
Coding: c.1097A>G
MANE Select: NM_016194
Type: single nucleotide variant
Location: chr15:52124552 (GRCh38)
Gene constraint: LOEUF 1.155 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.92 · 37 PDB

Full GNB5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GNB5 p.Arg288Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
GNB5 p.Ser123Leu Pathogenic ★★ same type
GNB5 p.Ser123Trp Likely pathogenic ★★ same type
GNB5 p.Tyr344Ter Pathogenic ★★ same type
GNB5 p.Ala142Thr Uncertain significance ★★ ⚠ same type
GNB5 p.Arg98Gly Uncertain significance ★★ ⚠ same type
GNB5 p.Asn252Ser Uncertain significance ★★ ⚠ same type
GNB5 p.Asn345Ser 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/gnb5-p-his366arg (accessed [today's date]).

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