Is GNB5 p.Ser376Phe (c.1127C>T) pathogenic?

GNB5 p.Ser376Phe (c.1127C>T) is classified Uncertain significance in GNB5 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-06). AlphaMissense: likely pathogenic (0.9928); Absent from gnomAD v4.1.

How common is GNB5 p.Ser376Phe (c.1127C>T) in the general population?

GNB5 p.Ser376Phe (c.1127C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GNB5 p.Ser376Phe (c.1127C>T)?

AlphaMissense predicts likely pathogenic (score 0.9928) — an in-silico prediction, not a clinical call.

GNB5 p.Ser376Phe

c.1127C>T · rs2141181411 · VCV1310997

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9928 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9928	likely pathogenic
REVEL	0.731	pathogenic-leaning
SaProt	LLR -12.59	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 62 kb · p 0.083 · regional, not allelic
Overall
CADD	29.0	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

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: GNB5
Protein: p.Ser376Phe
Coding: c.1127C>T
MANE Select: NM_016194
dbSNP: rs2141181411
Type: single nucleotide variant
Location: chr15:52124522 (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-ser376phe (accessed [today's date]).

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