Is GNB5 p.Lys115Thr (c.344A>C) pathogenic?

GNB5 p.Lys115Thr (c.344A>C) is classified Uncertain significance in GNB5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-25). AlphaMissense: likely benign (0.2292); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with GNB5 p.Lys115Thr (c.344A>C)?

GNB5 p.Lys115Thr (c.344A>C) is associated with Inborn genetic diseases (ClinVar).

How common is GNB5 p.Lys115Thr (c.344A>C) in the general population?

GNB5 p.Lys115Thr (c.344A>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about GNB5 p.Lys115Thr (c.344A>C)?

AlphaMissense predicts likely benign (score 0.2292) — an in-silico prediction, not a clinical call.

GNB5 p.Lys115Thr

c.344A>C · VCV4264648

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2292 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2292	likely benign
REVEL	0.264	benign-leaning
SaProt	LLR -6.45	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP -0.66, phastCons 0.97
Regional constraint	o/e 0.92	unconstrained · MANE · 62 kb · p 0.083 · regional, not allelic
Overall
CADD	18.53	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00167% Admixed American · 1/60,022 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,624 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,022
European (non-Finnish)	0.00017%	589,929

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.Lys115Thr
Coding: c.344A>C
MANE Select: NM_016194
Type: single nucleotide variant
Location: chr15:52153971 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GNB5 p.Lys115Glu Uncertain significance ★ ⚠ same residue
GNB5 p.Ala142Thr Uncertain significance ★★ ⚠ same condition
GNB5 p.Asn345Ser Uncertain significance ★★ ⚠ same condition
GNB5 p.Phe364Leu Uncertain significance ★★ ⚠ same condition
GNB5 p.Ser292Thr Uncertain significance ★★ ⚠ same condition
GNB5 p.Val274Met Uncertain significance ★★ ⚠ same condition
GNB5 p.Val370Ile Uncertain significance ★★ ⚠ same condition
GNB5 p.Trp222Ter Pathogenic ★ same condition

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-lys115thr (accessed [today's date]).

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