Is GUSB p.Glu646Gly (c.1937A>G) pathogenic?

GUSB p.Glu646Gly (c.1937A>G) is classified Likely benign in GUSB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-04). AlphaMissense: likely benign (0.0629); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with GUSB p.Glu646Gly (c.1937A>G)?

GUSB p.Glu646Gly (c.1937A>G) is associated with Inborn genetic diseases (ClinVar).

How common is GUSB p.Glu646Gly (c.1937A>G) in the general population?

GUSB p.Glu646Gly (c.1937A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GUSB p.Glu646Gly (c.1937A>G)?

AlphaMissense predicts likely benign (score 0.0629) — an in-silico prediction, not a clinical call.

GUSB p.Glu646Gly

c.1937A>G · VCV3523457

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0629 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0629	likely benign
REVEL	0.254	benign-leaning
SaProt	LLR -6.14	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 -0.055	GERP -3.3
Regional constraint	o/e 0.75	unconstrained · MANE · 15 kb · p 3.7e-08 · regional, not allelic
Overall
CADD	0.42	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: GUSB
Protein: p.Glu646Gly
Coding: c.1937A>G
MANE Select: NM_000181
Type: single nucleotide variant
Location: chr7:65960916 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.35 · 2 PDB

Full GUSB 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

GUSB p.Ala380Thr Uncertain significance ★★ ⚠ same condition
GUSB p.Arg116His Uncertain significance ★★ ⚠ same condition
GUSB p.Arg57Gly Uncertain significance ★★ ⚠ same condition
GUSB p.Asn254His Uncertain significance ★★ ⚠ same condition
GUSB p.His509Gln Uncertain significance ★★ ⚠ same condition
GUSB p.Lys606Glu Uncertain significance ★★ ⚠ same condition
GUSB p.Pro178Thr Uncertain significance ★★ ⚠ same condition
GUSB p.Thr232Ala Uncertain significance ★★ ⚠ 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/gusb-p-glu646gly (accessed [today's date]).

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