Is GBA2 p.Leu577= (c.1731G>C) pathogenic?

GBA2 p.Leu577= (c.1731G>C) is classified Likely benign in GBA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-29). Absent from gnomAD v4.1; Associated with Spastic paraplegia.

What condition is associated with GBA2 p.Leu577= (c.1731G>C)?

GBA2 p.Leu577= (c.1731G>C) is associated with Spastic paraplegia (ClinVar).

How common is GBA2 p.Leu577= (c.1731G>C) in the general population?

GBA2 p.Leu577= (c.1731G>C) is absent from gnomAD v4.1 (gnomAD).

GBA2 p.Leu577=

c.1731G>C · rs1588008179 · VCV764382

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.12	GERP -1.6, phastCons 0.93
Overall
CADD	7.525	PHRED · no single calibrated threshold — expert panels disagree

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: GBA2
Protein: p.Leu577=
Coding: c.1731G>C
MANE Select: NM_020944
dbSNP: rs1588008179
Type: single nucleotide variant
Location: chr9:35739066 (GRCh38)
Gene constraint: LOEUF 0.773 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.77
Residue 577: a UniProt-annotated variant site (in spg46; loss of glucosylceramide catabolic process)

Full GBA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Spastic paraplegia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GBA2 p.Arg234Ter Pathogenic ★★ same condition
GBA2 p.Arg340Ter Pathogenic ★★ same condition
GBA2 p.Arg574Ter Pathogenic ★★ same condition
GBA2 p.Ala187Thr Uncertain significance ★★ ⚠ same condition
GBA2 p.Arg215His Uncertain significance ★★ ⚠ same condition
GBA2 p.Arg514Cys Uncertain significance ★★ ⚠ same condition
GBA2 p.Arg575Gln Uncertain significance ★★ ⚠ same condition
GBA2 p.Arg575Trp 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/gba2-p-leu577 (accessed [today's date]).

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