Is GBA2 p.Arg728= (c.2182A>C) pathogenic?

GBA2 p.Arg728= (c.2182A>C) is classified Likely benign in GBA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-12). Very rare (popmax 0.000508%, nfe); Associated with Spastic paraplegia.

What condition is associated with GBA2 p.Arg728= (c.2182A>C)?

GBA2 p.Arg728= (c.2182A>C) is associated with Spastic paraplegia (ClinVar).

How common is GBA2 p.Arg728= (c.2182A>C) in the general population?

GBA2 p.Arg728= (c.2182A>C) is very rare (popmax 0.000508%, nfe) (gnomAD).

GBA2 p.Arg728=

c.2182A>C · rs753292162 · VCV2067102

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Conditions

Spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.087	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 1.6, phastCons 1
Overall
CADD	9.504	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000508% European (non-Finnish) · 6/1,180,030 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,614,170 alleles · very rare exomes 6/1,461,882 · genomes 0/152,288 · 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: GBA2
Protein: p.Arg728=
Coding: c.2182A>C
MANE Select: NM_020944
dbSNP: rs753292162
Type: single nucleotide variant
Location: chr9:35738247 (GRCh38)
Gene constraint: LOEUF 0.773 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.77
Residue 728: 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-arg728 (accessed [today's date]).

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