Is GBA2 p.Val809Ile (c.2425G>A) pathogenic?

GBA2 p.Val809Ile (c.2425G>A) is classified Conflicting classifications of pathogenicity in GBA2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-04-10). AlphaMissense: likely benign (0.0648); Ultra-rare (popmax 0.0493%, mid); Associated with Spastic paraplegia.

What condition is associated with GBA2 p.Val809Ile (c.2425G>A)?

GBA2 p.Val809Ile (c.2425G>A) is associated with Spastic paraplegia (ClinVar).

How common is GBA2 p.Val809Ile (c.2425G>A) in the general population?

GBA2 p.Val809Ile (c.2425G>A) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

What do computational predictors say about GBA2 p.Val809Ile (c.2425G>A)?

AlphaMissense predicts likely benign (score 0.0648) — an in-silico prediction, not a clinical call.

GBA2 p.Val809Ile

c.2425G>A · rs778985234 · VCV652063

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0648 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.0648	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -7.72	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 1.8	GERP 0.7, phastCons 0.94
Regional constraint	o/e 0.88	unconstrained · MANE · 12 kb · p 2e-05 · regional, not allelic
Overall
CADD	17.44	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

Grpmax group 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00715%

Overall 0.00843% 136/1,613,800 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0675%	1,480
Middle Easterngrpmax	0.0493%	2,028
Admixed American	0.01%	10,000
Remaining individualsnot grpmax-eligible	0.0096%	10,413
European (non-Finnish)	0.00822%	12,164
South Asian	0.00439%	22,766

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val809Ile
Coding: c.2425G>A
MANE Select: NM_020944
dbSNP: rs778985234
Type: single nucleotide variant
Location: chr9:35737828 (GRCh38)
Gene constraint: LOEUF 0.773 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.77
Residue 809: 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-val809ile (accessed [today's date]).

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