Is GBA2 p.Phe271fs (c.812_813del) pathogenic?

GBA2 p.Phe271fs (c.812813del) is classified Likely pathogenic in GBA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-28). Associated with hereditary spastic paraplegia 46.

What condition is associated with GBA2 p.Phe271fs (c.812_813del)?

GBA2 p.Phe271fs (c.812_813del) is associated with hereditary spastic paraplegia 46 (ClinVar).

How is Autosomal recessive spastic paraplegia type 46 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

GBA2 p.Phe271fs

c.812_813del · VCV3896872

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

hereditary spastic paraplegia 46

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: GBA2
Protein: p.Phe271fs
Coding: c.812_813del
MANE Select: NM_020944
Type: Deletion
Location: chr9:35741038 (GRCh38)
Gene constraint: LOEUF 0.773 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.77
Residue 271: 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

hereditary spastic paraplegia 46 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive spastic paraplegia type 46 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

GBA2 p.Tyr735fs Pathogenic/Likely pathogenic ★★ same condition
GBA2 p.Gly722_Gln723insTer Pathogenic ★ same condition
GBA2 p.Leu108fs Pathogenic ★ same condition
GBA2 p.Met750fs Pathogenic ★ same condition
GBA2 p.Tyr676fs Pathogenic ★ same condition
GBA2 p.Arg470fs Uncertain significance ★ same condition
GBA2 c.1582+2T>G Likely pathogenic ★★ same condition
GBA2 p.Arg234Ter 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/gba2-p-phe271fs (accessed [today's date]).

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