Is GBA2 p.Cys89Ser (c.266G>C) pathogenic?

GBA2 p.Cys89Ser (c.266G>C) is classified Uncertain significance in GBA2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-11-01). AlphaMissense: likely pathogenic (0.6085); Rare (popmax 0.115%, mid); Associated with hereditary spastic paraplegia 46.

What condition is associated with GBA2 p.Cys89Ser (c.266G>C)?

GBA2 p.Cys89Ser (c.266G>C) is associated with hereditary spastic paraplegia 46 (ClinVar).

How common is GBA2 p.Cys89Ser (c.266G>C) in the general population?

GBA2 p.Cys89Ser (c.266G>C) is rare (popmax 0.115%, mid) (gnomAD).

How is Autosomal recessive spastic paraplegia type 46 inherited?

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

What do computational predictors say about GBA2 p.Cys89Ser (c.266G>C)?

AlphaMissense predicts likely pathogenic (score 0.6085) — an in-silico prediction, not a clinical call.

GBA2 p.Cys89Ser

c.266G>C · rs143885818 · VCV657136

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.6085 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.115%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 46

Computational evidence

Protein change
AlphaMissense	0.6085	likely pathogenic
REVEL	0.243	benign-leaning
SaProt	LLR -3.24	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.86, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 12 kb · p 2e-05 · regional, not allelic
Overall
CADD	23.4	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 0.115% Middle Eastern · 7/6,062 alleles

Filtering AF 0.0542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0384%

Overall 0.00613% 99/1,614,206 alleles · rare exomes 86/1,461,880 · genomes 13/152,326 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.115%	866
African / African-American	0.0546%	1,830
Remaining individualsnot grpmax-eligible	0.0384%	2,605
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
European (non-Finnish)	0.0022%	45,386

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.Cys89Ser
Coding: c.266G>C
MANE Select: NM_020944
dbSNP: rs143885818
Type: single nucleotide variant
Location: chr9:35748439 (GRCh38)
Gene constraint: LOEUF 0.773 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.77

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 c.1582+2T>G Likely pathogenic ★★ same condition
GBA2 p.Arg234Ter Pathogenic ★★ same condition
GBA2 p.Arg340Ter Pathogenic ★★ same condition
GBA2 p.Arg574Ter Pathogenic ★★ same condition
GBA2 p.Arg630Trp Pathogenic/Likely pathogenic ★★ same condition
GBA2 p.Arg870Ter Likely pathogenic ★★ same condition
GBA2 p.Arg873His Pathogenic/Likely pathogenic ★★ same condition
GBA2 p.Ala344Pro 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-cys89ser (accessed [today's date]).

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