Is GBA2 p.Cys45Ser (c.134G>C) pathogenic?

GBA2 p.Cys45Ser (c.134G>C) is classified Uncertain significance in GBA2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-09-27). AlphaMissense: likely benign (0.0784); Rare (popmax 0.528%, mid); Associated with Inborn genetic diseases.

What condition is associated with GBA2 p.Cys45Ser (c.134G>C)?

GBA2 p.Cys45Ser (c.134G>C) is associated with Inborn genetic diseases, hereditary spastic paraplegia 46 (ClinVar).

How common is GBA2 p.Cys45Ser (c.134G>C) in the general population?

GBA2 p.Cys45Ser (c.134G>C) is rare (popmax 0.528%, mid) (gnomAD).

What do computational predictors say about GBA2 p.Cys45Ser (c.134G>C)?

AlphaMissense predicts likely benign (score 0.0784) — an in-silico prediction, not a clinical call.

GBA2 p.Cys45Ser

c.134G>C · rs776346547 · VCV218781

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0784 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.528%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0784	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -5.11	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 0.62	GERP 0.86
Regional constraint	o/e 0.88	unconstrained · MANE · 12 kb · p 2e-05 · regional, not allelic
Overall
CADD	7.988	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.528% Middle Eastern · 32/6,062 alleles

Filtering AF 0.384% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.335%

Overall 0.00297% 48/1,614,098 alleles · rare exomes 39/1,461,798 · genomes 9/152,300 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.528%	189
African / African-American	0.004%	25,012
Remaining individualsnot grpmax-eligible	0.0032%	31,255
East Asian	0.00223%	44,880
South Asian	0.0022%	45,542
European (non-Finnish)	0.000678%	147,495

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.Cys45Ser
Coding: c.134G>C
MANE Select: NM_020944
dbSNP: rs776346547
Type: single nucleotide variant
Location: chr9:35748571 (GRCh38)
Gene constraint: LOEUF 0.773 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.77
Residue 45: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary spastic paraplegia 46

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-cys45ser (accessed [today's date]).

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