Is GBA2 p.Arg399Pro (c.1196G>C) pathogenic?

GBA2 p.Arg399Pro (c.1196G>C) is classified Conflicting classifications of pathogenicity in GBA2 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2025-12-23). AlphaMissense: likely benign (0.0556); Rare (popmax 0.287%, nfe); Associated with Spastic paraplegia.

What condition is associated with GBA2 p.Arg399Pro (c.1196G>C)?

GBA2 p.Arg399Pro (c.1196G>C) is associated with Spastic paraplegia, hereditary spastic paraplegia (ClinVar).

How common is GBA2 p.Arg399Pro (c.1196G>C) in the general population?

GBA2 p.Arg399Pro (c.1196G>C) is rare (popmax 0.287%, nfe) (gnomAD).

What do computational predictors say about GBA2 p.Arg399Pro (c.1196G>C)?

AlphaMissense predicts likely benign (score 0.0556) — an in-silico prediction, not a clinical call.

GBA2 p.Arg399Pro

c.1196G>C · rs142607078 · VCV241327

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0556 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.287%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.0556	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -2.95	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 1.9	GERP -2.8, phastCons 0.97
Regional constraint	o/e 0.88	unconstrained · MANE · 12 kb · p 2e-05 · regional, not allelic
Overall
CADD	7.852	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 0.287% European (non-Finnish) · 3,386/1,180,014 alleles

Filtering AF 0.279% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.276%

Overall 0.226% 3,644/1,613,942 alleles · rare exomes 3,435/1,461,798 · genomes 209/152,144 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.287%	348
Remaining individualsnot grpmax-eligible	0.163%	613
Admixed American	0.11%	909
South Asian	0.0538%	1,859
Middle Eastern	0.0329%	3,042
African / African-American	0.032%	3,121
Finnishnot grpmax-eligible	0.0172%	5,816
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,400

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.Arg399Pro
Coding: c.1196G>C
MANE Select: NM_020944
dbSNP: rs142607078
Type: single nucleotide variant
Location: chr9:35740296 (GRCh38)
Gene constraint: LOEUF 0.773 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.77
Residue 399: 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

Also linked: hereditary spastic paraplegia

Similar variants

GBA2 p.Arg399Ter Pathogenic ★ same residue
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.Arg873His Pathogenic/Likely pathogenic ★★ same condition
GBA2 p.Ala187Thr Uncertain significance ★★ ⚠ same condition
GBA2 p.Ala235Gly 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-arg399pro (accessed [today's date]).

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