Is GBA2 p.Ile138= (c.414C>T) pathogenic?

GBA2 p.Ile138= (c.414C>T) is classified Likely benign in GBA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-07). Ultra-rare (popmax 0.01%, amr); Associated with Spastic paraplegia.

What condition is associated with GBA2 p.Ile138= (c.414C>T)?

GBA2 p.Ile138= (c.414C>T) is associated with Spastic paraplegia (ClinVar).

How common is GBA2 p.Ile138= (c.414C>T) in the general population?

GBA2 p.Ile138= (c.414C>T) is ultra-rare (popmax 0.01%, amr) (gnomAD).

GBA2 p.Ile138=

c.414C>T · rs751158195 · VCV2737760

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Conditions

Spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.1	GERP -3.5
Overall
CADD	9.571	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/59,990 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00087% 14/1,609,626 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,998
East Asian	0.00223%	44,866
Remaining individualsnot grpmax-eligible	0.0016%	62,354
South Asian	0.0011%	90,982
European (non-Finnish)	0.000425%	235,209

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.Ile138=
Coding: c.414C>T
MANE Select: NM_020944
dbSNP: rs751158195
Type: single nucleotide variant
Location: chr9:35744652 (GRCh38)
Gene constraint: LOEUF 0.773 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.77
Residue 138: 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-ile138 (accessed [today's date]).

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