Is GBA2 p.Thr342= (c.1026G>A) pathogenic?

GBA2 p.Thr342= (c.1026G>A) is classified Uncertain significance in GBA2 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-06-29). Very rare (popmax 0.00223%, eas); Associated with Spastic paraplegia.

What condition is associated with GBA2 p.Thr342= (c.1026G>A)?

GBA2 p.Thr342= (c.1026G>A) is associated with Spastic paraplegia (ClinVar).

How common is GBA2 p.Thr342= (c.1026G>A) in the general population?

GBA2 p.Thr342= (c.1026G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

GBA2 p.Thr342=

c.1026G>A · rs148717501 · VCV2030823

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.25 · evaluated, not missing
Pangolin	Δ0.21	loss · gain 0.01 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 2.7	GERP 1.6, phastCons 1
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,900 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000744% 12/1,613,866 alleles · very rare exomes 11/1,461,746 · genomes 1/152,120 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,233
East Asiangrpmax	0.00223%	44,900
South Asian	0.0022%	45,537
Admixed American	0.00167%	59,980
European (non-Finnish)	0.000509%	196,656

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr342=
Coding: c.1026G>A
MANE Select: NM_020944
dbSNP: rs148717501
Type: single nucleotide variant
Location: chr9:35740825 (GRCh38)
Gene constraint: LOEUF 0.773 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.77
Residue 342: 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.Thr342Met Uncertain significance ★★ ⚠ same residue
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

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-thr342 (accessed [today's date]).

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