Is GBA2 p.Val581Met (c.1741G>A) pathogenic?

GBA2 p.Val581Met (c.1741G>A) is classified Uncertain significance in GBA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-24). AlphaMissense: likely benign (0.0794); Ultra-rare (popmax 0.0496%, mid); Associated with Inborn genetic diseases.

What condition is associated with GBA2 p.Val581Met (c.1741G>A)?

GBA2 p.Val581Met (c.1741G>A) is associated with Inborn genetic diseases (ClinVar).

How common is GBA2 p.Val581Met (c.1741G>A) in the general population?

GBA2 p.Val581Met (c.1741G>A) is ultra-rare (popmax 0.0496%, mid) (gnomAD).

What do computational predictors say about GBA2 p.Val581Met (c.1741G>A)?

AlphaMissense predicts likely benign (score 0.0794) — an in-silico prediction, not a clinical call.

GBA2 p.Val581Met

c.1741G>A · VCV3519156

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0794 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0496%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0794	likely benign
REVEL	0.012	strongly benign-leaning
SaProt	LLR -7.83	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 -0.25	GERP -0.94
Regional constraint	o/e 0.88	unconstrained · MANE · 12 kb · p 2e-05 · regional, not allelic
Overall
CADD	12.64	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 0.0496% Middle Eastern · 3/6,054 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00719%

Overall 0.000205% 3/1,461,442 alleles · ultra-rare

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.Val581Met
Coding: c.1741G>A
MANE Select: NM_020944
Type: single nucleotide variant
Location: chr9:35739056 (GRCh38)
Gene constraint: LOEUF 0.773 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.77
Residue 581: 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

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

Similar variants

GBA2 p.Ala344Pro Uncertain significance ★★ ⚠ same condition
GBA2 p.Ala479Val Uncertain significance ★★ ⚠ same condition
GBA2 p.Arg164His Uncertain significance ★★ same condition
GBA2 p.Arg429Trp Uncertain significance ★★ ⚠ same condition
GBA2 p.Arg573Trp Uncertain significance ★★ ⚠ same condition
GBA2 p.Arg734Cys Uncertain significance ★★ ⚠ same condition
GBA2 p.Arg747His Uncertain significance ★★ ⚠ same condition
GBA2 p.Arg855His 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-val581met (accessed [today's date]).

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