# NM_020944.3(GBA2):c.164_165del (p.Lys55fs)

https://sugi.bio/variant/gba2-p-lys55fs

## Summary

**GBA2 p.Lys55fs (c.164_165del)** is classified **Conflicting classifications of pathogenicity** in GBA2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-12-09). No gnomAD frequency available for this variant; Associated with Spastic paraplegia.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1827116262 · 2 submitters · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the GBA2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to Spastic paraplegia.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GBA2](https://sugi.bio/atlas/gene/GBA2/) |
| Protein change (HGVS p.) | p.Lys55fs |
| Coding change (HGVS c.) | c.164_165del |
| MANE Select transcript | [NM_020944](https://www.ncbi.nlm.nih.gov/nuccore/NM_020944) |
| dbSNP | [rs1827116262](https://www.ncbi.nlm.nih.gov/snp/rs1827116262/) |
| Variant type | Deletion |
| Location | chr9:35748540-35748541 (GRCh38) |
| ClinVar | [VCV986271](https://www.ncbi.nlm.nih.gov/clinvar/variation/986271/) |

**All HGVS expressions:** `NC_000009.11:g.35748539_35748540del`, `NC_000009.12:g.35748542_35748543del`, `NG_033899.1:g.5688_5689del`, `NM_001330660.2:c.164_165del`, `NM_020944.3:c.164_165del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 1.081, GERP 0.869, phastCons 0.028 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.773, pLI 4.857e-13. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 17**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**GBA2** population constraint: LOEUF 0.773, pLI 4.857e-13, missense-Z 1.9266; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **complex hereditary spastic paraplegia** — Definitive (AR)

## Protein context {#protein}

Residue **55** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 89.77, 84% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of GBA2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** GBA2's established molecular role includes glucosylceramidase activity. p.Lys55fs falls in the disordered region.


### Pathways affected {#pathways}

GBA2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Glycosphingolipid catabolism](https://reactome.org/content/detail/R-HSA-9840310) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** glucosylceramidase activity, beta-glucosidase activity.

**Biological process:** glucosylceramide catabolic process, bile acid metabolic process, glycoside catabolic process, central nervous system neuron development.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-12-09.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Pathogenic).

**Submission history:** 2 submissions (2019–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-10-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-12-09 |

## Associated conditions {#conditions}

[Spastic paraplegia](https://sugi.bio/atlas/disease/spastic-paraplegia/).

**Reported phenotype names (ClinVar):** Spastic paraplegia, Inborn genetic diseases.

## Similar variants {#similar}

Related GBA2 variant pages (same residue, condition, or type): [GBA2 p.Met510fs](/variant/gba2-p-met510fs), [GBA2 p.Trp551fs](/variant/gba2-p-trp551fs), [GBA2 c.1129+11del](/variant/gba2-c-1129-plus-11del), [GBA2 c.1130-15_1130-14del](/variant/gba2-c-1130-minus-15-1130-minus-14del), [GBA2 p.Arg234Ter](/variant/gba2-p-arg234ter), [GBA2 p.Arg340Ter](/variant/gba2-p-arg340ter), [GBA2 p.Arg574Ter](/variant/gba2-p-arg574ter), [GBA2 p.Ala187Thr](/variant/gba2-p-ala187thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 986271). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*