# NM_000152.5(GAA):c.993G>A (p.Arg331=)

https://sugi.bio/variant/gaa-p-arg331

## Summary

**GAA p.Arg331= (c.993G>A)** is classified **Conflicting classifications of pathogenicity** in GAA (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-01). Ultra-rare (popmax 0.0329%, mid); Associated with glycogen storage disease II.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs749831587 · 4 submitters · 1 linked condition · ultra-rare (popmax 0.0329%, mid)

## For patients & families {#patients}

This is a change in the GAA gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, and is linked to glycogen storage disease II.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 129 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | GAA is a diagnostic-grade gene on 15 Genomics England panels |

**Commonly reported features of Glycogen storage disease due to acid maltase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Muscle weakness — Very frequent (99-80%)
- Progressive proximal muscle weakness — Very frequent (99-80%)
- Oligosacchariduria — Very frequent (99-80%)
- Decreased circulating acid maltase activity — Very frequent (99-80%)
- Gait disturbance — Frequent (79-30%)
- Hypomimic face — Frequent (79-30%)
- Delayed speech and language development — Frequent (79-30%)
- Hyporeflexia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005714/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GAA](https://sugi.bio/atlas/gene/GAA/) |
| Protein change (HGVS p.) | p.Arg331= |
| Coding change (HGVS c.) | c.993G>A |
| MANE Select transcript | [NM_000152](https://www.ncbi.nlm.nih.gov/nuccore/NM_000152) |
| dbSNP | [rs749831587](https://www.ncbi.nlm.nih.gov/snp/rs749831587/) |
| Variant type | single nucleotide variant |
| Location | chr17:80108327-80108327 (GRCh38) |
| ClinVar | [VCV289912](https://www.ncbi.nlm.nih.gov/clinvar/variation/289912/) |

**All HGVS expressions:** `LRG_673:g.11772G>A`, `NC_000017.10:g.78082126G>A`, `NC_000017.11:g.80108327G>A`, `NG_009822.1:g.11772G>A`, `NM_000152.5:c.993G>A`, `NM_001079803.3:c.993G>A`, `NM_001079804.3:c.993G>A`

## 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 1.762, GERP -3.85, phastCons 0.961 — weakly conserved position
- CADD: **PHRED 11.76**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0329%** (mid) · FAF95 0.0058% · FAF99 0.00241% · 2/6,084 in the highest group · 9/1,613,588 alleles overall — ultra-rare (popmax 0.0329%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0329% | 3,042 |
| South Asian | 0.00329% | 30,365 |
| African / African-American | 0.00267% | 37,468 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,480 |
| European (non-Finnish) | 8.47e-05% | 1,180,040 |

*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}

**GAA** population constraint: LOEUF 1.008, pLI 2.0036e-25, missense-Z -0.31627. *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):

- **glycogen storage disease II** — Definitive (AR)

## Protein context {#protein}

Residue **331** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 92.32, 88% of residues very-high.

**19 experimental structure(s)** (PDB): [5KZW](https://www.rcsb.org/structure/5KZW), [5KZX](https://www.rcsb.org/structure/5KZX), [5NN3](https://www.rcsb.org/structure/5NN3), [5NN4](https://www.rcsb.org/structure/5NN4), [5NN5](https://www.rcsb.org/structure/5NN5), [5NN6](https://www.rcsb.org/structure/5NN6).

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

*Describes the biological roles of GAA (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:** GAA's established molecular role includes alpha-1,4-glucosidase activity. In Reactome, GAA is annotated in disease pathway(s) including **Glycogen storage disease type II (GAA)**.

**Disease mechanism (Reactome):** GAA loss or alteration is curated in [Glycogen storage disease type II (GAA)](https://reactome.org/content/detail/R-HSA-5357609).

### Pathways affected {#pathways}

GAA participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Glycogen storage disease type II (GAA)](https://reactome.org/content/detail/R-HSA-5357609) | curated |
| [Glycogen breakdown (glycogenolysis)](https://reactome.org/content/detail/R-HSA-70221) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |

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

**Molecular function:** alpha-1,4-glucosidase activity, glucan 1,6-alpha-glucosidase activity, alpha-glucosidase activity.

**Biological process:** diaphragm contraction, glycogen catabolic process, lysosome organization, glycophagy.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-11-01.

**Submitter consensus:** conflicting (2 Uncertain significance, 2 Likely benign).

**Submission history:** 4 submissions (2016–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-08-12 |
| Genome-Nilou Lab | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-07-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-01-05 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-01 |

## Associated conditions {#conditions}

[glycogen storage disease II](https://sugi.bio/atlas/disease/glycogen-storage-disease-ii/).

**Reported phenotype names (ClinVar):** Glycogen storage disease, type II, not provided, none provided, CARDIOMEGALIA GLYCOGENICA DIFFUSA, GLYCOGENOSIS, GENERALIZED, CARDIAC FORM, Glucosidase acid-1,4-alpha deficiency, Pompe Disease, GSD II, Glycogen storage disease type 2, Acid maltase deficiency disease.

## Similar variants {#similar}

Related GAA variant pages (same residue, condition, or type): [GAA c.1076-1G>C](/variant/gaa-c-1076-minus-1g-c), [GAA c.1076-22T>G](/variant/gaa-c-1076-minus-22t-g), [GAA c.1194+5G>A](/variant/gaa-c-1194-plus-5g-a), [GAA c.1326+1G>A](/variant/gaa-c-1326-plus-1g-a), [GAA c.1327-2A>G](/variant/gaa-c-1327-minus-2a-g), [GAA c.1437+1G>A](/variant/gaa-c-1437-plus-1g-a), [GAA c.1437+2T>C](/variant/gaa-c-1437-plus-2t-c), [GAA c.1438-1G>C](/variant/gaa-c-1438-minus-1g-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 289912). 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.*