# NM_000152.5(GAA):c.1445C>G (p.Pro482Arg)

https://sugi.bio/variant/gaa-p-pro482arg

## Summary

**GAA p.Pro482Arg (c.1445C>G)** is classified **Likely pathogenic** in GAA (ClinVar, Expert panel, 8 submitters; last evaluated 2025-10-28). AlphaMissense: likely pathogenic (0.8474); Absent from gnomAD v4.1; Associated with glycogen storage disease II.

**At a glance:** Likely pathogenic · review: Expert panel · rsID rs2039212985 · 8 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the GAA gene that is considered likely disease-causing, submitted by 8 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.Pro482Arg |
| Coding change (HGVS c.) | c.1445C>G |
| MANE Select transcript | [NM_000152](https://www.ncbi.nlm.nih.gov/nuccore/NM_000152) |
| dbSNP | [rs2039212985](https://www.ncbi.nlm.nih.gov/snp/rs2039212985/) |
| Variant type | single nucleotide variant |
| Location | chr17:80110734-80110734 (GRCh38) |
| ClinVar | [VCV1067574](https://www.ncbi.nlm.nih.gov/clinvar/variation/1067574/) |

**All HGVS expressions:** `LRG_673:g.14179C>G`, `LRG_673t1:c.1445C>G`, `NC_000017.10:g.78084533C>G`, `NC_000017.11:g.80110734C>G`, `NG_009822.1:g.14179C>G`, `NM_000152.5:c.1445C>G`, `NM_001079803.3:c.1445C>G`, `NM_001079804.3:c.1445C>G`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.8474) — concordant with the pathogenic call
- REVEL 0.948 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.14 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.516, GERP 1.6, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 26.0**. 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.*
- Regional missense constraint: **o/e 1.03** across the covering region of the MANE Select transcript (80,104,587–80,119,328), spanning 14,741 bp. Chi-square p 0.22. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **482** lies in a UniProt-annotated variant site (in iopd).

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}

**Likely pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2025-10-28.

**Submitter consensus:** conflicting (6 Likely pathogenic, 1 Likely Pathogenic, 1 Pathogenic).

**Submission history:** 8 submissions (2020–2026); classifications have differed over time.

**ClinGen expert panel:** Likely Pathogenic — Lysosomal Diseases VCEP (glycogen storage disease II). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2_Supporting`, `PS3_Moderate`, `PM5_Supporting`, `PP3`, `PP4`, `PM3`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_000152.5:c.1445C>G variant in GAA is a missense variant predicted to cause substitution of proline by arginine at amino acid 482 (p.Pro482Arg). One proband with this variant was reported to be on enzyme replacement therapy for Pompe disease (PMID: 31392188) (PP4). This variant has been detected two apparently unrelated probands and one sibling with late onset Pompe disease who were compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic for Pompe disease by the ClinGen LD VCEP, c.-32-13T>G; the phase is unknown (PMID: 24383498, 29122469, 31392188, 31710733, 38313679); 2 x 0.5pt) (PM3). This variant is absent in gnomAD v4.1.0.. (PM2_Supporting). Expression of the variant in COS7 or HEK293 cells resulted in 0% GAA activity in cells and 0% in medium, and evidence of abnormal synthesis and processing on Western blot, indicating that this variant may impact protein function (PMID 22644586) (PS3_Moderate). The computational predictor REVEL gives a score of 0.948 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Two other missense variants at the same amino acids have been reported in patients with Pompe disease; c.1445C>T (p.Pro482Leu) (ClinVar Variation ID: 982297) has been classified as likely pathogenic by the ClinGen LD VCEP, c.1444C>T (p.Pro482Ser) has not yet been classified by the VCEP (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 1067574).  In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen LD VCEP (Specifications Version 2.0.0): PM3, PS3_Moderate, PP3, PP4, PM2_Supporting, PM5_Supporting (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 28, 2025).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50009 · approved 2025-10-28 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/32998b1b-724b-48dd-8e77-ff28373954c1).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Likely pathogenic | no assertion criteria provided | clinical testing | 2021-10-13 |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-05-17 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-01-26 |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2020-06-19 |
| Myriad Genetics, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-01-28 |
| ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel | Likely Pathogenic | reviewed by expert panel | curation | 2025-10-28 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-05 |
| Genomenon, Inc, Genomenon, Inc | Likely pathogenic | criteria provided, single submitter | curation | 2026-07-01 |

## 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, POMPE DISEASE, INFANTILE-ONSET, GLYCOGEN STORAGE DISEASE II, INFANTILE-ONSET, ACID ALPHA-GLUCOSIDASE DEFICIENCY, INFANTILE-ONSET, GAA DEFICIENCY, INFANTILE-ONSET, ACID MALTASE DEFICIENCY, INFANTILE-ONSET, Glucosidase acid-1,4-alpha deficiency, CARDIOMEGALIA GLYCOGENICA DIFFUSA, GLYCOGENOSIS, GENERALIZED, CARDIAC FORM.

## Same-residue context {#hotspot}

Residue **482** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [GAA p.Pro482Leu](/variant/gaa-p-pro482leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related GAA variant pages (same residue, condition, or type): [GAA p.Pro482Leu](/variant/gaa-p-pro482leu), [GAA p.Pro482=](/variant/gaa-p-pro482), [GAA p.Pro482Ser](/variant/gaa-p-pro482ser), [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).

### 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 1067574). 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.*