# NM_000152.5(GAA):c.1352C>G (p.Pro451Arg)

https://sugi.bio/variant/gaa-p-pro451arg

## Summary

**GAA p.Pro451Arg (c.1352C>G)** is classified **Likely benign** in GAA (ClinVar, Expert panel, 12 submitters; last evaluated 2025-05-20). AlphaMissense: likely benign (0.103); Rare (popmax 0.483%, afr); Associated with glycogen storage disease II.

**At a glance:** Likely benign · review: Expert panel · rsID rs7215458 · 12 submitters · 1 linked condition · AlphaMissense likely benign · rare (popmax 0.483%, afr)

## For patients & families {#patients}

This is a change in the GAA gene that is classified as likely benign — not considered disease-causing, submitted by 12 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.Pro451Arg |
| Coding change (HGVS c.) | c.1352C>G |
| MANE Select transcript | [NM_000152](https://www.ncbi.nlm.nih.gov/nuccore/NM_000152) |
| dbSNP | [rs7215458](https://www.ncbi.nlm.nih.gov/snp/rs7215458/) |
| Variant type | single nucleotide variant |
| Location | chr17:80109970-80109970 (GRCh38) |
| ClinVar | [VCV281330](https://www.ncbi.nlm.nih.gov/clinvar/variation/281330/) |

**All HGVS expressions:** `LRG_673:g.13415C>G`, `LRG_673t1:c.1352C>G`, `NC_000017.10:g.78083769C>G`, `NC_000017.11:g.80109970C>G`, `NG_009822.1:g.13415C>G`, `NM_000152.4:c.1352C>G`, `NM_000152.5:c.1352C>G`, `NM_001079803.3:c.1352C>G`, `NM_001079804.3:c.1352C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.103)
- REVEL 0.449 (indeterminate)
- SaProt LLR -10.394 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL makes no call
- Conservation: phyloP 3.822, GERP 1.44, phastCons 0.74 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.7**. 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 (gnomAD v4.1): grpmax **0.483%** (afr) · FAF95 0.443% · FAF99 0.426% · 363/75,080 in the highest group · 507/1,613,394 alleles overall — rare (popmax 0.483%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.483% | 207 |
| Middle Eastern | 0.182% | 551 |
| Remaining individuals (not grpmax-eligible) | 0.0608% | 1,644 |
| Admixed American | 0.0367% | 2,728 |
| South Asian | 0.00769% | 13,011 |
| European (non-Finnish) | 0.00551% | 18,153 |
| Finnish (not grpmax-eligible) | 0.00158% | 63,316 |

*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}


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 benign** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2025-05-20.

**Submitter consensus:** conflicting (10 Likely benign, 2 Uncertain significance).

**Submission history:** 12 submissions (2016–2026); classifications have differed over time.

**ClinGen expert panel:** Likely Benign — Lysosomal Diseases VCEP (glycogen storage disease II). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `BS1`, `BP4`.
*Considered but not met:* `PP4`, `PM3`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_000152.5:c.1352C>G variant in GAA is a missense variant predicted to result in the substitution of proline by arginine at amino acid 451 (p.Pro451Arg). The highest population minor allele frequency in gnomAD v4.1.0 is 0.004835 (363/75080) alleles, including 4 homozygotes) in the African/African-American population. This allele frequency meets the ClinGen LD VCEP threshold (>0.005) for BS1 (after rounding up). The variant was reported in a patient with limb-girdle muscle weakness but was not thought to be causative of the symptoms (PMID: 29149851). The variant was also reported in a patient with autism spectrum disorder but no reported diagnosis of Pompe disease (PMID:  37492102). The computational predictor REVEL gives a score of 0.449 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function, and SpliceAI predicts no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 281330). In summary, this variant meets the criteria to be classified as likely benign for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BS1, BP4. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert panel on May 20, 2025)
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50009 · approved 2025-05-20 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/b11d7715-7a62-4071-9760-f92fefa72998).*
*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 |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-08-23 |
| Eurofins Ntd Llc (ga) | Likely benign | criteria provided, single submitter | clinical testing | 2016-01-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-26 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Likely benign | criteria provided, single submitter | clinical testing | 2023-01-03 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2020-02-07 |
| ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel | Likely benign | reviewed by expert panel | curation | 2025-05-20 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2021-02-23 |
| Natera, Inc. | Likely benign | no assertion criteria provided | clinical testing | 2021-02-26 |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-12-03 |
| Mayo Clinic Laboratories, Mayo Clinic | Likely benign | criteria provided, single submitter | clinical testing | 2025-04-29 |
| Genomenon, Inc, Genomenon, Inc | Uncertain significance | 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 specified, not provided, GAA-related disorder, Cardiovascular phenotype, GAA-related condition, AllHighlyPenetrant, none provided, Glucosidase acid-1,4-alpha deficiency, Glycogen storage disease type 2.

## Similar variants {#similar}

Related GAA variant pages (same residue, condition, or type): [GAA p.Pro451Thr](/variant/gaa-p-pro451thr), [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).

### 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 281330). 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.*