# NM_000152.5(GAA):c.1532C>A (p.Pro511His)

https://sugi.bio/variant/gaa-p-pro511his

## Summary

**GAA p.Pro511His (c.1532C>A)** is classified **Likely pathogenic** in GAA (ClinVar, Single submitter, 1 submitter; last evaluated 2026-07-01). AlphaMissense: likely benign (0.1828); Absent from gnomAD v4.1; Associated with glycogen storage disease II.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · 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 1 submitter, 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.Pro511His |
| Coding change (HGVS c.) | c.1532C>A |
| MANE Select transcript | [NM_000152](https://www.ncbi.nlm.nih.gov/nuccore/NM_000152) |
| Variant type | single nucleotide variant |
| Location | chr17:80110821-80110821 (GRCh38) |
| ClinVar | [VCV4876632](https://www.ncbi.nlm.nih.gov/clinvar/variation/4876632/) |

**All HGVS expressions:** `LRG_673:g.14266C>A`, `LRG_673t1:c.1532C>A`, `NC_000017.10:g.78084620C>A`, `NC_000017.11:g.80110821C>A`, `NG_009822.1:g.14266C>A`, `NG_137935.1:g.1111C>A`, `NM_000152.5:c.1532C>A`, `NM_001079803.3:c.1532C>A`, `NM_001079804.3:c.1532C>A`, `NM_001406741.1:c.1532C>A`, `NM_001406742.1:c.1532C>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.1828) — ⚠ discordant with the pathogenic call
- REVEL 0.794 (moderately pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -10.673 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- Conservation: phyloP 7.513, GERP 1.52, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 27.1**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.68 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- 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}


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 Single submitter *(criteria provided, single submitter)*, last evaluated 2026-07-01.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| 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, Pompe Disease, CARDIOMEGALIA GLYCOGENICA DIFFUSA, GLYCOGENOSIS, GENERALIZED, CARDIAC FORM, GSD II, 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.

## Similar variants {#similar}

Related GAA variant pages (same residue, condition, or type): [GAA p.Pro511Leu](/variant/gaa-p-pro511leu), [GAA p.Pro511Thr](/variant/gaa-p-pro511thr), [GAA p.Pro511=](/variant/gaa-p-pro511), [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 2026-10-06); 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 4876632). 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.*