# NM_000152.5(GAA):c.1392G>C (p.Arg464Ser)

https://sugi.bio/variant/gaa-p-arg464ser

## Summary

**GAA p.Arg464Ser (c.1392G>C)** is classified **Uncertain significance** in GAA (ClinVar, Expert panel, 10 submitters; last evaluated 2025-11-17). AlphaMissense: ambiguous (0.4182); Ultra-rare (popmax 0.0186%, nfe); Associated with glycogen storage disease II.

**At a glance:** Uncertain significance · review: Expert panel · rsID rs372786811 · 10 submitters · 1 linked condition · AlphaMissense ambiguous · ultra-rare (popmax 0.0186%, nfe)

## For patients & families {#patients}

This is a change in the GAA gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 10 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.Arg464Ser |
| Coding change (HGVS c.) | c.1392G>C |
| MANE Select transcript | [NM_000152](https://www.ncbi.nlm.nih.gov/nuccore/NM_000152) |
| dbSNP | [rs372786811](https://www.ncbi.nlm.nih.gov/snp/rs372786811/) |
| Variant type | single nucleotide variant |
| Location | chr17:80110010-80110010 (GRCh38) |
| ClinVar | [VCV432217](https://www.ncbi.nlm.nih.gov/clinvar/variation/432217/) |

**All HGVS expressions:** `LRG_673:g.13455G>C`, `LRG_673t1:c.1392G>C`, `NC_000017.10:g.78083809G>C`, `NC_000017.11:g.80110010G>C`, `NG_009822.1:g.13455G>C`, `NM_000152.5:c.1392G>C`, `NM_001079803.3:c.1392G>C`, `NM_001079804.3:c.1392G>C`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL are indeterminate here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.4182) — no call either way
- REVEL 0.631 (indeterminate)
- SaProt LLR -8.647 (tolerated)
- Conservation: phyloP 1.389, GERP -3.19, phastCons 1 — weakly conserved position
- CADD: **PHRED 16.85**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for GAA (1,240 scored positions, the nearest 1 base away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.0186%** (nfe) · FAF95 0.0165% · FAF99 0.0157% · 219/1,179,922 in the highest group · 237/1,613,246 alleles overall — ultra-rare (popmax 0.0186%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0192% | 5,206 |
| European (non-Finnish) (grpmax) | 0.0186% | 5,388 |
| Admixed American | 0.005% | 20,002 |
| South Asian | 0.00329% | 30,356 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **464** lies in an α-helix.

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}

**Uncertain significance** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2025-11-17.

**Submitter consensus:** conflicting (8 Uncertain significance, 1 Likely pathogenic, 1 Uncertain Significance).

**Submission history:** 10 submissions (2018–2026); classifications have differed over time.

**ClinGen expert panel:** Uncertain Significance — Lysosomal Diseases VCEP (glycogen storage disease II). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2_Supporting`.
*Considered but not met:* `PP3`, `PM3`, `PM5`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_000152.5c.1392G>C variant in GAA is a missense variant predicted to cause substitution of Arginine by Serine at amino acid 464 (p.Arg464Ser). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00019 (219/1179922 alleles) in the European (non-Finnish) population, which is lower than the ClinGen LD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion. The computational predictor REVEL gives a score of 0.631 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. Another missense variant c.1390A>T, p.Arg464Trp in the same codon has been reported in a patient with Pompe disease (ClinVar Variation ID: 843677). However, this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen LD VCEP. There is a ClinVar entry for this variant (Variation ID: 432217, 3-star review status) with 6 submitters classifying the variant as Uncertain Significance and 1 submitter classifying the variant as Likely Pathogenic. In summary, this variant meets the criteria to be classified as Uncertain Significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Disease Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting. (Classification approved by the ClinGen Lysosomal Disease Variant Curation Expert Panel on November 17, 2025)
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50009 · approved 2025-11-17 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/5ff4c67a-40fc-4de5-ac2f-2d74e46aee54).*
*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 |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-10-31 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2018-08-14 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-02-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-08-22 |
| Genome-Nilou Lab | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-07-22 |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-01-02 |
| ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel | Uncertain Significance | reviewed by expert panel | curation | 2025-11-17 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-09-22 |
| Genomenon, Inc, Genomenon, Inc | Uncertain significance | criteria provided, single submitter | curation | 2026-07-01 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-08-12 |

## 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, not specified, AllHighlyPenetrant, none provided, Glycogen storage disease type 2, Acid maltase deficiency disease, Aglucosidase alfa, Deficiency of alpha-glucosidase, Deficiency of lysosomal alpha-glucosidase.

## Similar variants {#similar}

Related GAA variant pages (same residue, condition, or type): [GAA p.Arg464Trp](/variant/gaa-p-arg464trp), [GAA p.Arg464=](/variant/gaa-p-arg464), [GAA p.Arg464_Gly465delinsSerTrp](/variant/gaa-p-arg464-gly465delinssertrp), [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 2026-10-15); 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 432217). 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.*