# NM_000642.3(AGL):c.880C>T (p.Pro294Ser)

https://sugi.bio/variant/agl-p-pro294ser

## Summary

**AGL p.Pro294Ser (c.880C>T)** is classified **Uncertain significance** in AGL (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-01-24). AlphaMissense: likely benign (0.1814); Very rare (popmax 0.00134%, afr); Associated with glycogen storage disease III.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs886044917 · 5 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00134%, afr)

## For patients & families {#patients}

This is a change in the AGL gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 5 submitters, and is linked to glycogen storage disease III.

*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) | Childhood, Infancy |
| Prevalence | 1-9 / 100 000 (United States) |
| Clinical trials | 8 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | AGL is a diagnostic-grade gene on 12 Genomics England panels |

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

- Full cheeks — Very frequent (99-80%)
- Intellectual disability, mild — Very frequent (99-80%)
- Hypoglycemia — Very frequent (99-80%)
- Hypertriglyceridemia — Very frequent (99-80%)
- Immunodeficiency — Very frequent (99-80%)
- Short stature — Very frequent (99-80%)
- Myopathy — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009442/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AGL](https://sugi.bio/atlas/gene/AGL/) |
| Protein change (HGVS p.) | p.Pro294Ser |
| Coding change (HGVS c.) | c.880C>T |
| MANE Select transcript | [NM_000642](https://www.ncbi.nlm.nih.gov/nuccore/NM_000642) |
| dbSNP | [rs886044917](https://www.ncbi.nlm.nih.gov/snp/rs886044917/) |
| Variant type | single nucleotide variant |
| Location | chr1:99870791-99870791 (GRCh38) |
| ClinVar | [VCV291328](https://www.ncbi.nlm.nih.gov/clinvar/variation/291328/) |

**All HGVS expressions:** `NC_000001.10:g.100336347C>T`, `NC_000001.11:g.99870791C>T`, `NG_012865.1:g.25708C>T`, `NM_000028.3:c.880C>T`, `NM_000642.3:c.880C>T`, `NM_000643.3:c.880C>T`, `NM_000644.3:c.880C>T`, `NM_000646.3:c.832C>T`, `NM_001425325.1:c.880C>T`, `NM_001425326.1:c.880C>T`, `NM_001425327.1:c.880C>T`, `NM_001425328.1:c.676C>T`, `NM_001425329.1:c.676C>T`, `NM_001425332.1:c.502C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1814)
- REVEL 0.646 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -11.194 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- SpliceAI predicts **acceptor loss** (Δ 0.20) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.686, GERP 1.71, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.0**. 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 0.99** across the covering region of the MANE Select transcript (99,851,043–99,921,648), spanning 70,605 bp. Chi-square p 0.78. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.20**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 33 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.00134%** (afr) · FAF95 0.000765% · FAF99 0.000606% · 1/74,758 in the highest group · 18/1,610,926 alleles overall — very rare (popmax 0.00134%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00321% | 31,181 |
| African / African-American (grpmax) | 0.00134% | 74,758 |
| European (non-Finnish) | 0.00127% | 78,508 |

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}

**AGL** population constraint: LOEUF 0.72, pLI 1.033e-22, missense-Z 0.87709. *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 III** — Definitive (AR)

## Protein context {#protein}

Residue **294** lies in the 'amylo-1,6-glucosidase' region; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 92.88, 80% of residues very-high.

**1 experimental structure(s)** (PDB): [8ZEQ](https://www.rcsb.org/structure/8ZEQ).

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

*Describes the biological roles of AGL (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:** AGL's established molecular role includes 4-alpha-glucanotransferase activity. p.Pro294Ser falls in the amylo-1,6-glucosidase region.


### Pathways affected {#pathways}

AGL participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [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:** 4-alpha-glucanotransferase activity, amylo-alpha-1,6-glucosidase activity.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-01-24.

**Submitter consensus:** unanimous (5/5 Uncertain significance).

**Submission history:** 5 submissions (2018–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Genome-Nilou Lab | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-07-15 |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-01-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-08-21 |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-01-24 |

## Associated conditions {#conditions}

[glycogen storage disease III](https://sugi.bio/atlas/disease/glycogen-storage-disease-iii/).

**Reported phenotype names (ClinVar):** Glycogen storage disease type III, not provided, none provided, FORBES DISEASE, Cori disease.

## Similar variants {#similar}

Related AGL variant pages (same residue, condition, or type): [AGL p.Pro294Ala](/variant/agl-p-pro294ala), [AGL c.1283+2T>C](/variant/agl-c-1283-plus-2t-c), [AGL c.1284-1G>A](/variant/agl-c-1284-minus-1g-a), [AGL c.1284-2A>G](/variant/agl-c-1284-minus-2a-g), [AGL c.1423+1G>A](/variant/agl-c-1423-plus-1g-a), [AGL c.1423+1G>C](/variant/agl-c-1423-plus-1g-c), [AGL c.1423+1G>T](/variant/agl-c-1423-plus-1g-t), [AGL c.1612-1G>A](/variant/agl-c-1612-minus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 291328). 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.*