# NM_000642.3(AGL):c.1777G>C (p.Val593Leu)

https://sugi.bio/variant/agl-p-val593leu

## Summary

**AGL p.Val593Leu (c.1777G>C)** is classified **Uncertain significance** in AGL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-31). AlphaMissense: likely pathogenic (0.8538); Absent from gnomAD v4.1; Associated with glycogen storage disease III.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1312675872 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## 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 2 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.Val593Leu |
| Coding change (HGVS c.) | c.1777G>C |
| MANE Select transcript | [NM_000642](https://www.ncbi.nlm.nih.gov/nuccore/NM_000642) |
| dbSNP | [rs1312675872](https://www.ncbi.nlm.nih.gov/snp/rs1312675872/) |
| Variant type | single nucleotide variant |
| Location | chr1:99880673-99880673 (GRCh38) |
| ClinVar | [VCV1410540](https://www.ncbi.nlm.nih.gov/clinvar/variation/1410540/) |

**All HGVS expressions:** `NC_000001.10:g.100346229G>C`, `NC_000001.11:g.99880673G>C`, `NG_012865.1:g.35590G>C`, `NM_000028.3:c.1777G>C`, `NM_000642.2:c.1777G>C`, `NM_000642.3:c.1777G>C`, `NM_000643.3:c.1777G>C`, `NM_000644.3:c.1777G>C`, `NM_000646.3:c.1729G>C`, `NM_001425325.1:c.1777G>C`, `NM_001425326.1:c.1777G>C`, `NM_001425327.1:c.1576G>C`, `NM_001425328.1:c.1573G>C`, `NM_001425329.1:c.1573G>C`, `NM_001425332.1:c.1399G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8538)
- REVEL 0.71 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -8.657 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- SpliceAI predicts **acceptor gain** (Δ 0.38) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.919, GERP 0.847, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 23.8**. 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 **0.00**, donor loss **0.00**, acceptor gain **0.38**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.38**, donor gain **0.00**.
- 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}

**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 **593** 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.Val593Leu 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 2025-08-31.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-07-25 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-31 |

## 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, Inborn genetic diseases, Cori disease, FORBES DISEASE.

## Same-residue context {#hotspot}

Residue **593** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [AGL p.Val593fs](/variant/agl-p-val593fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related AGL variant pages (same residue, condition, or type): [AGL p.Val593fs](/variant/agl-p-val593fs), [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 2026-10-14); 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 1410540). 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.*