# NM_000642.3(AGL):c.22C>T (p.Arg8Ter)

https://sugi.bio/variant/agl-p-arg8ter

## Summary

**AGL p.Arg8Ter (c.22C>T)** is classified **Pathogenic/Likely pathogenic** in AGL (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-12). Very rare (popmax 0.000339%, nfe); Associated with glycogen storage disease III.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1057516870 · 6 submitters · 1 linked condition · very rare (popmax 0.000339%, nfe)

## For patients & families {#patients}

This is a change in the AGL gene that is considered likely disease-causing, submitted by 6 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.Arg8Ter |
| Coding change (HGVS c.) | c.22C>T |
| MANE Select transcript | [NM_000642](https://www.ncbi.nlm.nih.gov/nuccore/NM_000642) |
| dbSNP | [rs1057516870](https://www.ncbi.nlm.nih.gov/snp/rs1057516870/) |
| Variant type | single nucleotide variant |
| Location | chr1:99851064-99851064 (GRCh38) |
| ClinVar | [VCV370924](https://www.ncbi.nlm.nih.gov/clinvar/variation/370924/) |

**All HGVS expressions:** `NC_000001.10:g.100316620C>T`, `NC_000001.11:g.99851064C>T`, `NG_012865.1:g.5981C>T`, `NG_091707.1:g.683C>T`, `NM_000028.3:c.22C>T`, `NM_000642.3:c.22C>T`, `NM_000643.3:c.22C>T`, `NM_000644.3:c.22C>T`, `NM_000646.3:c.-170C>T`, `NM_001425325.1:c.22C>T`, `NM_001425326.1:c.22C>T`, `NM_001425327.1:c.22C>T`, `NM_001425328.1:c.22C>T`, `NM_001425329.1:c.22C>T`, `NM_001425332.1:c.22C>T`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 1.755, GERP -3.16, phastCons 1 — weakly conserved position
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.72, pLI 1.033e-22. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 34**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 36.0**. 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.*
- 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 **0.000339%** (nfe) · FAF95 7.9e-05% · FAF99 5.4e-05% · 4/1,179,916 in the highest group · 4/1,613,882 alleles overall — very rare (popmax 0.000339%, nfe).

*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 **8** lies in the 'amylo-1,6-glucosidase' region; a β-strand.

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.Arg8Ter 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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-12.

**Submitter consensus:** conflicting (4 Pathogenic, 2 Likely pathogenic).

**Submission history:** 6 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Counsyl | Likely pathogenic | no assertion criteria provided | clinical testing | 2016-05-18 |
| Genome-Nilou Lab | Pathogenic | criteria provided, single submitter | clinical testing | 2021-07-15 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-04-18 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-11-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-13 |
| Natera, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-12 |

## 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, Cori disease, FORBES DISEASE.

## Same-residue context {#hotspot}

Residue **8** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [AGL p.Arg8fs](/variant/agl-p-arg8fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related AGL variant pages (same residue, condition, or type): [AGL p.Arg8Gly](/variant/agl-p-arg8gly), [AGL p.Arg8fs](/variant/agl-p-arg8fs), [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).

### 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 370924). 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.*