Is AGL p.Pro294Ser (c.880C>T) pathogenic?

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.

What condition is associated with AGL p.Pro294Ser (c.880C>T)?

AGL p.Pro294Ser (c.880C>T) is associated with glycogen storage disease III (ClinVar).

How common is AGL p.Pro294Ser (c.880C>T) in the general population?

AGL p.Pro294Ser (c.880C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about AGL p.Pro294Ser (c.880C>T)?

AlphaMissense predicts likely benign (score 0.1814) — an in-silico prediction, not a clinical call.

AGL p.Pro294Ser

Q: How is Glycogen storage disease due to glycogen debranching enzyme deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.880C>T · rs886044917 · VCV291328

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1814 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease III

Computational evidence

Protein change
AlphaMissense	0.1814	likely benign
REVEL	0.646	pathogenic-leaning
SaProt	LLR -11.19	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	Δ0.20	acceptor loss, 33 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 71 kb · p 0.78 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,758 alleles

Filtering AF 0.000765% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000606%

Overall 0.00112% 18/1,610,926 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00321%	31,181
African / African-Americangrpmax	0.00134%	74,758
European (non-Finnish)	0.00127%	78,508

Remaining individuals shows a higher raw frequency than the grpmax group above it. 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.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: AGL
Protein: p.Pro294Ser
Coding: c.880C>T
MANE Select: NM_000642
dbSNP: rs886044917
Type: single nucleotide variant
Location: chr1:99870791 (GRCh38)
Gene constraint: LOEUF 0.72 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.88 · 1 PDB
Residue 294: the 'amylo-1,6-glucosidase' region; an α-helix

Full AGL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

glycogen storage disease III — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Glycogen storage disease due to glycogen debranching enzyme deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy
Prevalence: 1-9 / 100 000 (United States)

Similar variants

AGL p.Pro294Ala Uncertain significance ★ ⚠ same residue
AGL c.1283+2T>C Likely pathogenic ★★ same condition
AGL c.1284-1G>A Likely pathogenic ★★ same condition
AGL c.1284-2A>G Likely pathogenic ★★ same condition
AGL c.1423+1G>A Pathogenic ★★ same condition
AGL c.1423+1G>C Pathogenic ★★ same condition
AGL c.1423+1G>T Pathogenic/Likely pathogenic ★★ same condition
AGL c.1612-1G>A Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/agl-p-pro294ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown