Is AGL p.Pro414Gln (c.1241C>A) pathogenic?

AGL p.Pro414Gln (c.1241C>A) is classified Uncertain significance in AGL (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-04-11). AlphaMissense: likely pathogenic (0.735); Very rare (popmax 0.00161%, nfe); Associated with glycogen storage disease III.

What condition is associated with AGL p.Pro414Gln (c.1241C>A)?

AGL p.Pro414Gln (c.1241C>A) is associated with glycogen storage disease III (ClinVar).

How common is AGL p.Pro414Gln (c.1241C>A) in the general population?

AGL p.Pro414Gln (c.1241C>A) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about AGL p.Pro414Gln (c.1241C>A)?

AlphaMissense predicts likely pathogenic (score 0.735) — an in-silico prediction, not a clinical call.

AGL p.Pro414Gln

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.1241C>A · rs758882822 · VCV967966

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.735 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease III

Computational evidence

Protein change
AlphaMissense	0.735	likely pathogenic
REVEL	0.81	moderately pathogenic-leaning
SaProt	LLR -10.10	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 71 kb · p 0.78 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00161% European (non-Finnish) · 19/1,180,016 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.0013% 19/1,461,828 alleles · very rare

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.Pro414Gln
Coding: c.1241C>A
MANE Select: NM_000642
dbSNP: rs758882822
Type: single nucleotide variant
Location: chr1:99875413 (GRCh38)
Gene constraint: LOEUF 0.72 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.88 · 1 PDB
Residue 414: the 'amylo-1,6-glucosidase' region

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.Pro414Leu 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-pro414gln (accessed [today's date]).

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