Is AGL p.Asp251fs (c.753_756del) pathogenic?

AGL p.Asp251fs (c.753756del) is classified Pathogenic in AGL (ClinVar, Multiple submitters, 14 submitters; last evaluated 2025-09-24). Ultra-rare (popmax 0.0132%, sas); Associated with AGL-related disorder.

What condition is associated with AGL p.Asp251fs (c.753_756del)?

AGL p.Asp251fs (c.753_756del) is associated with AGL-related disorder, glycogen storage disease III (ClinVar).

How common is AGL p.Asp251fs (c.753_756del) in the general population?

AGL p.Asp251fs (c.753_756del) is ultra-rare (popmax 0.0132%, sas) (gnomAD).

AGL p.Asp251fs

c.753_756del · rs748789700 · VCV370509

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, sas)

Conditions

AGL-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 34
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.2	GERP 1.7, phastCons 1
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0132% South Asian · 12/91,086 alleles

Filtering AF 0.00751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.0018% 29/1,613,940 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0132%	7,590
Admixed American	0.00167%	59,996
Remaining individualsnot grpmax-eligible	0.0016%	62,484
Finnishnot grpmax-eligible	0.00156%	64,028
African / African-American	0.00133%	74,942
European (non-Finnish)	0.0011%	90,766

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.Asp251fs
Coding: c.753_756del
MANE Select: NM_000642
dbSNP: rs748789700
Type: Deletion
Location: chr1:99870485 (GRCh38)
Gene constraint: LOEUF 0.72 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.88 · 1 PDB
Residue 251: 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

AGL-related disorder

Also linked: glycogen storage disease III

Similar variants

AGL p.Asp251= Likely benign ★ same residue
AGL c.293+1del Pathogenic/Likely pathogenic ★★ same condition
AGL c.3481_3589-407del Pathogenic ★★ same condition
AGL c.3588_3588+14del Pathogenic/Likely pathogenic ★★ same condition
AGL p.Ala117fs Pathogenic ★★ same condition
AGL p.Ala1222fs Pathogenic ★★ same condition
AGL p.Ala1388_Pro1389insTer Pathogenic/Likely pathogenic ★★ same condition
AGL p.Ala1400fs 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-asp251fs (accessed [today's date]).

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