Is AGL p.Arg1253Ser (c.3757C>A) pathogenic?

AGL p.Arg1253Ser (c.3757C>A) is classified Uncertain significance in AGL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-21). AlphaMissense: ambiguous (0.4326); Very rare (popmax 0.00153%, nfe); Associated with glycogen storage disease III.

What condition is associated with AGL p.Arg1253Ser (c.3757C>A)?

AGL p.Arg1253Ser (c.3757C>A) is associated with glycogen storage disease III (ClinVar).

How common is AGL p.Arg1253Ser (c.3757C>A) in the general population?

AGL p.Arg1253Ser (c.3757C>A) is very rare (popmax 0.00153%, nfe) (gnomAD).

What do computational predictors say about AGL p.Arg1253Ser (c.3757C>A)?

AlphaMissense predicts ambiguous (score 0.4326) — an in-silico prediction, not a clinical call.

AGL p.Arg1253Ser

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.3757C>A · rs375531470 · VCV1397753

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4326 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

glycogen storage disease III

Computational evidence

Protein change
AlphaMissense	0.4326	ambiguous
REVEL	0.256	benign-leaning
SaProt	LLR -7.79	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 0.86, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 71 kb · p 0.78 · regional, not allelic
Overall
CADD	22.2	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 0.00153% European (non-Finnish) · 18/1,178,738 alleles

Filtering AF 0.000954% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00118% 19/1,612,200 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00153%	65,485
South Asian	0.0011%	91,010

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.Arg1253Ser
Coding: c.3757C>A
MANE Select: NM_000642
dbSNP: rs375531470
Type: single nucleotide variant
Location: chr1:99910768 (GRCh38)
Gene constraint: LOEUF 0.72 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.88 · 1 PDB
Residue 1253: a UniProt-annotated variant site (in); 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.Arg1253His Benign/Likely benign ★★ ⚠ same residue
AGL p.Arg1253Cys Uncertain significance ★ ⚠ same residue
AGL p.Arg1253fs Pathogenic ★ 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

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-arg1253ser (accessed [today's date]).

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