Is AGL p.Met281Val (c.841A>G) pathogenic?

AGL p.Met281Val (c.841A>G) is classified Uncertain significance in AGL (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-01). AlphaMissense: likely benign (0.0905); Ultra-rare (popmax 0.0267%, amr); Associated with glycogen storage disease III.

What condition is associated with AGL p.Met281Val (c.841A>G)?

AGL p.Met281Val (c.841A>G) is associated with glycogen storage disease III (ClinVar).

How common is AGL p.Met281Val (c.841A>G) in the general population?

AGL p.Met281Val (c.841A>G) is ultra-rare (popmax 0.0267%, amr) (gnomAD).

What do computational predictors say about AGL p.Met281Val (c.841A>G)?

AlphaMissense predicts likely benign (score 0.0905) — an in-silico prediction, not a clinical call.

AGL p.Met281Val

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.841A>G · rs185838959 · VCV571944

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0905 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease III

Computational evidence

Protein change
AlphaMissense	0.0905	likely benign
REVEL	0.195	benign-leaning
SaProt	LLR -6.32	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 71 kb · p 0.78 · regional, not allelic
Overall
CADD	17.04	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0267% Admixed American · 16/60,028 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00204% 33/1,614,048 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0267%	3,752
Remaining individualsnot grpmax-eligible	0.0016%	62,502
European (non-Finnish)	0.00136%	73,746

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.Met281Val
Coding: c.841A>G
MANE Select: NM_000642
dbSNP: rs185838959
Type: single nucleotide variant
Location: chr1:99870576 (GRCh38)
Gene constraint: LOEUF 0.72 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.88 · 1 PDB
Residue 281: 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 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
AGL c.1735+1G>T 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-met281val (accessed [today's date]).

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