Is AGL p.Met445Val (c.1333A>G) pathogenic?

AGL p.Met445Val (c.1333A>G) is classified Conflicting classifications of pathogenicity in AGL (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.0578); Ultra-rare (popmax 0.0855%, afr); Associated with glycogen storage disease III.

What condition is associated with AGL p.Met445Val (c.1333A>G)?

AGL p.Met445Val (c.1333A>G) is associated with glycogen storage disease III (ClinVar).

How common is AGL p.Met445Val (c.1333A>G) in the general population?

AGL p.Met445Val (c.1333A>G) is ultra-rare (popmax 0.0855%, afr) (gnomAD).

What do computational predictors say about AGL p.Met445Val (c.1333A>G)?

AlphaMissense predicts likely benign (score 0.0578) — an in-silico prediction, not a clinical call.

AGL p.Met445Val

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.1333A>G · rs140375476 · VCV526590

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0578 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0855%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease III

Computational evidence

Protein change
AlphaMissense	0.0578	likely benign
REVEL	0.098	moderately benign-leaning
SaProt	LLR -5.15	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 2.4	GERP -1, phastCons 0.93
Regional constraint	o/e 0.99	unconstrained · MANE · 71 kb · p 0.78 · regional, not allelic
Overall
CADD	14.09	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 0.0855% African / African-American · 64/74,882 alleles

Filtering AF 0.0687% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0625%

Overall 0.00478% 77/1,611,624 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0855%	1,170
Remaining individualsnot grpmax-eligible	0.00481%	20,802
Admixed American	0.00333%	29,996
South Asian	0.0022%	45,508
European (non-Finnish)	0.000509%	196,311

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.Met445Val
Coding: c.1333A>G
MANE Select: NM_000642
dbSNP: rs140375476
Type: single nucleotide variant
Location: chr1:99876507 (GRCh38)
Gene constraint: LOEUF 0.72 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.88 · 1 PDB
Residue 445: 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-met445val (accessed [today's date]).

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