Is AGL p.Trp1451Cys (c.4353G>T) pathogenic?

AGL p.Trp1451Cys (c.4353G>T) is classified Pathogenic/Likely pathogenic in AGL (ClinVar, Multiple submitters, 7 submitters; last evaluated 2024-10-10). AlphaMissense: likely pathogenic (0.9893); Ultra-rare (popmax 0.033%, mid); Associated with AGL-related disorder.

What condition is associated with AGL p.Trp1451Cys (c.4353G>T)?

AGL p.Trp1451Cys (c.4353G>T) is associated with AGL-related disorder, glycogen storage disease III (ClinVar).

How common is AGL p.Trp1451Cys (c.4353G>T) in the general population?

AGL p.Trp1451Cys (c.4353G>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about AGL p.Trp1451Cys (c.4353G>T)?

AlphaMissense predicts likely pathogenic (score 0.9893) — an in-silico prediction, not a clinical call.

AGL p.Trp1451Cys

c.4353G>T · rs775685508 · VCV374339

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9893 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

AGL-related disorder

Computational evidence

Protein change
AlphaMissense	0.9893	likely pathogenic ✓ concordant with ClinVar · top 4% in AGL
REVEL	0.889	moderately pathogenic-leaning
SaProt	LLR -13.24	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 71 kb · p 0.78 · regional, not allelic
Overall
CADD	33.0	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 0.033% Middle Eastern · 2/6,054 alleles

Filtering AF 0.00583% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.000684% 10/1,460,982 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,027
South Asian	0.00769%	13,006
African / African-American	0.00133%	74,912

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.Trp1451Cys
Coding: c.4353G>T
MANE Select: NM_000642
dbSNP: rs775685508
Type: single nucleotide variant
Location: chr1:99916603 (GRCh38)
Gene constraint: LOEUF 0.72 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.88 · 1 PDB
Residue 1451: the 'amylo-1,6-glucosidase' region

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.Trp1451Leu Likely pathogenic ★ same residue
AGL p.Trp1451Ter Pathogenic ★ same residue
AGL p.Trp1451fs 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-trp1451cys (accessed [today's date]).

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