Is AGL p.Pro474Arg (c.1421C>G) pathogenic?

AGL p.Pro474Arg (c.1421C>G) is classified Uncertain significance in AGL (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-10-24). AlphaMissense: likely benign (0.1449); Very rare (popmax 0.000509%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AGL p.Pro474Arg (c.1421C>G)?

AGL p.Pro474Arg (c.1421C>G) is associated with Inborn genetic diseases, glycogen storage disease III (ClinVar).

How common is AGL p.Pro474Arg (c.1421C>G) in the general population?

AGL p.Pro474Arg (c.1421C>G) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about AGL p.Pro474Arg (c.1421C>G)?

AlphaMissense predicts likely benign (score 0.1449) — an in-silico prediction, not a clinical call.

AGL p.Pro474Arg

c.1421C>G · rs146493448 · VCV652006

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1449 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1449	likely benign
REVEL	0.656	pathogenic-leaning
SaProt	LLR -7.47	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 71 kb · p 0.78 · regional, not allelic
Overall
CADD	28.5	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 0.000509% European (non-Finnish) · 6/1,179,932 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000496% 8/1,613,746 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00312%	32,001
European (non-Finnish)grpmax	0.000509%	196,655

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro474Arg
Coding: c.1421C>G
MANE Select: NM_000642
dbSNP: rs146493448
Type: single nucleotide variant
Location: chr1:99876595 (GRCh38)
Gene constraint: LOEUF 0.72 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.88 · 1 PDB
Residue 474: the 'amylo-1,6-glucosidase' region; a β-strand

Full AGL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: glycogen storage disease III

Similar variants

AGL p.Pro474= Uncertain significance ★ same residue
AGL p.Pro474Leu Uncertain significance ★ ⚠ 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
AGL c.1423+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-pro474arg (accessed [today's date]).

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