Is GAA p.Arg154Pro (c.461G>C) pathogenic?

GAA p.Arg154Pro (c.461G>C) is classified Conflicting classifications of pathogenicity in GAA (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-07-01). AlphaMissense: likely pathogenic (0.9358); Very rare (popmax 6.2e-05%); Associated with glycogen storage disease II.

What condition is associated with GAA p.Arg154Pro (c.461G>C)?

GAA p.Arg154Pro (c.461G>C) is associated with glycogen storage disease II (ClinVar).

How common is GAA p.Arg154Pro (c.461G>C) in the general population?

GAA p.Arg154Pro (c.461G>C) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about GAA p.Arg154Pro (c.461G>C)?

AlphaMissense predicts likely pathogenic (score 0.9358) — an in-silico prediction, not a clinical call.

GAA p.Arg154Pro

Q: How is Glycogen storage disease due to acid maltase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.461G>C · rs781124934 · VCV930446

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9358 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease II

Computational evidence

Protein change
AlphaMissense	0.9358	likely pathogenic · top 7% in GAA
REVEL	0.783	moderately pathogenic-leaning
SaProt	LLR -9.78	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.7	GERP 1.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 15 kb · p 0.22 · regional, not allelic
Overall
CADD	25.8	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 6.2e-05%

Overall 6.2e-05% 1/1,612,876 alleles · very rare exomes 1/1,460,566 · genomes 0/152,310 · joint denominator

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: GAA
Protein: p.Arg154Pro
Coding: c.461G>C
MANE Select: NM_000152
dbSNP: rs781124934
Type: single nucleotide variant
Location: chr17:80105047 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.32 · 19 PDB

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

Disease context

glycogen storage disease II — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Glycogen storage disease due to acid maltase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

GAA p.Arg154His Uncertain significance ★★ ⚠ same residue
GAA p.Arg154Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
GAA p.Arg154= Likely benign same residue
GAA p.Arg154_Thr155del Likely pathogenic ★★★ same residue
GAA p.Arg154_Thr156del Likely pathogenic ★★★ same residue
GAA p.Arg154Gly Uncertain significance ★ ⚠ same residue
GAA c.1076-1G>C Pathogenic ★★★ same condition
GAA c.1076-22T>G 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/gaa-p-arg154pro (accessed [today's date]).

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