Is GAA p.Pro425Leu (c.1274C>T) pathogenic?

GAA p.Pro425Leu (c.1274C>T) is classified Uncertain significance in GAA (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-10-07). AlphaMissense: likely benign (0.2113); Very rare (popmax 0.00229%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with GAA p.Pro425Leu (c.1274C>T)?

GAA p.Pro425Leu (c.1274C>T) is associated with Cardiovascular phenotype, glycogen storage disease II (ClinVar).

How common is GAA p.Pro425Leu (c.1274C>T) in the general population?

GAA p.Pro425Leu (c.1274C>T) is very rare (popmax 0.00229%, nfe) (gnomAD).

What do computational predictors say about GAA p.Pro425Leu (c.1274C>T)?

AlphaMissense predicts likely benign (score 0.2113) — an in-silico prediction, not a clinical call.

GAA p.Pro425Leu

c.1274C>T · rs765235868 · VCV456372

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.2113 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00229%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2113	likely benign
REVEL	0.692	pathogenic-leaning
SaProt	LLR -13.80	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 1.7, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 15 kb · p 0.22 · regional, not allelic
Overall
CADD	26.8	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 0.00229% European (non-Finnish) · 27/1,178,230 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.0018% 29/1,608,918 alleles · very rare exomes 28/1,456,744 · genomes 1/152,174 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00229%	43,638
Remaining individualsnot grpmax-eligible	0.00161%	62,256
African / African-American	0.00134%	74,830

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.Pro425Leu
Coding: c.1274C>T
MANE Select: NM_000152
dbSNP: rs765235868
Type: single nucleotide variant
Location: chr17:80108776 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.32 · 19 PDB
Residue 425: an α-helix

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: glycogen storage disease II

Similar variants

GAA p.Pro425Ser Uncertain significance ★★ ⚠ same residue
GAA p.Pro425= Likely benign ★★ same residue
GAA p.Pro425Thr Uncertain significance ★ ⚠ same residue
GAA p.Pro425fs Pathogenic ★ same residue
GAA c.1076-1G>C Pathogenic ★★★ same condition
GAA c.1076-22T>G Pathogenic ★★★ same condition
GAA c.1194+5G>A Likely pathogenic ★★★ same condition
GAA c.1326+1G>A 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-pro425leu (accessed [today's date]).

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