Is GAA p.Phe512= (c.1536C>T) pathogenic?

GAA p.Phe512= (c.1536C>T) is classified Conflicting classifications of pathogenicity in GAA (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-16). Ultra-rare (popmax 0.0366%, amr); Associated with Cardiovascular phenotype.

What condition is associated with GAA p.Phe512= (c.1536C>T)?

GAA p.Phe512= (c.1536C>T) is associated with Cardiovascular phenotype, glycogen storage disease II (ClinVar).

How common is GAA p.Phe512= (c.1536C>T) in the general population?

GAA p.Phe512= (c.1536C>T) is ultra-rare (popmax 0.0366%, amr) (gnomAD).

GAA p.Phe512=

c.1536C>T · rs143491365 · VCV284111

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0366%, amr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.3	GERP -3
Overall
CADD	3.604	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0366% Admixed American · 22/60,030 alleles

Filtering AF 0.0248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0209%

Overall 0.00192% 31/1,614,112 alleles · ultra-rare exomes 27/1,461,830 · genomes 4/152,282 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0366%	2,729
South Asian	0.00659%	15,180
European (non-Finnish)	0.000254%	393,340

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.Phe512=
Coding: c.1536C>T
MANE Select: NM_000152
dbSNP: rs143491365
Type: single nucleotide variant
Location: chr17:80110825 (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

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

Also linked: glycogen storage disease II

Similar variants

GAA p.Phe512Leu Uncertain significance ★★ ⚠ 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
GAA c.1327-2A>G Pathogenic ★★★ same condition
GAA c.1437+1G>A Likely pathogenic ★★★ same condition
GAA c.1437+2T>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/gaa-p-phe512 (accessed [today's date]).

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