Is GAA p.Asp459= (c.1377C>T) pathogenic?

GAA p.Asp459= (c.1377C>T) is classified Benign/Likely benign in GAA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-21). Ultra-rare (popmax 0.0571%, sas); Associated with Cardiovascular phenotype.

What condition is associated with GAA p.Asp459= (c.1377C>T)?

GAA p.Asp459= (c.1377C>T) is associated with Cardiovascular phenotype, glycogen storage disease II (ClinVar).

How common is GAA p.Asp459= (c.1377C>T) in the general population?

GAA p.Asp459= (c.1377C>T) is ultra-rare (popmax 0.0571%, sas) (gnomAD).

GAA p.Asp459=

c.1377C>T · rs778121058 · VCV1164610

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0571%, sas)

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 -10	GERP -3.2
Overall
CADD	2.208	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0571% South Asian · 52/91,054 alleles

Filtering AF 0.0447% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0403%

Overall 0.00508% 82/1,613,158 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0571%	1,751
Middle Eastern	0.0165%	6,060
Finnishnot grpmax-eligible	0.00948%	10,544
African / African-American	0.00933%	10,721
East Asian	0.00446%	22,432
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.0011%	90,759

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.Asp459=
Coding: c.1377C>T
MANE Select: NM_000152
dbSNP: rs778121058
Type: single nucleotide variant
Location: chr17:80109995 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.32 · 19 PDB
Residue 459: an α-helix; a UniProt-annotated variant site (in iopd)

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.Asp459Glu Uncertain significance ★★ ⚠ same residue
GAA p.Asp459Val Likely pathogenic ★ same residue
GAA p.Asp459His Conflicting classifications of pathogenicity ★ ⚠ same residue
GAA p.Asp459Tyr Uncertain significance ★ ⚠ same residue
GAA p.Asp459Asn Pathogenic ★ same residue
GAA p.Asp459fs Pathogenic ★ same residue
GAA p.Asp459_Glu460insAsp Uncertain significance ★ same residue
GAA p.Asp459del Uncertain significance ★ same residue

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-asp459 (accessed [today's date]).

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