Is GAA p.Ala554Val (c.1661C>T) pathogenic?

GAA p.Ala554Val (c.1661C>T) is classified Uncertain significance in GAA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-25). AlphaMissense: likely benign (0.1696); Very rare (popmax 0.00878%, sas); Associated with glycogen storage disease II.

What condition is associated with GAA p.Ala554Val (c.1661C>T)?

GAA p.Ala554Val (c.1661C>T) is associated with glycogen storage disease II (ClinVar).

How common is GAA p.Ala554Val (c.1661C>T) in the general population?

GAA p.Ala554Val (c.1661C>T) is very rare (popmax 0.00878%, sas) (gnomAD).

What do computational predictors say about GAA p.Ala554Val (c.1661C>T)?

AlphaMissense predicts likely benign (score 0.1696) — an in-silico prediction, not a clinical call.

GAA p.Ala554Val

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.1661C>T · rs772260861 · VCV498953

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1696 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00878%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

glycogen storage disease II

Computational evidence

Protein change
AlphaMissense	0.1696	likely benign
REVEL	0.386	indeterminate
SaProt	LLR -4.65	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 0.11, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 15 kb · p 0.22 · regional, not allelic
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00878% South Asian · 8/91,094 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00105% 17/1,613,724 alleles · very rare exomes 13/1,461,534 · genomes 4/152,190 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00878%	11,387
East Asian	0.00446%	22,443
African / African-American	0.00134%	74,900
European (non-Finnish)	0.000509%	196,653

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.Ala554Val
Coding: c.1661C>T
MANE Select: NM_000152
dbSNP: rs772260861
Type: single nucleotide variant
Location: chr17:80112007 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.32 · 19 PDB
Residue 554: a turn

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.Ala554= Likely benign ★★ same residue
GAA p.Ala554Pro 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

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-ala554val (accessed [today's date]).

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