Is GAA p.Pro86Arg (c.257C>G) pathogenic?

GAA p.Pro86Arg (c.257C>G) is classified Conflicting classifications of pathogenicity in GAA (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2026-07-01). AlphaMissense: likely benign (0.0965); Rare (popmax 0.709%, eas); Associated with Cardiovascular phenotype.

What condition is associated with GAA p.Pro86Arg (c.257C>G)?

GAA p.Pro86Arg (c.257C>G) is associated with Cardiovascular phenotype, glycogen storage disease II (ClinVar).

How common is GAA p.Pro86Arg (c.257C>G) in the general population?

GAA p.Pro86Arg (c.257C>G) is rare (popmax 0.709%, eas) (gnomAD).

What do computational predictors say about GAA p.Pro86Arg (c.257C>G)?

AlphaMissense predicts likely benign (score 0.0965) — an in-silico prediction, not a clinical call.

GAA p.Pro86Arg

c.257C>G · rs2229222 · VCV325776

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.0965 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.709%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0965	likely benign
REVEL	0.303	indeterminate
SaProt	LLR -7.01	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 0.23, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 15 kb · p 0.22 · regional, not allelic
Overall
CADD	19.65	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 0.709% East Asian · 318/44,842 alleles

Filtering AF 0.645% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.62%

Overall 0.0291% 469/1,612,876 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.709%	141
Middle Eastern	0.033%	3,030
South Asian	0.0253%	3,959
Remaining individualsnot grpmax-eligible	0.0208%	4,807
European (non-Finnish)	0.00924%	10,825
Finnishnot grpmax-eligible	0.00318%	31,471
Admixed American	0.00167%	60,012
African / African-American	0.00133%	75,052

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.Pro86Arg
Coding: c.257C>G
MANE Select: NM_000152
dbSNP: rs2229222
Type: single nucleotide variant
Location: chr17:80104843 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.32 · 19 PDB
Residue 86: an α-helix; a disulfide bond; the p-type domain

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.Pro86His Uncertain significance ★★ ⚠ same residue
GAA p.Pro86= Likely benign ★ same residue
GAA p.Pro86Ser 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

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-pro86arg (accessed [today's date]).

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