Is ALDOA p.Arg227His (c.680G>A) pathogenic?

ALDOA p.Arg227His (c.680G>A) is classified Uncertain significance in ALDOA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-30). AlphaMissense: likely pathogenic (0.9319); Very rare (popmax 0.0022%, sas); Associated with glycogen storage disease due to aldolase A deficiency.

What condition is associated with ALDOA p.Arg227His (c.680G>A)?

ALDOA p.Arg227His (c.680G>A) is associated with glycogen storage disease due to aldolase A deficiency (ClinVar).

How common is ALDOA p.Arg227His (c.680G>A) in the general population?

ALDOA p.Arg227His (c.680G>A) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about ALDOA p.Arg227His (c.680G>A)?

AlphaMissense predicts likely pathogenic (score 0.9319) — an in-silico prediction, not a clinical call.

ALDOA p.Arg227His

Q: How is Glycogen storage disease due to aldolase A deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.680G>A · rs769563671 · VCV2438980

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9319 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease due to aldolase A deficiency

Computational evidence

Protein change
AlphaMissense	0.9319	likely pathogenic
REVEL	0.861	moderately pathogenic-leaning
SaProt	LLR -14.23	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.84, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 3,311 bp · p 0.028 · regional, not allelic
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

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

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R173H vs ClinVar R227H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,082 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000479% 7/1,461,886 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,541
European (non-Finnish)	0.000424%	236,008

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: ALDOA
Protein: p.Arg227His
Coding: c.680G>A
MANE Select: NM_001243177
dbSNP: rs769563671
Type: single nucleotide variant
Location: chr16:30068956 (GRCh38)
Gene constraint: LOEUF 0.821 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.53 · 8 PDB

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

Disease context

glycogen storage disease due to aldolase A deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Glycogen storage disease due to aldolase A deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

ALDOA p.Arg227Cys Uncertain significance ★★ ⚠ same residue
ALDOA p.Ala334Val Pathogenic/Likely pathogenic ★★ same condition
ALDOA c.274+5G>A Uncertain significance ★★ same condition
ALDOA p.Ala142Val Uncertain significance ★★ same condition
ALDOA p.Ala217Thr Uncertain significance ★★ same condition
ALDOA p.Ala310Val Uncertain significance ★★ same condition
ALDOA p.Ala377Ser Uncertain significance ★★ same condition
ALDOA p.Ala74Thr Uncertain significance ★★ 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/aldoa-p-arg227his (accessed [today's date]).

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