Is ALDOA p.Arg76Cys (c.226C>T) pathogenic?

ALDOA p.Arg76Cys (c.226C>T) is classified Uncertain significance in ALDOA (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-12-21). AlphaMissense: likely benign (0.2327); Rare (popmax 0.113%, sas); Associated with glycogen storage disease due to aldolase A deficiency.

What condition is associated with ALDOA p.Arg76Cys (c.226C>T)?

ALDOA p.Arg76Cys (c.226C>T) is associated with glycogen storage disease due to aldolase A deficiency (ClinVar).

How common is ALDOA p.Arg76Cys (c.226C>T) in the general population?

ALDOA p.Arg76Cys (c.226C>T) is rare (popmax 0.113%, sas) (gnomAD).

What do computational predictors say about ALDOA p.Arg76Cys (c.226C>T)?

AlphaMissense predicts likely benign (score 0.2327) — an in-silico prediction, not a clinical call.

ALDOA p.Arg76Cys

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.226C>T · rs145582724 · VCV318826

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2327 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.113%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease due to aldolase A deficiency

Computational evidence

Protein change
AlphaMissense	0.2327	likely benign
REVEL	0.646	pathogenic-leaning
SaProt	LLR -9.76	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 0.86, phastCons 0.98
Regional constraint	o/e 0.91	unconstrained · MANE · 3,311 bp · p 0.028 · regional, not allelic
Overall
CADD	28.9	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R22C vs ClinVar R76C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.113% South Asian · 103/91,044 alleles

Filtering AF 0.0954% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0888%

Overall 0.00831% 134/1,613,434 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.113%	884
Middle Eastern	0.0366%	2,734
Remaining individualsnot grpmax-eligible	0.00801%	12,490
African / African-American	0.00533%	18,749
European (non-Finnish)	0.00169%	59,002

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.Arg76Cys
Coding: c.226C>T
MANE Select: NM_001243177
dbSNP: rs145582724
Type: single nucleotide variant
Location: chr16:30067318 (GRCh38)
Gene constraint: LOEUF 0.821 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.53 · 8 PDB
Residue 76: a β-strand

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.Arg76His 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-arg76cys (accessed [today's date]).

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