Is ALDOA p.Leu375Pro (c.1124T>C) pathogenic?

ALDOA p.Leu375Pro (c.1124T>C) is classified Uncertain significance in ALDOA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-05). AlphaMissense: ambiguous (0.5262); Very rare (popmax 0.00446%, eas); Associated with glycogen storage disease due to aldolase A deficiency.

What condition is associated with ALDOA p.Leu375Pro (c.1124T>C)?

ALDOA p.Leu375Pro (c.1124T>C) is associated with glycogen storage disease due to aldolase A deficiency (ClinVar).

How common is ALDOA p.Leu375Pro (c.1124T>C) in the general population?

ALDOA p.Leu375Pro (c.1124T>C) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about ALDOA p.Leu375Pro (c.1124T>C)?

AlphaMissense predicts ambiguous (score 0.5262) — an in-silico prediction, not a clinical call.

ALDOA p.Leu375Pro

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.1124T>C · rs146116144 · VCV2109238

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5262 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

glycogen storage disease due to aldolase A deficiency

Computational evidence

Protein change
AlphaMissense	0.5262	ambiguous
REVEL	0.474	indeterminate
SaProt	LLR -13.15	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -0.12, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 3,311 bp · p 0.028 · regional, not allelic
Overall
CADD	18.64	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 L321P vs ClinVar L375P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,854 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000205% 3/1,461,564 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,427
European (non-Finnish)	8.47e-05%	1,179,994

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.Leu375Pro
Coding: c.1124T>C
MANE Select: NM_001243177
dbSNP: rs146116144
Type: single nucleotide variant
Location: chr16:30069992 (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.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
ALDOA p.Arg146Cys 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-leu375pro (accessed [today's date]).

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