Is ALDOA p.Ala217Thr (c.649G>A) pathogenic?

ALDOA p.Ala217Thr (c.649G>A) is classified Uncertain significance in ALDOA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-07). AlphaMissense: likely pathogenic (0.8463); Ultra-rare (popmax 0.0132%, sas); Associated with Inborn genetic diseases.

What condition is associated with ALDOA p.Ala217Thr (c.649G>A)?

ALDOA p.Ala217Thr (c.649G>A) is associated with Inborn genetic diseases, glycogen storage disease due to aldolase A deficiency (ClinVar).

How common is ALDOA p.Ala217Thr (c.649G>A) in the general population?

ALDOA p.Ala217Thr (c.649G>A) is ultra-rare (popmax 0.0132%, sas) (gnomAD).

What do computational predictors say about ALDOA p.Ala217Thr (c.649G>A)?

AlphaMissense predicts likely pathogenic (score 0.8463) — an in-silico prediction, not a clinical call.

ALDOA p.Ala217Thr

c.649G>A · rs761705909 · VCV2177784

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8463 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8463	likely pathogenic
REVEL	0.9	moderately pathogenic-leaning
SaProt	LLR -13.18	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 10	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 3,311 bp · p 0.028 · regional, not allelic
Overall
CADD	26.0	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 A163T vs ClinVar A217T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0132% South Asian · 12/91,094 alleles

Filtering AF 0.0075% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.00322% 52/1,614,074 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0132%	7,591
African / African-American	0.00667%	14,983
Remaining individualsnot grpmax-eligible	0.0032%	31,244
European (non-Finnish)	0.0028%	35,759

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.Ala217Thr
Coding: c.649G>A
MANE Select: NM_001243177
dbSNP: rs761705909
Type: single nucleotide variant
Location: chr16:30068925 (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 217: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: glycogen storage disease due to aldolase A deficiency

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.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
ALDOA p.Arg188Cys 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-ala217thr (accessed [today's date]).

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