Is ALDOA p.Arg123Cys (c.367C>T) pathogenic?

ALDOA p.Arg123Cys (c.367C>T) is classified Uncertain significance in ALDOA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-30). AlphaMissense: ambiguous (0.3417); Very rare (popmax 0.00439%, sas).

How common is ALDOA p.Arg123Cys (c.367C>T) in the general population?

ALDOA p.Arg123Cys (c.367C>T) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about ALDOA p.Arg123Cys (c.367C>T)?

AlphaMissense predicts ambiguous (score 0.3417) — an in-silico prediction, not a clinical call.

ALDOA p.Arg123Cys

c.367C>T · VCV3380381

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3417 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Computational evidence

Protein change
AlphaMissense	0.3417	ambiguous
REVEL	0.54	indeterminate
SaProt	LLR -10.81	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 3,311 bp · p 0.028 · regional, not allelic
Overall
CADD	29.7	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 R69C vs ClinVar R123C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00439% South Asian · 4/91,080 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000868% 14/1,613,734 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,770
African / African-American	0.00134%	74,870
European (non-Finnish)	0.000763%	131,114

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.Arg123Cys
Coding: c.367C>T
MANE Select: NM_001243177
Type: single nucleotide variant
Location: chr16:30067542 (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 123: a β-strand

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

Similar variants

ALDOA p.Arg123His Uncertain significance ★ same residue
ALDOA p.Arg123= Likely benign ★ same residue
ALDOA p.Ala334Val Pathogenic/Likely pathogenic ★★ same type
ALDOA c.274+5G>A Uncertain significance ★★ same type
ALDOA p.Ala142Val Uncertain significance ★★ same type
ALDOA p.Ala217Thr Uncertain significance ★★ same type
ALDOA p.Ala310Val Uncertain significance ★★ same type
ALDOA p.Ala377Ser Uncertain significance ★★ same type

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-arg123cys (accessed [today's date]).

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