Is ALDOB p.Arg46Trp (c.136A>T) pathogenic?

ALDOB p.Arg46Trp (c.136A>T) is classified Uncertain significance in ALDOB (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-07-22). AlphaMissense: likely benign (0.3103); Ultra-rare (popmax 0.0166%, mid); Associated with ALDOB-related disorder.

What condition is associated with ALDOB p.Arg46Trp (c.136A>T)?

ALDOB p.Arg46Trp (c.136A>T) is associated with ALDOB-related disorder, hereditary fructose intolerance (ClinVar).

How common is ALDOB p.Arg46Trp (c.136A>T) in the general population?

ALDOB p.Arg46Trp (c.136A>T) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about ALDOB p.Arg46Trp (c.136A>T)?

AlphaMissense predicts likely benign (score 0.3103) — an in-silico prediction, not a clinical call.

ALDOB p.Arg46Trp

c.136A>T · rs41281039 · VCV30979

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.3103 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ALDOB-related disorder

Computational evidence

Protein change
AlphaMissense	0.3103	likely benign
REVEL	0.573	indeterminate
SaProt	LLR -8.79	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP -2.5, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 9,075 bp · p 0.00067 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,040 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00186% 30/1,614,144 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,040
Admixed American	0.00666%	15,004
European (non-Finnish)	0.00212%	47,201

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: ALDOB
Protein: p.Arg46Trp
Coding: c.136A>T
MANE Select: NM_000035
dbSNP: rs41281039
Type: single nucleotide variant
Location: chr9:101429943 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.12 · 4 PDB
Residue 46: a UniProt-annotated variant site (in hfi; reduced enzymatic activity); an α-helix

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

Disease context

ALDOB-related disorder

Also linked: hereditary fructose intolerance

Similar variants

ALDOB p.Arg46Lys Uncertain significance ★ ⚠ same residue
ALDOB p.Arg46fs Pathogenic ★ same residue
ALDOB c.113-1G>C Pathogenic/Likely pathogenic ★★ same condition
ALDOB c.324+1G>A Pathogenic ★★ same condition
ALDOB c.324+2T>A Pathogenic ★★ same condition
ALDOB c.379+1G>A Likely pathogenic ★★ same condition
ALDOB c.379+1G>T Pathogenic/Likely pathogenic ★★ same condition
ALDOB c.380-1G>A Pathogenic/Likely pathogenic ★★ 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/aldob-p-arg46trp (accessed [today's date]).

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