Is ALDOB p.Arg134Ser (c.400C>A) pathogenic?

ALDOB p.Arg134Ser (c.400C>A) is classified Benign/Likely benign in ALDOB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-31). AlphaMissense: likely pathogenic (0.8648); Rare (popmax 0.652%, afr); Associated with hereditary fructose intolerance.

What condition is associated with ALDOB p.Arg134Ser (c.400C>A)?

ALDOB p.Arg134Ser (c.400C>A) is associated with hereditary fructose intolerance (ClinVar).

How common is ALDOB p.Arg134Ser (c.400C>A) in the general population?

ALDOB p.Arg134Ser (c.400C>A) is rare (popmax 0.652%, afr) (gnomAD).

How is Hereditary fructose intolerance inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ALDOB p.Arg134Ser (c.400C>A)?

AlphaMissense predicts likely pathogenic (score 0.8648) — an in-silico prediction, not a clinical call.

ALDOB p.Arg134Ser

c.400C>A · rs10123355 · VCV732136

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8648 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.652%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary fructose intolerance

Computational evidence

Protein change
AlphaMissense	0.8648	likely pathogenic
REVEL	0.72	pathogenic-leaning
SaProt	LLR -14.80	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 9,075 bp · p 0.00067 · regional, not allelic
Overall
CADD	28.1	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.652% African / African-American · 489/75,014 alleles

Filtering AF 0.604% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.585%

Overall 0.0912% 1,472/1,614,094 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.3%	77
African / African-Americangrpmax	0.652%	153
Remaining individualsnot grpmax-eligible	0.0816%	1,226
Middle Eastern	0.0495%	2,020
Admixed American	0.0133%	7,502
European (non-Finnish)	0.00746%	13,409
East Asian	0.00223%	44,868
South Asian	0.0022%	45,541

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg134Ser
Coding: c.400C>A
MANE Select: NM_000035
dbSNP: rs10123355
Type: single nucleotide variant
Location: chr9:101427622 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.12 · 4 PDB
Residue 134: a UniProt-annotated variant site (in); an α-helix

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

Disease context

hereditary fructose intolerance — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary fructose intolerance (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

ALDOB p.Arg134His Uncertain significance ★★ ⚠ same residue
ALDOB p.Arg134= Likely benign ★ same residue
ALDOB p.Arg134Cys Uncertain significance ★ ⚠ 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

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-arg134ser (accessed [today's date]).

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