# NM_000035.4(ALDOB):c.282C>T (p.Phe94=)

https://sugi.bio/variant/aldob-p-phe94

## Summary

**ALDOB p.Phe94= (c.282C>T)** is classified **Conflicting classifications of pathogenicity** in ALDOB (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-28). Ultra-rare (popmax 0.0165%, mid); Associated with hereditary fructose intolerance.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs549682194 · 5 submitters · 1 linked condition · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the ALDOB gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 submitters, and is linked to hereditary fructose intolerance.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 10 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ALDOB is a diagnostic-grade gene on 10 Genomics England panels |

**Commonly reported features of Hereditary fructose intolerance** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abdominal pain — Very frequent (99-80%)
- Reduced aldolase level — Very frequent (99-80%)
- Growth delay — Frequent (79-30%)
- Diarrhea — Frequent (79-30%)
- Nausea — Frequent (79-30%)
- Renal insufficiency — Occasional (29-5%)
- Jaundice — Occasional (29-5%)
- Episodic hyperhidrosis — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006622/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ALDOB](https://sugi.bio/atlas/gene/ALDOB/) |
| Protein change (HGVS p.) | p.Phe94= |
| Coding change (HGVS c.) | c.282C>T |
| MANE Select transcript | [NM_000035](https://www.ncbi.nlm.nih.gov/nuccore/NM_000035) |
| dbSNP | [rs549682194](https://www.ncbi.nlm.nih.gov/snp/rs549682194/) |
| Variant type | single nucleotide variant |
| Location | chr9:101429797-101429797 (GRCh38) |
| ClinVar | [VCV758843](https://www.ncbi.nlm.nih.gov/clinvar/variation/758843/) |

**All HGVS expressions:** `LRG_1244:g.10984C>T`, `LRG_1244t1:c.282C>T`, `NC_000009.11:g.104192079G>A`, `NC_000009.12:g.101429797G>A`, `NG_012387.1:g.10984C>T`, `NM_000035.4:c.282C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 5.198, GERP 1.02, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 7.527**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0165%** (mid) · FAF95 0.00174% · FAF99 0.00104% · 1/6,062 in the highest group · 22/1,614,172 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,062 |
| African / African-American | 0.00533% | 18,763 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,836 |
| Admixed American | 0.00167% | 60,024 |
| European (non-Finnish) | 0.0011% | 90,770 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ALDOB** population constraint: LOEUF 1.183, pLI 2.3588e-11, missense-Z -0.75151. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **hereditary fructose intolerance** — Definitive (AR)

## Protein context {#protein}

Residue **94** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 96.12, 93% of residues very-high.

**4 experimental structure(s)** (PDB): [1QO5](https://www.rcsb.org/structure/1QO5), [1XDL](https://www.rcsb.org/structure/1XDL), [1XDM](https://www.rcsb.org/structure/1XDM), [8D44](https://www.rcsb.org/structure/8D44).

## What this gene does {#gene-function}

*Describes the biological roles of ALDOB (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ALDOB's established molecular role includes fructose-bisphosphate aldolase activity. In Reactome, ALDOB is annotated in disease pathway(s) including **Hereditary fructose intolerance**.

**Disease mechanism (Reactome):** ALDOB loss or alteration is curated in [Hereditary fructose intolerance](https://reactome.org/content/detail/R-HSA-5657560).

### Pathways affected {#pathways}

ALDOB participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Hereditary fructose intolerance](https://reactome.org/content/detail/R-HSA-5657560) | curated |
| [Fructose catabolism](https://reactome.org/content/detail/R-HSA-70350) | curated |
| [Gluconeogenesis](https://reactome.org/content/detail/R-HSA-70263) | curated |
| [Glycolysis](https://reactome.org/content/detail/R-HSA-70171) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** fructose-bisphosphate aldolase activity, cytoskeletal protein binding, identical protein binding, ATPase binding, molecular adaptor activity, fructose-1-phosphate aldolase activity.

**Biological process:** fructose metabolic process, glycolytic process, fructose 1,6-bisphosphate metabolic process, vacuolar proton-transporting V-type ATPase complex assembly, negative regulation of pentose-phosphate shunt.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-28.

**Submitter consensus:** conflicting (3 Likely benign, 2 Uncertain significance).

**Submission history:** 5 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-03-11 |
| Genome-Nilou Lab | Likely benign | criteria provided, single submitter | clinical testing | 2021-05-18 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-28 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2023-07-25 |

## Associated conditions {#conditions}

[hereditary fructose intolerance](https://sugi.bio/atlas/disease/hereditary-fructose-intolerance/).

**Reported phenotype names (ClinVar):** Hereditary fructosuria, ALDOB-related disorder, ALDOB-related condition, Fructose intolerance, ALDOB DEFICIENCY, ALDOLASE B DEFICIENCY, FRUCTOSE-1,6-BISPHOSPHATE ALDOLASE B DEFICIENCY, FRUCTOSE-1-PHOSPHATE ALDOLASE DEFICIENCY, FRUCTOSEMIA, Hereditary fructose intolerance.

## Similar variants {#similar}

Related ALDOB variant pages (same residue, condition, or type): [ALDOB p.Phe94Leu](/variant/aldob-p-phe94leu), [ALDOB c.113-1G>C](/variant/aldob-c-113-minus-1g-c), [ALDOB c.324+1G>A](/variant/aldob-c-324-plus-1g-a), [ALDOB c.324+2T>A](/variant/aldob-c-324-plus-2t-a), [ALDOB c.379+1G>A](/variant/aldob-c-379-plus-1g-a), [ALDOB c.379+1G>T](/variant/aldob-c-379-plus-1g-t), [ALDOB c.380-1G>A](/variant/aldob-c-380-minus-1g-a), [ALDOB c.380-2A>G](/variant/aldob-c-380-minus-2a-g).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 758843). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*