# NM_000035.4(ALDOB):c.911G>C (p.Arg304Pro)

https://sugi.bio/variant/aldob-p-arg304pro

## Summary

**ALDOB p.Arg304Pro (c.911G>C)** is classified **Uncertain significance** in ALDOB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-03). AlphaMissense: likely pathogenic (0.9852); Very rare (popmax 0.000124%).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs145078268 · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.000124%)

## For patients & families {#patients}

This is a change in the ALDOB gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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.*

**Support & next steps:** [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.Arg304Pro |
| Coding change (HGVS c.) | c.911G>C |
| MANE Select transcript | [NM_000035](https://www.ncbi.nlm.nih.gov/nuccore/NM_000035) |
| dbSNP | [rs145078268](https://www.ncbi.nlm.nih.gov/snp/rs145078268/) |
| Variant type | single nucleotide variant |
| Location | chr9:101424931-101424931 (GRCh38) |
| ClinVar | [VCV3251577](https://www.ncbi.nlm.nih.gov/clinvar/variation/3251577/) |

**All HGVS expressions:** `LRG_1244:g.15850G>C`, `LRG_1244t1:c.911G>C`, `NC_000009.11:g.104187213C>G`, `NC_000009.12:g.101424931C>G`, `NG_012387.1:g.15850G>C`, `NM_000035.4:c.911G>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9852)
- REVEL 0.952 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.671 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.672, GERP 2.05, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 3%** most-pathogenic-predicted substitutions in ALDOB (of 2,145 modeled).
- CADD: **PHRED 32.0**. 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.*
- Regional missense constraint: **o/e 1.16** across the covering region of the MANE Select transcript (101,421,812–101,430,887), spanning 9,075 bp. Chi-square p 0.00067. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>T, Δ0.42 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): global (via dbSNP) **0.000124%** · 2/1,614,018 alleles overall — very rare (popmax 0.000124%).

*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 **304** lies in a UniProt-annotated variant site (in hfi; 100-fold decrease in catalytic efficiency for substrates f1,6bp and f1p); a UniProt-annotated variant site (in hfi; turkey; 4800-fold decrease in catalytic efficiency for f1,6bp and inactive with f1p); a binding site; 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-04-03.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-03 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related ALDOB variant pages (same residue, condition, or type): [ALDOB p.Arg304Gln](/variant/aldob-p-arg304gln), [ALDOB p.Arg304Trp](/variant/aldob-p-arg304trp), [ALDOB p.Arg304=](/variant/aldob-p-arg304), [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).

### 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 3251577). 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.*