# NM_001243177.4(ALDOA):c.733A>G (p.Ile245Val)

https://sugi.bio/variant/aldoa-p-ile245val

## Summary

**ALDOA p.Ile245Val (c.733A>G)** is classified **Uncertain significance** in ALDOA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-08). AlphaMissense: likely benign (0.1379); Ultra-rare (popmax 0.02%, amr); Associated with glycogen storage disease due to aldolase A deficiency.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1239332534 · 1 submitter · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.02%, amr)

## For patients & families {#patients}

This is a change in the ALDOA gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to glycogen storage disease due to aldolase A deficiency.

*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) | Neonatal |

**Commonly reported features of Glycogen storage disease due to aldolase A deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Fever — Very frequent (99-80%)
- Reduced aldolase level — Very frequent (99-80%)
- Muscle weakness — Frequent (79-30%)
- Hemolytic anemia — Frequent (79-30%)
- Myalgia — Frequent (79-30%)
- EMG: myopathic abnormalities — Frequent (79-30%)
- Viral infection-induced rhabdomyolysis — Frequent (79-30%)
- Skeletal myopathy — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000600/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ALDOA](https://sugi.bio/atlas/gene/ALDOA/) |
| Protein change (HGVS p.) | p.Ile245Val |
| Coding change (HGVS c.) | c.733A>G |
| dbSNP | [rs1239332534](https://www.ncbi.nlm.nih.gov/snp/rs1239332534/) |
| Variant type | single nucleotide variant |
| Location | chr16:30069336-30069336 (GRCh38) |
| ClinVar | [VCV1964812](https://www.ncbi.nlm.nih.gov/clinvar/variation/1964812/) |

**All HGVS expressions:** `LRG_1180:g.21167A>G`, `LRG_1180t1:c.571A>G`, `LRG_1180t2:c.733A>G`, `NC_000016.10:g.30069336A>G`, `NC_000016.9:g.30080657A>G`, `NG_008010.1:g.21167A>G`, `NM_001127617.2:c.571A>G`, `NM_001243177.4:c.733A>G`, `NM_001365304.2:c.*1080A>G`, `NM_001365305.2:c.*1080A>G`, `NM_001365307.2:c.*1080A>G`, `NM_184041.5:c.571A>G`, `NM_184043.2:c.571A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1379)
- REVEL 0.288 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.241 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 9.364, GERP 1.93, phastCons 1 — highly conserved (differs from AlphaMissense)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **I191V** vs ClinVar **I245V**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 21.5**. 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 0.91** across the covering region of the MANE Select transcript (30,066,898–30,070,209), spanning 3,311 bp. Chi-square p 0.028. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.02%** (amr) · FAF95 0.0115% · FAF99 0.00898% · 12/59,998 in the highest group · 12/1,613,938 alleles overall — ultra-rare (popmax 0.02%, amr).

*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.*

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-05-08.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-05-08 |

## Associated conditions {#conditions}

[glycogen storage disease due to aldolase A deficiency](https://sugi.bio/atlas/disease/glycogen-storage-disease-due-to-aldolase-a-deficiency/).

**Reported phenotype names (ClinVar):** HNSHA due to aldolase A deficiency, GLYCOGEN STORAGE DISEASE XII, GSD XII, RED CELL ALDOLASE DEFICIENCY, Glycogen storage disease due to aldolase A deficiency.

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 1964812). 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.*