# NM_001243177.4(ALDOA):c.715C>T (p.Pro239Ser)

https://sugi.bio/variant/aldoa-p-pro239ser

## Summary

**ALDOA p.Pro239Ser (c.715C>T)** is classified **Uncertain significance** in ALDOA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-29). AlphaMissense: likely pathogenic (0.9924); Very rare (popmax 0.00407%, nfe); Associated with glycogen storage disease due to aldolase A deficiency.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00407%, nfe)

## 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.Pro239Ser |
| Coding change (HGVS c.) | c.715C>T |
| Variant type | single nucleotide variant |
| Location | chr16:30069318-30069318 (GRCh38) |
| ClinVar | [VCV4077902](https://www.ncbi.nlm.nih.gov/clinvar/variation/4077902/) |

**All HGVS expressions:** `LRG_1180:g.21149C>T`, `LRG_1180t1:c.553C>T`, `LRG_1180t2:c.715C>T`, `NC_000016.10:g.30069318C>T`, `NC_000016.9:g.30080639C>T`, `NG_008010.1:g.21149C>T`, `NM_001127617.2:c.553C>T`, `NM_001243177.4:c.715C>T`, `NM_001365304.2:c.*1062C>T`, `NM_001365305.2:c.*1062C>T`, `NM_001365307.2:c.*1062C>T`, `NM_184041.5:c.553C>T`, `NM_184043.2:c.553C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9924)
- REVEL 0.979 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.99 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 5.988, GERP 0.84, phastCons 1 — highly conserved (agrees)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **P185S** vs ClinVar **P239S**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 26.9**. 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 **0.00407%** (nfe) · FAF95 0.00315% · FAF99 0.00279% · 48/1,180,038 in the highest group · 49/1,614,068 alleles overall — very rare (popmax 0.00407%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00407% | 24,584 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,486 |

*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 2024-05-29.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-05-29 |

## 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 2026-10-11); 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 4077902). 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.*