# NM_000290.4(PGAM2):c.28C>T (p.Arg10Trp)

https://sugi.bio/variant/pgam2-p-arg10trp

## Summary

**PGAM2 p.Arg10Trp (c.28C>T)** is classified **Uncertain significance** in PGAM2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-07-04). AlphaMissense: likely pathogenic (0.9852); Ultra-rare (popmax 0.0212%, nfe); Associated with glycogen storage disease due to phosphoglycerate mutase deficiency.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs529371882 · 4 submitters · 1 linked condition · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0212%, nfe)

## For patients & families {#patients}

This is a change in the PGAM2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 4 submitters, and is linked to glycogen storage disease due to phosphoglycerate mutase 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) | Adolescent, Childhood |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009964/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PGAM2](https://sugi.bio/atlas/gene/PGAM2/) |
| Protein change (HGVS p.) | p.Arg10Trp |
| Coding change (HGVS c.) | c.28C>T |
| MANE Select transcript | [NM_001014436](https://www.ncbi.nlm.nih.gov/nuccore/NM_001014436) (variant reported on NM_000290) |
| dbSNP | [rs529371882](https://www.ncbi.nlm.nih.gov/snp/rs529371882/) |
| Variant type | single nucleotide variant |
| Location | chr7:44065502-44065502 (GRCh38) |
| ClinVar | [VCV2060414](https://www.ncbi.nlm.nih.gov/clinvar/variation/2060414/) |

**All HGVS expressions:** `NC_000007.13:g.44105101G>A`, `NC_000007.14:g.44065502G>A`, `NG_013016.1:g.5086C>T`, `NM_000290.4:c.28C>T`, `NM_001014436.3:c.*4586G>A`, `NM_001122956.2:c.*4586G>A`, `NM_001284313.2:c.*4586G>A`, `NM_001284315.2:c.*4586G>A`, `NM_001362723.2:c.*4586G>A`, `NM_014063.7:c.*4586G>A`

## 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 0.849 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.266 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.528, GERP 1.84, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 28.0**. 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 0.98** across the covering region of the MANE Select transcript (44,062,767–44,065,529), spanning 2,762 bp. Chi-square p 0.7. 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 **0.0212%** (nfe) · FAF95 0.019% · FAF99 0.0182% · 250/1,180,036 in the highest group · 266/1,613,890 alleles overall — ultra-rare (popmax 0.0212%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0212% | 4,720 |
| South Asian | 0.00659% | 15,182 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,827 |
| African / African-American | 0.004% | 24,975 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,606 |
| Finnish (not grpmax-eligible) | 0.00313% | 31,926 |
| Admixed American | 0.00167% | 60,008 |

*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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-07-04.

**Submitter consensus:** unanimous (4/4 Uncertain significance).

**Submission history:** 4 submissions (2022–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-06-28 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-28 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-04 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-07-18 |

## Associated conditions {#conditions}

[glycogen storage disease due to phosphoglycerate mutase deficiency](https://sugi.bio/atlas/disease/glycogen-storage-disease-due-to-phosphoglycerate-mutase-deficiency/).

**Reported phenotype names (ClinVar):** Glycogen storage disease type X, Inborn genetic diseases, not provided, Glycogen storage disease due to phosphoglycerate mutase deficiency, GSD X, MYOPATHY DUE TO PHOSPHOGLYCERATE MUTASE DEFICIENCY, PGAMM DEFICIENCY, PHOSPHOGLYCERATE MUTASE, MUSCLE, DEFICIENCY OF, Dimauro disease, none provided.

### 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 2060414). 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.*