# NM_000290.4(PGAM2):c.14G>A (p.Arg5His)

https://sugi.bio/variant/pgam2-p-arg5his

## Summary

**PGAM2 p.Arg5His (c.14G>A)** is classified **Uncertain significance** in PGAM2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-12). AlphaMissense: likely benign (0.1457); Ultra-rare (popmax 0.0164%, mid); Associated with glycogen storage disease due to phosphoglycerate mutase deficiency.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs756010000 · 2 submitters · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0164%, mid)

## 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 2 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.Arg5His |
| Coding change (HGVS c.) | c.14G>A |
| MANE Select transcript | [NM_001014436](https://www.ncbi.nlm.nih.gov/nuccore/NM_001014436) (variant reported on NM_000290) |
| dbSNP | [rs756010000](https://www.ncbi.nlm.nih.gov/snp/rs756010000/) |
| Variant type | single nucleotide variant |
| Location | chr7:44065516-44065516 (GRCh38) |
| ClinVar | [VCV2184837](https://www.ncbi.nlm.nih.gov/clinvar/variation/2184837/) |

**All HGVS expressions:** `NC_000007.13:g.44105115C>T`, `NC_000007.14:g.44065516C>T`, `NG_013016.1:g.5072G>A`, `NM_000290.4:c.14G>A`, `NM_001014436.3:c.*4600C>T`, `NM_001122956.2:c.*4600C>T`, `NM_001284313.2:c.*4600C>T`, `NM_001284315.2:c.*4600C>T`, `NM_001362723.2:c.*4600C>T`, `NM_014063.7:c.*4600C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1457)
- REVEL 0.599 (indeterminate)
- SaProt LLR -7.254 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 0.596, GERP 0.749, phastCons 0.948 — weakly conserved position
- CADD: **PHRED 24.8**. 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 **0.0164%** (mid) · FAF95 0.00286% · FAF99 0.00195% · 1/6,084 in the highest group · 33/1,613,854 alleles overall — ultra-rare (popmax 0.0164%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0164% | 6,084 |
| South Asian | 0.00659% | 15,181 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,621 |
| European (non-Finnish) | 0.00186% | 53,637 |

*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 2024-04-12.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-03-29 |

## 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, not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided, Glycogen storage disease due to phosphoglycerate mutase deficiency, PGAMM DEFICIENCY, PHOSPHOGLYCERATE MUTASE, MUSCLE, DEFICIENCY OF, Dimauro disease, GSD X.

### 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 2184837). 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.*