# NM_000290.4(PGAM2):c.363C>T (p.Ile121=)

https://sugi.bio/variant/pgam2-p-ile121

## Summary

**PGAM2 p.Ile121= (c.363C>T)** is classified **Likely benign** in PGAM2 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-04-26). Very rare (popmax 0.00801%, afr); Associated with glycogen storage disease due to phosphoglycerate mutase deficiency.

**At a glance:** Likely benign · review: Single submitter · rsID rs768642477 · 2 submitters · 1 linked condition · very rare (popmax 0.00801%, afr)

## For patients & families {#patients}

This is a change in the PGAM2 gene that is classified as likely benign — not considered disease-causing, 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.Ile121= |
| Coding change (HGVS c.) | c.363C>T |
| MANE Select transcript | [NM_001014436](https://www.ncbi.nlm.nih.gov/nuccore/NM_001014436) (variant reported on NM_000290) |
| dbSNP | [rs768642477](https://www.ncbi.nlm.nih.gov/snp/rs768642477/) |
| Variant type | single nucleotide variant |
| Location | chr7:44065167-44065167 (GRCh38) |
| ClinVar | [VCV1602236](https://www.ncbi.nlm.nih.gov/clinvar/variation/1602236/) |

**All HGVS expressions:** `NC_000007.13:g.44104766G>A`, `NC_000007.14:g.44065167G>A`, `NG_013016.1:g.5421C>T`, `NG_177788.1:g.114G>A`, `NG_177789.1:g.4G>A`, `NM_000290.4:c.363C>T`, `NM_001014436.3:c.*4251G>A`, `NM_001122956.2:c.*4251G>A`, `NM_001284313.2:c.*4251G>A`, `NM_001284315.2:c.*4251G>A`, `NM_001362723.2:c.*4251G>A`, `NM_014063.7:c.*4251G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 2.489, GERP 0.704, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 14.0**. 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.*
- 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 **0.00801%** (afr) · FAF95 0.00347% · FAF99 0.00229% · 6/74,874 in the highest group · 8/1,613,818 alleles overall — very rare (popmax 0.00801%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00801% | 12,479 |
| Admixed American | 0.00167% | 59,986 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,482 |

*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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-04-26.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2023–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2023-08-30 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-04-26 |

## 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, PGAM2-related disorder, PGAMM DEFICIENCY, PHOSPHOGLYCERATE MUTASE, MUSCLE, DEFICIENCY OF, Dimauro disease, Glycogen storage disease due to phosphoglycerate mutase deficiency, GSD X, MYOPATHY DUE TO PHOSPHOGLYCERATE MUTASE DEFICIENCY, PGAM2-related condition.

### 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 1602236). 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.*