# NM_002633.3(PGM1):c.1137C>T (p.Phe379=)

https://sugi.bio/variant/pgm1-p-phe379

## Summary

**PGM1 p.Phe379= (c.1137C>T)** is classified **Likely benign** in PGM1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-03). Ultra-rare (popmax 0.0521%, afr); Associated with PGM1-congenital disorder of glycosylation.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs367648776 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0521%, afr)

## For patients & families {#patients}

This is a change in the PGM1 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to PGM1-congenital disorder of glycosylation.

*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) | Infancy, Neonatal |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | PGM1 is a diagnostic-grade gene on 16 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0004329/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PGM1](https://sugi.bio/atlas/gene/PGM1/) |
| Protein change (HGVS p.) | p.Phe379= |
| Coding change (HGVS c.) | c.1137C>T |
| MANE Select transcript | [NM_002633](https://www.ncbi.nlm.nih.gov/nuccore/NM_002633) |
| dbSNP | [rs367648776](https://www.ncbi.nlm.nih.gov/snp/rs367648776/) |
| Variant type | single nucleotide variant |
| Location | chr1:63638793-63638793 (GRCh38) |
| ClinVar | [VCV518065](https://www.ncbi.nlm.nih.gov/clinvar/variation/518065/) |

**All HGVS expressions:** `NC_000001.10:g.64104464C>T`, `NC_000001.11:g.63638793C>T`, `NG_016966.1:g.50518C>T`, `NM_001172818.1:c.1191C>T`, `NM_001172819.2:c.546C>T`, `NM_002633.3:c.1137C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.23) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.694, GERP -3.25, phastCons 0.008 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 10.88**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.23**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.23**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.20** (loss), gain 0.00 / loss 0.20. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0521%** (afr) · FAF95 0.0391% · FAF99 0.0346% · 39/74,852 in the highest group · 154/1,610,822 alleles overall — ultra-rare (popmax 0.0521%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0521% | 1,919 |
| Admixed American | 0.0467% | 2,142 |
| Remaining individuals (not grpmax-eligible) | 0.016% | 6,238 |
| South Asian | 0.0121% | 8,275 |
| East Asian | 0.0111% | 8,974 |
| European (non-Finnish) | 0.0051% | 19,619 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,034 |

*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.*

## Gene constraint & dosage {#gene-context}

**PGM1** population constraint: LOEUF 1.189, pLI 6.9806e-17, missense-Z 0.48596; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **PGM1-congenital disorder of glycosylation** — Definitive (AR)

## Protein context {#protein}

Residue **379** lies in a turn.

AlphaFold model confidence (whole protein): pLDDT 97.27, 97% of residues very-high.

**16 experimental structure(s)** (PDB): [5EPC](https://www.rcsb.org/structure/5EPC), [5F9C](https://www.rcsb.org/structure/5F9C), [5HSH](https://www.rcsb.org/structure/5HSH), [5JN5](https://www.rcsb.org/structure/5JN5), [5TR2](https://www.rcsb.org/structure/5TR2), [5VBI](https://www.rcsb.org/structure/5VBI) — incl. mutant structure 5F9C.

## What this gene does {#gene-function}

*Describes the biological roles of PGM1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** PGM1's established molecular role includes magnesium ion binding. In Reactome, PGM1 is annotated in disease pathway(s) including **Defective PGM1 causes PGM1-CDG**.

**Disease mechanism (Reactome):** PGM1 loss or alteration is curated in [Defective PGM1 causes PGM1-CDG](https://reactome.org/content/detail/R-HSA-5609974).

### Pathways affected {#pathways}

PGM1 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective PGM1 causes PGM1-CDG](https://reactome.org/content/detail/R-HSA-5609974) | curated |
| [Galactose catabolism](https://reactome.org/content/detail/R-HSA-70370) | curated |
| [Glycogen breakdown (glycogenolysis)](https://reactome.org/content/detail/R-HSA-70221) | curated |
| [Glycogen synthesis](https://reactome.org/content/detail/R-HSA-3322077) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** magnesium ion binding, phosphoglucomutase activity.

**Biological process:** glycogen catabolic process, glucose metabolic process, beta-D-galactose catabolic process via UDP-galactose, Leloir pathway.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-03.

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

**Submission history:** 2 submissions (2017–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2017-07-07 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-10-03 |

## Associated conditions {#conditions}

[PGM1-congenital disorder of glycosylation](https://sugi.bio/atlas/disease/pgm1-congenital-disorder-of-glycosylation/).

**Reported phenotype names (ClinVar):** PGM1-congenital disorder of glycosylation, not specified, AllHighlyPenetrant, GSD XIV, CDG It, Congenital disorder of glycosylation type 1t, PHOSPHOGLUCOMUTASE 1 DEFICIENCY, PGM1 DEFICIENCY, GLYCOGEN STORAGE DISEASE XIV.

## Similar variants {#similar}

Related PGM1 variant pages (same residue, condition, or type): [PGM1 p.Arg217Ter](/variant/pgm1-p-arg217ter), [PGM1 p.Arg293Ter](/variant/pgm1-p-arg293ter), [PGM1 p.Arg499Ter](/variant/pgm1-p-arg499ter), [PGM1 p.Arg503Ter](/variant/pgm1-p-arg503ter), [PGM1 p.Arg515Gln](/variant/pgm1-p-arg515gln), [PGM1 p.Asp263Tyr](/variant/pgm1-p-asp263tyr), [PGM1 p.Gly291Arg](/variant/pgm1-p-gly291arg), [PGM1 p.Gly330Arg](/variant/pgm1-p-gly330arg).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 518065). 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.*