# NM_000289.6(PFKM):c.1956C>T (p.Phe652=)

https://sugi.bio/variant/pfkm-p-phe652

## Summary

**PFKM p.Phe652= (c.1956C>T)** is classified **Likely benign** in PFKM (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-21). Ultra-rare (popmax 0.016%, afr); Associated with glycogen storage disease VII.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs771733776 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.016%, afr)

## For patients & families {#patients}

This is a change in the PFKM gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to glycogen storage disease VII.

*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, Adult, Childhood, Infancy |
| Clinical trials | 4 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | PFKM is a diagnostic-grade gene on 15 Genomics England panels |

**Commonly reported features of Glycogen storage disease due to muscle phosphofructokinase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Anemia — Very frequent (99-80%)
- Myotonia — Very frequent (99-80%)
- Increased muscle glycogen content — Very frequent (99-80%)
- Muscle weakness — Frequent (79-30%)
- Hyperuricemia — Frequent (79-30%)
- Skeletal muscle atrophy — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005686/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PFKM](https://sugi.bio/atlas/gene/PFKM/) |
| Protein change (HGVS p.) | p.Phe652= |
| Coding change (HGVS c.) | c.1956C>T |
| MANE Select transcript | [NM_000289](https://www.ncbi.nlm.nih.gov/nuccore/NM_000289) |
| dbSNP | [rs771733776](https://www.ncbi.nlm.nih.gov/snp/rs771733776/) |
| Variant type | single nucleotide variant |
| Location | chr12:48144121-48144121 (GRCh38) |
| ClinVar | [VCV1096409](https://www.ncbi.nlm.nih.gov/clinvar/variation/1096409/) |

**All HGVS expressions:** `LRG_1177:g.43869C>T`, `LRG_1177t1:c.1956C>T`, `NC_000012.11:g.48537904C>T`, `NC_000012.12:g.48144121C>T`, `NG_016199.2:g.43869C>T`, `NM_000289.6:c.1956C>T`, `NM_001166686.2:c.2169C>T`, `NM_001166687.2:c.1956C>T`, `NM_001166688.2:c.1956C>T`, `NM_001354735.1:c.2265C>T`, `NM_001354736.1:c.2265C>T`, `NM_001354737.1:c.2169C>T`, `NM_001354738.1:c.2169C>T`, `NM_001354739.1:c.2169C>T`, `NM_001354740.1:c.2100C>T`, `NM_001354741.2:c.1980C>T`, `NM_001354742.2:c.1956C>T`, `NM_001354743.2:c.1956C>T`, `NM_001354744.2:c.1956C>T`, `NM_001354745.2:c.1869C>T`, `NM_001354746.2:c.1830C>T`, `NM_001354747.2:c.1806C>T`, `NM_001354748.2:c.1806C>T`, `NM_001363619.2:c.1863C>T`, `NR_148954.2:n.2259C>T`, `NR_148955.1:n.3029C>T`, `NR_148956.2:n.2185C>T`, `NR_148957.2:n.2414C>T`, `NR_148958.2:n.2162C>T`, `NR_148959.2:n.2088C>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 (below), not from a missing predictor score.
- Conservation: phyloP -4.392, GERP -4.05 — fast-evolving / accelerated position
- CADD: **PHRED 8.034**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.63 donor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.016%** (afr) · FAF95 0.00921% · FAF99 0.00722% · 12/74,920 in the highest group · 35/1,613,272 alleles overall — ultra-rare (popmax 0.016%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.016% | 6,243 |
| Admixed American | 0.005% | 19,997 |
| European (non-Finnish) | 0.00161% | 62,072 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,458 |

*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}

**PFKM** population constraint: LOEUF 0.774, pLI 9.8978e-10, missense-Z 4.0772. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **652** lies in the 'c-terminal regulatory pfk domain 2' region.

AlphaFold model confidence (whole protein): pLDDT 91.66, 83% of residues very-high.

**1 experimental structure(s)** (PDB): [4OMT](https://www.rcsb.org/structure/4OMT).

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

*Describes the biological roles of PFKM (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:** PFKM's established molecular role includes 6-phosphofructokinase activity. p.Phe652= falls in the c-terminal regulatory pfk domain 2 region.


### Pathways affected {#pathways}

PFKM participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Glycolysis](https://reactome.org/content/detail/R-HSA-70171) | curated |

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

**Molecular function:** 6-phosphofructokinase activity, ATP binding, kinase binding, identical protein binding, fructose binding.

**Biological process:** fructose 6-phosphate metabolic process, glycolytic process, positive regulation of transcription by RNA polymerase II, muscle cell cellular homeostasis, glycolytic process through fructose-6-phosphate.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-21.

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

**Submission history:** 2 submissions (2024–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-21 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2024-05-01 |

## Associated conditions {#conditions}

[glycogen storage disease VII](https://sugi.bio/atlas/disease/glycogen-storage-disease-vii/).

**Reported phenotype names (ClinVar):** Glycogen storage disease, type VII, not provided, none provided, GSD VII, MUSCLE PHOSPHOFRUCTOKINASE DEFICIENCY, PFKM DEFICIENCY, TARUI DISEASE.

## Similar variants {#similar}

Related PFKM variant pages (same residue, condition, or type): [PFKM c.1062+1G>A](/variant/pfkm-c-1062-plus-1g-a), [PFKM c.1128-2A>G](/variant/pfkm-c-1128-minus-2a-g), [PFKM c.1191+1G>A](/variant/pfkm-c-1191-plus-1g-a), [PFKM c.1412+1G>T](/variant/pfkm-c-1412-plus-1g-t), [PFKM c.1412+2T>C](/variant/pfkm-c-1412-plus-2t-c), [PFKM c.1413-2A>G](/variant/pfkm-c-1413-minus-2a-g), [PFKM c.1413-64A>G](/variant/pfkm-c-1413-minus-64a-g), [PFKM c.1500+1G>A](/variant/pfkm-c-1500-plus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 1096409). 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.*