# NM_000340.2(SLC2A2):c.240T>C (p.Pro80=)

https://sugi.bio/variant/slc2a2-p-pro80

## Summary

**SLC2A2 p.Pro80= (c.240T>C)** is classified **Likely benign** in SLC2A2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-09-27). Ultra-rare (popmax 0.0164%, mid); Associated with glycogen storage disease due to GLUT2 deficiency.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs756220231 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0164%, mid)

## For patients & families {#patients}

This is a change in the SLC2A2 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to glycogen storage disease due to GLUT2 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) | Infancy, Neonatal |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | SLC2A2 is a diagnostic-grade gene on 11 Genomics England panels |

**Commonly reported features of Fanconi-Bickel syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Failure to thrive — Very frequent (99-80%)
- Renal tubular acidosis — Very frequent (99-80%)
- Hypophosphatemia — Very frequent (99-80%)
- Hyperphosphaturia — Very frequent (99-80%)
- Galactose intolerance — Very frequent (99-80%)
- Increased hepatic glycogen content — Very frequent (99-80%)
- Impaired glucose tolerance — Very frequent (99-80%)
- Abnormal hepatic glycogen storage — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002268/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SLC2A2](https://sugi.bio/atlas/gene/SLC2A2/) |
| Protein change (HGVS p.) | p.Pro80= |
| Coding change (HGVS c.) | c.240T>C |
| MANE Select transcript | [NM_000340](https://www.ncbi.nlm.nih.gov/nuccore/NM_000340) |
| dbSNP | [rs756220231](https://www.ncbi.nlm.nih.gov/snp/rs756220231/) |
| Variant type | single nucleotide variant |
| Location | chr3:171014600-171014600 (GRCh38) |
| ClinVar | [VCV385035](https://www.ncbi.nlm.nih.gov/clinvar/variation/385035/) |

**All HGVS expressions:** `NC_000003.11:g.170732389A>G`, `NC_000003.12:g.171014600A>G`, `NG_008108.1:g.17380T>C`, `NM_000340.2:c.240T>C`, `NM_001278658.2:c.14+3931T>C`, `NM_001278659.2:c.-155T>C`

## 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 -1.666, GERP -3.31 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.519**. 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 assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0164%** (mid) · FAF95 0.00138% · FAF99 0.00116% · 1/6,084 in the highest group · 28/1,613,988 alleles overall — ultra-rare (popmax 0.0164%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0164% | 6,084 |
| East Asian | 0.00223% | 44,892 |
| European (non-Finnish) | 0.00203% | 49,167 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,486 |
| African / African-American | 0.00134% | 74,890 |

*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}

**SLC2A2** population constraint: LOEUF 0.858, pLI 5.1541e-06, missense-Z 1.5839. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 86.56, 65% of residues very-high.

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

*Describes the biological roles of SLC2A2 (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:** SLC2A2's established molecular role includes fructose transmembrane transporter activity. In Reactome, SLC2A2 is annotated in disease pathway(s) including **Defective SLC2A2 causes Fanconi-Bickel syndrome (FBS)**.

**Disease mechanism (Reactome):** SLC2A2 loss or alteration is curated in [Defective SLC2A2 causes Fanconi-Bickel syndrome (FBS)](https://reactome.org/content/detail/R-HSA-5619098).

### Pathways affected {#pathways}

SLC2A2 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective SLC2A2 causes Fanconi-Bickel syndrome (FBS)](https://reactome.org/content/detail/R-HSA-5619098) | curated |
| [Cellular hexose transport](https://reactome.org/content/detail/R-HSA-189200) | curated |
| [Intestinal hexose absorption](https://reactome.org/content/detail/R-HSA-8981373) | curated |
| [Regulation of insulin secretion](https://reactome.org/content/detail/R-HSA-422356) | curated |
| [Regulation of gene expression in beta cells](https://reactome.org/content/detail/R-HSA-210745) | electronic |

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

**Molecular function:** fructose transmembrane transporter activity, galactose transmembrane transporter activity, dehydroascorbic acid transmembrane transporter activity, D-glucose transmembrane transporter activity.

**Biological process:** fructose transmembrane transport, galactose transmembrane transport, dehydroascorbic acid transport, D-glucose transmembrane transport.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-09-27.

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

**Submission history:** 2 submissions (2016–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2016-04-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-09-27 |

## Associated conditions {#conditions}

[glycogen storage disease due to GLUT2 deficiency](https://sugi.bio/atlas/disease/glycogen-storage-disease-due-to-glut2-deficiency/).

**Reported phenotype names (ClinVar):** Fanconi-Bickel syndrome, not specified, AllHighlyPenetrant, Glycogen storage disease due to GLUT2 deficiency, PSEUDO-PHLORIZIN DIABETES, FANCONI SYNDROME WITH INTESTINAL MALABSORPTION AND GALACTOSE INTOLERANCE, HEPATIC GLYCOGENOSIS WITH AMINO ACIDURIA AND GLUCOSURIA, HEPATIC GLYCOGENOSIS WITH FANCONI NEPHROPATHY, HEPATORENAL GLYCOGENOSIS WITH RENAL FANCONI SYNDROME.

## Same-residue context {#hotspot}

Residue **80** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [SLC2A2 p.Pro80fs](/variant/slc2a2-p-pro80fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related SLC2A2 variant pages (same residue, condition, or type): [SLC2A2 p.Pro80fs](/variant/slc2a2-p-pro80fs), [SLC2A2 c.497-2A>G](/variant/slc2a2-c-497-minus-2a-g), [SLC2A2 c.775+1G>A](/variant/slc2a2-c-775-plus-1g-a), [SLC2A2 c.963+1G>A](/variant/slc2a2-c-963-plus-1g-a), [SLC2A2 p.Arg158Ser](/variant/slc2a2-p-arg158ser), [SLC2A2 p.Arg228Ter](/variant/slc2a2-p-arg228ter), [SLC2A2 p.Arg301Ter](/variant/slc2a2-p-arg301ter), [SLC2A2 p.Arg365Ter](/variant/slc2a2-p-arg365ter).

### 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 385035). 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.*