# NM_000340.2(SLC2A2):c.1221T>C (p.Phe407=)

https://sugi.bio/variant/slc2a2-p-phe407

## Summary

**SLC2A2 p.Phe407= (c.1221T>C)** is classified **Uncertain significance** in SLC2A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Very rare (popmax 0.00017%, nfe); Associated with glycogen storage disease due to GLUT2 deficiency.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs775605288 · 1 submitter · 1 linked condition · very rare (popmax 0.00017%, nfe)

## For patients & families {#patients}

This is a change in the SLC2A2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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.Phe407= |
| Coding change (HGVS c.) | c.1221T>C |
| MANE Select transcript | [NM_000340](https://www.ncbi.nlm.nih.gov/nuccore/NM_000340) |
| dbSNP | [rs775605288](https://www.ncbi.nlm.nih.gov/snp/rs775605288/) |
| Variant type | single nucleotide variant |
| Location | chr3:170998346-170998346 (GRCh38) |
| ClinVar | [VCV344162](https://www.ncbi.nlm.nih.gov/clinvar/variation/344162/) |

**All HGVS expressions:** `NC_000003.11:g.170716135A>G`, `NC_000003.12:g.170998346A>G`, `NG_008108.1:g.33634T>C`, `NM_000340.2:c.1221T>C`, `NM_001278658.2:c.864T>C`, `NM_001278659.2:c.702T>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.35) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -0.305, GERP -3.19 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 5.363**. 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 **0.35**, donor loss **0.00**, acceptor gain **0.02**, donor gain **0.00**. Largest is acceptor loss, 6 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.00017%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,179,772 in the highest group · 2/1,613,736 alleles overall — very rare (popmax 0.00017%, nfe).

*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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-01-13.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |

## 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, HEPATIC GLYCOGENOSIS WITH FANCONI NEPHROPATHY, HEPATORENAL GLYCOGENOSIS WITH RENAL FANCONI SYNDROME, PSEUDO-PHLORIZIN DIABETES, Glycogen storage disease due to GLUT2 deficiency, FANCONI SYNDROME WITH INTESTINAL MALABSORPTION AND GALACTOSE INTOLERANCE, HEPATIC GLYCOGENOSIS WITH AMINO ACIDURIA AND GLUCOSURIA.

## Similar variants {#similar}

Related SLC2A2 variant pages (same residue, condition, or type): [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), [SLC2A2 p.Glu84Ter](/variant/slc2a2-p-glu84ter).

### 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 344162). 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.*