# NM_006516.4(SLC2A1):c.163_164dup (p.Ser55fs)

https://sugi.bio/variant/slc2a1-p-ser55fs

## Summary

**SLC2A1 p.Ser55fs (c.163_164dup)** is classified **Pathogenic** in SLC2A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-07). No gnomAD frequency available for this variant; Associated with GLUT1 deficiency syndrome 1, autosomal recessive.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2524999574 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the SLC2A1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to GLUT1 deficiency syndrome 1, autosomal recessive.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SLC2A1](https://sugi.bio/atlas/gene/SLC2A1/) |
| Protein change (HGVS p.) | p.Ser55fs |
| Coding change (HGVS c.) | c.163_164dup |
| MANE Select transcript | [NM_006516](https://www.ncbi.nlm.nih.gov/nuccore/NM_006516) |
| dbSNP | [rs2524999574](https://www.ncbi.nlm.nih.gov/snp/rs2524999574/) |
| Variant type | Microsatellite |
| Location | chr1:42931156-42931157 (GRCh38) |
| ClinVar | [VCV2022504](https://www.ncbi.nlm.nih.gov/clinvar/variation/2022504/) |

**All HGVS expressions:** `LRG_1132:g.33017AG[3]`, `LRG_1132t1:c.160_161GA[3]`, `NC_000001.10:g.43396829TC[3]`, `NC_000001.11:g.42931158TC[3]`, `NG_008232.1:g.33017AG[3]`, `NM_006516.4:c.163_164dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 5.209, GERP 0.564, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.139, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 10**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**SLC2A1** population constraint: LOEUF 0.139, pLI 1, missense-Z 4.6812; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **GLUT1 deficiency syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **55** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 90.30, 74% of residues very-high.

**5 experimental structure(s)** (PDB): [4PYP](https://www.rcsb.org/structure/4PYP), [5EQG](https://www.rcsb.org/structure/5EQG), [5EQH](https://www.rcsb.org/structure/5EQH), [5EQI](https://www.rcsb.org/structure/5EQI), [6THA](https://www.rcsb.org/structure/6THA).

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

*Describes the biological roles of SLC2A1 (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:** SLC2A1's established molecular role includes long-chain fatty acid transmembrane transporter activity. In Reactome, SLC2A1 is annotated in disease pathway(s) including **Defective SLC2A1 causes GLUT1 deficiency syndrome 1 (GLUT1DS1)**.

**Disease mechanism (Reactome):** SLC2A1 loss or alteration is curated in [Defective SLC2A1 causes GLUT1 deficiency syndrome 1 (GLUT1DS1)](https://reactome.org/content/detail/R-HSA-5619043).

### Pathways affected {#pathways}

SLC2A1 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective SLC2A1 causes GLUT1 deficiency syndrome 1 (GLUT1DS1)](https://reactome.org/content/detail/R-HSA-5619043) | curated |
| [Cellular hexose transport](https://reactome.org/content/detail/R-HSA-189200) | curated |
| [Lactose synthesis](https://reactome.org/content/detail/R-HSA-5653890) | curated |
| [Regulation of insulin secretion](https://reactome.org/content/detail/R-HSA-422356) | curated |
| [Vitamin C (ascorbate) metabolism](https://reactome.org/content/detail/R-HSA-196836) | curated |

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

**Molecular function:** long-chain fatty acid transmembrane transporter activity, dehydroascorbic acid transmembrane transporter activity, identical protein binding, D-glucose transmembrane transporter activity.

**Biological process:** central nervous system development, long-chain fatty acid import across plasma membrane, photoreceptor cell maintenance, protein-containing complex assembly, D-glucose import across plasma membrane, transport across blood-brain barrier.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-08-07.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-08-07 |

## Associated conditions {#conditions}

[GLUT1 deficiency syndrome 1, autosomal recessive](https://sugi.bio/atlas/disease/glut1-deficiency-syndrome-1-autosomal-recessive/).

**Reported phenotype names (ClinVar):** GLUT1 deficiency syndrome 1, autosomal recessive.

## Similar variants {#similar}

Related SLC2A1 variant pages (same residue, condition, or type): [SLC2A1 p.Val166del](/variant/slc2a1-p-val166del), [SLC2A1 p.Val83fs](/variant/slc2a1-p-val83fs), [SLC2A1 c.1279-11_1279-8del](/variant/slc2a1-c-1279-minus-11-1279-minus-8del), [SLC2A1 p.59TTL[1]](/variant/slc2a1-p-59ttl-1), [SLC2A1 p.Glu221del](/variant/slc2a1-p-glu221del), [SLC2A1 p.Leu204del](/variant/slc2a1-p-leu204del), [SLC2A1 p.Phe379del](/variant/slc2a1-p-phe379del), [SLC2A1 p.Ser55Thr](/variant/slc2a1-p-ser55thr).

### 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 2022504). 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.*