# NM_006516.4(SLC2A1):c.1196C>G (p.Pro399Arg)

https://sugi.bio/variant/slc2a1-p-pro399arg

## Summary

**SLC2A1 p.Pro399Arg (c.1196C>G)** is classified **Conflicting classifications of pathogenicity** in SLC2A1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-04-10). AlphaMissense: likely pathogenic (0.9225); Absent from gnomAD v4.1; Associated with GLUT1 deficiency syndrome 1, autosomal recessive.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1643442142 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the SLC2A1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, 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.Pro399Arg |
| Coding change (HGVS c.) | c.1196C>G |
| MANE Select transcript | [NM_006516](https://www.ncbi.nlm.nih.gov/nuccore/NM_006516) |
| dbSNP | [rs1643442142](https://www.ncbi.nlm.nih.gov/snp/rs1643442142/) |
| Variant type | single nucleotide variant |
| Location | chr1:42927687-42927687 (GRCh38) |
| ClinVar | [VCV1011273](https://www.ncbi.nlm.nih.gov/clinvar/variation/1011273/) |

**All HGVS expressions:** `LRG_1132:g.36490C>G`, `NC_000001.10:g.43393358G>C`, `NC_000001.11:g.42927687G>C`, `NG_008232.1:g.36490C>G`, `NM_006516.4:c.1196C>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.9225)
- REVEL 0.778 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -17.768 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.913, GERP 1.87, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 31.0**. 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.*
- Regional missense constraint: **o/e 0.33** across the covering region of the MANE Select transcript (42,927,151–42,927,772), spanning 621 bp — the region is depleted of missense variation. Chi-square p 3e-12. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **399** lies in a turn.

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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-04-10.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Uncertain significance).

**Submission history:** 2 submissions (2024–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Cytogénomique, Hospices Civils de Lyon | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-04-10 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-22 |

## 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, Seizure, Seizures.

## Similar variants {#similar}

Related SLC2A1 variant pages (same residue, condition, or type): [SLC2A1 c.1279-2A>G](/variant/slc2a1-c-1279-minus-2a-g), [SLC2A1 c.-107G>A](/variant/slc2a1-c-minus-107g-a), [SLC2A1 p.Asn34Asp](/variant/slc2a1-p-asn34asp), [SLC2A1 p.Gln200Ter](/variant/slc2a1-p-gln200ter), [SLC2A1 p.Leu215Phe](/variant/slc2a1-p-leu215phe), [SLC2A1 p.Met420Thr](/variant/slc2a1-p-met420thr), [SLC2A1 p.Met96Val](/variant/slc2a1-p-met96val), [SLC2A1 p.Pro211Ser](/variant/slc2a1-p-pro211ser).

### 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 1011273). 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.*