# NM_194255.4(SLC19A1):c.1771del (p.Gln591fs)

https://sugi.bio/variant/slc19a1-p-gln591fs

## Summary

**SLC19A1 p.Gln591fs (c.1771del)** is classified **Uncertain significance** in SLC19A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-18). No gnomAD frequency available for this variant.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2517961370 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the SLC19A1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [SLC19A1](https://sugi.bio/atlas/gene/SLC19A1/) |
| Protein change (HGVS p.) | p.Gln591fs |
| Coding change (HGVS c.) | c.1771del |
| MANE Select transcript | [NM_194255](https://www.ncbi.nlm.nih.gov/nuccore/NM_194255) |
| dbSNP | [rs2517961370](https://www.ncbi.nlm.nih.gov/snp/rs2517961370/) |
| Variant type | Deletion |
| Location | chr21:45515663-45515663 (GRCh38) |
| ClinVar | [VCV2697096](https://www.ncbi.nlm.nih.gov/clinvar/variation/2697096/) |

**All HGVS expressions:** `NC_000021.8:g.46935578del`, `NC_000021.9:g.45515664del`, `NG_011903.1:g.115473del`, `NG_028278.2:g.52481del`, `NM_001205206.4:c.1294-511del`, `NM_001205207.3:c.1651del`, `NM_001352510.2:c.1417del`, `NM_001352511.3:c.1294-511del`, `NM_001352512.2:c.1771del`, `NM_194255.4:c.1771del`

## 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, GERP 0.921 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.585, pLI 1.1764e-15. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (6 of 6)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion 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}

**SLC19A1** population constraint: LOEUF 1.585, pLI 1.1764e-15, missense-Z -0.70012. *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):

- **immunodeficiency 114, folate-responsive** — Limited (AR)
- **cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 73.30, 46% of residues very-high.

**19 experimental structure(s)** (PDB): [7TX6](https://www.rcsb.org/structure/7TX6), [7TX7](https://www.rcsb.org/structure/7TX7), [7XPZ](https://www.rcsb.org/structure/7XPZ), [7XQ0](https://www.rcsb.org/structure/7XQ0), [7XQ1](https://www.rcsb.org/structure/7XQ1), [7XQ2](https://www.rcsb.org/structure/7XQ2).

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

*Describes the biological roles of SLC19A1 (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:** SLC19A1's established molecular role includes folic acid transmembrane transporter activity.


### Pathways affected {#pathways}

SLC19A1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Metabolism of folate and pterines](https://reactome.org/content/detail/R-HSA-196757) | curated |

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

**Molecular function:** folic acid transmembrane transporter activity, folate:monoatomic anion antiporter activity, antiporter activity, methotrexate transmembrane transporter activity, 2',3'-cyclic GMP-AMP binding, cyclic-GMP-AMP transmembrane transporter activity.

**Biological process:** folic acid transport, methotrexate transport, folate transmembrane transport, cyclic-GMP-AMP transmembrane import across plasma membrane, positive regulation of cGAS/STING signaling pathway, folate import across plasma membrane.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-11-18.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-11-18 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related SLC19A1 variant pages (same residue, condition, or type): [COL18A1 p.Gly1178fs](/variant/col18a1-p-gly1178fs), [COL18A1 p.Pro993fs](/variant/col18a1-p-pro993fs), [COL18A1 p.Cys1291fs](/variant/col18a1-p-cys1291fs), [COL18A1 p.Gly1197fs](/variant/col18a1-p-gly1197fs), [COL18A1 p.Gly1248fs](/variant/col18a1-p-gly1248fs), [COL18A1 p.Gly942fs](/variant/col18a1-p-gly942fs), [COL18A1 p.His1157fs](/variant/col18a1-p-his1157fs), [COL18A1 p.Pro1017fs](/variant/col18a1-p-pro1017fs).

### 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 2697096). 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.*