# NM_194255.4(SLC19A1):c.1200C>T (p.Phe400=)

https://sugi.bio/variant/slc19a1-p-phe400

## Summary

**SLC19A1 p.Phe400= (c.1200C>T)** is classified **Likely benign** in SLC19A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-02). Ultra-rare (popmax 0.033%, mid).

**At a glance:** Likely benign · review: Single submitter · rsID rs149270420 · 1 submitter · ultra-rare (popmax 0.033%, mid)

## For patients & families {#patients}

This is a change in the SLC19A1 gene that is classified as likely benign — not considered disease-causing, 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.Phe400= |
| Coding change (HGVS c.) | c.1200C>T |
| MANE Select transcript | [NM_194255](https://www.ncbi.nlm.nih.gov/nuccore/NM_194255) |
| dbSNP | [rs149270420](https://www.ncbi.nlm.nih.gov/snp/rs149270420/) |
| Variant type | single nucleotide variant |
| Location | chr21:45525910-45525910 (GRCh38) |
| ClinVar | [VCV729425](https://www.ncbi.nlm.nih.gov/clinvar/variation/729425/) |

**All HGVS expressions:** `NC_000021.8:g.46945824G>A`, `NC_000021.9:g.45525910G>A`, `NG_028278.2:g.42234C>T`, `NM_001205206.4:c.1200C>T`, `NM_001205207.3:c.1080C>T`, `NM_001352510.2:c.846C>T`, `NM_001352511.3:c.1200C>T`, `NM_001352512.2:c.1200C>T`, `NM_194255.4:c.1200C>T`

## 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 -3.808, GERP -3.46 — fast-evolving / accelerated position
- CADD: **PHRED 2.648**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.42 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.033%** (mid) · FAF95 0.0239% · FAF99 0.0229% · 2/6,060 in the highest group · 357/1,613,682 alleles overall — ultra-rare (popmax 0.033%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.033% | 3,030 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.027% | 3,701 |
| European (non-Finnish) | 0.0264% | 3,794 |
| Remaining individuals (not grpmax-eligible) | 0.0208% | 4,807 |
| Admixed American | 0.02% | 5,003 |
| African / African-American | 0.00666% | 15,014 |
| South Asian | 0.00549% | 18,216 |
| East Asian | 0.00223% | 44,884 |

*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}

Residue **400** lies in an α-helix; a binding site.

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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-12-02.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-12-02 |

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

## Similar variants {#similar}

Related SLC19A1 variant pages (same residue, condition, or type): [COL18A1 p.Arg1081Ter](/variant/col18a1-p-arg1081ter), [COL18A1 p.Arg915Ter](/variant/col18a1-p-arg915ter), [RFC1 p.Arg383Ter](/variant/rfc1-p-arg383ter), [COL18A1 c.*30G>A](/variant/col18a1-c-star-30g-a), [COL18A1 p.Ala1089Thr](/variant/col18a1-p-ala1089thr), [COL18A1 p.Ala1254Val](/variant/col18a1-p-ala1254val), [COL18A1 p.Arg1081Gln](/variant/col18a1-p-arg1081gln), [COL18A1 p.Arg1183His](/variant/col18a1-p-arg1183his).

### 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 729425). 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.*