# NM_194255.4(SLC19A1):c.631TTC[1] (p.Phe212del)

https://sugi.bio/variant/slc19a1-p-phe212del

## Summary

**SLC19A1 p.Phe212del (c.631TTC[1])** is classified **Uncertain significance** in SLC19A1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-29). Ultra-rare (popmax 0.0109%, nfe); Associated with megaloblastic anemia, folate-responsive.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs757838708 · 3 submitters · 1 linked condition · ultra-rare (popmax 0.0109%, nfe)

## 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 3 submitters, and is linked to megaloblastic anemia, folate-responsive.

*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.*

|  |  |
| --- | --- |
| Age of onset (of this condition) | Infancy, Neonatal |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0027127/index) · [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.Phe212del |
| Coding change (HGVS c.) | c.631TTC[1] |
| MANE Select transcript | [NM_194255](https://www.ncbi.nlm.nih.gov/nuccore/NM_194255) |
| dbSNP | [rs757838708](https://www.ncbi.nlm.nih.gov/snp/rs757838708/) |
| Variant type | Microsatellite |
| Location | chr21:45531702-45531704 (GRCh38) |
| ClinVar | [VCV1054650](https://www.ncbi.nlm.nih.gov/clinvar/variation/1054650/) |

**All HGVS expressions:** `NC_000021.8:g.46951618AGA[1]`, `NC_000021.9:g.45531704AGA[1]`, `NG_028278.2:g.36437TTC[1]`, `NM_001205206.4:c.631TTC[1]`, `NM_001205207.3:c.511TTC[1]`, `NM_001352510.2:c.277TTC[1]`, `NM_001352511.3:c.631TTC[1]`, `NM_001352512.2:c.631TTC[1]`, `NM_194255.4:c.631TTC[1]`, `NM_194255.4:c.634_636delTTC`

## 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 1.419, GERP -0.519, phastCons 1 — weakly conserved position
- Molecular consequence: **in-frame indel**.
- CADD: **PHRED 17.66**. 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: **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 (gnomAD v4.1): grpmax **0.0109%** (nfe) · FAF95 0.00936% · FAF99 0.0088% · 129/1,179,746 in the highest group · 160/1,612,604 alleles overall — ultra-rare (popmax 0.0109%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0913% | 1,095 |
| European (non-Finnish) (grpmax) | 0.0109% | 9,145 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,815 |
| Admixed American | 0.00167% | 59,952 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **212** lies in a β-strand; a UniProt-annotated variant site (in megaf; loss of cellular uptake of folates, including methotrexate).

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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-29.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 Pathogenic).

**Submission history:** 3 submissions (2021–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2021-04-08 |
| Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-29 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-18 |

## Associated conditions {#conditions}

[megaloblastic anemia, folate-responsive](https://sugi.bio/atlas/disease/megaloblastic-anemia-folate-responsive/).

**Reported phenotype names (ClinVar):** Megaloblastic anemia, folate-responsive, not provided, not specified, AllHighlyPenetrant, Folate level in erythrocytes, none provided.

## Similar variants {#similar}

Related SLC19A1 variant pages (same residue, condition, or type): [SLC19A1 p.Phe212Leu](/variant/slc19a1-p-phe212leu), [SLC19A1 p.Ser46Cys](/variant/slc19a1-p-ser46cys), [COL18A1 p.985GPP[5]](/variant/col18a1-p-985gpp-5), [RFC1 c.132+2923=](/variant/rfc1-c-132-plus-2923).

### 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 1054650). 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.*