# NM_006996.3(SLC19A2):c.725del (p.Pro242fs)

https://sugi.bio/variant/slc19a2-p-pro242fs

## Summary

**SLC19A2 p.Pro242fs (c.725del)** is classified **Pathogenic** in SLC19A2 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-09-19). Ultra-rare (popmax 0.0165%, mid); Associated with thiamine-responsive megaloblastic anemia syndrome.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1571537544 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the SLC19A2 gene that is reported as disease-causing, but on limited review, submitted by 2 submitters, and is linked to thiamine-responsive megaloblastic anemia syndrome.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood |
| Diagnostic panels | SLC19A2 is a diagnostic-grade gene on 13 Genomics England panels |

**Commonly reported features of Thiamine-responsive megaloblastic anemia syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Sensorineural hearing impairment — Very frequent (99-80%)
- Diabetes mellitus — Very frequent (99-80%)
- Pallor — Very frequent (99-80%)
- Lethargy — Very frequent (99-80%)
- Megaloblastic anemia — Very frequent (99-80%)
- Diarrhea — Very frequent (99-80%)
- Anorexia — Very frequent (99-80%)
- Headache — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009210/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SLC19A2](https://sugi.bio/atlas/gene/SLC19A2/) |
| Protein change (HGVS p.) | p.Pro242fs |
| Coding change (HGVS c.) | c.725del |
| MANE Select transcript | [NM_006996](https://www.ncbi.nlm.nih.gov/nuccore/NM_006996) |
| dbSNP | [rs1571537544](https://www.ncbi.nlm.nih.gov/snp/rs1571537544/) |
| Variant type | Deletion |
| Location | chr1:169477237-169477237 (GRCh38) |
| ClinVar | [VCV5956](https://www.ncbi.nlm.nih.gov/clinvar/variation/5956/) |

**All HGVS expressions:** `NC_000001.10:g.169446478del`, `NC_000001.11:g.169477240del`, `NG_008255.1:g.13734del`, `NM_001319667.1:c.205-7051del`, `NM_006996.3:c.725del`

## 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 -0.218, GERP -2.64, phastCons 0.297 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.852, pLI 2.0312e-06. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 6**, so the transcript is predicted to undergo NMD.
- 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 (gnomAD v4.1): grpmax **0.0165%** (mid) · 1/6,050 in the highest group · 1/1,614,160 alleles overall — ultra-rare (popmax 0.0165%, mid).

*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}

**SLC19A2** population constraint: LOEUF 0.852, pLI 2.0312e-06, missense-Z 0.8925. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 80.99, 54% of residues very-high.

**2 experimental structure(s)** (PDB): [8Z7Z](https://www.rcsb.org/structure/8Z7Z), [8Z80](https://www.rcsb.org/structure/8Z80).

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

*Describes the biological roles of SLC19A2 (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:** SLC19A2's established molecular role includes thiamine transmembrane transporter activity.


### Pathways affected {#pathways}

SLC19A2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Vitamin B1 (thiamin) metabolism](https://reactome.org/content/detail/R-HSA-196819) | curated |

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

**Molecular function:** thiamine transmembrane transporter activity.

**Biological process:** thiamine transport, pyridoxine transport.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-09-19.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (1999–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1999-07-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-09-19 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Megaloblastic anemia, thiamine-responsive, with diabetes mellitus and sensorineural deafness, not provided, none provided, Thiamine-Responsive Megaloblastic Anemia Syndrome, ROGERS SYNDROME, THIAMINE-RESPONSIVE ANEMIA SYNDROME, THIAMINE-RESPONSIVE MYELODYSPLASIA, THIAMINE METABOLISM DYSFUNCTION SYNDROME 1 (MEGALOBLASTIC ANEMIA, DIABETES MELLITUS, AND DEAFNESS TYPE).

## Similar variants {#similar}

Related SLC19A2 variant pages (same residue, condition, or type): [SLC19A2 p.Tyr144fs](/variant/slc19a2-p-tyr144fs), [SLC19A2 p.Ile354del](/variant/slc19a2-p-ile354del), [SLC19A2 p.Leu304fs](/variant/slc19a2-p-leu304fs), [SLC19A2 p.Pro242=](/variant/slc19a2-p-pro242), [SLC19A2 p.Ile145fs](/variant/slc19a2-p-ile145fs), [SLC19A2 p.Leu195fs](/variant/slc19a2-p-leu195fs), [SLC19A2 p.Leu296fs](/variant/slc19a2-p-leu296fs), [SLC19A2 p.Thr22fs](/variant/slc19a2-p-thr22fs).

### 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 5956). 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.*