# NM_194255.4(SLC19A1):c.972G>A (p.Ala324=)

https://sugi.bio/variant/slc19a1-p-ala324

## Summary

**SLC19A1 p.Ala324= (c.972G>A)** is classified **Benign** in SLC19A1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). Common (popmax 10.5%, sas) — too common for a highly-penetrant pathogenic allele.

**At a glance:** Benign · review: Multiple submitters · rsID rs79091853 · 3 submitters · common (popmax 10.5%, sas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the SLC19A1 gene that is classified as benign — not considered disease-causing, submitted by 3 submitters.

*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.Ala324= |
| Coding change (HGVS c.) | c.972G>A |
| MANE Select transcript | [NM_194255](https://www.ncbi.nlm.nih.gov/nuccore/NM_194255) |
| dbSNP | [rs79091853](https://www.ncbi.nlm.nih.gov/snp/rs79091853/) |
| Variant type | single nucleotide variant |
| Location | chr21:45530949-45530949 (GRCh38) |
| ClinVar | [VCV1637940](https://www.ncbi.nlm.nih.gov/clinvar/variation/1637940/) |

**All HGVS expressions:** `NC_000021.8:g.46950863C>T`, `NC_000021.9:g.45530949C>T`, `NG_028278.2:g.37195G>A`, `NM_001205206.4:c.972G>A`, `NM_001205207.3:c.852G>A`, `NM_001352510.2:c.618G>A`, `NM_001352511.3:c.972G>A`, `NM_001352512.2:c.972G>A`, `NM_194255.4:c.972G>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 10.5%, sas) — too common for a highly-penetrant pathogenic allele.

- **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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.79) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -11.193, GERP -3.42 — fast-evolving / accelerated position
- CADD: **PHRED 17.23**. 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 deltas (raw): acceptor loss **0.14**, donor loss **0.00**, acceptor gain **0.79**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.14**, donor loss **0.00**, acceptor gain **0.79**, donor gain **0.00**.
- Pangolin: Δ**0.30** (gain), gain 0.30 / loss 0.11. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **10.5%** (sas) · FAF95 10.3% · FAF99 10.2% · 7,051/67,200 in the highest group · 23,381/1,433,842 alleles overall — common (popmax 10.5%, sas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 10.5% | 10 |
| East Asian | 9.07% | 11 |
| Admixed American | 5.37% | 19 |
| Ashkenazi Jewish (not grpmax-eligible) | 5.06% | 20 |
| Middle Eastern | 3.05% | 33 |
| Remaining individuals (not grpmax-eligible) | 2.43% | 41 |
| Finnish (not grpmax-eligible) | 2.37% | 42 |
| Amish (not grpmax-eligible) | 1.92% | 52 |
| European (non-Finnish) | 0.657% | 152 |
| African / African-American | 0.214% | 467 |

*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 **324** lies in a turn.

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}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-02.

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

**Submission history:** 36 submissions (2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-02 |

**Reported phenotype names (ClinVar):** not provided, Uveal melanoma, Colon adenocarcinoma, Colorectal cancer, Sarcoma, Cervical cancer, Clear cell carcinoma of kidney, Ovarian serous cystadenocarcinoma, Uterine corpus endometrial carcinoma, Thyroid cancer, nonmedullary, 1.

## Similar variants {#similar}

Related SLC19A1 variant pages (same residue, condition, or type): [SLC19A1 p.Ala324Val](/variant/slc19a1-p-ala324val), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1637940). 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.*