# NM_001025248.2(DUT):c.298C>T (p.Pro100Ser)

https://sugi.bio/variant/dut-p-pro100ser

## Summary

**DUT p.Pro100Ser (c.298C>T)** is classified **Uncertain significance** in DUT (ClinVar, Single submitter, 2 submitters; last evaluated 2025-08-07). AlphaMissense: likely benign (0.2461); Ultra-rare (popmax 0.0832%, eas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs28381104 · 2 submitters · AlphaMissense likely benign · ultra-rare (popmax 0.0832%, eas)

## For patients & families {#patients}

This is a change in the DUT gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 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 | [DUT](https://sugi.bio/atlas/gene/DUT/) |
| Protein change (HGVS p.) | p.Pro100Ser |
| Coding change (HGVS c.) | c.298C>T |
| MANE Select transcript | [NM_001025248](https://www.ncbi.nlm.nih.gov/nuccore/NM_001025248) |
| dbSNP | [rs28381104](https://www.ncbi.nlm.nih.gov/snp/rs28381104/) |
| Variant type | single nucleotide variant |
| Location | chr15:48332285-48332285 (GRCh38) |
| ClinVar | [VCV623429](https://www.ncbi.nlm.nih.gov/clinvar/variation/623429/) |

**All HGVS expressions:** `NC_000015.10:g.48332285C>T`, `NC_000015.9:g.48624482C>T`, `NG_029497.1:g.5862C>T`, `NM_001025248.2:c.298C>T`, `NM_001025249.1:c.-36C>T`, `NM_001330286.2:c.43C>T`, `NM_001948.4:c.34C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.2461)
- REVEL 0.053 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.646 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 3.469, GERP 3.35, phastCons 0.995 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 20.8**. 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.*
- Regional missense constraint: **o/e 0.98** across the covering region of the MANE Select transcript (48,331,516–48,342,075), spanning 10,559 bp. Chi-square p 0.68. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.27 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 **0.0832%** (eas) · FAF95 0.062% · FAF99 0.0547% · 37/44,468 in the highest group · 39/1,608,920 alleles overall — ultra-rare (popmax 0.0832%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0832% | 1,202 |
| European (non-Finnish) | 0.00017% | 589,258 |

*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}

**DUT** population constraint: LOEUF 1.684, pLI 3.3881e-07, missense-Z -1.2104. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **100** lies in a UniProt-annotated variant site (in); the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 75.51, 53% of residues very-high.

**12 experimental structure(s)** (PDB): [1Q5H](https://www.rcsb.org/structure/1Q5H), [1Q5U](https://www.rcsb.org/structure/1Q5U), [2HQU](https://www.rcsb.org/structure/2HQU), [3ARA](https://www.rcsb.org/structure/3ARA), [3ARN](https://www.rcsb.org/structure/3ARN), [3EHW](https://www.rcsb.org/structure/3EHW) — incl. mutant structure 4MZ6.

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

*Describes the biological roles of DUT (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:** DUT's established molecular role includes RNA binding. p.Pro100Ser falls in the disordered region.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Interconversion of nucleotide di- and triphosphates](https://reactome.org/content/detail/R-HSA-499943) | other |

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

**Molecular function:** RNA binding, dUTP diphosphatase activity.

**Biological process:** dTMP biosynthetic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-07.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2018–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Human Genetics, Polish Academy of Sciences | Uncertain significance | no assertion criteria provided | research | 2018-12-17 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-07 |

**Reported phenotype names (ClinVar):** High myopia, not specified, AllHighlyPenetrant, Severe Myopia.

## Similar variants {#similar}

Related DUT variant pages (same residue, condition, or type): [DUT p.Pro100Leu](/variant/dut-p-pro100leu), [DUT p.Tyr142Cys](/variant/dut-p-tyr142cys), [DUT p.Ala235Ser](/variant/dut-p-ala235ser), [DUT p.Arg173Trp](/variant/dut-p-arg173trp), [DUT p.Arg216Gln](/variant/dut-p-arg216gln), [DUT p.Asp192His](/variant/dut-p-asp192his), [DUT p.Gln219His](/variant/dut-p-gln219his), [DUT p.Glu223Lys](/variant/dut-p-glu223lys).

### 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 623429). 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.*