# NM_032482.3(DOT1L):c.399C>T (p.Pro133=)

https://sugi.bio/variant/dot1l-p-pro133

## Summary

**DOT1L p.Pro133= (c.399C>T)** is classified **Likely benign** in DOT1L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-01). Ultra-rare (popmax 0.0187%, afr).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · ultra-rare (popmax 0.0187%, afr)

## For patients & families {#patients}

This is a change in the DOT1L 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 | [DOT1L](https://sugi.bio/atlas/gene/DOT1L/) |
| Protein change (HGVS p.) | p.Pro133= |
| Coding change (HGVS c.) | c.399C>T |
| MANE Select transcript | [NM_032482](https://www.ncbi.nlm.nih.gov/nuccore/NM_032482) |
| Variant type | single nucleotide variant |
| Location | chr19:2191146-2191146 (GRCh38) |
| ClinVar | [VCV4533668](https://www.ncbi.nlm.nih.gov/clinvar/variation/4533668/) |

**All HGVS expressions:** `NC_000019.10:g.2191146C>T`, `NC_000019.9:g.2191145C>T`, `NG_029793.1:g.31998C>T`, `NM_001411141.1:c.399C>T`, `NM_032482.3:c.399C>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 -14.148, GERP -2.39 — fast-evolving / accelerated position
- CADD: **PHRED 0.047**. 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** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0187%** (afr) · FAF95 0.0164% · FAF99 0.0156% · 14/74,930 in the highest group · 1,215/1,613,774 alleles overall — ultra-rare (popmax 0.0187%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 2.89% | 35 |
| Remaining individuals (not grpmax-eligible) | 0.19% | 525 |
| African / African-American (grpmax) | 0.0187% | 5,352 |
| European (non-Finnish) | 0.0184% | 5,438 |
| South Asian | 0.00659% | 15,175 |
| Finnish (not grpmax-eligible) | 0.00313% | 31,963 |
| East Asian | 0.00223% | 44,820 |
| Admixed American | 0.00167% | 60,000 |

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}

**DOT1L** population constraint: LOEUF 0.321, pLI 1, missense-Z 1.3785. *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 **133** lies in the dot1 domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 54.11, 20% of residues very-high.

**48 experimental structure(s)** (PDB): [1NW3](https://www.rcsb.org/structure/1NW3), [2MV7](https://www.rcsb.org/structure/2MV7), [3QOW](https://www.rcsb.org/structure/3QOW), [3QOX](https://www.rcsb.org/structure/3QOX), [3SR4](https://www.rcsb.org/structure/3SR4), [3SX0](https://www.rcsb.org/structure/3SX0).

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

*Describes the biological roles of DOT1L (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:** DOT1L's established molecular role includes nucleic acid binding. p.Pro133= falls in the dot1 domain.


### Pathways affected {#pathways}

DOT1L participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [PKMTs methylate histone lysines](https://reactome.org/content/detail/R-HSA-3214841) | curated |

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

**Molecular function:** nucleic acid binding, DNA binding, transcription coactivator activity, histone H3K79 methyltransferase activity, histone methyltransferase activity, RNA polymerase II-specific DNA-binding transcription factor binding.

**Biological process:** positive regulation of transcription by RNA polymerase II, regulation of receptor signaling pathway via JAK-STAT, regulation of transcription regulatory region DNA binding.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-10-01 |

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

## Similar variants {#similar}

Related DOT1L variant pages (same residue, condition, or type): [DOT1L p.Asp189Asn](/variant/dot1l-p-asp189asn), [DOT1L p.Ala1101=](/variant/dot1l-p-ala1101), [DOT1L p.Arg73=](/variant/dot1l-p-arg73), [DOT1L p.Arg893=](/variant/dot1l-p-arg893), [DOT1L p.Asp155=](/variant/dot1l-p-asp155), [DOT1L p.Pro758=](/variant/dot1l-p-pro758), [DOT1L p.Thr1068=](/variant/dot1l-p-thr1068), [DOT1L p.Thr957Ile](/variant/dot1l-p-thr957ile).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 4533668). 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.*