# NM_022552.5(DNMT3A):c.1243del (p.Gln415fs)

https://sugi.bio/variant/dnmt3a-p-gln415fs

## Summary

**DNMT3A p.Gln415fs (c.1243del)** is classified **Pathogenic** in DNMT3A (ClinVar, Single submitter, 1 submitter; last evaluated 2018-05-30). Very rare (popmax 0.00017%, nfe); Associated with Tatton-Brown-Rahman overgrowth syndrome.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1558669964 · 1 submitter · 1 linked condition · very rare (popmax 0.00017%, nfe)

## For patients & families {#patients}

This is a change in the DNMT3A gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Tatton-Brown-Rahman overgrowth 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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017674/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DNMT3A](https://sugi.bio/atlas/gene/DNMT3A/) |
| Protein change (HGVS p.) | p.Gln415fs |
| Coding change (HGVS c.) | c.1243del |
| MANE Select transcript | [NM_022552](https://www.ncbi.nlm.nih.gov/nuccore/NM_022552) |
| dbSNP | [rs1558669964](https://www.ncbi.nlm.nih.gov/snp/rs1558669964/) |
| Variant type | Deletion |
| Location | chr2:25246656-25246656 (GRCh38) |
| ClinVar | [VCV574227](https://www.ncbi.nlm.nih.gov/clinvar/variation/574227/) |

**All HGVS expressions:** `LRG_459:g.100935del`, `LRG_459t2:c.676del`, `LRG_459t4:c.1243del`, `NC_000002.11:g.25469526del`, `NC_000002.12:g.25246657del`, `NG_029465.2:g.100935del`, `NM_001320893.1:c.787del`, `NM_001375819.1:c.574del`, `NM_022552.5:c.1243del`, `NM_153759.3:c.676del`, `NM_175629.2:c.1243del`, `NM_175629.2:c.1243delC`, `NR_135490.2:n.1474del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 7.837, GERP 1.7, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 10 of 23**, 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 **0.00017%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,179,932 in the highest group · 3/1,461,074 alleles overall — very rare (popmax 0.00017%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,488 |
| European (non-Finnish) (grpmax) | 0.00017% | 589,967 |

Remaining individuals 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}

**DNMT3A** population constraint: LOEUF 1.998, pLI 3.0684e-146, missense-Z 1.997; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *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):

- **Heyn-Sproul-Jackson syndrome** — Limited (AD)
- **Tatton-Brown-Rahman overgrowth syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **415** lies in a turn.

AlphaFold model confidence (whole protein): pLDDT 73.97, 51% of residues very-high.

**47 experimental structure(s)** (PDB): [11NZ](https://www.rcsb.org/structure/11NZ), [11OA](https://www.rcsb.org/structure/11OA), [11OH](https://www.rcsb.org/structure/11OH), [11OI](https://www.rcsb.org/structure/11OI), [2QRV](https://www.rcsb.org/structure/2QRV), [3A1A](https://www.rcsb.org/structure/3A1A) — incl. mutant structure 4QBR.

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

*Describes the biological roles of DNMT3A (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:** DNMT3A's established molecular role includes RNA polymerase II cis-regulatory region sequence-specific DNA binding. In Reactome, DNMT3A is annotated in disease pathway(s) including **Defective pyroptosis**.

**Disease mechanism (Reactome):** DNMT3A loss or alteration is curated in [Defective pyroptosis](https://reactome.org/content/detail/R-HSA-9710421).

### Pathways affected {#pathways}

DNMT3A participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective pyroptosis](https://reactome.org/content/detail/R-HSA-9710421) | curated |
| [PRC2 methylates histones and DNA](https://reactome.org/content/detail/R-HSA-212300) | curated |
| [RMTs methylate histone arginines](https://reactome.org/content/detail/R-HSA-3214858) | curated |
| [DNA methylation](https://reactome.org/content/detail/R-HSA-5334118) | electronic |
| [Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)](https://reactome.org/content/detail/R-HSA-9845323) | electronic |
| [SUMOylation of DNA methylation proteins](https://reactome.org/content/detail/R-HSA-4655427) | electronic |

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

**Molecular function:** RNA polymerase II cis-regulatory region sequence-specific DNA binding, DNA binding, DNA (cytosine-5-)-methyltransferase activity, unmethylated CpG binding, RNA polymerase II-specific DNA-binding transcription factor binding, lncRNA binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, DNA methylation-dependent constitutive heterochromatin formation, regulatory ncRNA-mediated heterochromatin formation, negative regulation of gene expression via chromosomal CpG island methylation.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-05-30.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2018-05-30 |

## Associated conditions {#conditions}

[Tatton-Brown-Rahman overgrowth syndrome](https://sugi.bio/atlas/disease/tatton-brown-rahman-overgrowth-syndrome/).

**Reported phenotype names (ClinVar):** Tatton-Brown-Rahman overgrowth syndrome, Tall stature-intellectual disability-facial dysmorphism syndrome, Tatton-Brown-Rahman syndrome.

## Same-residue context {#hotspot}

Residue **415** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [DNMT3A p.Gln415Ter](/variant/dnmt3a-p-gln415ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related DNMT3A variant pages (same residue, condition, or type): [DNMT3A p.Gln415Ter](/variant/dnmt3a-p-gln415ter), [DNMT3A p.Gln415=](/variant/dnmt3a-p-gln415), [DNMT3A c.1123del](/variant/dnmt3a-c-1123del), [DNMT3A p.Ala246fs](/variant/dnmt3a-p-ala246fs), [DNMT3A p.Arg598fs](/variant/dnmt3a-p-arg598fs), [DNMT3A p.Arg891fs](/variant/dnmt3a-p-arg891fs), [DNMT3A p.Asp11fs](/variant/dnmt3a-p-asp11fs), [DNMT3A p.Asp394fs](/variant/dnmt3a-p-asp394fs).

### 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 574227). 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.*