# NM_022552.5(DNMT3A):c.2067C>T (p.Ser689=)

https://sugi.bio/variant/dnmt3a-p-ser689

## Summary

**DNMT3A p.Ser689= (c.2067C>T)** is classified **Likely benign** in DNMT3A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). Very rare (popmax 0.00167%, amr); Associated with Tatton-Brown-Rahman overgrowth syndrome.

**At a glance:** Likely benign · review: Single submitter · rsID rs1267320725 · 1 submitter · 1 linked condition · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the DNMT3A gene that is classified as likely benign — not considered disease-causing, 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.Ser689= |
| Coding change (HGVS c.) | c.2067C>T |
| MANE Select transcript | [NM_022552](https://www.ncbi.nlm.nih.gov/nuccore/NM_022552) |
| dbSNP | [rs1267320725](https://www.ncbi.nlm.nih.gov/snp/rs1267320725/) |
| Variant type | single nucleotide variant |
| Location | chr2:25241577-25241577 (GRCh38) |
| ClinVar | [VCV1947553](https://www.ncbi.nlm.nih.gov/clinvar/variation/1947553/) |

**All HGVS expressions:** `LRG_459:g.106014C>T`, `LRG_459t1:c.2067C>T`, `LRG_459t2:c.1500C>T`, `LRG_459t4:c.2067C>T`, `NC_000002.11:g.25464446G>A`, `NC_000002.12:g.25241577G>A`, `NG_029465.2:g.106014C>T`, `NM_001320893.1:c.1611C>T`, `NM_001375819.1:c.1398C>T`, `NM_022552.5:c.2067C>T`, `NM_153759.3:c.1500C>T`, `NM_175629.2:c.2067C>T`, `NR_135490.2:n.2298C>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 6.507, GERP -0.209, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 16.81**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.22 donor 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 **0.00167%** (amr) · FAF95 2.8e-05% · FAF99 1.1e-05% · 1/59,902 in the highest group · 3/1,613,652 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00167% | 59,902 |
| European (non-Finnish) | 0.00017% | 589,936 |

*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 **689** lies in an α-helix; the sam-dependent mtase c5-type domain.

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. p.Ser689= falls in the sam-dependent mtase c5-type domain. 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-09-10.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-10 |

## 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.

## Similar variants {#similar}

Related DNMT3A variant pages (same residue, condition, or type): [DNMT3A c.1667+1G>A](/variant/dnmt3a-c-1667-plus-1g-a), [DNMT3A c.1937-2A>G](/variant/dnmt3a-c-1937-minus-2a-g), [DNMT3A c.2478+1G>A](/variant/dnmt3a-c-2478-plus-1g-a), [DNMT3A c.2479-1G>A](/variant/dnmt3a-c-2479-minus-1g-a), [DNMT3A p.Arg143Ter](/variant/dnmt3a-p-arg143ter), [DNMT3A p.Arg320Ter](/variant/dnmt3a-p-arg320ter), [DNMT3A p.Arg598Ter](/variant/dnmt3a-p-arg598ter), [DNMT3A p.Arg688His](/variant/dnmt3a-p-arg688his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 1947553). 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.*