# NM_022552.5(DNMT3A):c.2114T>G (p.Ile705Ser)

https://sugi.bio/variant/dnmt3a-p-ile705ser

## Summary

**DNMT3A p.Ile705Ser (c.2114T>G)** is classified **Uncertain significance** in DNMT3A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-09). AlphaMissense: likely pathogenic (0.9966); No allele count reported in gnomAD v4.1 (AN 1,614,030).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs777037011 · 1 submitter · AlphaMissense likely pathogenic · no allele count reported in gnomAD v4.1 (AN 1,614,030)

## For patients & families {#patients}

This is a change in the DNMT3A gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [DNMT3A](https://sugi.bio/atlas/gene/DNMT3A/) |
| Protein change (HGVS p.) | p.Ile705Ser |
| Coding change (HGVS c.) | c.2114T>G |
| MANE Select transcript | [NM_022552](https://www.ncbi.nlm.nih.gov/nuccore/NM_022552) |
| dbSNP | [rs777037011](https://www.ncbi.nlm.nih.gov/snp/rs777037011/) |
| Variant type | single nucleotide variant |
| Location | chr2:25240699-25240699 (GRCh38) |
| ClinVar | [VCV2663162](https://www.ncbi.nlm.nih.gov/clinvar/variation/2663162/) |

**All HGVS expressions:** `LRG_459:g.106892T>G`, `LRG_459t1:c.2114T>G`, `LRG_459t2:c.1547T>G`, `LRG_459t4:c.2114T>G`, `NC_000002.11:g.25463568A>C`, `NC_000002.12:g.25240699A>C`, `NG_029465.2:g.106892T>G`, `NM_001320893.1:c.1658T>G`, `NM_001375819.1:c.1445T>G`, `NM_022552.5:c.2114T>G`, `NM_153759.3:c.1547T>G`, `NM_175629.2:c.2114T>G`, `NR_135490.2:n.2345T>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9966)
- REVEL 0.938 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -16.054 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **donor gain** (Δ 0.27) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.294, GERP 1.85, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 34.0**. 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 1.40** across the covering region of the MANE Select transcript (25,239,130–25,243,936), spanning 4,806 bp. Chi-square p 8.9e-10. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.03**, donor loss **0.00**, acceptor gain **0.02**, donor gain **0.27**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.03**, donor loss **0.00**, acceptor gain **0.02**, donor gain **0.27**.
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,614,030)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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 **705** lies in a β-strand; 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.Ile705Ser 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-05-09.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-05-09 |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related DNMT3A variant pages (same residue, condition, or type): [DNMT3A p.Ile705=](/variant/dnmt3a-p-ile705), [DNMT3A p.Ile705Met](/variant/dnmt3a-p-ile705met), [DNMT3A p.Ile705Thr](/variant/dnmt3a-p-ile705thr), [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).

### 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 2663162). 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.*