# NM_006892.4(DNMT3B):c.2340G>A (p.Ser780=)

https://sugi.bio/variant/dnmt3b-p-ser780

## Summary

**DNMT3B p.Ser780= (c.2340G>A)** is classified **Likely benign** in DNMT3B (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-06-01). Ultra-rare (popmax 0.0506%, afr); Associated with immunodeficiency-centromeric instability-facial anomalies syndrome.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs151108199 · 3 submitters · 1 linked condition · ultra-rare (popmax 0.0506%, afr)

## For patients & families {#patients}

This is a change in the DNMT3B gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters, and is linked to immunodeficiency-centromeric instability-facial anomalies 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/0002945/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DNMT3B](https://sugi.bio/atlas/gene/DNMT3B/) |
| Protein change (HGVS p.) | p.Ser780= |
| Coding change (HGVS c.) | c.2340G>A |
| MANE Select transcript | [NM_006892](https://www.ncbi.nlm.nih.gov/nuccore/NM_006892) |
| dbSNP | [rs151108199](https://www.ncbi.nlm.nih.gov/snp/rs151108199/) |
| Variant type | single nucleotide variant |
| Location | chr20:32806247-32806247 (GRCh38) |
| ClinVar | [VCV2052111](https://www.ncbi.nlm.nih.gov/clinvar/variation/2052111/) |

**All HGVS expressions:** `LRG_56:g.48863G>A`, `LRG_56t1:c.2340G>A`, `NC_000020.10:g.31394053G>A`, `NC_000020.11:g.32806247G>A`, `NG_007290.1:g.48863G>A`, `NM_001207055.2:c.2046-1515G>A`, `NM_001207056.2:c.1944-1515G>A`, `NM_006892.4:c.2340G>A`, `NM_175848.2:c.2280G>A`, `NM_175849.2:c.2172-1515G>A`, `NM_175850.3:c.2316G>A`

## 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 0.772, GERP -3.84, phastCons 0.999 — weakly conserved position
- CADD: **PHRED 7.992**. 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>T, Δ0.20 acceptor loss), 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 **0.0506%** (afr) · FAF95 0.0379% · FAF99 0.0334% · 38/75,030 in the highest group · 59/1,614,166 alleles overall — ultra-rare (popmax 0.0506%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0506% | 1,974 |
| Admixed American | 0.005% | 20,008 |
| Finnish (not grpmax-eligible) | 0.00469% | 21,341 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,254 |
| South Asian | 0.0011% | 91,064 |
| European (non-Finnish) | 0.00102% | 98,337 |

*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}

**DNMT3B** population constraint: LOEUF 0.396, pLI 1, missense-Z 3.3349. *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):

- **immunodeficiency-centromeric instability-facial anomalies syndrome 1** — Definitive (AR)

## Protein context {#protein}

Residue **780** lies in an α-helix; the sam-dependent mtase c5-type domain.

AlphaFold model confidence (whole protein): pLDDT 73.18, 50% of residues very-high.

**47 experimental structure(s)** (PDB): [3FLG](https://www.rcsb.org/structure/3FLG), [3QKJ](https://www.rcsb.org/structure/3QKJ), [5CIU](https://www.rcsb.org/structure/5CIU), [5NR3](https://www.rcsb.org/structure/5NR3), [5NRR](https://www.rcsb.org/structure/5NRR), [5NRS](https://www.rcsb.org/structure/5NRS) — incl. mutant structure 8XEE.

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

*Describes the biological roles of DNMT3B (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:** DNMT3B's established molecular role includes transcription corepressor activity. p.Ser780= falls in the sam-dependent mtase c5-type domain. In Reactome, DNMT3B is annotated in disease pathway(s) including **Defective pyroptosis**.

**Disease mechanism (Reactome):** DNMT3B loss or alteration is curated in [Defective pyroptosis](https://reactome.org/content/detail/R-HSA-9710421).

### Pathways affected {#pathways}

DNMT3B participates in **5 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 |
| [SUMOylation of DNA methylation proteins](https://reactome.org/content/detail/R-HSA-4655427) | curated |
| [DNA methylation](https://reactome.org/content/detail/R-HSA-5334118) | electronic |
| [NoRC negatively regulates rRNA expression](https://reactome.org/content/detail/R-HSA-427413) | electronic |

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

**Molecular function:** transcription corepressor activity, DNA (cytosine-5-)-methyltransferase activity.

**Biological process:** negative regulation of transcription by RNA polymerase II, positive regulation of gene expression.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-06-01.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2024–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-29 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-06-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-05 |

## Associated conditions {#conditions}

[immunodeficiency-centromeric instability-facial anomalies syndrome](https://sugi.bio/atlas/disease/immunodeficiency-centromeric-instability-facial-anomalies-syndrome/).

**Reported phenotype names (ClinVar):** Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency, not provided, not specified, AllHighlyPenetrant, CENTROMERIC INSTABILITY, IMMUNODEFICIENCY SYNDROME, Immunodeficiency-centromeric instability-facial anomalies, IMMUNE DEFICIENCY, VARIABLE, WITH CENTROMERIC INSTABILITY OF CHROMOSOMES 1, 9, AND 16, IMMUNODEFICIENCY SYNDROME, VARIABLE, none provided.

## Similar variants {#similar}

Related DNMT3B variant pages (same residue, condition, or type): [DNMT3B c.2421-11G>A](/variant/dnmt3b-c-2421-minus-11g-a), [DNMT3B p.Ala603Thr](/variant/dnmt3b-p-ala603thr), [DNMT3B p.Arg826Cys](/variant/dnmt3b-p-arg826cys), [DNMT3B p.Arg840Gln](/variant/dnmt3b-p-arg840gln), [DNMT3B p.Asp653Asn](/variant/dnmt3b-p-asp653asn), [DNMT3B p.His814Arg](/variant/dnmt3b-p-his814arg), [DNMT3B p.Val613Ala](/variant/dnmt3b-p-val613ala), [DNMT3B p.Val726Gly](/variant/dnmt3b-p-val726gly).

### 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 2052111). 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.*