# NM_024757.5(EHMT1):c.2214_2230dup (p.Phe744fs)

https://sugi.bio/variant/ehmt1-p-phe744fs

## Summary

**EHMT1 p.Phe744fs (c.2214_2230dup)** is classified **Pathogenic** in EHMT1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2017-03-14). No gnomAD frequency available for this variant; Associated with Kleefstra syndrome 1.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs1554880275 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the EHMT1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Kleefstra syndrome 1.

*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/0025497/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [EHMT1](https://sugi.bio/atlas/gene/EHMT1/) |
| Protein change (HGVS p.) | p.Phe744fs |
| Coding change (HGVS c.) | c.2214_2230dup |
| MANE Select transcript | [NM_024757](https://www.ncbi.nlm.nih.gov/nuccore/NM_024757) |
| dbSNP | [rs1554880275](https://www.ncbi.nlm.nih.gov/snp/rs1554880275/) |
| Variant type | Duplication |
| Location | chr9:137779655-137779656 (GRCh38) |
| ClinVar | [VCV438289](https://www.ncbi.nlm.nih.gov/clinvar/variation/438289/) |

**All HGVS expressions:** `NC_000009.11:g.140674108_140674124dup`, `NC_000009.12:g.137779656_137779672dup`, `NG_011776.1:g.165665_165681dup`, `NM_001145527.2:c.2214_2230dup`, `NM_001354259.2:c.2121_2137dup`, `NM_001354263.2:c.2193_2209dup`, `NM_024757.4:c.2214_2230dupCCCAAAGCAGCTGTACT`, `NM_024757.5:c.2214_2230dup`

## 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 10.827, GERP 1.95, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.159, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 14 of 27**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — 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}

**EHMT1** population constraint: LOEUF 0.159, pLI 1, missense-Z 1.9902. *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):

- **Kleefstra syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **744** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 64.89, 36% of residues very-high.

**22 experimental structure(s)** (PDB): [2IGQ](https://www.rcsb.org/structure/2IGQ), [2RFI](https://www.rcsb.org/structure/2RFI), [3B7B](https://www.rcsb.org/structure/3B7B), [3B95](https://www.rcsb.org/structure/3B95), [3FPD](https://www.rcsb.org/structure/3FPD), [3HNA](https://www.rcsb.org/structure/3HNA) — incl. mutant structure 4I51.

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

*Describes the biological roles of EHMT1 (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:** EHMT1's established molecular role includes transcription corepressor binding.


### Pathways affected {#pathways}

EHMT1 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [PKMTs methylate histone lysines](https://reactome.org/content/detail/R-HSA-3214841) | curated |
| [Regulation of TP53 Activity through Methylation](https://reactome.org/content/detail/R-HSA-6804760) | curated |
| [Senescence-Associated Secretory Phenotype (SASP)](https://reactome.org/content/detail/R-HSA-2559582) | curated |
| [Transcriptional Regulation by E2F6](https://reactome.org/content/detail/R-HSA-8953750) | curated |
| [Transcriptional Regulation by VENTX](https://reactome.org/content/detail/R-HSA-8853884) | curated |
| [Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex](https://reactome.org/content/detail/R-HSA-9843970) | electronic |

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

**Molecular function:** transcription corepressor binding, p53 binding, methyltransferase activity, protein-lysine N-methyltransferase activity, histone H3K9 methyltransferase activity.

**Biological process:** chromatin organization, peptidyl-lysine dimethylation.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2017-03-14.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals | Pathogenic | no assertion criteria provided | clinical testing | 2017-03-14 |

## Associated conditions {#conditions}

[Kleefstra syndrome 1](https://sugi.bio/atlas/disease/kleefstra-syndrome-1/).

**Reported phenotype names (ClinVar):** Kleefstra syndrome 1.

## Similar variants {#similar}

Related EHMT1 variant pages (same residue, condition, or type): [EHMT1 p.Phe253fs](/variant/ehmt1-p-phe253fs), [EHMT1 p.Glu531_Ala536dup](/variant/ehmt1-p-glu531-ala536dup), [EHMT1 p.Ala193fs](/variant/ehmt1-p-ala193fs), [EHMT1 p.Arg291fs](/variant/ehmt1-p-arg291fs), [EHMT1 p.Asn1106fs](/variant/ehmt1-p-asn1106fs), [EHMT1 p.Asn240fs](/variant/ehmt1-p-asn240fs), [EHMT1 p.Asn599Ter](/variant/ehmt1-p-asn599ter), [EHMT1 p.Asp349fs](/variant/ehmt1-p-asp349fs).

### 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 438289). 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.*