# NM_024757.5(EHMT1):c.444T>C (p.Pro148=)

https://sugi.bio/variant/ehmt1-p-pro148

## Summary

**EHMT1 p.Pro148= (c.444T>C)** is classified **Benign** in EHMT1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). Common (popmax 44.6%, amr) — too common for a highly-penetrant pathogenic allele; Associated with Inborn genetic diseases.

**At a glance:** Benign · review: Multiple submitters · rsID rs3812497 · 9 submitters · 2 linked conditions · common (popmax 44.6%, amr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the EHMT1 gene that is classified as benign — not considered disease-causing, submitted by 9 submitters, and is linked to Inborn genetic diseases.

*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 | [EHMT1](https://sugi.bio/atlas/gene/EHMT1/) |
| Protein change (HGVS p.) | p.Pro148= |
| Coding change (HGVS c.) | c.444T>C |
| MANE Select transcript | [NM_024757](https://www.ncbi.nlm.nih.gov/nuccore/NM_024757) |
| dbSNP | [rs3812497](https://www.ncbi.nlm.nih.gov/snp/rs3812497/) |
| Variant type | single nucleotide variant |
| Location | chr9:137716984-137716984 (GRCh38) |
| ClinVar | [VCV65738](https://www.ncbi.nlm.nih.gov/clinvar/variation/65738/) |

**All HGVS expressions:** `NC_000009.11:g.140611436T>C`, `NC_000009.12:g.137716984T>C`, `NG_011776.1:g.102993T>C`, `NM_001145527.2:c.444T>C`, `NM_001354259.2:c.351T>C`, `NM_001354263.2:c.444T>C`, `NM_001354611.2:c.444T>C`, `NM_001354612.2:c.351T>C`, `NM_024757.5:c.444T>C`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 44.6%, amr) — too common for a highly-penetrant pathogenic allele.

- **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 -2.629, GERP -2.11 — fast-evolving / accelerated position
- CADD: **PHRED 6.184**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **44.6%** (amr) · FAF95 44.2% · FAF99 44% · 26,697/59,836 in the highest group · 437,510/1,608,838 alleles overall — common (popmax 44.6%, amr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 44.6% | 2 |
| Ashkenazi Jewish (not grpmax-eligible) | 34.8% | 3 |
| Amish (not grpmax-eligible) | 33.4% | 3 |
| South Asian | 31.7% | 3 |
| Middle Eastern | 30.1% | 3 |
| European (non-Finnish) | 27.4% | 4 |
| Remaining individuals (not grpmax-eligible) | 26.4% | 4 |
| Finnish (not grpmax-eligible) | 25.3% | 4 |
| East Asian | 14.6% | 7 |
| African / African-American | 11.3% | 9 |

*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 **148** lies in the 'disordered' region.

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. p.Pro148= falls in the disordered region.


### 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}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (8 Benign, 1 Likely benign).

**Submission history:** 9 submissions (2014–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Likely benign | no assertion criteria provided | clinical testing |  |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2018-07-05 |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2016-03-11 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2014-05-23 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2021-11-29 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-07-30 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [Kleefstra syndrome 1](https://sugi.bio/atlas/disease/kleefstra-syndrome-1/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not specified, Kleefstra syndrome 1, not provided, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related EHMT1 variant pages (same residue, condition, or type): [EHMT1 p.Pro148Arg](/variant/ehmt1-p-pro148arg), [EHMT1 c.1370-1G>C](/variant/ehmt1-c-1370-minus-1g-c), [EHMT1 c.1647+2T>C](/variant/ehmt1-c-1647-plus-2t-c), [EHMT1 c.2193-1G>C](/variant/ehmt1-c-2193-minus-1g-c), [EHMT1 c.2276-2A>G](/variant/ehmt1-c-2276-minus-2a-g), [EHMT1 c.2712+1G>A](/variant/ehmt1-c-2712-plus-1g-a), [EHMT1 c.2867+2T>C](/variant/ehmt1-c-2867-plus-2t-c), [EHMT1 c.3036-1G>A](/variant/ehmt1-c-3036-minus-1g-a).

### 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 65738). 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.*