# NM_003797.5(EED):c.906A>C (p.Arg302Ser)

https://sugi.bio/variant/eed-p-arg302ser

## Summary

**EED p.Arg302Ser (c.906A>C)** is classified **Likely pathogenic** in EED (ClinVar, Single submitter, 2 submitters; last evaluated 2026-01-11). AlphaMissense: likely pathogenic (0.9998); Absent from gnomAD v4.1; Associated with Cohen-Gibson syndrome.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs1131692173 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the EED gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to Cohen-Gibson 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/0016235/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [EED](https://sugi.bio/atlas/gene/EED/) |
| Protein change (HGVS p.) | p.Arg302Ser |
| Coding change (HGVS c.) | c.906A>C |
| MANE Select transcript | [NM_003797](https://www.ncbi.nlm.nih.gov/nuccore/NM_003797) |
| dbSNP | [rs1131692173](https://www.ncbi.nlm.nih.gov/snp/rs1131692173/) |
| Variant type | single nucleotide variant |
| Location | chr11:86268501-86268501 (GRCh38) |
| ClinVar | [VCV430643](https://www.ncbi.nlm.nih.gov/clinvar/variation/430643/) |

**All HGVS expressions:** `NC_000011.10:g.86268501A>C`, `NC_000011.9:g.85979543A>C`, `NG_029595.1:g.28738A>C`, `NM_001308007.2:c.906A>C`, `NM_001330334.2:c.726+4238A>C`, `NM_003797.5:c.906A>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9998) — concordant with the pathogenic call
- REVEL 0.447 (indeterminate)
- SaProt LLR -10.572 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- SpliceAI predicts **acceptor gain** (Δ 0.22) — consistent with the pathogenic call
- Conservation: phyloP 9.185, GERP 2.41, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 8%** most-pathogenic-predicted substitutions in EED (of 2,616 modeled).
- CADD: **PHRED 26.8**. 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 0.45** across the covering region of the MANE Select transcript (86,250,376–86,278,522), spanning 28,146 bp. Chi-square p 8.5e-32. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.22**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.22**, donor gain **0.00**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**EED** population constraint: LOEUF 0.41, pLI 0.99914, missense-Z 2.9266. *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):

- **Cohen-Gibson syndrome** — Moderate (AD)

## Protein context {#protein}

Residue **302** lies in the 'interaction with ezh2' region; the 'required for interaction with the matrix protein ma of hiv-1' region; a UniProt-annotated variant site (in cogis); a UniProt-annotated variant site (in cogis; decreased trimethylation of 'lys-27' of histone h3); a β-strand.

AlphaFold model confidence (whole protein): pLDDT 87.21, 80% of residues very-high.

**81 experimental structure(s)** (PDB): [3IIW](https://www.rcsb.org/structure/3IIW), [3IIY](https://www.rcsb.org/structure/3IIY), [3IJ0](https://www.rcsb.org/structure/3IJ0), [3IJ1](https://www.rcsb.org/structure/3IJ1), [3IJC](https://www.rcsb.org/structure/3IJC), [3JPX](https://www.rcsb.org/structure/3JPX) — incl. mutant structure 5IJ8.

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

*Describes the biological roles of EED (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:** EED's established molecular role includes transcription corepressor binding. p.Arg302Ser falls in the interaction with ezh2 region. In Reactome, EED is annotated in disease pathway(s) including **Defective pyroptosis**, **HCMV Early Events**.

**Disease mechanism (Reactome):** EED loss or alteration is curated in [Defective pyroptosis](https://reactome.org/content/detail/R-HSA-9710421), [HCMV Early Events](https://reactome.org/content/detail/R-HSA-9609690).

### Pathways affected {#pathways}

EED participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective pyroptosis](https://reactome.org/content/detail/R-HSA-9710421) | curated |
| ⚕ [HCMV Early Events](https://reactome.org/content/detail/R-HSA-9609690) | curated |
| [Negative Regulation of CDH1 Gene Transcription](https://reactome.org/content/detail/R-HSA-9764725) | curated |
| [Oxidative Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559580) | curated |
| [PKMTs methylate histone lysines](https://reactome.org/content/detail/R-HSA-3214841) | curated |
| [PRC2 methylates histones and DNA](https://reactome.org/content/detail/R-HSA-212300) | curated |
| [Regulation of PD-L1(CD274) transcription](https://reactome.org/content/detail/R-HSA-9909649) | curated |
| [Transcriptional Regulation by E2F6](https://reactome.org/content/detail/R-HSA-8953750) | curated |
| [Activation of anterior HOX genes in hindbrain development during early embryogenesis](https://reactome.org/content/detail/R-HSA-5617472) | electronic |
| [Regulation of PTEN gene transcription](https://reactome.org/content/detail/R-HSA-8943724) | electronic |

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

**Molecular function:** transcription corepressor binding, enzyme activator activity, identical protein binding.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-01-11.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Likely pathogenic).

**Submission history:** 2 submissions (2017–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2017-07-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-01-11 |

## Associated conditions {#conditions}

[Cohen-Gibson syndrome](https://sugi.bio/atlas/disease/cohen-gibson-syndrome/).

**Reported phenotype names (ClinVar):** Cohen-Gibson syndrome, EED-Related Overgrowth.

## Same-residue context {#hotspot}

Residue **302** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [EED p.Arg302Gly](/variant/eed-p-arg302gly). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related EED variant pages (same residue, condition, or type): [EED p.Arg302Gly](/variant/eed-p-arg302gly), [EED p.Asn194Ser](/variant/eed-p-asn194ser), [EED p.Asp237Gly](/variant/eed-p-asp237gly), [EED p.Ala17Val](/variant/eed-p-ala17val), [EED p.Arg4Met](/variant/eed-p-arg4met), [EED p.Lys83Ile](/variant/eed-p-lys83ile), [EED c.267+20C>G](/variant/eed-c-267-plus-20c-g), [EED c.361-19G>A](/variant/eed-c-361-minus-19g-a).

### 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 430643). 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.*