# NM_001271.4(CHD2):c.2598G>T (p.Ser866=)

https://sugi.bio/variant/chd2-p-ser866

## Summary

**CHD2 p.Ser866= (c.2598G>T)** is classified **Uncertain significance** in CHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-11). Very rare (popmax 0.0011%, sas); Associated with developmental and epileptic encephalopathy 94.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs953120105 · 1 submitter · 1 linked condition · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the CHD2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to developmental and epileptic encephalopathy 94.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Multigenic/multifactorial, Not applicable |
| Age of onset (of this condition) | Childhood, Infancy |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CHD2 is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Lennox-Gastaut syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Intellectual disability — Very frequent (99-80%)
- Encephalopathy — Very frequent (99-80%)
- EEG with focal sharp slow waves — Very frequent (99-80%)
- Atypical behavior — Frequent (79-30%)
- Aggressive behavior — Frequent (79-30%)
- Autistic behavior — Frequent (79-30%)
- Irritability — Frequent (79-30%)
- Hyperactivity — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0013197/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CHD2](https://sugi.bio/atlas/gene/CHD2/) |
| Protein change (HGVS p.) | p.Ser866= |
| Coding change (HGVS c.) | c.2598G>T |
| MANE Select transcript | [NM_001271](https://www.ncbi.nlm.nih.gov/nuccore/NM_001271) |
| dbSNP | [rs953120105](https://www.ncbi.nlm.nih.gov/snp/rs953120105/) |
| Variant type | single nucleotide variant |
| Location | chr15:92978254-92978254 (GRCh38) |
| ClinVar | [VCV2093165](https://www.ncbi.nlm.nih.gov/clinvar/variation/2093165/) |

**All HGVS expressions:** `LRG_1425:g.82934G>T`, `LRG_1425t1:c.2598G>T`, `NC_000015.10:g.92978254G>T`, `NC_000015.9:g.93521484G>T`, `NG_012826.2:g.82934G>T`, `NM_001271.4:c.2598G>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.36) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -0.384, GERP -3.32, phastCons 0.007 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 6.691**. 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 deltas (raw): acceptor loss **0.03**, donor loss **0.00**, acceptor gain **0.36**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.36**, donor gain **0.00**.
- Pangolin: Δ**0.28** (gain), gain 0.28 / loss 0.19. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (sas) · 1/91,078 in the highest group · 3/1,461,860 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,253 |
| South Asian (grpmax) | 0.0011% | 91,078 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**CHD2** population constraint: LOEUF 0.174, pLI 1, missense-Z 6.0349; 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):

- **complex neurodevelopmental disorder** — Definitive (AD)

## Protein context {#protein}

Residue **866** lies in the helicase c-terminal domain; a UniProt-annotated variant site (in dee94); a UniProt-annotated variant site (found in a patient with progressive myoclonus epilepsy; uncertain significance).

AlphaFold model confidence (whole protein): pLDDT 60.81, 7% of residues very-high.

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

*Describes the biological roles of CHD2 (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:** CHD2's established molecular role includes RNA binding. p.Ser866= falls in the helicase c-terminal domain.


### Pathways affected {#pathways}

CHD2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CHD1 and CHD2 subfamily](https://reactome.org/content/detail/R-HSA-9943411) | electronic |

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

**Molecular function:** RNA binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-11.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-11 |

## Associated conditions {#conditions}

[developmental and epileptic encephalopathy 94](https://sugi.bio/atlas/disease/developmental-and-epileptic-encephalopathy-94/).

**Reported phenotype names (ClinVar):** Developmental and epileptic encephalopathy 94, Epileptic encephalopathy, childhood-onset, CHD2-Related Neurodevelopmental Disorders.

## Same-residue context {#hotspot}

Residue **866** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CHD2 p.Ser866Ter](/variant/chd2-p-ser866ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CHD2 variant pages (same residue, condition, or type): [CHD2 p.Ser866Ter](/variant/chd2-p-ser866ter), [CHD2 p.Ser866Leu](/variant/chd2-p-ser866leu), [CHD2 p.Ser866Pro](/variant/chd2-p-ser866pro), [CHD2 c.1153+1G>C](/variant/chd2-c-1153-plus-1g-c), [CHD2 c.1809+1G>A](/variant/chd2-c-1809-plus-1g-a), [CHD2 c.294+1G>T](/variant/chd2-c-294-plus-1g-t), [CHD2 c.443+1G>A](/variant/chd2-c-443-plus-1g-a), [CHD2 c.693-1G>A](/variant/chd2-c-693-minus-1g-a).

### 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 2093165). 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.*