# NM_001271.4(CHD2):c.991A>G (p.Lys331Glu)

https://sugi.bio/variant/chd2-p-lys331glu

## Summary

**CHD2 p.Lys331Glu (c.991A>G)** is classified **Uncertain significance** in CHD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-01). AlphaMissense: likely pathogenic (0.5954); Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy 94.

**At a glance:** Uncertain significance · review: Multiple submitters · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## 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 2 submitters, 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.Lys331Glu |
| Coding change (HGVS c.) | c.991A>G |
| MANE Select transcript | [NM_001271](https://www.ncbi.nlm.nih.gov/nuccore/NM_001271) |
| Variant type | single nucleotide variant |
| Location | chr15:92943007-92943007 (GRCh38) |
| ClinVar | [VCV3365140](https://www.ncbi.nlm.nih.gov/clinvar/variation/3365140/) |

**All HGVS expressions:** `LRG_1425:g.47687A>G`, `LRG_1425t1:c.991A>G`, `LRG_1425t2:c.991A>G`, `NC_000015.10:g.92943007A>G`, `NC_000015.9:g.93486237A>G`, `NG_012826.2:g.47687A>G`, `NM_001042572.3:c.991A>G`, `NM_001271.4:c.991A>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.5954)
- REVEL 0.274 (benign-leaning) — differs from AlphaMissense
- SaProt LLR -9.647 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; REVEL and SaProt do not
- Conservation: phyloP 11.248, GERP 2.93, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 24.5**. 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 0.68** across the covering region of the MANE Select transcript (92,939,668–92,948,967), spanning 9,299 bp. Chi-square p 6.4e-08. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (A>T, Δ0.99 donor gain), 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: **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}

**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 **331** lies in the chromo 1 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.Lys331Glu falls in the chromo 1 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-01.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2023–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-10-01 |

## 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, not provided, Epileptic encephalopathy, childhood-onset, CHD2-Related Neurodevelopmental Disorders, none provided.

## Similar variants {#similar}

Related CHD2 variant pages (same residue, condition, or type): [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), [CHD2 p.Ala879Val](/variant/chd2-p-ala879val), [CHD2 p.Arg1072Ter](/variant/chd2-p-arg1072ter), [CHD2 p.Arg1137Ter](/variant/chd2-p-arg1137ter).

### 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 3365140). 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.*