# NM_001271.4(CHD2):c.2759C>T (p.Thr920Ile)

https://sugi.bio/variant/chd2-p-thr920ile

## Summary

**CHD2 p.Thr920Ile (c.2759C>T)** is classified **Conflicting classifications of pathogenicity** in CHD2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2021-09-02). AlphaMissense: likely pathogenic (0.998); Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy 94.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs2141844210 · 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 of uncertain or conflicting significance (submitters disagree on it), 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.Thr920Ile |
| Coding change (HGVS c.) | c.2759C>T |
| MANE Select transcript | [NM_001271](https://www.ncbi.nlm.nih.gov/nuccore/NM_001271) |
| dbSNP | [rs2141844210](https://www.ncbi.nlm.nih.gov/snp/rs2141844210/) |
| Variant type | single nucleotide variant |
| Location | chr15:92979166-92979166 (GRCh38) |
| ClinVar | [VCV1311457](https://www.ncbi.nlm.nih.gov/clinvar/variation/1311457/) |

**All HGVS expressions:** `LRG_1425:g.83846C>T`, `LRG_1425t1:c.2759C>T`, `NC_000015.10:g.92979166C>T`, `NC_000015.9:g.93522396C>T`, `NG_012826.2:g.83846C>T`, `NM_001271.4:c.2759C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.998)
- REVEL 0.778 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.543 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.64, GERP 2.93, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 8%** most-pathogenic-predicted substitutions in CHD2 (of 10,781 modeled).
- CADD: **PHRED 28.0**. 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 0.16** across the covering region of the MANE Select transcript (92,974,942–92,979,247), spanning 4,305 bp — the region is depleted of missense variation. Chi-square p 1.3e-19. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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: **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 **920** 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.Thr920Ile 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2021-09-02.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Pathogenic).

**Submission history:** 2 submissions (2020–2021); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-09-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2021-09-02 |

## 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, CHD2-Related Neurodevelopmental Disorders, Epileptic encephalopathy, childhood-onset, 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 1311457). 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.*