# NM_001170629.2(CHD8):c.4373G>A (p.Trp1458Ter)

https://sugi.bio/variant/chd8-p-trp1458ter

## Summary

**CHD8 p.Trp1458Ter (c.4373G>A)** is classified **Pathogenic** in CHD8 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-04-15). Absent from gnomAD v4.1.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2501888861 · 2 submitters · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CHD8 gene that is reported as disease-causing, but on limited review, submitted by 2 submitters.

*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 | [CHD8](https://sugi.bio/atlas/gene/CHD8/) |
| Protein change (HGVS p.) | p.Trp1458Ter |
| Coding change (HGVS c.) | c.4373G>A |
| MANE Select transcript | [NM_001170629](https://www.ncbi.nlm.nih.gov/nuccore/NM_001170629) |
| dbSNP | [rs2501888861](https://www.ncbi.nlm.nih.gov/snp/rs2501888861/) |
| Variant type | single nucleotide variant |
| Location | chr14:21400610-21400610 (GRCh38) |
| ClinVar | [VCV2782314](https://www.ncbi.nlm.nih.gov/clinvar/variation/2782314/) |

**All HGVS expressions:** `NC_000014.8:g.21868769C>T`, `NC_000014.9:g.21400610C>T`, `NG_021249.1:g.41689G>A`, `NG_021249.2:g.60513G>A`, `NM_001170629.1:c.4373G>A`, `NM_001170629.2:c.4373G>A`, `NM_020920.4:c.3536G>A`

## Computational & population evidence {#evidence}

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

- **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 0.44) — consistent with the pathogenic call
- Conservation: phyloP 7.724, GERP 2.46, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.154, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 23 of 38**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 47.0**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.08**, donor loss **0.00**, acceptor gain **0.44**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.44**, 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}

**CHD8** population constraint: LOEUF 0.154, pLI 1, missense-Z 7.0384; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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}


AlphaFold model confidence (whole protein): pLDDT 55.17, 6% of residues very-high.

**2 experimental structure(s)** (PDB): [2CKA](https://www.rcsb.org/structure/2CKA), [2DL6](https://www.rcsb.org/structure/2DL6).

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

*Describes the biological roles of CHD8 (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:** CHD8's established molecular role includes DNA binding.


### Pathways affected {#pathways}

CHD8 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CHD6, CHD7, CHD8, CHD9 subfamily](https://reactome.org/content/detail/R-HSA-9943962) | curated |
| [Deactivation of the beta-catenin transactivating complex](https://reactome.org/content/detail/R-HSA-3769402) | curated |

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

**Molecular function:** DNA binding, chromatin binding, ATP binding, beta-catenin binding, histone H3K4me3 reader activity, ATP-dependent chromatin remodeler activity.

**Biological process:** negative regulation of transcription by RNA polymerase II, chromatin remodeling, mRNA processing, brain development, negative regulation of DNA-templated transcription, positive regulation of DNA-templated transcription.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-04-15.

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

**Submission history:** 2 submissions (2023–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely pathogenic | no assertion criteria provided | clinical testing | 2024-02-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-04-15 |

**Reported phenotype names (ClinVar):** not provided, CHD8-related disorder, CHD8-related condition, CHD8-related disorders, none provided.

## Similar variants {#similar}

Related CHD8 variant pages (same residue, condition, or type): [CHD8 c.3882+1G>A](/variant/chd8-c-3882-plus-1g-a), [CHD8 p.Arg1188Ter](/variant/chd8-p-arg1188ter), [CHD8 p.Arg1242Gln](/variant/chd8-p-arg1242gln), [CHD8 p.Arg1242Ter](/variant/chd8-p-arg1242ter), [CHD8 p.Arg1245Ter](/variant/chd8-p-arg1245ter), [CHD8 p.Arg1337Ter](/variant/chd8-p-arg1337ter), [CHD8 p.Arg1402Ter](/variant/chd8-p-arg1402ter), [CHD8 p.Arg1460Ter](/variant/chd8-p-arg1460ter).

### 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 2782314). 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.*