# NM_001170629.2(CHD8):c.117_133del (p.Pro40fs)

https://sugi.bio/variant/chd8-p-pro40fs

## Summary

**CHD8 p.Pro40fs (c.117_133del)** is classified **Pathogenic** in CHD8 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-10-18). No gnomAD frequency available for this variant; Associated with intellectual developmental disorder with autism and macrocephaly.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1566446604 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CHD8 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to intellectual developmental disorder with autism and macrocephaly.

*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 |
| Age of onset (of this condition) | No data available |
| Diagnostic panels | CHD8 is a diagnostic-grade gene on 6 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024965/index) · [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.Pro40fs |
| Coding change (HGVS c.) | c.117_133del |
| MANE Select transcript | [NM_001170629](https://www.ncbi.nlm.nih.gov/nuccore/NM_001170629) |
| dbSNP | [rs1566446604](https://www.ncbi.nlm.nih.gov/snp/rs1566446604/) |
| Variant type | Deletion |
| Location | chr14:21431511-21431527 (GRCh38) |
| ClinVar | [VCV560292](https://www.ncbi.nlm.nih.gov/clinvar/variation/560292/) |

**All HGVS expressions:** `NC_000014.8:g.21899676_21899692del`, `NC_000014.9:g.21431517_21431533del`, `NG_021249.1:g.10772_10788del`, `NM_001170629.1:c.117_133del17`, `NM_001170629.2:c.117_133del`, `NM_020920.4:c.6+284_6+300del`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 11.827, GERP 2.69, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — 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 2 of 38**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

Residue **40** lies in the 'disordered' region.

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. p.Pro40fs falls in the disordered region.


### 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 2017-10-18.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Geisinger Autism and Developmental Medicine Institute, Geisinger Health System | Pathogenic | criteria provided, single submitter | provider interpretation | 2017-10-18 |

## Associated conditions {#conditions}

[intellectual developmental disorder with autism and macrocephaly](https://sugi.bio/atlas/disease/intellectual-developmental-disorder-with-autism-and-macrocephaly/).

**Reported phenotype names (ClinVar):** Intellectual developmental disorder with autism and macrocephaly, Autism, susceptibility to, 18, CHD8-Related Neurodevelopmental Disorder with Overgrowth.

## Similar variants {#similar}

Related CHD8 variant pages (same residue, condition, or type): [CHD8 p.Arg2150fs](/variant/chd8-p-arg2150fs), [CHD8 p.Lys1537_Val1538insTer](/variant/chd8-p-lys1537-val1538inster), [CHD8 c.4727+1del](/variant/chd8-c-4727-plus-1del), [CHD8 c.4729del](/variant/chd8-c-4729del), [CHD8 p.Arg1895fs](/variant/chd8-p-arg1895fs), [CHD8 p.Asn855fs](/variant/chd8-p-asn855fs), [CHD8 p.Asp1686_Phe1687insTer](/variant/chd8-p-asp1686-phe1687inster), [CHD8 p.Gln1520fs](/variant/chd8-p-gln1520fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 560292). 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.*