# NM_001170629.2(CHD8):c.6601C>T (p.Pro2201Ser)

https://sugi.bio/variant/chd8-p-pro2201ser

## Summary

**CHD8 p.Pro2201Ser (c.6601C>T)** is classified **Uncertain significance** in CHD8 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-28). AlphaMissense: likely benign (0.0761); Absent from gnomAD v4.1; Associated with intellectual developmental disorder with autism and macrocephaly.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2501849885 · 1 submitter · 1 linked condition · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CHD8 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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.Pro2201Ser |
| Coding change (HGVS c.) | c.6601C>T |
| MANE Select transcript | [NM_001170629](https://www.ncbi.nlm.nih.gov/nuccore/NM_001170629) |
| dbSNP | [rs2501849885](https://www.ncbi.nlm.nih.gov/snp/rs2501849885/) |
| Variant type | single nucleotide variant |
| Location | chr14:21392677-21392677 (GRCh38) |
| ClinVar | [VCV1805505](https://www.ncbi.nlm.nih.gov/clinvar/variation/1805505/) |

**All HGVS expressions:** `NC_000014.8:g.21860836G>A`, `NC_000014.9:g.21392677G>A`, `NG_021249.2:g.68446C>T`, `NM_001170629.2:c.6601C>T`, `NM_020920.4:c.5764C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0761)
- REVEL 0.341 (indeterminate)
- SaProt LLR -6.147 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 10.017, GERP 2.18, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.6**. 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 0.80** across the covering region of the MANE Select transcript (21,392,533–21,395,032), spanning 2,499 bp. Chi-square p 8e-07. 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}

**CHD8** population constraint: LOEUF 0.154, pLI 1, missense-Z 7.0384; 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 **2201** lies in the 'interaction with fam124b' region; 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.Pro2201Ser falls in the interaction with fam124b 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-08-28.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-08-28 |

## 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, CHD8-Related Neurodevelopmental Disorder with Overgrowth, Autism, susceptibility to, 18.

## 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.Arg1337Ter](/variant/chd8-p-arg1337ter), [CHD8 p.Arg1402Ter](/variant/chd8-p-arg1402ter), [CHD8 p.Arg1460Ter](/variant/chd8-p-arg1460ter), [CHD8 p.Arg1462Ter](/variant/chd8-p-arg1462ter).

### 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 2026-07-14); 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 1805505). 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.*