# NM_001005273.3(CHD3):c.3496G>C (p.Ala1166Pro)

https://sugi.bio/variant/chd3-p-ala1166pro

## Summary

**CHD3 p.Ala1166Pro (c.3496G>C)** is classified **Likely pathogenic** in CHD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-03). AlphaMissense: likely pathogenic (0.9968); Absent from gnomAD v4.1.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2151603267 · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CHD3 gene that is considered likely disease-causing, submitted by 1 submitter.

*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 | [CHD3](https://sugi.bio/atlas/gene/CHD3/) |
| Protein change (HGVS p.) | p.Ala1166Pro |
| Coding change (HGVS c.) | c.3496G>C |
| MANE Select transcript | [NM_001005273](https://www.ncbi.nlm.nih.gov/nuccore/NM_001005273) |
| dbSNP | [rs2151603267](https://www.ncbi.nlm.nih.gov/snp/rs2151603267/) |
| Variant type | single nucleotide variant |
| Location | chr17:7903272-7903272 (GRCh38) |
| ClinVar | [VCV1319379](https://www.ncbi.nlm.nih.gov/clinvar/variation/1319379/) |

**All HGVS expressions:** `NC_000017.10:g.7806590G>C`, `NC_000017.11:g.7903272G>C`, `NM_001005271.3:c.3673G>C`, `NM_001005273.3:c.3496G>C`, `NM_005852.4:c.3496G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9968) — concordant with the pathogenic call
- REVEL 0.909 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.816 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.935, GERP 1.9, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 34.0**. 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 0.08** across the covering region of the MANE Select transcript (7,902,945–7,903,333), spanning 388 bp — the region is depleted of missense variation. Chi-square p 5.3e-16. 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}

**CHD3** population constraint: LOEUF 0.257, pLI 1, missense-Z 8.4269. *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):

- **Snijders Blok-Campeau syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **1166** lies in the helicase c-terminal domain; a UniProt-annotated variant site (in snibcps).

AlphaFold model confidence (whole protein): pLDDT 63.21, 15% of residues very-high.

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

*Describes the biological roles of CHD3 (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:** CHD3's established molecular role includes transcription cis-regulatory region binding. p.Ala1166Pro falls in the helicase c-terminal domain. In Reactome, CHD3 is annotated in disease pathway(s) including **Potential therapeutics for SARS**.

**Disease mechanism (Reactome):** CHD3 loss or alteration is curated in [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191).

### Pathways affected {#pathways}

CHD3 participates in **13 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191) | curated |
| [HDACs deacetylate histones](https://reactome.org/content/detail/R-HSA-3214815) | curated |
| [Interaction of NuRD complexes with transcription factors](https://reactome.org/content/detail/R-HSA-9940951) | curated |
| [NuRD complex assembly](https://reactome.org/content/detail/R-HSA-9937850) | curated |
| [RNA Polymerase I Transcription Initiation](https://reactome.org/content/detail/R-HSA-73762) | curated |
| [Regulation of TP53 Activity through Acetylation](https://reactome.org/content/detail/R-HSA-6804758) | curated |
| [SUMOylation of chromatin organization proteins](https://reactome.org/content/detail/R-HSA-4551638) | curated |
| [Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)](https://reactome.org/content/detail/R-HSA-9976102) | electronic |
| [ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression](https://reactome.org/content/detail/R-HSA-427389) | electronic |
| [Regulation of PTEN gene transcription](https://reactome.org/content/detail/R-HSA-8943724) | electronic |
| [Regulation of endogenous retroelements by KRAB-ZFP proteins](https://reactome.org/content/detail/R-HSA-9843940) | electronic |
| [Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)](https://reactome.org/content/detail/R-HSA-9845323) | electronic |
| [Transcriptional regulation of brown and beige adipocyte differentiation by EBF2](https://reactome.org/content/detail/R-HSA-9844594) | electronic |

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

**Molecular function:** transcription cis-regulatory region binding, RNA binding, ATP hydrolysis activity, ATP-dependent chromatin remodeler activity.

**Biological process:** negative regulation of transcription by RNA polymerase II, chromatin remodeling, spindle organization, centrosome cycle.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-11-03.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-11-03 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related CHD3 variant pages (same residue, condition, or type): [CHD3 c.4073-2A>C](/variant/chd3-c-4073-minus-2a-c), [CHD3 p.Arg103Ter](/variant/chd3-p-arg103ter), [CHD3 p.Arg1078Gln](/variant/chd3-p-arg1078gln), [CHD3 p.Arg1121Pro](/variant/chd3-p-arg1121pro), [CHD3 p.Arg1169Gln](/variant/chd3-p-arg1169gln), [CHD3 p.Arg1169Pro](/variant/chd3-p-arg1169pro), [CHD3 p.Arg1169Trp](/variant/chd3-p-arg1169trp), [CHD3 p.Arg1172Gln](/variant/chd3-p-arg1172gln).

### 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 1319379). 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.*