# NM_001005271.3(CHD3):c.250C>T (p.Pro84Ser)

https://sugi.bio/variant/chd3-p-pro84ser

## Summary

**CHD3 p.Pro84Ser (c.250C>T)** is classified **Uncertain significance** in CHD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-28). Very rare (popmax 0.000119%, nfe); Associated with Snijders Blok-Campeau syndrome.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1329540442 · 1 submitter · 1 linked condition · very rare (popmax 0.000119%, nfe)

## For patients & families {#patients}

This is a change in the CHD3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Snijders Blok-Campeau syndrome.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0013806/index) · [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.Pro84Ser |
| Coding change (HGVS c.) | c.250C>T |
| MANE Select transcript | [NM_001005273](https://www.ncbi.nlm.nih.gov/nuccore/NM_001005273) (variant reported on NM_001005271) |
| dbSNP | [rs1329540442](https://www.ncbi.nlm.nih.gov/snp/rs1329540442/) |
| Variant type | single nucleotide variant |
| Location | chr17:7885056-7885056 (GRCh38) |
| ClinVar | [VCV1679699](https://www.ncbi.nlm.nih.gov/clinvar/variation/1679699/) |

**All HGVS expressions:** `NC_000017.10:g.7788374C>T`, `NC_000017.11:g.7885056C>T`, `NM_001005271.3:c.250C>T`, `NM_001330111.2:c.-167+109G>A`, `NM_001437504.1:c.250C>T`, `NM_001437507.1:c.250C>T`, `NM_001437508.1:c.250C>T`, `NM_001437509.1:c.250C>T`

## Computational & population evidence {#evidence}

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

- **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 4.947, GERP 0.2, phastCons 0.998 — highly conserved position (PP3-type support)
- CADD: **PHRED 13.19**. 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: **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 (gnomAD v4.1): grpmax **0.000119%** (nfe) · 1/841,922 in the highest group · 1/999,416 alleles overall — very rare (popmax 0.000119%, nfe).

*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 **84** lies in the 'disordered' region.

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.Pro84Ser falls in the disordered region. 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-05-28.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| New York Genome Center | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-05-28 |

## Associated conditions {#conditions}

[Snijders Blok-Campeau syndrome](https://sugi.bio/atlas/disease/snijders-blok-campeau-syndrome/).

**Reported phenotype names (ClinVar):** Snijders Blok-Campeau syndrome, INTELLECTUAL DEVELOPMENTAL DISORDER WITH MACROCEPHALY, SPEECH DELAY, AND DYSMORPHIC FACIES.

## Similar variants {#similar}

Related CHD3 variant pages (same residue, condition, or type): [CHD3 p.Pro84Thr](/variant/chd3-p-pro84thr), [CHD3 p.Pro84Leu](/variant/chd3-p-pro84leu), [CHD3 c.4073-2A>C](/variant/chd3-c-4073-minus-2a-c), [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).

### 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 1679699). 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.*