# NM_001005273.3(CHD3):c.5054G>C (p.Arg1685Pro)

https://sugi.bio/variant/chd3-p-arg1685pro

## Summary

**CHD3 p.Arg1685Pro (c.5054G>C)** is classified **Uncertain significance** in CHD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-20). AlphaMissense: likely benign (0.1398); Ultra-rare (popmax 0.0227%, afr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0227%, afr)

## 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 Inborn genetic diseases.

*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.Arg1685Pro |
| Coding change (HGVS c.) | c.5054G>C |
| MANE Select transcript | [NM_001005273](https://www.ncbi.nlm.nih.gov/nuccore/NM_001005273) |
| Variant type | single nucleotide variant |
| Location | chr17:7907921-7907921 (GRCh38) |
| ClinVar | [VCV4829007](https://www.ncbi.nlm.nih.gov/clinvar/variation/4829007/) |

**All HGVS expressions:** `NC_000017.10:g.7811239G>C`, `NC_000017.11:g.7907921G>C`, `NM_001005271.3:c.5231G>C`, `NM_001005273.3:c.5054G>C`, `NM_001437504.1:c.5231G>C`, `NM_001437507.1:c.5219G>C`, `NM_001437508.1:c.5117G>C`, `NM_001437509.1:c.5222G>C`, `NM_005852.4:c.4952G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1398)
- REVEL 0.461 (indeterminate)
- SaProt LLR -5.65 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- SpliceAI predicts **acceptor gain** (Δ 0.33) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.797, GERP 1.59, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.4**. 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 0.95** across the covering region of the MANE Select transcript (7,906,885–7,907,998), spanning 1,113 bp. Chi-square p 0.44. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.03**, donor loss **0.00**, acceptor gain **0.33**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.33**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0227%** (afr) · FAF95 0.0144% · FAF99 0.0119% · 17/74,842 in the highest group · 28/1,612,466 alleles overall — ultra-rare (popmax 0.0227%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0227% | 4,402 |
| Remaining individuals (not grpmax-eligible) | 0.0112% | 8,917 |
| South Asian | 0.0033% | 30,331 |
| Admixed American | 0.00167% | 59,878 |

*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 **1685** lies in the 'disordered' region; the 'required for interaction with pcnt' region; 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.Arg1685Pro 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 2026-01-20.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-01-20 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Same-residue context {#hotspot}

Residue **1685** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CHD3 p.Arg1685Ter](/variant/chd3-p-arg1685ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CHD3 variant pages (same residue, condition, or type): [CHD3 p.Arg1685Gln](/variant/chd3-p-arg1685gln), [CHD3 p.Arg1685Ter](/variant/chd3-p-arg1685ter), [CHD3 p.Arg103Ter](/variant/chd3-p-arg103ter), [CHD3 p.Arg1078Gln](/variant/chd3-p-arg1078gln), [CHD3 p.Arg966Trp](/variant/chd3-p-arg966trp), [CHD3 p.Arg985Trp](/variant/chd3-p-arg985trp), [CHD3 p.Pro1918=](/variant/chd3-p-pro1918), [CHD3 p.Arg1266Trp](/variant/chd3-p-arg1266trp).

### 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 4829007). 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.*