# NM_001005273.3(CHD3):c.1392C>T (p.Asp464=)

https://sugi.bio/variant/chd3-p-asp464

## Summary

**CHD3 p.Asp464= (c.1392C>T)** is classified **Likely benign** in CHD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-01). Ultra-rare (popmax 0.0165%, mid).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the CHD3 gene that is classified as likely benign — not considered 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.Asp464= |
| Coding change (HGVS c.) | c.1392C>T |
| MANE Select transcript | [NM_001005273](https://www.ncbi.nlm.nih.gov/nuccore/NM_001005273) |
| Variant type | single nucleotide variant |
| Location | chr17:7895039-7895039 (GRCh38) |
| ClinVar | [VCV4681339](https://www.ncbi.nlm.nih.gov/clinvar/variation/4681339/) |

**All HGVS expressions:** `NC_000017.10:g.7798357C>T`, `NC_000017.11:g.7895039C>T`, `NG_086982.1:g.1392C>T`, `NM_001005271.3:c.1569C>T`, `NM_001005273.3:c.1392C>T`, `NM_001437504.1:c.1569C>T`, `NM_001437507.1:c.1557C>T`, `NM_001437508.1:c.1557C>T`, `NM_001437509.1:c.1557C>T`, `NM_005852.4:c.1392C>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 -11.065, GERP -3.8 — fast-evolving / accelerated position
- CADD: **PHRED 6.487**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.28 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0165%** (mid) · FAF95 0.01% · FAF99 0.00939% · 1/6,062 in the highest group · 153/1,614,090 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,062 |
| European (non-Finnish) | 0.0116% | 8,613 |
| Admixed American | 0.00833% | 12,004 |
| Remaining individuals (not grpmax-eligible) | 0.008% | 12,502 |
| African / African-American | 0.004% | 25,000 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,604 |
| East Asian | 0.00223% | 44,862 |

*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 **464** lies in 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. 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 benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-01 |

**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 2026-10-14); 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 4681339). 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.*