# NM_001273.5(CHD4):c.1442del (p.Pro481fs)

https://sugi.bio/variant/chd4-p-pro481fs

## Summary

**CHD4 p.Pro481fs (c.1442del)** is classified **Uncertain significance** in CHD4 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-01-18). No gnomAD frequency available for this variant; Associated with Sifrim-Hitz-Weiss syndrome.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2136222835 · 2 submitters · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CHD4 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to Sifrim-Hitz-Weiss 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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Childhood, Infancy |
| Diagnostic panels | CHD4 is a diagnostic-grade gene on 8 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0025038/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CHD4](https://sugi.bio/atlas/gene/CHD4/) |
| Protein change (HGVS p.) | p.Pro481fs |
| Coding change (HGVS c.) | c.1442del |
| MANE Select transcript | [NM_001273](https://www.ncbi.nlm.nih.gov/nuccore/NM_001273) |
| dbSNP | [rs2136222835](https://www.ncbi.nlm.nih.gov/snp/rs2136222835/) |
| Variant type | Deletion |
| Location | chr12:6599813-6599813 (GRCh38) |
| ClinVar | [VCV1697098](https://www.ncbi.nlm.nih.gov/clinvar/variation/1697098/) |

**All HGVS expressions:** `NC_000012.11:g.6708980del`, `NC_000012.12:g.6599814del`, `NG_052823.1:g.12627del`, `NM_001273.5:c.1442del`, `NM_001297553.2:c.1421del`, `NM_001363606.2:c.1403del`

## 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 -3.151, GERP -3.69 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.192, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 10 of 40**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**CHD4** population constraint: LOEUF 0.192, pLI 1, missense-Z 8.6275; ClinGen dosage — haploinsufficiency 1/3, triplosensitivity 0/3. *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):

- **syndromic intellectual disability** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 65.41, 17% of residues very-high.

**12 experimental structure(s)** (PDB): [1MM2](https://www.rcsb.org/structure/1MM2), [1MM3](https://www.rcsb.org/structure/1MM3), [2EE1](https://www.rcsb.org/structure/2EE1), [2L5U](https://www.rcsb.org/structure/2L5U), [2L75](https://www.rcsb.org/structure/2L75), [2N5N](https://www.rcsb.org/structure/2N5N).

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

*Describes the biological roles of CHD4 (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:** CHD4's established molecular role includes transcription coregulator binding. In Reactome, CHD4 is annotated in disease pathway(s) including **Potential therapeutics for SARS**.

**Disease mechanism (Reactome):** CHD4 loss or alteration is curated in [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191).

### Pathways affected {#pathways}

CHD4 participates in **14 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 |
| [NGF-stimulated transcription](https://reactome.org/content/detail/R-HSA-9031628) | 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 |
| [ChAHP complex assembly](https://reactome.org/content/detail/R-HSA-9940465) | electronic |
| [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 coregulator binding, transcription corepressor activity, ATP hydrolysis activity, histone deacetylase binding, RNA polymerase II-specific DNA-binding transcription factor binding, ATP-dependent chromatin remodeler activity.

**Biological process:** double-strand break repair via homologous recombination, chromatin remodeling, negative regulation of gene expression.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-01-18.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Pathogenic).

**Submission history:** 2 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-01-18 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2025-03-14 |

## Associated conditions {#conditions}

[Sifrim-Hitz-Weiss syndrome](https://sugi.bio/atlas/disease/sifrim-hitz-weiss-syndrome/).

**Reported phenotype names (ClinVar):** not provided, Sifrim-Hitz-Weiss syndrome, SIFRIM-HITZ-WEISS MULTIPLE CONGENITAL ANOMALIES-MENTAL RETARDATION SYNDROME, CHD4 Neurodevelopmental Disorder, none provided.

## Similar variants {#similar}

Related CHD4 variant pages (same residue, condition, or type): [CHD4 p.Leu1219fs](/variant/chd4-p-leu1219fs), [CHD4 p.Asn1362_Asp1365del](/variant/chd4-p-asn1362-asp1365del), [CHD4 p.Gln542fs](/variant/chd4-p-gln542fs), [CHD4 p.Arg1068His](/variant/chd4-p-arg1068his), [CHD4 p.Arg1173Gln](/variant/chd4-p-arg1173gln), [CHD4 p.Arg1173Trp](/variant/chd4-p-arg1173trp), [CHD4 p.Arg1177Cys](/variant/chd4-p-arg1177cys), [CHD4 p.Arg1183Cys](/variant/chd4-p-arg1183cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1697098). 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.*