# NM_001273.5(CHD4):c.1011C>T (p.Ser337=)

https://sugi.bio/variant/chd4-p-ser337

## Summary

**CHD4 p.Ser337= (c.1011C>T)** is classified **Likely benign** in CHD4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-06-18). Very rare (popmax 0.00401%, afr); Associated with CHD4-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · 1 submitter · 1 linked condition · very rare (popmax 0.00401%, afr)

## For patients & families {#patients}

This is a change in the CHD4 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to CHD4-related disorder.

*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 | [CHD4](https://sugi.bio/atlas/gene/CHD4/) |
| Protein change (HGVS p.) | p.Ser337= |
| Coding change (HGVS c.) | c.1011C>T |
| MANE Select transcript | [NM_001273](https://www.ncbi.nlm.nih.gov/nuccore/NM_001273) |
| Variant type | single nucleotide variant |
| Location | chr12:6600586-6600586 (GRCh38) |
| ClinVar | [VCV3347484](https://www.ncbi.nlm.nih.gov/clinvar/variation/3347484/) |

**All HGVS expressions:** `NC_000012.11:g.6709752G>A`, `NC_000012.12:g.6600586G>A`, `NG_052823.1:g.11854C>T`, `NM_001273.5:c.1011C>T`, `NM_001297553.2:c.990C>T`, `NM_001363606.2:c.1011C>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 0.971, GERP 1.69, phastCons 1 — weakly conserved position
- CADD: **PHRED 8.834**. 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 (G>C, Δ0.25 acceptor 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 **0.00401%** (afr) · FAF95 0.00106% · FAF99 0.000495% · 3/74,872 in the highest group · 3/1,613,932 alleles overall — very rare (popmax 0.00401%, afr).

*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}

Residue **337** lies in the 'disordered' region.

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. p.Ser337= falls in the disordered region. 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}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2024-06-18.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2024-06-18 |

## Associated conditions {#conditions}

[CHD4-related disorder](https://sugi.bio/atlas/disease/chd4-related-disorder/).

**Reported phenotype names (ClinVar):** CHD4-related disorder, CHD4-related condition.

## Similar variants {#similar}

Related CHD4 variant pages (same residue, condition, or type): [CHD4 p.Glu536Val](/variant/chd4-p-glu536val), [CHD4 p.Thr709Ala](/variant/chd4-p-thr709ala), [CHD4 p.Arg1068Ser](/variant/chd4-p-arg1068ser), [CHD4 p.Arg877Gln](/variant/chd4-p-arg877gln), [CHD4 p.Cys376Ter](/variant/chd4-p-cys376ter), [CHD4 p.Met1210Thr](/variant/chd4-p-met1210thr), [CHD4 p.Ala1601Ser](/variant/chd4-p-ala1601ser), [CHD4 p.Arg1899Gly](/variant/chd4-p-arg1899gly).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 3347484). 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.*