# NM_001273.5(CHD4):c.1548C>T (p.Pro516=)

https://sugi.bio/variant/chd4-p-pro516

## Summary

**CHD4 p.Pro516= (c.1548C>T)** is classified **Benign** in CHD4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 16.2%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with Sifrim-Hitz-Weiss syndrome.

**At a glance:** Benign · review: Multiple submitters · rsID rs11539543 · 4 submitters · 1 linked condition · common (popmax 16.2%, nfe) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the CHD4 gene that is classified as benign — not considered disease-causing, submitted by 4 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.Pro516= |
| Coding change (HGVS c.) | c.1548C>T |
| MANE Select transcript | [NM_001273](https://www.ncbi.nlm.nih.gov/nuccore/NM_001273) |
| dbSNP | [rs11539543](https://www.ncbi.nlm.nih.gov/snp/rs11539543/) |
| Variant type | single nucleotide variant |
| Location | chr12:6598360-6598360 (GRCh38) |
| ClinVar | [VCV1209740](https://www.ncbi.nlm.nih.gov/clinvar/variation/1209740/) |

**All HGVS expressions:** `NC_000012.11:g.6707526G>A`, `NC_000012.12:g.6598360G>A`, `NG_052823.1:g.14080C>T`, `NM_001273.5:c.1548C>T`, `NM_001297553.2:c.1527C>T`, `NM_001363606.2:c.1509C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 16.2%, nfe) — too common for a highly-penetrant pathogenic allele.

- **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 0.743, GERP -3.69, phastCons 0.998 — weakly conserved position
- CADD: **PHRED 7.93**. 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 **16.2%** (nfe) · FAF95 16.1% · FAF99 16.1% · 190,618/1,179,754 in the highest group · 240,966/1,613,668 alleles overall — common (popmax 16.2%, nfe) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 16.2% | 6 |
| Finnish (not grpmax-eligible) | 16.1% | 6 |
| South Asian | 15% | 7 |
| African / African-American | 13.6% | 7 |
| Remaining individuals (not grpmax-eligible) | 13.5% | 7 |
| Middle Eastern | 12% | 8 |
| Amish (not grpmax-eligible) | 11% | 9 |
| Ashkenazi Jewish (not grpmax-eligible) | 9.19% | 11 |
| Admixed American | 6.85% | 15 |
| East Asian | 0.176% | 568 |

*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, triplosensitivity 0 (0–3 scale). *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 **516** lies in the chromo 1 domain; an α-helix; 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.Pro516= falls in the chromo 1 domain. 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}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** unanimous (4/4 Benign).

**Submission history:** 4 submissions (2018–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2018-09-17 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-07-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Sifrim-Hitz-Weiss syndrome, not provided, 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.Pro516Leu](/variant/chd4-p-pro516leu), [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), [CHD4 p.Arg1183His](/variant/chd4-p-arg1183his), [CHD4 p.Arg1340Cys](/variant/chd4-p-arg1340cys).

### 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 1209740). 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.*