# NM_018486.3(HDAC8):c.111G>C (p.Arg37=)

https://sugi.bio/variant/hdac8-p-arg37

## Summary

**HDAC8 p.Arg37= (c.111G>C)** is classified **Uncertain significance** in HDAC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-22). Absent from gnomAD v4.1; Associated with Cornelia de Lange syndrome 5.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2522253474 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the HDAC8 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Cornelia de Lange syndrome 5.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015271/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [HDAC8](https://sugi.bio/atlas/gene/HDAC8/) |
| Protein change (HGVS p.) | p.Arg37= |
| Coding change (HGVS c.) | c.111G>C |
| MANE Select transcript | [NM_018486](https://www.ncbi.nlm.nih.gov/nuccore/NM_018486) |
| dbSNP | [rs2522253474](https://www.ncbi.nlm.nih.gov/snp/rs2522253474/) |
| Variant type | single nucleotide variant |
| Location | chrX:72572651-72572651 (GRCh38) |
| ClinVar | [VCV2853907](https://www.ncbi.nlm.nih.gov/clinvar/variation/2853907/) |

**All HGVS expressions:** `NC_000023.10:g.71792501C>G`, `NC_000023.11:g.72572651C>G`, `NG_015851.1:g.5453G>C`, `NM_001166418.2:c.111G>C`, `NM_001166419.2:c.111G>C`, `NM_001166420.2:c.111G>C`, `NM_001166422.2:c.111G>C`, `NM_001166448.2:c.111G>C`, `NM_001410725.1:c.111G>C`, `NM_001410727.1:c.111G>C`, `NM_001410728.1:c.111G>C`, `NM_001410729.1:c.111G>C`, `NM_001410730.1:c.111G>C`, `NM_018486.3:c.111G>C`, `NR_051952.2:n.193G>C`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.48) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.367, GERP 1.57, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 36.0**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.11**, acceptor gain **0.00**, donor gain **0.48**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.11**, acceptor gain **0.00**, donor gain **0.48**.
- Pangolin: Δ**0.34** (loss), gain 0.32 / loss 0.34. SpliceAI calls gain. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**HDAC8** population constraint: ClinGen dosage — haploinsufficiency 3/3, 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):

- **Cornelia de Lange syndrome** — Definitive (XL)

## Protein context {#protein}

Residue **37** lies in the 'histone deacetylase' region; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 95.45, 93% of residues very-high.

**53 experimental structure(s)** (PDB): [1T64](https://www.rcsb.org/structure/1T64), [1T67](https://www.rcsb.org/structure/1T67), [1T69](https://www.rcsb.org/structure/1T69), [1VKG](https://www.rcsb.org/structure/1VKG), [1W22](https://www.rcsb.org/structure/1W22), [2V5W](https://www.rcsb.org/structure/2V5W) — incl. mutant structure 3EW8.

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

*Describes the biological roles of HDAC8 (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:** HDAC8's established molecular role includes histone deacetylase activity. p.Arg37= falls in the histone deacetylase region. In Reactome, HDAC8 is annotated in disease pathway(s) including **Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants**, **Constitutive Signaling by NOTCH1 PEST Domain Mutants**.

**Disease mechanism (Reactome):** HDAC8 loss or alteration is curated in [Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2894862), [Constitutive Signaling by NOTCH1 PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2644606).

### Pathways affected {#pathways}

HDAC8 participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2894862) | curated |
| ⚕ [Constitutive Signaling by NOTCH1 PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2644606) | curated |
| [HDACs deacetylate histones](https://reactome.org/content/detail/R-HSA-3214815) | curated |
| [Notch-HLH transcription pathway](https://reactome.org/content/detail/R-HSA-350054) | curated |
| [Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)](https://reactome.org/content/detail/R-HSA-9976102) | electronic |
| [NOTCH1 Intracellular Domain Regulates Transcription](https://reactome.org/content/detail/R-HSA-2122947) | electronic |
| [Resolution of Sister Chromatid Cohesion](https://reactome.org/content/detail/R-HSA-2500257) | other |
| [Separation of Sister Chromatids](https://reactome.org/content/detail/R-HSA-2467813) | other |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** histone deacetylase activity, Hsp70 protein binding, protein lysine deacetylase activity, Hsp90 protein binding, histone decrotonylase activity.

**Biological process:** mitotic sister chromatid cohesion, negative regulation of protein ubiquitination, regulation of protein stability, regulation of telomere maintenance.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-04-22.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-04-22 |

## Associated conditions {#conditions}

[Cornelia de Lange syndrome 5](https://sugi.bio/atlas/disease/cornelia-de-lange-syndrome-5/).

**Reported phenotype names (ClinVar):** Cornelia de Lange syndrome 5, HDAC8-Related Cornelia de Lange Syndrome.

## Same-residue context {#hotspot}

Residue **37** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [HDAC8 p.Arg37Gln](/variant/hdac8-p-arg37gln). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related HDAC8 variant pages (same residue, condition, or type): [HDAC8 p.Arg37Gln](/variant/hdac8-p-arg37gln), [HDAC8 c.165-2A>G](/variant/hdac8-c-165-minus-2a-g), [HDAC8 c.738-1G>A](/variant/hdac8-c-738-minus-1g-a), [HDAC8 c.738-2A>G](/variant/hdac8-c-738-minus-2a-g), [HDAC8 p.Arg164Ter](/variant/hdac8-p-arg164ter), [HDAC8 p.Arg313Ter](/variant/hdac8-p-arg313ter), [HDAC8 p.Asn156Ser](/variant/hdac8-p-asn156ser), [HDAC8 p.Gln263Ter](/variant/hdac8-p-gln263ter).

### 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 2853907). 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.*