# NM_018486.3(HDAC8):c.20C>G (p.Pro7Arg)

https://sugi.bio/variant/hdac8-p-pro7arg

## Summary

**HDAC8 p.Pro7Arg (c.20C>G)** is classified **Benign/Likely benign** in HDAC8 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-19). AlphaMissense: likely benign (0.0896); Ultra-rare (popmax 0.0457%, mid); Associated with Inborn genetic diseases.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs147689487 · 5 submitters · 2 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0457%, mid)

## For patients & families {#patients}

This is a change in the HDAC8 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 5 submitters, and is linked to Inborn genetic diseases.

*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 | [HDAC8](https://sugi.bio/atlas/gene/HDAC8/) |
| Protein change (HGVS p.) | p.Pro7Arg |
| Coding change (HGVS c.) | c.20C>G |
| MANE Select transcript | [NM_018486](https://www.ncbi.nlm.nih.gov/nuccore/NM_018486) |
| dbSNP | [rs147689487](https://www.ncbi.nlm.nih.gov/snp/rs147689487/) |
| Variant type | single nucleotide variant |
| Location | chrX:72572742-72572742 (GRCh38) |
| ClinVar | [VCV211140](https://www.ncbi.nlm.nih.gov/clinvar/variation/211140/) |

**All HGVS expressions:** `NC_000023.10:g.71792592G>C`, `NC_000023.11:g.72572742G>C`, `NG_015851.1:g.5362C>G`, `NM_001166418.2:c.20C>G`, `NM_001166419.2:c.20C>G`, `NM_001166420.2:c.20C>G`, `NM_001166422.2:c.20C>G`, `NM_001166448.2:c.20C>G`, `NM_018486.3:c.20C>G`, `NR_051952.2:n.102C>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.0896)
- REVEL 0.061 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.479 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 2.532, GERP -0.46, phastCons 0.998 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 18.9**. 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.*
- Regional missense constraint: **o/e 0.70** across the covering region of the MANE Select transcript (72,568,851–72,572,761), spanning 3,910 bp. Chi-square p 0.027. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.0457%** (mid) · FAF95 0.0195% · FAF99 0.0185% · 2/4,372 in the highest group · 202/1,207,058 alleles overall — ultra-rare (popmax 0.0457%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0457% | 2,186 |
| European (non-Finnish) | 0.022% | 4,537 |
| African / African-American | 0.00354% | 28,276 |
| Remaining individuals (not grpmax-eligible) | 0.0021% | 47,514 |

*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}


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. 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-19.

**Submitter consensus:** conflicting (4 Likely benign, 1 Benign).

**Submission history:** 5 submissions (2015–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Likely benign | criteria provided, single submitter | clinical testing | 2015-07-21 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2017-06-13 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-05-23 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-12-19 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-02-01 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not specified, Cornelia de Lange syndrome 5, not provided, AllHighlyPenetrant, none provided, HDAC8-Related Cornelia de Lange Syndrome.

## Similar variants {#similar}

Related HDAC8 variant pages (same residue, condition, or type): [HDAC8 p.Pro7=](/variant/hdac8-p-pro7), [HDAC8 p.Pro7Gln](/variant/hdac8-p-pro7gln), [HDAC8 p.Pro7_Ala8insGluGluPro](/variant/hdac8-p-pro7-ala8insgluglupro), [HDAC8 p.Pro7Leu](/variant/hdac8-p-pro7leu), [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).

### 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 211140). 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.*