# NM_018486.3(HDAC8):c.889G>C (p.Ala297Pro)

https://sugi.bio/variant/hdac8-p-ala297pro

## Summary

**HDAC8 p.Ala297Pro (c.889G>C)** is classified **Uncertain significance** in HDAC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-08). AlphaMissense: likely benign (0.0602); Very rare (popmax 0.000784%, nfe); Associated with Cornelia de Lange syndrome 5.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs781944571 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.000784%, nfe)

## 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.Ala297Pro |
| Coding change (HGVS c.) | c.889G>C |
| MANE Select transcript | [NM_018486](https://www.ncbi.nlm.nih.gov/nuccore/NM_018486) |
| dbSNP | [rs781944571](https://www.ncbi.nlm.nih.gov/snp/rs781944571/) |
| Variant type | single nucleotide variant |
| Location | chrX:72464580-72464580 (GRCh38) |
| ClinVar | [VCV2895517](https://www.ncbi.nlm.nih.gov/clinvar/variation/2895517/) |

**All HGVS expressions:** `NC_000023.10:g.71684430C>G`, `NC_000023.11:g.72464580C>G`, `NG_015851.1:g.113524G>C`, `NM_001166418.2:c.616G>C`, `NM_001410725.1:c.889G>C`, `NM_001410727.1:c.811G>C`, `NM_001410728.1:c.616G>C`, `NM_001410729.1:c.889G>C`, `NM_018486.3:c.889G>C`, `NR_051952.2:n.829G>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0602)
- REVEL 0.164 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR 1.839 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 5.886, GERP 1.91, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 15.91**. 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 0.31** across the covering region of the MANE Select transcript (72,464,578–72,568,850), spanning 104,272 bp — the region is depleted of missense variation. Chi-square p 1.9e-20. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for HDAC8 (837 scored positions, the nearest 1 base away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.000784%** (nfe) · FAF95 0.000326% · FAF99 0.00021% · 7/893,171 in the highest group · 7/1,207,550 alleles overall — very rare (popmax 0.000784%, nfe).

*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 **297** lies in the 'histone deacetylase' region; a β-strand.

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.Ala297Pro 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 2024-01-08.

**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 | 2024-01-08 |

## 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.

## Similar variants {#similar}

Related HDAC8 variant pages (same residue, condition, or type): [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.Arg37Gln](/variant/hdac8-p-arg37gln), [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 2026-10-15); 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 2895517). 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.*