Is HDAC8 p.Asp128= (c.384C>T) pathogenic?

HDAC8 p.Asp128= (c.384C>T) is classified Likely benign in HDAC8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-15). Very rare (popmax 0.00525%, afr); Associated with Cornelia de Lange syndrome 5.

What condition is associated with HDAC8 p.Asp128= (c.384C>T)?

HDAC8 p.Asp128= (c.384C>T) is associated with Cornelia de Lange syndrome 5 (ClinVar).

How common is HDAC8 p.Asp128= (c.384C>T) in the general population?

HDAC8 p.Asp128= (c.384C>T) is very rare (popmax 0.00525%, afr) (gnomAD).

HDAC8 p.Asp128=

c.384C>T · rs1250641302 · VCV1643044

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00525%, afr)

Conditions

Cornelia de Lange syndrome 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.28	GERP -3.2, phastCons 0.004
Overall
CADD	1.09	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00525% African / African-American · 3/57,148 alleles

Filtering AF 0.00151% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00128%

Overall 0.00215% 26/1,209,526 alleles · very rare exomes 18/1,097,713 · genomes 8/111,813 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00525%	19,049
European (non-Finnish)	0.00235%	42,612
Admixed American	0.00219%	45,725
Remaining individualsnot grpmax-eligible	0.0021%	47,579

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: HDAC8
Protein: p.Asp128=
Coding: c.384C>T
MANE Select: NM_018486
dbSNP: rs1250641302
Type: single nucleotide variant
Location: chrX:72567942 (GRCh38)
Structure: AlphaFold pLDDT 95.45 · 53 PDB
Residue 128: the 'histone deacetylase' region; a β-strand

Full HDAC8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cornelia de Lange syndrome 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HDAC8 p.Asp128Val Uncertain significance ★★ ⚠ same residue
HDAC8 c.165-2A>G Pathogenic ★★ same condition
HDAC8 c.738-1G>A Pathogenic ★★ same condition
HDAC8 c.738-2A>G Pathogenic/Likely pathogenic ★★ same condition
HDAC8 p.Arg164Ter Pathogenic ★★ same condition
HDAC8 p.Arg313Ter Pathogenic ★★ same condition
HDAC8 p.Arg37Gln Pathogenic/Likely pathogenic ★★ same condition
HDAC8 p.Asn156Ser Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/hdac8-p-asp128 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown