Is HDAC8 p.Arg223= (c.669G>T) pathogenic?

HDAC8 p.Arg223= (c.669G>T) is classified Benign in HDAC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-17). Ultra-rare (popmax 0.0269%, eas); Associated with Cornelia de Lange syndrome 5.

What condition is associated with HDAC8 p.Arg223= (c.669G>T)?

HDAC8 p.Arg223= (c.669G>T) is associated with Cornelia de Lange syndrome 5 (ClinVar).

How common is HDAC8 p.Arg223= (c.669G>T) in the general population?

HDAC8 p.Arg223= (c.669G>T) is ultra-rare (popmax 0.0269%, eas) (gnomAD).

HDAC8 p.Arg223=

c.669G>T · rs781936798 · VCV2729166

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0269%, eas)

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 -0.33	GERP -2.2, phastCons 0.16
Overall
CADD	7.485	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0269% East Asian · 9/33,469 alleles

Filtering AF 0.014% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0104%

Overall 0.000754% 9/1,193,539 alleles · ultra-rare

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.Arg223=
Coding: c.669G>T
MANE Select: NM_018486
dbSNP: rs781936798
Type: single nucleotide variant
Location: chrX:72489001 (GRCh38)
Structure: AlphaFold pLDDT 95.45 · 53 PDB
Residue 223: the 'histone deacetylase' region

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.Arg223Trp Conflicting classifications of pathogenicity ★ ⚠ 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-arg223 (accessed [today's date]).

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