Is HDAC8 p.Pro205= (c.615A>G) pathogenic?

HDAC8 p.Pro205= (c.615A>G) is classified Likely benign in HDAC8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-08). Very rare (popmax 0.00642%, nfe); Associated with Cornelia de Lange syndrome 5.

What condition is associated with HDAC8 p.Pro205= (c.615A>G)?

HDAC8 p.Pro205= (c.615A>G) is associated with Cornelia de Lange syndrome 5 (ClinVar).

How common is HDAC8 p.Pro205= (c.615A>G) in the general population?

HDAC8 p.Pro205= (c.615A>G) is very rare (popmax 0.00642%, nfe) (gnomAD).

HDAC8 p.Pro205=

c.615A>G · rs782771783 · VCV2167277

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00642%, nfe)

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 -6	GERP -5.2
Overall
CADD	2.442	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00642% European (non-Finnish) · 57/887,777 alleles

Filtering AF 0.00502% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00458%

Overall 0.00508% 61/1,201,152 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00846%	11,827
European (non-Finnish)grpmax	0.00642%	15,575

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro205=
Coding: c.615A>G
MANE Select: NM_018486
dbSNP: rs782771783
Type: single nucleotide variant
Location: chrX:72490942 (GRCh38)
Structure: AlphaFold pLDDT 95.45 · 53 PDB
Residue 205: 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 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
HDAC8 p.Gln263Ter 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-pro205 (accessed [today's date]).

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