Is HDAC8 p.Ala266Pro (c.796G>C) pathogenic?

HDAC8 p.Ala266Pro (c.796G>C) is classified Likely pathogenic in HDAC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-05-18). AlphaMissense: likely pathogenic (0.9691); Absent from gnomAD v4.1; Associated with Cornelia de Lange syndrome 5.

What condition is associated with HDAC8 p.Ala266Pro (c.796G>C)?

HDAC8 p.Ala266Pro (c.796G>C) is associated with Cornelia de Lange syndrome 5 (ClinVar).

How common is HDAC8 p.Ala266Pro (c.796G>C) in the general population?

HDAC8 p.Ala266Pro (c.796G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HDAC8 p.Ala266Pro (c.796G>C)?

AlphaMissense predicts likely pathogenic (score 0.9691) — an in-silico prediction, not a clinical call.

HDAC8 p.Ala266Pro

c.796G>C · rs1569317995 · VCV560685

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9691 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cornelia de Lange syndrome 5

Computational evidence

Protein change
AlphaMissense	0.9691	likely pathogenic ✓ concordant with ClinVar
REVEL	0.872	moderately pathogenic-leaning
SaProt	LLR -9.78	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.8, phastCons 1
Regional constraint	o/e 0.31	constrained · MANE · 104 kb · p 1.9e-20 · regional, not allelic
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HDAC8
Protein: p.Ala266Pro
Coding: c.796G>C
MANE Select: NM_018486
dbSNP: rs1569317995
Type: single nucleotide variant
Location: chrX:72464673 (GRCh38)
Structure: AlphaFold pLDDT 95.45 · 53 PDB
Residue 266: the 'histone deacetylase' region; an α-helix

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-ala266pro (accessed [today's date]).

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