Is HDAC8 p.Arg167Pro (c.500G>C) pathogenic?

HDAC8 p.Arg167Pro (c.500G>C) is classified Uncertain significance in HDAC8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-15). AlphaMissense: likely pathogenic (0.9312); Very rare (popmax 0.000784%, nfe); Associated with Cornelia de Lange syndrome 5.

What condition is associated with HDAC8 p.Arg167Pro (c.500G>C)?

HDAC8 p.Arg167Pro (c.500G>C) is associated with Cornelia de Lange syndrome 5 (ClinVar).

How common is HDAC8 p.Arg167Pro (c.500G>C) in the general population?

HDAC8 p.Arg167Pro (c.500G>C) is very rare (popmax 0.000784%, nfe) (gnomAD).

What do computational predictors say about HDAC8 p.Arg167Pro (c.500G>C)?

AlphaMissense predicts likely pathogenic (score 0.9312) — an in-silico prediction, not a clinical call.

HDAC8 p.Arg167Pro

c.500G>C · rs1308079591 · VCV1308382

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9312 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000784%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cornelia de Lange syndrome 5

Computational evidence

Protein change
AlphaMissense	0.9312	likely pathogenic
REVEL	0.646	pathogenic-leaning
SaProt	LLR -12.16	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.31	constrained · MANE · 104 kb · p 1.9e-20 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000784% European (non-Finnish) · 7/892,947 alleles

Filtering AF 0.000326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00021%

Overall 0.00058% 7/1,206,743 alleles · very 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.Arg167Pro
Coding: c.500G>C
MANE Select: NM_018486
dbSNP: rs1308079591
Type: single nucleotide variant
Location: chrX:72495206 (GRCh38)
Structure: AlphaFold pLDDT 95.45 · 53 PDB
Residue 167: the 'histone deacetylase' region; a turn

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.Arg167Trp Likely benign ★★ same residue
HDAC8 p.Arg167Gln 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

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-arg167pro (accessed [today's date]).

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