Is HDAC8 p.Ser199Phe (c.596C>T) pathogenic?

HDAC8 p.Ser199Phe (c.596C>T) is classified Likely pathogenic in HDAC8 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.998); Absent from gnomAD v4.1; Associated with Cornelia de Lange syndrome 5.

What condition is associated with HDAC8 p.Ser199Phe (c.596C>T)?

HDAC8 p.Ser199Phe (c.596C>T) is associated with Cornelia de Lange syndrome 5 (ClinVar).

How common is HDAC8 p.Ser199Phe (c.596C>T) in the general population?

HDAC8 p.Ser199Phe (c.596C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HDAC8 p.Ser199Phe (c.596C>T)?

AlphaMissense predicts likely pathogenic (score 0.998) — an in-silico prediction, not a clinical call.

HDAC8 p.Ser199Phe

c.596C>T · VCV3382667

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.998 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cornelia de Lange syndrome 5

Computational evidence

Protein change
AlphaMissense	0.998	likely pathogenic ✓ concordant with ClinVar · top 4% in HDAC8
REVEL	0.95	strongly pathogenic-leaning
SaProt	LLR -16.09	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 7.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.31	constrained · MANE · 104 kb · p 1.9e-20 · regional, not allelic
Overall
CADD	29.5	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.Ser199Phe
Coding: c.596C>T
MANE Select: NM_018486
Type: single nucleotide variant
Location: chrX:72490961 (GRCh38)
Structure: AlphaFold pLDDT 95.45 · 53 PDB
Residue 199: 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.Ser199Thr Likely pathogenic ★ 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-ser199phe (accessed [today's date]).

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