Is HDAC8 p.Pro35Thr (c.103C>A) pathogenic?

HDAC8 p.Pro35Thr (c.103C>A) is classified Uncertain significance in HDAC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-21). AlphaMissense: likely benign (0.1792); Absent from gnomAD v4.1; Associated with Cornelia de Lange syndrome 5.

What condition is associated with HDAC8 p.Pro35Thr (c.103C>A)?

HDAC8 p.Pro35Thr (c.103C>A) is associated with Cornelia de Lange syndrome 5 (ClinVar).

How common is HDAC8 p.Pro35Thr (c.103C>A) in the general population?

HDAC8 p.Pro35Thr (c.103C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HDAC8 p.Pro35Thr (c.103C>A)?

AlphaMissense predicts likely benign (score 0.1792) — an in-silico prediction, not a clinical call.

HDAC8 p.Pro35Thr

c.103C>A · VCV4769031

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1792 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,167,303)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cornelia de Lange syndrome 5

Computational evidence

Protein change
AlphaMissense	0.1792	likely benign
REVEL	0.738	pathogenic-leaning
SaProt	LLR -10.41	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.1	GERP 1.6, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 3,910 bp · p 0.027 · regional, not allelic
Overall
CADD	22.7	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

No allele count reported in gnomAD v4.1 (AN 1,167,303). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: HDAC8
Protein: p.Pro35Thr
Coding: c.103C>A
MANE Select: NM_018486
Type: single nucleotide variant
Location: chrX:72572659 (GRCh38)
Structure: AlphaFold pLDDT 95.45 · 53 PDB
Residue 35: 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.Pro35Leu Uncertain significance ★ ⚠ same residue
HDAC8 p.Pro35fs 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

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-pro35thr (accessed [today's date]).

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