Is HDAC8 p.Pro4Leu (c.11C>T) pathogenic?

HDAC8 p.Pro4Leu (c.11C>T) is classified Benign in HDAC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-18). AlphaMissense: likely benign (0.0761); Very rare (popmax 0.00176%, sas); Associated with Cornelia de Lange syndrome 5.

What condition is associated with HDAC8 p.Pro4Leu (c.11C>T)?

HDAC8 p.Pro4Leu (c.11C>T) is associated with Cornelia de Lange syndrome 5 (ClinVar).

How common is HDAC8 p.Pro4Leu (c.11C>T) in the general population?

HDAC8 p.Pro4Leu (c.11C>T) is very rare (popmax 0.00176%, sas) (gnomAD).

What do computational predictors say about HDAC8 p.Pro4Leu (c.11C>T)?

AlphaMissense predicts likely benign (score 0.0761) — an in-silico prediction, not a clinical call.

HDAC8 p.Pro4Leu

c.11C>T · rs1556166880 · VCV1902488

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0761 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00176%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cornelia de Lange syndrome 5

Computational evidence

Protein change
AlphaMissense	0.0761	likely benign
REVEL	0.117	moderately benign-leaning
SaProt	LLR -6.63	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -0.34, phastCons 0.075
Regional constraint	o/e 0.70	unconstrained · MANE · 3,910 bp · p 0.027 · regional, not allelic
Overall
CADD	19.53	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

Grpmax group 0.00176% South Asian · 1/56,889 alleles

Overall 0.000183% 2/1,095,549 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00176%	56,889
European (non-Finnish)	0.000112%	893,144

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.Pro4Leu
Coding: c.11C>T
MANE Select: NM_018486
dbSNP: rs1556166880
Type: single nucleotide variant
Location: chrX:72572751 (GRCh38)
Structure: AlphaFold pLDDT 95.45 · 53 PDB

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.Pro4= Benign ★ 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-pro4leu (accessed [today's date]).

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