Is HDAC8 p.Pro7Leu (c.20C>T) pathogenic?

HDAC8 p.Pro7Leu (c.20C>T) is classified Benign in HDAC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-11-14). AlphaMissense: likely benign (0.0725); Very rare (popmax 0.00707%, sas).

How common is HDAC8 p.Pro7Leu (c.20C>T) in the general population?

HDAC8 p.Pro7Leu (c.20C>T) is very rare (popmax 0.00707%, sas) (gnomAD).

What do computational predictors say about HDAC8 p.Pro7Leu (c.20C>T)?

AlphaMissense predicts likely benign (score 0.0725) — an in-silico prediction, not a clinical call.

HDAC8 p.Pro7Leu

c.20C>T · rs147689487 · VCV599425

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0725 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00707%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0725	likely benign
REVEL	0.135	moderately benign-leaning
SaProt	LLR -6.98	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 2.5	GERP -0.46, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 3,910 bp · p 0.027 · regional, not allelic
Overall
CADD	18.82	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 0.00707% South Asian · 4/56,601 alleles

Filtering AF 0.00235% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00141%

Overall 0.000828% 10/1,207,060 alleles · very rare exomes 9/1,096,802 · genomes 1/110,258 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00707%	14,150
Remaining individualsnot grpmax-eligible	0.0021%	47,514
European (non-Finnish)	0.000559%	178,752

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.Pro7Leu
Coding: c.20C>T
MANE Select: NM_018486
dbSNP: rs147689487
Type: single nucleotide variant
Location: chrX:72572742 (GRCh38)
Structure: AlphaFold pLDDT 95.45 · 53 PDB

Full HDAC8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HDAC8 p.Pro7Arg Benign/Likely benign ★★ same residue
HDAC8 p.Pro7= Likely benign ★ same residue
HDAC8 p.Pro7Gln Benign ★ same residue
HDAC8 p.Pro7_Ala8insGluGluPro Conflicting classifications of pathogenicity ★ same residue
HDAC8 c.165-2A>G Pathogenic ★★ same type
HDAC8 c.738-1G>A Pathogenic ★★ same type
HDAC8 c.738-2A>G Pathogenic/Likely pathogenic ★★ same type
HDAC8 p.Ala188Thr Pathogenic/Likely pathogenic ★★ same type

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-pro7leu (accessed [today's date]).

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