Is HDAC5 p.Pro756Ser (c.2266C>T) pathogenic?

HDAC5 p.Pro756Ser (c.2266C>T) is classified Uncertain significance in HDAC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-10). AlphaMissense: likely pathogenic (0.6314); Very rare (popmax 0.000508%, nfe).

How common is HDAC5 p.Pro756Ser (c.2266C>T) in the general population?

HDAC5 p.Pro756Ser (c.2266C>T) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about HDAC5 p.Pro756Ser (c.2266C>T)?

AlphaMissense predicts likely pathogenic (score 0.6314) — an in-silico prediction, not a clinical call.

HDAC5 p.Pro756Ser

c.2266C>T · VCV4675170

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6314 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6314	likely pathogenic
REVEL	0.336	indeterminate
SaProt	LLR -10.80	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 761 bp · p 0.45 · regional, not allelic
Overall
CADD	26.5	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 0.000508% European (non-Finnish) · 6/1,180,034 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,614,032 alleles · very rare exomes 4/1,461,850 · genomes 2/152,182 · joint denominator

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: HDAC5
Protein: p.Pro756Ser
Coding: c.2266C>T
MANE Select: NM_005474
Type: single nucleotide variant
Location: chr17:44084594 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.14 · 2 PDB
Residue 756: the 'histone deacetylase' region

Full HDAC5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HDAC5 p.Pro756Ala Uncertain significance ★ same residue
HDAC5 c.2608-3T>C Benign ★★ same type
HDAC5 c.3164-9C>T Benign ★★ same type
HDAC5 p.Ala1102Val Benign ★★ same type
HDAC5 p.Ala82= Benign ★★ same type
HDAC5 p.Asp593Glu Benign ★★ same type
HDAC5 p.Gly565Ala Benign ★★ same type
HDAC5 p.Lys172= Likely benign ★★ 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/hdac5-p-pro756ser (accessed [today's date]).

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