Is HDAC5 p.Pro1109Ser (c.3325C>T) pathogenic?

HDAC5 p.Pro1109Ser (c.3325C>T) is classified Uncertain significance in HDAC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely benign (0.0724); Very rare (popmax 0.00534%, afr).

How common is HDAC5 p.Pro1109Ser (c.3325C>T) in the general population?

HDAC5 p.Pro1109Ser (c.3325C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about HDAC5 p.Pro1109Ser (c.3325C>T)?

AlphaMissense predicts likely benign (score 0.0724) — an in-silico prediction, not a clinical call.

HDAC5 p.Pro1109Ser

c.3325C>T · VCV4269313

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0724 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0724	likely benign
REVEL	0.085	moderately benign-leaning
SaProt	LLR -6.30	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 7.4	GERP -0.24, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 443 bp · p 0.23 · regional, not allelic
Overall
CADD	15.94	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00534% African / African-American · 4/74,860 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000373% 6/1,607,208 alleles · very rare exomes 3/1,454,956 · genomes 3/152,252 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,715
South Asian	0.00221%	45,159

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.Pro1109Ser
Coding: c.3325C>T
MANE Select: NM_005474
Type: single nucleotide variant
Location: chr17:44078504 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.14 · 2 PDB
Residue 1109: the 'disordered' region

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

Similar variants

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
HDAC5 c.22+1436G>T Uncertain significance ★ 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-pro1109ser (accessed [today's date]).

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