Is HDAC5 p.Pro305Ala (c.913C>G) pathogenic?

HDAC5 p.Pro305Ala (c.913C>G) is classified Uncertain significance in HDAC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely benign (0.0573); Very rare (popmax 0.000509%, nfe).

How common is HDAC5 p.Pro305Ala (c.913C>G) in the general population?

HDAC5 p.Pro305Ala (c.913C>G) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about HDAC5 p.Pro305Ala (c.913C>G)?

AlphaMissense predicts likely benign (score 0.0573) — an in-silico prediction, not a clinical call.

HDAC5 p.Pro305Ala

c.913C>G · VCV4269311

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0573 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0573	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -5.04	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Pangolin	Δ0.20	loss · gain 0.16 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 4.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 5,898 bp · p 1.9e-05 · regional, not allelic
Overall
CADD	21.3	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 0.000509% European (non-Finnish) · 6/1,178,712 alleles

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

Overall 0.000372% 6/1,612,370 alleles · very rare exomes 5/1,460,228 · genomes 1/152,142 · 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.Pro305Ala
Coding: c.913C>G
MANE Select: NM_005474
Type: single nucleotide variant
Location: chr17:44092387 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.14 · 2 PDB
Residue 305: 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-pro305ala (accessed [today's date]).

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