Is HDAC9 p.Ala339Ser (c.1015G>T) pathogenic?

HDAC9 p.Ala339Ser (c.1015G>T) is classified Uncertain significance in HDAC9 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-06). AlphaMissense: likely benign (0.098); Very rare (popmax 0.00212%, nfe).

How common is HDAC9 p.Ala339Ser (c.1015G>T) in the general population?

HDAC9 p.Ala339Ser (c.1015G>T) is very rare (popmax 0.00212%, nfe) (gnomAD).

What do computational predictors say about HDAC9 p.Ala339Ser (c.1015G>T)?

AlphaMissense predicts likely benign (score 0.098) — an in-silico prediction, not a clinical call.

HDAC9 p.Ala339Ser

c.1015G>T · rs755314928 · VCV3104646

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.098 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00212%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.098	likely benign
REVEL	0.22	benign-leaning
SaProt	LLR -5.61	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 8.5	GERP 2.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 19 kb · p 0.55 · regional, not allelic
Overall
CADD	25.0	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A336S vs ClinVar A339S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00212% European (non-Finnish) · 25/1,178,482 alleles

Filtering AF 0.00146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00168% 27/1,611,000 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00212%	47,139
African / African-American	0.00134%	74,720
South Asian	0.0011%	90,780

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: HDAC9
Protein: p.Ala339Ser
Coding: c.1015G>T
MANE Select: NM_178425
dbSNP: rs755314928
Type: single nucleotide variant
Location: chr7:18644773 (GRCh38)
Gene constraint: LOEUF 0.377 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.48 · 2 PDB
Residue 339: the 'interaction with mapk10' region

Full HDAC9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HDAC9 p.Pro390= Benign ★★ same type
HDAC9 c.1910-2A>G Uncertain significance ★ same type
HDAC9 p.Ala1028Val Uncertain significance ★ same type
HDAC9 p.Ala1068Val Uncertain significance ★ same type
HDAC9 p.Ala140Ser Uncertain significance ★ ⚠ same type
HDAC9 p.Ala238Thr Uncertain significance ★ ⚠ same type
HDAC9 p.Ala346Thr Uncertain significance ★ ⚠ same type
HDAC9 p.Ala346Val 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/hdac9-p-ala339ser (accessed [today's date]).

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